Class 2 Transferases: EC 2.7.11.17-2.8 (Springer Handbook of Enzymes)

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Springer Handbook of Enzymes Supplement Volume S4

Dietmar Schomburg and Ida Schomburg (Eds.)

Springer Handbook of Enzymes Supplement Volume S4 Class 2 Transferases EC 2.7.11.17–2.8 coedited by Antje Chang

Second Edition

13

Professor Dietmar Schomburg e-mail: [email protected] Dr. Ida Schomburg e-mail: [email protected]

Technical University Braunschweig Bioinformatics & Systems Biology Langer Kamp 19b 38106 Braunschweig Germany

Dr. Antje Chang e-mail: [email protected]

Library of Congress Control Number: applied for

ISBN 978-3-540-85700-6

2nd Edition Springer Berlin Heidelberg New York

The first edition was published as the “Enzyme Handbook, edited by D. and I. Schomburg”.

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media springer.com # Springer-Verlag Berlin Heidelberg 2009 Printed in Germany The use of general descriptive names, registered names, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and free for general use. The publisher cannot assume any legal responsibility for given data, especially as far as directions for the use and the handling of chemicals and biological material are concerned. This information can be obtained from the instructions on safe laboratory practice and from the manufacturers of chemicals and laboratory equipment. Cover design: Erich Kirchner, Heidelberg Typesetting: medionet Publishing Services Ltd., Berlin Printed on acid-free paper

2/3141m-5 4 3 2 1 0

Preface

Today, as the full information about the genome is becoming available for a rapidly increasing number of organisms and transcriptome and proteome analyses are beginning to provide us with a much wider image of protein regulation and function, it is obvious that there are limitations to our ability to access functional data for the gene products – the proteins and, in particular, for enzymes. Those data are inherently very difficult to collect, interpret and standardize as they are widely distributed among journals from different fields and are often subject to experimental conditions. Nevertheless a systematic collection is essential for our interpretation of genome information and more so for applications of this knowledge in the fields of medicine, agriculture, etc. Progress on enzyme immobilisation, enzyme production, enzyme inhibition, coenzyme regeneration and enzyme engineering has opened up fascinating new fields for the potential application of enzymes in a wide range of different areas. The development of the enzyme data information system BRENDAwas started in 1987 at the German National Research Centre for Biotechnology in Braunschweig (GBF), continued at the University of Cologne from 1996 to 2007, and then returned to Braunschweig, to the Technical University, Institute of Bioinformatics & Systems Biology. The present book “Springer Handbook of Enzymes” represents the printed version of this data bank. The information system has been developed into a full metabolic database. The enzymes in this Handbook are arranged according to the Enzyme Commission list of enzymes. Some 5,000 “different” enzymes are covered. Frequently enzymes with very different properties are included under the same EC-number. Although we intend to give a representative overview on the characteristics and variability of each enzyme, the Handbook is not a compendium. The reader will have to go to the primary literature for more detailed information. Naturally it is not possible to cover all the numerous literature references for each enzyme (for some enzymes up to 40,000) if the data representation is to be concise as is intended. It should be mentioned here that the data have been extracted from the literature and critically evaluated by qualified scientists. On the other hand, the original authors’ nomenclature for enzyme forms and subunits is retained. In order to keep the tables concise, redundant information is avoided as far as possible (e.g. if Km values are measured in the presence of an obvious cosubstrate, only the name of the cosubstrate is given in parentheses as a commentary without reference to its specific role). The authors are grateful to the following biologists and chemists for invaluable help in the compilation of data: Cornelia Munaretto and Dr. Antje Chang. Braunschweig Spring 2009

Dietmar Schomburg, Ida Schomburg

VII

List of Abbreviations

A Ac ADP Ala All Alt AMP Ara Arg Asn Asp ATP Bicine C cal CDP CDTA CMP CoA CTP Cys d dDFP DNA DPN DTNB DTT EC E. coli EDTA EGTA ER Et EXAFS FAD FMN Fru Fuc G Gal

adenine acetyl adenosine 5’-diphosphate alanine allose altrose adenosine 5’-monophosphate arabinose arginine asparagine aspartic acid adenosine 5’-triphosphate N,N’-bis(2-hydroxyethyl)glycine cytosine calorie cytidine 5’-diphosphate trans-1,2-diaminocyclohexane-N,N,N,N-tetraacetic acid cytidine 5’-monophosphate coenzyme A cytidine 5’-triphosphate cysteine deoxy(and l-) prefixes indicating configuration diisopropyl fluorophosphate deoxyribonucleic acid diphosphopyridinium nucleotide (now NAD+ ) 5,5’-dithiobis(2-nitrobenzoate) dithiothreitol (i.e. Cleland’s reagent) number of enzyme in Enzyme Commission’s system Escherichia coli ethylene diaminetetraacetate ethylene glycol bis(-aminoethyl ether) tetraacetate endoplasmic reticulum ethyl extended X-ray absorption fine structure flavin-adenine dinucleotide flavin mononucleotide (riboflavin 5’-monophosphate) fructose fucose guanine galactose

IX

List of Abbreviations

GDP Glc GlcN GlcNAc Gln Glu Gly GMP GSH GSSG GTP Gul h H4 HEPES His HPLC Hyl Hyp IAA IC 50 Ig Ile Ido IDP IMP ITP Km lLeu Lys Lyx M mM mMan MES Met min MOPS Mur MW NAD+ NADH NADP+ NADPH NAD(P)H

X

guanosine 5’-diphosphate glucose glucosamine N-acetylglucosamine glutamine glutamic acid glycine guanosine 5’-monophosphate glutathione oxidized glutathione guanosine 5’-triphosphate gulose hour tetrahydro 4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid histidine high performance liquid chromatography hydroxylysine hydroxyproline iodoacetamide 50% inhibitory concentration immunoglobulin isoleucine idose inosine 5’-diphosphate inosine 5’-monophosphate inosine 5’-triphosphate Michaelis constant (and d-) prefixes indicating configuration leucine lysine lyxose mol/l millimol/l metamannose 2-(N-morpholino)ethane sulfonate methionine minute 3-(N-morpholino)propane sulfonate muramic acid molecular weight nicotinamide-adenine dinucleotide reduced NAD NAD phosphate reduced NADP indicates either NADH or NADPH

List of Abbreviations

NBS NDP NEM Neu NMN NMP NTP oOrn pPBS PCMB PEP pH Ph Phe PHMB PIXE PMSF p-NPP Pro Q10 Rha Rib RNA mRNA rRNA tRNA Sar SDS-PAGE Ser T tH Tal TDP TEA Thr TLCK Tm TMP TosTPN Tris Trp TTP Tyr U

N-bromosuccinimide nucleoside 5’-diphosphate N-ethylmaleimide neuraminic acid nicotinamide mononucleotide nucleoside 5’-monophosphate nucleoside 5’-triphosphate orthoornithine paraphosphate-buffered saline p-chloromercuribenzoate phosphoenolpyruvate -log10[H+ ] phenyl phenylalanine p-hydroxymercuribenzoate proton-induced X-ray emission phenylmethane-sulfonylfluoride p-nitrophenyl phosphate proline factor for the change in reaction rate for a 10 C temperature increase rhamnose ribose ribonucleic acid messenger RNA ribosomal RNA transfer RNA N-methylglycine (sarcosine) sodium dodecyl sulfate polyacrylamide gel electrophoresis serine thymine time for half-completion of reaction talose thymidine 5’-diphosphate triethanolamine threonine Na-p-tosyl-l-lysine chloromethyl ketone melting temperature thymidine 5’-monophosphate tosyl- (p-toluenesulfonyl-) triphosphopyridinium nucleotide (now NADP+ ) tris(hydroxymethyl)-aminomethane tryptophan thymidine 5’-triphosphate tyrosine uridine

XI

List of Abbreviations

U/mg UDP UMP UTP Val Xaa XAS Xyl

XII

mmol/(mg*min) uridine 5’-diphosphate uridine 5’-monophosphate uridine 5’-triphosphate valine symbol for an amino acid of unknown constitution in peptide formula X-ray absorption spectroscopy xylose

Index of Recommended Enzyme Names

EC-No.

Recommended Name

2.7.11.27 2.8.2.33 2.7.11.17 2.7.11.22 2.7.12.1 2.7.11.20 2.8.2.34 2.7.13.3 2.7.11.31 2.8.1.8 2.7.11.29 2.7.11.24 2.7.12.2 2.7.11.25 2.7.11.18 2.8.2.31 2.7.11.19 2.7.11.21 2.7.13.1 2.7.13.2 2.7.11.30 2.7.11.23 2.8.2.32 2.7.11.26 2.7.99.1 2.7.11.28

[acetyl-CoA carboxylase] kinase . . . . . . . . . . . N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase . . Ca2+ /calmodulin-dependent protein kinase . . . . . . cyclin-dependent kinase. . . . . . . . . . . . . . . dual-specificity kinase . . . . . . . . . . . . . . . elongation factor 2 kinase . . . . . . . . . . . . . . glycochenodeoxycholate sulfotransferase . . . . . . . histidine kinase . . . . . . . . . . . . . . . . . . [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase lipoyl synthase . . . . . . . . . . . . . . . . . . . low-density-lipoprotein receptor kinase . . . . . . . . mitogen-activated protein kinase . . . . . . . . . . . mitogen-activated protein kinase kinase . . . . . . . . mitogen-activated protein kinase kinase kinase. . . . . myosin-light-chain kinase . . . . . . . . . . . . . . petromyzonol sulfotransferase . . . . . . . . . . . . phosphorylase kinase . . . . . . . . . . . . . . . . polo kinase . . . . . . . . . . . . . . . . . . . . protein-histidine pros-kinase . . . . . . . . . . . . protein-histidine tele-kinase . . . . . . . . . . . . . receptor protein serine/threonine kinase . . . . . . . [RNA-polymerase]-subunit kinase . . . . . . . . . . scymnol sulfotransferase . . . . . . . . . . . . . . t-protein kinase . . . . . . . . . . . . . . . . . . triphosphate-protein phosphotransferase . . . . . . . tropomyosin kinase. . . . . . . . . . . . . . . . .

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326 489 1 156 372 126 495 420 355 478 337 233 392 278 54 482 89 134 414 418 340 220 484 303 475 333

XIII

Description of Data Fields

All information except the nomenclature of the enzymes (which is based on the recommendations of the Nomenclature Committee of IUBMB (International Union of Biochemistry and Molecular Biology) and IUPAC (International Union of Pure and Applied Chemistry) is extracted from original literature (or reviews for very well characterized enzymes). The quality and reliability of the data depends on the method of determination, and for older literature on the techniques available at that time. This is especially true for the fields Molecular Weight and Subunits. The general structure of the fields is: Information – Organism – Commentary – Literature The information can be found in the form of numerical values (temperature, pH, Km etc.) or as text (cofactors, inhibitors etc.). Sometimes data are classified as Additional Information. Here you may find data that cannot be recalculated to the units required for a field or also general information being valid for all values. For example, for Inhibitors, Additional Information may contain a list of compounds that are not inhibitory. The detailed structure and contents of each field is described below. If one of these fields is missing for a particular enzyme, this means that for this field, no data are available.

1 Nomenclature EC number The number is as given by the IUBMB, classes of enzymes and subclasses defined according to the reaction catalyzed. Systematic name This is the name as given by the IUBMB/IUPAC Nomenclature Committee Recommended name This is the name as given by the IUBMB/IUPAC Nomenclature Committee Synonyms Synonyms which are found in other databases or in the literature, abbreviations, names of commercially available products. If identical names are frequently used for different enzymes, these will be mentioned here, cross references are given. If another EC number has been included in this entry, it is mentioned here.

XV

Description of Data Fields

CAS registry number The majority of enzymes have a single chemical abstract (CAS) number. Some have no number at all, some have two or more numbers. Sometimes two enzymes share a common number. When this occurs, it is mentioned in the commentary.

2 Source Organism For listing organisms their systematic name is preferred. If these are not mentioned in the literature, the names from the respective literature are used. For example if an enzyme from yeast is described without being specified further, yeast will be the entry. This field defines the code numbers for the organisms in which the enzyme with the respective EC number is found. These code numbers (form ) are displayed together with each entry in all fields of BRENDA where organism-specific information is given.

3 Reaction and Specificity Catalyzed reaction The reaction as defined by the IUBMB. The commentary gives information on the mechanism, the stereochemistry, or on thermodynamic data of the reaction. Reaction type According to the enzyme class a type can be attributed. These can be oxidation, reduction, elimination, addition, or a name (e.g. Knorr reaction) Natural substrates and products These are substrates and products which are metabolized in vivo. A natural substrate is only given if it is mentioned in the literature. The commentary gives information on the pathways for which this enzyme is important. If the enzyme is induced by a specific compound or growth conditions, this will be included in the commentary. In Additional information you will find comments on the metabolic role, sometimes only assumptions can be found in the references or the natural substrates are unknown. In the listings, each natural substrate (indicated by a bold S) is followed by its respective product (indicated by a bold P). Products are given with organisms and references included only if the respective authors were able to demonstrate the formation of the specific product. If only the disappearance of the substrate was observed, the product is included without organisms of references. In cases with unclear product formation only a ? as a dummy is given. Substrates and products All natural or synthetic substrates are listed (not in stoichiometric quantities). The commentary gives information on the reversibility of the reaction,

XVI

Description of Data Fields

on isomers accepted as substrates and it compares the efficiency of substrates. If a specific substrate is accepted by only one of several isozymes, this will be stated here. The field Additional Information summarizes compounds that are not accepted as substrates or general comments which are valid for all substrates. In the listings, each substrate (indicated by a bold S) is followed by its respective product (indicated by a bold P). Products are given with organisms and references included if the respective authors demonstrated the formation of the specific product. If only the disappearance of the substrate was observed, the product will be included without organisms or references. In cases with unclear product formation only a ? as a dummy is given. Inhibitors Compounds found to be inhibitory are listed. The commentary may explain experimental conditions, the concentration yielding a specific degree of inhibition or the inhibition constant. If a substance is activating at a specific concentration but inhibiting at a higher or lower value, the commentary will explain this. Cofactors, prosthetic groups This field contains cofactors which participate in the reaction but are not bound to the enzyme, and prosthetic groups being tightly bound. The commentary explains the function or, if known, the stereochemistry, or whether the cofactor can be replaced by a similar compound with higher or lower efficiency. Activating Compounds This field lists compounds with a positive effect on the activity. The enzyme may be inactive in the absence of certain compounds or may require activating molecules like sulfhydryl compounds, chelating agents, or lipids. If a substance is activating at a specific concentration but inhibiting at a higher or lower value, the commentary will explain this. Metals, ions This field lists all metals or ions that have activating effects. The commentary explains the role each of the cited metal has, being either bound e.g. as Fe-S centers or being required in solution. If an ion plays a dual role, activating at a certain concentration but inhibiting at a higher or lower concentration, this will be given in the commentary. Turnover number (min- 1) The kcat is given in the unit min-1 . The commentary lists the names of the substrates, sometimes with information on the reaction conditions or the type of reaction if the enzyme is capable of catalyzing different reactions with a single substrate. For cases where it is impossible to give the turnover number in the defined unit (e.g., substrates without a defined molecular weight, or an undefined amount of protein) this is summarized in Additional Information.

XVII

Description of Data Fields

Specific activity (U/mg) The unit is micromol/minute/milligram of protein. The commentary may contain information on specific assay conditions or if another than the natural substrate was used in the assay. Entries in Additional Information are included if the units of the activity are missing in the literature or are not calculable to the obligatory unit. Information on literature with a detailed description of the assay method may also be found. Km-Value (mM) The unit is mM. Each value is connected to a substrate name. The commentary gives, if available, information on specific reaction condition, isozymes or presence of activators. The references for values which cannot be expressed in mM (e.g. for macromolecular, not precisely defined substrates) are given in Additional Information. In this field we also cite literature with detailed kinetic analyses. Ki-Value (mM) The unit of the inhibition constant is mM. Each value is connected to an inhibitor name. The commentary gives, if available, the type of inhibition (e.g. competitive, non-competitive) and the reaction conditions (pH-value and the temperature). Values which cannot be expressed in the requested unit and references for detailed inhibition studies are summerized under Additional information. pH-Optimum The value is given to one decimal place. The commentary may contain information on specific assay conditions, such as temperature, presence of activators or if this optimum is valid for only one of several isozymes. If the enzyme has a second optimum, this will be mentioned here. pH-Range Mostly given as a range e.g. 4.0–7.0 with an added commentary explaining the activity in this range. Sometimes, not a range but a single value indicating the upper or lower limit of enzyme activity is given. In this case, the commentary is obligatory. Temperature optimum ( C) Sometimes, if no temperature optimum is found in the literature, the temperature of the assay is given instead. This is always mentioned in the commentary. Temperature range ( C) This is the range over which the enzyme is active. The commentary may give the percentage of activity at the outer limits. Also commentaries on specific assay conditions, additives etc.

XVIII

Description of Data Fields

4 Enzyme Structure Molecular weight This field gives the molecular weight of the holoenzyme. For monomeric enzymes it is identical to the value given for subunits. As the accuracy depends on the method of determination this is given in the commentary if provided in the literature. Some enzymes are only active as multienzyme complexes for which the names and/or EC numbers of all participating enzymes are given in the commentary. Subunits The tertiary structure of the active species is described. The enzyme can be active as a monomer a dimer, trimer and so on. The stoichiometry of subunit composition is given. Some enzymes can be active in more than one state of complexation with differing effectivities. The analytical method is included. Posttranslational modifications The main entries in this field may be proteolytic modification, or side-chain modification, or no modification. The commentary will give details of the modifications e.g.: – proteolytic modification (, propeptide Name) [1]; – side-chain modification (, N-glycosylated, 12% mannose) [2]; – no modification [3]

5 Isolation / Preparation / Mutation / Application Source / tissue For multicellular organisms, the tissue used for isolation of the enzyme or the tissue in which the enzyme is present is given. Cell-lines may also be a source of enzymes. Localization The subcellular localization is described. Typical entries are: cytoplasm, nucleus, extracellular, membrane. Purification The field consists of an organism and a reference. Only references with a detailed description of the purification procedure are cited. Renaturation Commentary on denaturant or renaturation procedure. Crystallization The literature is cited which describes the procedure of crystallization, or the X-ray structure.

XIX

Description of Data Fields

Cloning Lists of organisms and references, sometimes a commentary about expression or gene structure. Engineering The properties of modified proteins are described. Application Actual or possible applications in the fields of pharmacology, medicine, synthesis, analysis, agriculture, nutrition are described.

6 Stability pH-Stability This field can either give a range in which the enzyme is stable or a single value. In the latter case the commentary is obligatory and explains the conditions and stability at this value. Temperature stability This field can either give a range in which the enzyme is stable or a single value. In the latter case the commentary is obligatory and explains the conditions and stability at this value. Oxidation stability Stability in the presence of oxidizing agents, e.g. O2, H2 O2, especially important for enzymes which are only active under anaerobic conditions. Organic solvent stability The stability in the presence of organic solvents is described. General stability information This field summarizes general information on stability, e.g., increased stability of immobilized enzymes, stabilization by SH-reagents, detergents, glycerol or albumins etc. Storage stability Storage conditions and reported stability or loss of activity during storage.

References Authors, Title, Journal, Volume, Pages, Year.

XX

Ca2+ /Calmodulin-dependent protein kinase

2.7.11.17

1 Nomenclature EC number 2.7.11.17 Systematic name ATP:protein phosphotransferase (Ca2+ /calmodulin-dependent) Recommended name Ca2+ /calmodulin-dependent protein kinase Synonyms ACMPK [40] CAKI [52] CAM kinase-GR CASK [75] CCaMK [83] CDPK [77] CL3 [114] CLICK-III [74] CLICK-III/CaMKIg [114] CMPK CPK-1 [77] Ca2+ -CaM-dependent protein kinase II [9] Ca2+ /CaMPK [92] Ca2+ /calmodulin-dependent kinase II [94] Ca2+ /calmodulin-dependent membrane-associated kinase [75] Ca2+ /calmodulin-dependent protein kinase [1, 27, 28, 29, 30, 31, 108] Ca2+ /calmodulin-dependent protein kinase II [43, 44, 45, 65, 66, 68, 76, 80, 85, 86, 87, 90, 97, 109, 111] Ca2+ /calmodulin-dependent protein kinase Ig [84] Ca2+ /calmodulin-dependent protein kinase kinase [13] Ca2+ /calmodulin-dependent protein kinase type IG [84] CaM kinase [34, 113] CaM kinase Gr [29] CaM kinase IG [74] CaM kinase II [65, 80, 86, 95, 99] CaM kinase IIa [86] CaM-K I [71] CaM-K II [71] CaM-K IIa [73]

1

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

CaM-K IV [71, 73] CaM-K Ia [73] CaM-K1d [72] CaM-KI [67, 69] CaM-KI LiKb [69] CaM-KII [67] CaM-KIa [69] CaM-KKb3 [72] CaM-activated enzyme CaM kinase II [99] CaM-dependent kinase [96] CaM-dependent protein kinase [64] CaM-dependent protein kinase I [73] CaM-dependent protein kinase II [73] CaM-kinase I [71] CaM-kinase II [71] CaM-kinase III [71] CaM-kinase IV [71] CaMK [64, 96] CaMK II [43, 93] CaMK-like CREB kinase-III [74] CaMK1 [96] CaMKI [11, 47, 84, 89, 103, 105, 115, 116] CaMKIG [74] CaMKII [9, 10, 66, 68, 76, 82, 85, 88, 89, 90, 91, 97, 98, 99, 100, 101, 102, 103, 104, 106, 108, 109, 111, 112, 117] CaMKIIa [81, 87] CaMKIIb [81, 87] CaMKIId [87] CaMKIIg [87] CaMKIIgB [81] CaMKIV [68, 70, 78, 79, 89, 103, 105, 115] CaMKIa [74] CaMKIg [74, 84] calspermin [30] Cam-II PK [12] Camk-2 [36] CamkG [84] MAP kinase MAP-2 kinase MAP-2 protein serine kinase PK70 [83] XCaM-KI LiKb [69] XCaM-KIa [69] aCaMKII [90, 94] calcium- and calmodulin-dependent kinase Ia [110] calcium-dependent protein kinase [77]

2

2.7.11.17

Ca2+/Calmodulin-dependent protein kinase

calcium-independent calcium/calmodulin-dependent protein kinase II [88] calcium/calmodulin dependent protein kinase II [95] calcium/calmodulin-dependent kinase [107] calcium/calmodulin-dependent kinase I [67] calcium/calmodulin-dependent protein kinase [40, 51, 52, 71, 96, 113] calcium/calmodulin-dependent protein kinase 1G [74] calcium/calmodulin-dependent protein kinase I [34, 35, 69, 73] calcium/calmodulin-dependent protein kinase II [34, 35, 73, 81, 82, 88, 91, 93, 98, 102, 106, 117] calcium/calmodulin-dependent protein kinase IIb [81] calcium/calmodulin-dependent protein kinase IV [78, 79] calcium/calmodulin-dependent protein kinase IV/protein serine/threonine phosphatase 2A signaling complex [78] calcium/calmodulin-dependent protein kinase Ia [69] calcium/calmodulin-dependent protein kinase type I [14, 47, 53, 54, 55, 57] calcium/calmodulin-dependent protein kinase type II a chain [1, 19, 20, 21, 22, 25, 26, 37, 38, 39] calcium/calmodulin-dependent protein kinase type II b chain [1, 15, 36] calcium/calmodulin-dependent protein kinase type II d chain [32, 33, 44, 46] calcium/calmodulin-dependent protein kinase type II g chain [1, 23, 24] calcium/calmodulin-dependent protein kinase type IV catalytic chain [16, 17, 18, 27, 48, 49, 50] calcium/calmodulin-dependent serine/threonine-protein kinase [41, 42] caldesmon calmodulin kinase I [89] calmodulin-dependent protein kinase [64] calmodulin-dependent protein kinase IV [70] kinase, caldesmon (phosphorylating) kinase, microtubule-associated protein 2 (phosphorylating) microtubule associated protein kinase microtubule-associated protein 2 kinase peripheral plasma membrane protein CaMGUK Additional information ( presumably identical with casein kinase II [61]; presumably identical with EC 2.7.1.117 [62]; cf. EC 2.7.11.26 [86]; CLICK-III belongs to the CaMKI family [74]; the enzyme belongs to the family of calmodulin-dependent kinases, cf. EC 2.7.11.18 [64]; the enzyme belongs to the family of CaM-kinases, overview [71]; the enzyme is a member of the MAGUK family [75]) [61, 62, 64, 71, 74, 75, 86]

3

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

CAS registry number 141467-21-2 93229-57-3 97350-82-8

2 Source Organism























4

Gallus gallus (no sequence specified) [58, 59, 60, 62, 63] Drosophila melanogaster (no sequence specified) [65, 88] mammalia (no sequence specified) [10, 11] eukaryota (no sequence specified) [9, 12] Mus musculus (no sequence specified) [68, 71, 78, 81, 89, 94, 101, 103, 105, 107, 108, 114, 115, 116, 117] Homo sapiens (no sequence specified) [68, 70, 71, 79, 82, 86, 91, 103, 106, 111] Rattus norvegicus (no sequence specified) [2, 3, 4, 5, 6, 65, 66, 68, 71, 73, 74, 75, 76, 81, 85, 86, 87, 89, 90, 93, 95, 97, 98, 100, 102, 104, 109, 110, 112, 116, 117] Sus scrofa (no sequence specified) [68, 81] Bos taurus (no sequence specified) [4, 8, 58] Oryctolagus cuniculus (no sequence specified) [68, 103] Ovis aries (no sequence specified) [61] Arabidopsis thaliana (no sequence specified) [77] Aplysia californica (no sequence specified) [2] Xenopus laevis (no sequence specified) [81, 99] Candida albicans (no sequence specified) [92] Xenopus sp. (no sequence specified) [7] Electrophorus electricus (no sequence specified) [80] Funaria hygrometrica (no sequence specified) [83] Rattus norvegicus (UNIPROT accession number: P08413) [15] Mus musculus (UNIPROT accession number: P08414) [16, 17, 18] Rattus norvegicus (UNIPROT accession number: P11275) [19, 20, 21, 22] Rattus norvegicus (UNIPROT accession number: P11730) [23, 24] Mus musculus (UNIPROT accession number: P11798) [25, 26] Rattus norvegicus (UNIPROT accession number: P13234) [27, 28, 29, 30, 31] Rattus norvegicus (UNIPROT accession number: P15791) [32, 33] Saccharomyces cerevisiae (UNIPROT accession number: P22517) [34, 35] Saccharomyces cerevisiae (UNIPROT accession number: P27466) [34, 35] Mus musculus (UNIPROT accession number: P28652) [36] Drosophila melanogaster (UNIPROT accession number: Q00168) [37, 38, 39] Emericella nidulans (UNIPROT accession number: Q00771) [40] Malus domestica (UNIPROT accession number: Q07250) [41, 42] Homo sapiens (UNIPROT accession number: Q13554) [1, 43, 44, 45] Homo sapiens (UNIPROT accession number: Q13557) [44, 46]

2.7.11.17













Ca2+/Calmodulin-dependent protein kinase

Homo sapiens (UNIPROT accession number: Q14012) [47, 67] Homo sapiens (UNIPROT accession number: Q16566) [48, 49, 50] Drosophila melanogaster (UNIPROT accession number: Q24210) [51, 52] Rattus norvegicus (UNIPROT accession number: Q63450) [53, 54, 55] Rattus norvegicus (UNIPROT accession number: Q64572) [13] Medicago sativa (UNIPROT accession number: Q9AR92) [56] Schizosaccharomyces pombe (UNIPROT accession number: Q9P7I2) [14, 57] Mus musculus (UNIPROT accession number: Q923T9) [1] Metarhizium anisopliae (UNIPROT accession number: O14408) [1] Homo sapiens (UNIPROT accession number: Q9UQM7) [1] Rattus norvegicus (UNIPROT accession number: Q7TNJ7) [84] Xenopus laevis (UNIPROT accession number: Q8AYR3) [69] Nicotiana tabacum (UNIPROT accession number: Q84ZT8) [96] Homo sapiens (UNIPROT accession number: Q8IU85) [72] Homo sapiens (UNIPROT accession number: Q96NX5) [74] Physarum polycephalum (UNIPROT accession number: Q8WSQ3) [64] Mus musculus (UNIPROT accession number: Q91VB2) [74] Stagonospora nodorum (UNIPROT accession number: Q00LS5) [113]

3 Reaction and Specificity Catalyzed reaction ATP + a protein = ADP + a phosphoprotein ( main phosphorylation site: Ser-73 [61]; casein kinase II as caldesmon kinase [61]; the reaction is an intramolecular autophosphorylation which is site-specific: predominantly serine with some threonine and no tyrosine residues are phosphorylated [58]; enzyme appears to be identical with caldesmon [58]; p42/p44erk mitogen-activated protein kinase appears to be the major caldesmon kinase, but a yet unidentified kinase, rather than mitogen-activated protein kinase, may be involved in regulation of the caldesmon function in vivo [63]; not identical but with strong binding affinity for caldesmon [62]; catalytic aspartate residue [11]) ATP + protein = ADP + O-phosphoprotein Reaction type phospho group transfer Natural substrates and products S ATP + Blc10 ( Bcl10 is essential for antigen receptor-induced NF-kB activation, interleukin-2 production, and T-cell proliferation but is not required for TCR-induced tyrosine phosphorylation, calcium flux, or extracellular signal-regulated kinase activation [111]) (Reversibility: ?) [111] P ADP + phosphorylated Blc10 S ATP + CARMA1 ( CaMKII is a modulator of CARMA1-mediated NF-kB activation, overview [111]) (Reversibility: ?) [111]

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P ADP + phosphorylated CARMA1 S ATP + Cabin1 ( a transcriptional corepressor of myocyte enhancer factor 2, phosphorylation by CaMKIV creates a docking site for protein 14-3-3, which causes nuclear export, CaMKIV regulates nuclear export of Cabin1 during Ca2+ -dependent T-cell activation, regulation overview [70]) (Reversibility: ?) [70] P ADP + phosphorylated Cabin1 S ATP + I-kB ( substrate of CaM-KII in T-lymphocytes and neurons, phosphorylation leads to activation of I-kB, which mediates activation of NF-kB [71]) (Reversibility: ?) [71] P ADP + phosphorylated I-kB S ATP + l-type Ca2+ channel ( inactivation, leading to increased Ca2+ channel open probability and increased arrhytmias [103]) (Reversibility: ?) [103] P ADP + phosphorylated L-type Ca2+ channel S ATP + MAP2 (Reversibility: ?) [65] P ADP + phosphorylated MAP2 S ATP + MEF-2A ( phosphorylation by CaMKIV [68]) (Reversibility: ?) [68] P ADP + phosphorylated MEF-2A S ATP + MEF-2C ( phosphorylation by CaMKIV [68]) (Reversibility: ?) [68] P ADP + phosphorylated MEF-2C S ATP + MEF-2D ( phosphorylation by CaMKIV [68]) (Reversibility: ?) [68] P ADP + phosphorylated MEF-2D S ATP + NFkB ( the nuclear CaMKII does not phosphorylate, in contrast to the cytoplasmic isozyme, CREB at S133 and NFkB at S536 [101]) (Reversibility: ?) [101] P ADP + phosphorylated NFkB S ATP + NHE-1 ( phosphorylation by CaMKII is regulated by phosphatase PP1 which is associated with the exchanger [104]) (Reversibility: ?) [104] P ADP + phosphorylated NHE-1 S ATP + Na+ -channel ( isozyme CaMKIId increases persistent/late inward INa and intracellular Na+ concentration regulazing Na+ channel activity, CaMKII expression is increased in heart failure and may be involved in Na+ channel regulation alterations via calmodulin, overview [108]) (Reversibility: ?) [108] P ADP + phosphorylated Na+ -channel S ATP + PLB ( a regulatory protein in Ca2+ signaling [103]) (Reversibility: ?) [103] P ADP + phosphorylated PLB S ATP + PLN ( phosphorylation contributes to mechanical recovery from acidosis by inhibiting SERCA2a inhibition [104]) (Reversibility: ?) [104] P ADP + phosphorylated PLN

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Ca2+/Calmodulin-dependent protein kinase

S ATP + PSD-95 ( high activity, CaMKII, smaller synapses show greater variability in PSD-95 phosphorylation [106]) (Reversibility: ?) [106] P ADP + phosphorylated PSD-95 S ATP + RyR ( a regulatory protein in Ca2+ signaling [103]) (Reversibility: ?) [103] P ADP + phosphorylated RyR S ATP + S6-kinase ( step of a protein kinase cascade initiated by insulin in a yet unidentified manner [7]) (Reversibility: ?) [7] P ? S ATP + Stargazin ( high activity, CaMKII, phosphatases limit phosphorylation of stargazin [106]) (Reversibility: ?) [106] P ADP + phosphorylated Stargazin S ATP + a protein ( the enzyme phosphorylates e.g. the synaptic vesicle-associated protein synapsin 1 and synapsin 2 [11]) (Reversibility: ?) [9, 10, 11, 12] P ADP + a phosphoprotein S ATP + cAMP response element-binding protein ( CaMKIV activates CREB by phosphorylation and stimulates CREB-mediated transcription [78]; i.e. CREB, phosphorylation by CaMK II at Ser133 [93]) (Reversibility: ?) [78, 93] P ADP + phosphorylated cAMP response element-binding protein S ATP + cAMP-response element binding protein ( i.e. CREB, phosphorylation by CaMKII and CaMKIV at Ser133 [68]; i.e. CREB, phosphorylation by CaMKII and CaMKIV at Ser133, and phosphorylation by CaMKII at Ser142 [68]) (Reversibility: ?) [68] P ADP + phosphorylated cAMP-response element binding protein S ATP + cAMP-responsive element-binding protein ( i.e. CREB, CaM kinase II, as part of the Ca2+ and CaMK signaling cascade, regulates the phosphorylation of CREB of spinal cord in rats following noxious stimulation, e.g. by capsaicin injection [95]) (Reversibility: ?) [95] P ADP + phosphorylated cAMP-responsive element-binding protein S ATP + caldesmon ( caldesmon plays a role in the regulation of smooth muscle contraction [58,60,63]) (Reversibility: r) [58, 59, 60, 62, 63] P ADP + caldesmon phosphate [58] S ATP + dystrophin Dp71d ( the phosphorylation process involves protein kinase C, EC 2.7.11.13, CAMKII-mediated phosphorylation modulates the Dp71 nuclear localization [109]) (Reversibility: ?) [109] P ADP + phosphorylated dystrophin Dp71d S ATP + glutamate receptor subunit GluR1 ( low activity, CaMKII, membrane localization of GluR1 restricts its phosphorylation [106]) (Reversibility: ?) [106] P ADP + phosphorylated glutamate receptor subunit GluR1 S ATP + glutamate receptor subunit NR2B ( low activity, CaMKII [106]) (Reversibility: ?) [106]

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Ca2+/Calmodulin-dependent protein kinase

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P ADP + phosphorylated glutamate receptor subunit NR2B S ATP + microtubule affinity regulating kinase 2 ( CaMKIa/microtubule affinity regulating kinase 2 signaling cascade mediates calcium-dependent neurite outgrowth/axonal extension [110]) (Reversibility: ?) [110] P ADP + phosphorylated microtubule affinity regulating kinase 2 S ATP + neuronal nitric-oxide synthase ( phosphorylation at Ser741 by CaM-K Ia, wild-type and truncation mutant 1-293 inhibits neuronal nitric-oxide synthase, nNOS, no substrate of CaM-K IIa and CaM-K IV [73]) (Reversibility: ?) [73] P ADP + phosphorylated neuronal nitric-oxide synthase S ATP + protein CREB ( activation by phosphorylation [107]; CaMKII regulates the phosphorylation of CREB in NMDA-induced retinal neurotoxicity [102]; the nuclear CaMKII does not phosphorylate, in contrast to the cytoplasmic isozyme, CREB at S133 and NFkB at S536 [101]) (Reversibility: ?) [101, 102, 107] P ADP + phosphorylated protein CREB S ATP + protein ERK ( activation by phosphorylation [107]) (Reversibility: ?) [107] P ADP + phosphorylated protein ERK S ATP + protein HDAC ( phosphorylation by nuclear CaMKII results in HDAC translocation from nucleus to cytoplasm [101]) (Reversibility: ?) [101] P ADP + phosphorylated protein HDAC S ATP + protein PLB ( a regulatory protein in Ca2+ signaling [103]) (Reversibility: ?) [103] P ADP + phosphorylated protein PLB S ATP + protein PLN ( PLN regulation through phosphorylation by CaMKII at Thr17 [101]) (Reversibility: ?) [101] P ADP + phosphorylated Pprotein LN S ATP + protein RyR ( a regulatory protein in Ca2+ signaling [103]) (Reversibility: ?) [103] P ADP + phosphorylated protein RyR S ATP + synGAP ( regulation and activation of the neuron-specific Ras GTPase-activating protein, synGAP, by phosphorylation through CaMKII in the postsynaptic density fraction of the forebrain, synGAP is part of the signaling complex attached to the cytoplasmic tail of the Nmethyl-d-aspartate-type glutamate receptor, overview [76]) (Reversibility: ?) [76] P ADP + phosphorylated synGAP S ATP + synapsin (Reversibility: ?) [65] P ADP + phosphorylated synapsin S ATP + tau protein ( phosphorylation at Ser416 by CaM kinase II is high in early stages of brain development [86]; phosphorylation at Ser416 by CaM kinase II is high in early stages of brain development, CaM kinase II is involved in the accumulation of tau in neuronal soma in Alzheimers disease brain [86]) (Reversibility: ?) [86] P ADP + phosphorylated tau protein

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Ca2+/Calmodulin-dependent protein kinase

S ATP + vimentin ( specific phosphorylation by CaMKII at Ser82 [82]) (Reversibility: ?) [82] P ADP + phosphorylated vimentin S Additional information ( involved in neuroplasticity. Mutant caki flies show reduced walking speed in Buridans paradigm [52]; may be important in cell cycle progression [57]; the enzyme is proposed to play a variety of important roles in brain function [19]; protein kinases and protein phosphatases regulate enzyme activities in the cell, overview [9]; Ca2+ signaling in T-cell activation involves transcriptional activity of MEF-2 and NFAT, which is repressed by Cabin1, activated CaMKIV can overcome the repression by Cabin1, crosstalk between Cabin1 and CaMKIV, dissociation of Cabin1 from MEF-2 by the enzyme requires calmodulin, overview [70]; calmodulin-dependent kinase kinase/calmodulin kinase I activity, not CaMKIV or CaMKII, gates extracellular-signal-regulated kinase-dependent long-term potentiation required for learning and memory, Ras-GRF1 and ERK are also involved, NMDA-dependent activation of ERK, CaMKK pathway regulation, overview [89]; CaM kinase II is strongly phosphorylated by protein kinase A PKA, EC 2.7.11.11, in electrocyte membranes, the activated CaM kinase II 2fold activates the Ca2+ pump and ATPase in the membranes, overview [80]; CaM kinase II plays a role in diverse cellular processes, overview [65]; CaM kinase II plays a role in diverse cellular processes, the neuronal CaM kinase II is involved in neurotransmitter synthesis and release, modulation of ion cannel activity, cellular transport, cell morphology, regulation of cytoskeleton, and neurite extension, synaptic plasticity, learning and memory, overview, CaM kinase II is involved in memory storage, functional characterization and mechanism, overview, CaMKII is involved in Ca2+ -dependent regulation of tyrosine hydroxylase and tryptophan hydroxylase in catecholamin and serotonin biosynthesis, and regulation of monoamine biosynthesis in the brain, CaMKII is involved in PSD in the postsynaptic space, functional analysis including the ion channel activity regulation, e.g. of the NMDA receptor and its NR2B subunit, the glutamate receptor, and the AMPA receptor, and postsynaptic signaling, overview [65]; CaM-KI and calcium/calmodulin-dependent kinase kinase CaM-KK participate in the control of cell cycle progression in MCF-7 human breast cancer cells, CaM-KK controls the G0-G1 restriction check point [67]; CaM-KI plays a role in cell structure regulation during early embryonic development [69]; CaM-Ks are involved in cell cycle regulation and centrosome replication, as well as in development of cancer via calmodulin activity, overview, CaM-KI is involved in CDK4/cyclin D1 activity in fibroblasts, CaM-KIV induces CREB-dependent transcription, regulation mechanism, overview, CaM-kinase signaling pathways, it plays a role in anti-apoptotic signaling, overview [71]; CaMKIg is involved in Ca2+ signal transduction in the cytoplasmic compartment of certain neuronal populations [84]; CaMKII Ca2+ /calmodulindependently potentiates ATP responses by promoting trafficking of P2X3

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receptors, electrical stimulation of dorsal root ganglion neurons or the sciatic nerve enhances the CaMKII-dependent receptor expression in membranes, overview [97]; CaMKII is a critical Ca2+ signaling transducer, CaMKII isozyme have special roles in regulating cardiac function determined by their subcellular localization, nuclear CaMKIIdB plays a key role in hypertrophic gene expression, cytosolic CaMKIIdC can affect excitation-contraction-coupling through phosphorylation of Ca2+ -regulatory proteins and may introduce signals leading to apoptosis, CaMKII is involved in cardiac hypertrophy and heart failure, signaling pathways, overview, CaMK is involved in regulation of various transcription factors and other DNA-binding proteins, overview [68]; CaMKII is a critical Ca2+ signaling transducer, CaMKII isozyme have special roles in regulating cardiac function determined by their subcellular localization, nuclear CaMKIIdB plays a key role in hypertrophic gene expression, cytosolic CaMKIIdC can affect excitation-contraction-coupling through phosphorylation of Ca2+ -regulatory proteins and may introduce signals leading to apoptosis, CaMKII is involved in cardiac hypertrophy, CaMKIIdB expression is increased in heart failure, about 2fold in failing cardiomyopathy, signaling pathways, overview, CaMK is involved in regulation of various transcription factors and other DNA-binding proteins, overview [68]; CaMKII is crucial for cellular and behavioral plasticity, autophosphorylation renders the enzyme independent on Ca2+ and calmodulin, which allows it to act as a molecular memory switch, CaMKII is required for memory formation of the brain in specific neurons, Ca2+ -independent CaMKII mutant T287D in the adult Drosophila melanogaster CNS enhances plasticity and the training of pheromonal cues, mechanism, overview [88]; CaMKII is involved in calcium signaling, synaptic plasticity, learning, and memory, CaMKII activity and expression are altered in the hippocampus of Pb2+ -exposed rats, reaction velocity is reduced by 41% and substrate affinity is increased by 22%, the rats exhibit deficits in hippocampal log-term potentiation and spatial learning [66]; CaMKII is required for gene transcription induced in the hippocampus by contextual fear conditioning, aCaMKII autophosphorylation is required for memory consolidation-specific transcription and formation of long term potentiation and memory, molecular mechanism, overview [94]; CaMKII is reversibly, Ca2+ /calmodulin-independently autophosphorylated at Thr286a and Thr287b with inhibitory effect, inactivated and made sedimentable by acute neuronal excitation in rats in vivo, regulation, overview [85]; CaMKIV regulation, overview, CaMKIV functions as a potent stimulator of Ca2+ -dependent gene expression [78]; CASK in inhibited by the plasma membrane Ca2+ pump 4b/CI, PMCA4b, via direct interaction with the C-terminus of the Ca2+ transporter [75]; components of the Ca2+ /calmodulin-dependent protein kinase cascade, overview [72]; glutamate receptor stimulation induces Ca2+ -dependent CaMKII translocation to synaptic and nonsynaptic sites [90]; isozyme CaMKIId3 is involved in the expression of brain-derive neurotrophic factor, BDNF, in the substantia nigra [87]; the enzyme is

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Ca2+/Calmodulin-dependent protein kinase

regulated by Ca2+ /calmodulin binding and reversible phosphorylation, overview, the autonomous, Ca2+ /calmodulin-independent activity of autophosphorylated Ca2+ /calmodulin-dependent protein kinase IV is required for its role in transcription [79]; the phosphatidylinositollinked dopamine receptor is involved in regulation of CaMK II enzyme activity in the brain [93]; Thr286-autophosphorylated CaMKII is associated with CaMKII-binding proteins densin-180, the N-methyl-daspartate receptor NR2B subunit, and a-actinin-2 in postsynaptic densityenriched rat brain fractions, the proteins influence each other in binding to CaMKII, interaction of binding proteins with CaMKII splicing variants, overview [81]; calmodulin/CaMKII and ANG II regulate surface expression, recycling, and functional activity of ion channel NBCe1 via separate mechanisms, CaMKII activates NBCe1 expression, overview [99]; CaMK activity is required for efficient induction of osteoclast differentiation and bone resorption by receptor activator of nuclear factor kB ligand, RANKL, overview [107]; CaMKI isozymes play distinct roles in hippocampal dendritic growth and neuronal development, overview [116]; CaMKII is a major component of the postsynaptic density of excitatory synapses, and plays a key role in the regulation of synaptic function in the mammalian brain, the unique molecular architecture of the postsynaptic density results in highly selective substrate discrimination by CaMKII, overview [106]; CaMKII is critical in regulating myocyte function with regard to excitation-contraction-relaxation cycles and excitation-transcription coupling [101]; CaMKII is involved in phorbol ester/ionomycin-induced NFkB activation, overview [112]; CaMKII isozymes have distinct cellular localizations and function, overview, release of acetylcholine from dual transmitting sympathetic neurons requires activation of both the p75 receptor and activated CaMKII, model for neurotrophin-dependent modulation of cholinergic transmission, neurotrophins can influence CaMKII signaling by regulating the production of CaMKII protein and/or by changing the level of CaMKII activation, overview [117]; CaMKII kinase modulates PC12 cell neuronal differentiation [109]; CaMKII signaling, overview, CaMKII is essential in the increasing of Ca2+ transient amplitude and production of mechanical contractile recovery from acidosis, two mechanisms, overview [104]; CaMKII substrates CARMA1 and Bcl10 functionally interact and control NF-kB signaling downstream of the T-cell receptor [111]; CpkA and CpkC are involved in pathogenicity while CpkB is redundant, CpkA is required for pycnidium development [113]; isozyme CaMKIId regulates cell proliferation of vascular smooth muscle cells, overview [98]; modulating role of CaMK in excitation-contraction coupling in the heart in response to Ca2+ levels, excitation-contraction coupling can be modulated by CaMKII by phosphorylation of several important Ca2+ regulatory proteins in the heart, overview [103]; Nmethyl-d-aspartate-induced neurotoxicity in the rat retina leads to increased levels of phopshorylated CaMKII and susequently of phosphorylated CREB, overview [102]; the enzyme is involved in dendritogen-

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esis in cortical neurons and is required for brain-derived neurotropic factor-stimulated dendritic growth, and regulation of dendritic morphogenesis via the lipid-raft-delineated CL3-STEF-RAc pathway contributing to the development of cortical dendrites, overview [114]) (Reversibility: ?) [9, 19, 52, 57, 65, 66, 67, 68, 69, 70, 71, 72, 75, 78, 79, 80, 81, 84, 85, 87, 88, 89, 90, 93, 94, 97, 98, 99, 101, 102, 103, 104, 106, 107, 109, 111, 112, 113, 114, 116, 117] P ? Substrates and products S ATP + 40S-ribosomal protein S6 ( not [5,6]; rat brain [2]) (Reversibility: ?) [2, 5, 6] P ? S ATP + Akt ( substrate of CaM-KII, phosphorylation at Thr308 [71]) (Reversibility: ?) [71] P ADP + phosphorylated Akt S ATP + Bcl10 ( phosphorylation by CaMKII at Ser138, recombinant FLAG-tagged Bcl10 substrate expressed in HEK-293T cells [112]) (Reversibility: ?) [112] P ADP + phosphorylated Bcl10 S ATP + Blc10 ( activation [111]; Bcl10 is essential for antigen receptor-induced NF-kB activation, interleukin-2 production, and T-cell proliferation but is not required for TCR-induced tyrosine phosphorylation, calcium flux, or extracellular signal-regulated kinase activation [111]) (Reversibility: ?) [111] P ADP + phosphorylated Blc10 S ATP + CARMA1 ( CaMKII is a modulator of CARMA1-mediated NF-kB activation, overview [111]; activation by phosphorylation at Ser109, interaction with Bcl10 is facilitated [111]) (Reversibility: ?) [111] P ADP + phosphorylated CARMA1 S ATP + CREB ( i.e. cAMP-response element binding protein, substrate of CaM-KI, phosphorylation at Ser133 [71]) (Reversibility: ?) [71] P ADP + phosphorylated CREB S ATP + Cabin1 ( a transcriptional corepressor of myocyte enhancer factor 2, phosphorylation by CaMKIV creates a docking site for protein 14-3-3, which causes nuclear export, CaMKIV regulates nuclear export of Cabin1 during Ca2+ -dependent T-cell activation, regulation overview [70]; a transcriptional corepressor of myocyte enhancer factor 2, phosphorylation at Ser2126 by CaMKIV creates a docking site for protein 14-3-3, which causes nuclear export, no activity with Cabin1 mutant S2126A [70]) (Reversibility: ?) [70] P ADP + phosphorylated Cabin1 S ATP + GABA-modulin (Reversibility: ?) [2] P ?

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S ATP + I-kB ( substrate of CaM-KII in T-lymphocytes and neurons, phosphorylation leads to activation of I-kB, which mediates activation of NF-kB [71]; substrate of CaM-KII [71]) (Reversibility: ?) [71] P ADP + phosphorylated I-kB S ATP + KKALRRQETVDAL ( i.e. autocamtide-2 [92]) (Reversibility: ?) [92] P ADP + KKALRRQET(P)VDAL S ATP + Kemptide ( i.e. LRRASLG, low activity [92]) (Reversibility: ?) [92] P ADP + LRRAS(P)LG S ATP + L-type Ca2+ channel ( inactivation, leading to increased Ca2+ channel open probability and increased arrhytmias [103]; inactivation by CaMKII [103]) (Reversibility: ?) [103] P ADP + phosphorylated L-type Ca2+ channel S ATP + MAP2 (Reversibility: ?) [65] P ADP + phosphorylated MAP2 S ATP + MEF-2A ( phosphorylation by CaMKIV [68]) (Reversibility: ?) [68] P ADP + phosphorylated MEF-2A S ATP + MEF-2C ( phosphorylation by CaMKIV [68]) (Reversibility: ?) [68] P ADP + phosphorylated MEF-2C S ATP + MEF-2D ( phosphorylation by CaMKIV [68]) (Reversibility: ?) [68] P ADP + phosphorylated MEF-2D S ATP + NFkB ( the nuclear CaMKII does not phosphorylate, in contrast to the cytoplasmic isozyme, CREB at S133 and NFkB at S536 [101]) (Reversibility: ?) [101] P ADP + phosphorylated NFkB S ATP + NHE-1 ( phosphorylation by CaMKII is regulated by phosphatase PP1 which is associated with the exchanger [104]; a Na+ -H+ -exchanging protein, phosphorylation by CaMKII at the intracellular cytoplasmic domain [104]) (Reversibility: ?) [104] P ADP + phosphorylated NHE-1 S ATP + Na+ -channel ( isozyme CaMKIId increases persistent/late inward INa and intracellular Na+ concentration regulazing Na+ channel activity, CaMKII expression is increased in heart failure and may be involved in Na+ channel regulation alterations via calmodulin, overview [108]) (Reversibility: ?) [108] P ADP + phosphorylated Na+ -channel S ATP + PC12 pheochromacytoma cell line protein substrate pp250 (Reversibility: ?) [3] P ? S ATP + PLB ( a regulatory protein in Ca2+ signaling [103]) (Reversibility: ?) [103] P ADP + phosphorylated PLB

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S ATP + PLN ( phosphorylation contributes to mechanical recovery from acidosis by inhibiting SERCA2a inhibition [104]; a sarcoplasmic reticulum protein, phosphorylation by CaMKII at Thr17 [104]) (Reversibility: ?) [104] P ADP + phosphorylated PLN S ATP + PLRRTLSVAA (Reversibility: ?) [78] P ADP + ? S ATP + PLRRTLSVAA-amide ( glycogen synthase-derived peptide GSP [85]) (Reversibility: ?) [85] P ADP + phosphorylated PLRRTLSVAA-amide S ATP + PSD-95 ( high activity, CaMKII, smaller synapses show greater variability in PSD-95 phosphorylation [106]; a protein implicated in the scaffolding and trafficking of AMPA receptors [106]) (Reversibility: ?) [106] P ADP + phosphorylated PSD-95 S ATP + RyR ( a regulatory protein in Ca2+ signaling [103]) (Reversibility: ?) [103] P ADP + phosphorylated RyR S ATP + S6-kinase ( step of a protein kinase cascade initiated by insulin in a yet unidentified manner [7]) (Reversibility: ?) [7] P ? S ATP + S6-kinase II ( phosphorylation sites: serine and threonine [7,8]) (Reversibility: ?) [7, 8] P ? S ATP + Stargazin ( high activity, CaMKII, phosphatases limit phosphorylation of stargazin [106]; a protein implicated in the scaffolding and trafficking of AMPA receptors [106]) (Reversibility: ?) [106] P ADP + phosphorylated Stargazin S ATP + YLRRRLSDSNF ( synapsin site I-derived peptide substrate [84]) (Reversibility: ?) [84] P ADP + ? S ATP + a protein ( the enzyme phosphorylates e.g. the synaptic vesicle-associated protein synapsin 1 and synapsin 2 [11]) (Reversibility: ?) [9, 10, 11, 12] P ADP + a phosphoprotein S ATP + actin ( not [58]) (Reversibility: ?) [58, 61] P ADP + phosphoactin S ATP + bovine serum albumin ( low activity [92]) (Reversibility: ?) [92] P ADP + phosphorylated bovine serum albumin S ATP + cAMP response element-binding protein ( CaMKIV activates CREB by phosphorylation and stimulates CREB-mediated transcription [78]; i.e. CREB, phosphorylation by CaMK II at Ser133 [93]; i.e. CREB [78]) (Reversibility: ?) [78, 93] P ADP + phosphorylated cAMP response element-binding protein S ATP + cAMP-response element binding protein ( i.e. CREB, phosphorylation by CaMKII and CaMKIV at Ser133 [68]; i.e. CREB, phosphorylation by CaMKII and CaMKIV at Ser133, and phosphorylation by CaMKII at Ser142 [68]) (Reversibility: ?) [68] ADP + phosphorylated cAMP-response element binding protein ATP + cAMP-response element-binding protein ( i.e. CREB, phosphorylation at S133, substrate of CaMKIV and CaMKII [9]) (Reversibility: ?) [9] ADP + phosphorylated cAMP-response element-binding protein ATP + cAMP-responsive element-binding protein ( i.e. CREB, CaM kinase II, as part of the Ca2+ and CaMK signaling cascade, regulates the phosphorylation of CREB of spinal cord in rats following noxious stimulation, e.g. by capsaicin injection [95]; i.e. CREB, phosphorylation at Ser133 [95]) (Reversibility: ?) [95] ADP + phosphorylated cAMP-responsive element-binding protein ATP + caldesmon ( less efficient than synapsin [62]; phosphorylated at 82% the rate of casein [61]; caldesmon plays a role in the regulation of smooth muscle contraction [58,60,63]) (Reversibility: r) [58, 59, 60, 61, 62, 63] ADP + caldesmon phosphate [58, 59, 60, 62, 63] ATP + casein ( best substrate [61]; phosphorylation at about 60% the rate of caldesmon [62]) (Reversibility: ?) [58, 61, 62] ADP + phosphocasein ATP + casein ( low activity [92]) (Reversibility: ?) [83, 92] ADP + phosphorylated casein ATP + casein ( not [6,8]; rat brain [2]) (Reversibility: ?) [2, 6, 8] ? ATP + dystrophin Dp71d ( the phosphorylation process involves protein kinase C, EC 2.7.11.13, CAMKII-mediated phosphorylation modulates the Dp71 nuclear localization [109]; a nuclear splicing isoform of Dp71, several potential sites for phosphorylation [109]) (Reversibility: ?) [109] ADP + phosphorylated dystrophin Dp71d ATP + estrogen-receptor from calf uterus (Reversibility: ?) [2] ? ATP + glutamate receptor subunit GluR1 ( low activity, CaMKII, membrane localization of GluR1 restricts its phosphorylation [106]; phosphorylation at Ser831 [106]) (Reversibility: ?) [106] ADP + phosphorylated glutamate receptor subunit GluR1 ATP + glutamate receptor subunit NR2B ( low activity, CaMKII [106]) (Reversibility: ?) [106] ADP + phosphorylated glutamate receptor subunit NR2B ATP + glycogen synthase (Reversibility: ?) [9] ADP + phosphorylated glycogen synthase ATP + glycogen synthase ( rat brain [2]) (Reversibility: ?) [2] ?

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S ATP + histone ( H1 (best substrate) [3,8]; H2a or H2b [8]; V-S [3]; 5S, 6S, 7S [5]; 3S [6]; 8S [5,6]; not: 2AS [5]) (Reversibility: ?) [3, 5, 6, 8] P ? S ATP + histone ( histone V-S [58]; calf thymus histone II- S, poor substrate [58,62]; histone III- S [58,61,62]) (Reversibility: ?) [58, 61, 62] P ADP + phosphohistone S ATP + histone IIA (Reversibility: ?) [83] P ADP + phosphorylated histone IIA S ATP + histone IIIS (Reversibility: ?) [83, 96] P ADP + phosphorylated histone IIIS S ATP + histone IIS (Reversibility: ?) [92] P ADP + phosphorylated histone IIS S ATP + histone VI (Reversibility: ?) [83] P ADP + phosphorylated histone VI S ATP + histone VIIS (Reversibility: ?) [83] P ADP + phosphorylated histone VIIS S ATP + histone VIS (Reversibility: ?) [83] P ADP + phosphorylated histone VIS S ATP + histone VS (Reversibility: ?) [83] P ADP + phosphorylated histone VS S ATP + microtubule affinity regulating kinase 2 ( CaMKIa/microtubule affinity regulating kinase 2 signaling cascade mediates calcium-dependent neurite outgrowth/axonal extension [110]; i.e. MARK2, recombinant myc-tagged MARK2 expressed in HEK-293 cells, mutational determination of phosphorylation sites, overview [110]) (Reversibility: ?) [110] P ADP + phosphorylated microtubule affinity regulating kinase 2 S ATP + microtubule-associated protein 2 ( as good as myelin basic protein [6]; rat brain: broad specificity [2]; ATP preferred to GTP [5]; not MAP-1 [2]; phosphorylation sites are serine and threonine [5,6]; i.e. MAP-2, preferred substrate [3]) (Reversibility: ?) [2, 3, 5, 6, 8] P ADP + microtubule-associated protein 2 phosphate [2] S ATP + microtubule-associated protein tau ( not [6]; Ca2+ /calmodulin dependent autophosphorylation [4]; all 4 t-species, but about 50% of tau1 and tau2 protein remains resistant to phosphorylation [4]) (Reversibility: ?) [2, 4, 6, 8] P ? S ATP + myelin basic protein ( best substrate [5]; phosphorylation sites: serine [6]; phosphorylation sites: threonine [5,6]) (Reversibility: ?) [3, 5, 6] P ? S ATP + myosin ( isolated light chain of smooth-muscle myosin, phosphorylated at 80% the rate of caldesmon [58,62]) (Reversibility: ?) [58, 61, 62]

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2.7.11.17

Ca2+/Calmodulin-dependent protein kinase

P ADP + phosphomyosin S ATP + myosin II light chain ( recombinant substrate from Physarum polycephalum, phosphorylation at Ser18, phosphorylation site analysis, no phosphorylation of substrate mutant S18A [64]) (Reversibility: ?) [64] P ADP + phosphorylated myosin II light chain S ATP + myosin light chain ( poor [5]; smooth-muscle, myosin, rat brain [2]; smooth-muscle, cardiac [5]; smooth-muscle, skeletal muscle [2]) (Reversibility: ?) [2, 5] P ? S ATP + neuronal nitric-oxide synthase ( phosphorylation at Ser741 by CaM-K Ia, wild-type and truncation mutant 1-293 inhibits neuronal nitric-oxide synthase, nNOS, no substrate of CaM-K IIa and CaM-K IV [73]; phosphorylation at Ser741 by CaM-K Ia, wild-type and truncation mutant 1-293 inhibits neuronal nitric-oxide synthase, nNOS, no substrate of CaM-K IIa and CaM-K IV, determination of phosphorylation sites by analytical SDS-PAGE [73]) (Reversibility: ?) [73] P ADP + phosphorylated neuronal nitric-oxide synthase S ATP + phosvitin (Reversibility: ?) [92] P ADP + phosphorylated phosvitin S ATP + protamin ( low activity [92]) (Reversibility: ?) [92] P ADP + phosphorylated protamin S ATP + protein ( autophosphorylation [37,55]; autophosphorylation at Thr177 [55]; autophosphorylation of Ca2+ / calmodulin-dependent protein kinase II converts the enzyme to a Ca2+ independent form, autophosphorylation site is Thr286 in the a subunit [22]) (Reversibility: ?) [22, 37, 55] P ADP + phosphoprotein S ATP + protein CREB ( activation by phosphorylation [107]; CaMKII regulates the phosphorylation of CREB in NMDA-induced retinal neurotoxicity [102]; the nuclear CaMKII does not phosphorylate, in contrast to the cytoplasmic isozyme, CREB at S133 and NFkB at S536 [101]; i.e. cyclic AMP-response element binding protein [102]) (Reversibility: ?) [101, 102, 107] P ADP + phosphorylated protein CREB S ATP + protein ERK ( activation by phosphorylation [107]) (Reversibility: ?) [107] P ADP + phosphorylated protein ERK S ATP + protein HDAC ( phosphorylation by nuclear CaMKII results in HDAC translocation from nucleus to cytoplasm [101]; nuclear CaMKII [101]) (Reversibility: ?) [101] P ADP + phosphorylated protein HDAC S ATP + protein PLB ( a regulatory protein in Ca2+ signaling [103]) (Reversibility: ?) [103] P ADP + phosphorylated protein PLB S ATP + protein PLN ( PLN regulation through phosphorylation by CaMKII at Thr17 [101]) (Reversibility: ?) [101]

17

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

P ADP + phosphorylated Pprotein LN S ATP + protein PLN ( a sarcoplasmic reticulum protein, phosphorylation by CaMKII at Thr17 [101]) (Reversibility: ?) [101] P ADP + phosphorylated protein PLN S ATP + protein RyR ( a regulatory protein in Ca2+ signaling [103]) (Reversibility: ?) [103] P ADP + phosphorylated protein RyR S ATP + synGAP ( regulation and activation of the neuron-specific Ras GTPase-activating protein, synGAP, by phosphorylation through CaMKII in the postsynaptic density fraction of the forebrain, synGAP is part of the signaling complex attached to the cytoplasmic tail of the Nmethyl-d-aspartate-type glutamate receptor, overview [76]; activation of the neuron-specific Ras GTPase-activating protein, synGAP, by phosphorylation through CaMKII at Ser1123, Ser1058, Ser750, Ser751, Ser756, Ser764, and Ser/65, reduced activity with synGAP serines phosphorylation site mutants, determination of phosphorylation sites by mass spectrometry, overview [76]) (Reversibility: ?) [76] P ADP + phosphorylated synGAP S ATP + synapsin (Reversibility: ?) [65] P ADP + phosphorylated synapsin S ATP + synapsin ( brain synapsin best substrate of chicken gizzard caldesmon kinase [58]; brain synapsin best substrate, phosphorylated at 950% the rate of caldesmon [62]) (Reversibility: ?) [58, 62] P ADP + phosphosynapsin S ATP + synapsin ( rat brain [2]) (Reversibility: ?) [2] P ? S ATP + synapsin I ( substrate of CaM-KI [71]) (Reversibility: ?) [71] P ADP + phosphorylated synapsin I S ATP + synapsin II ( substrate of CaM-KI [71]) (Reversibility: ?) [71] P ADP + phosphorylated synapsin II S ATP + synthide-2 (Reversibility: ?) [72] P ADP + phorphorylated synthide-2 S ATP + syntide-2 ( i.e. PLARTLSVAGLPGKK [69,92]; i.e. PLARTLSVAGLPGKK, synthetic peptide substrate [96]) (Reversibility: ?) [69, 92, 96] P ADP + phosphorylated syntide-2 S ATP + tau peptide 408-420 ( recombinant substrate expressed in Escherichia coli, phosphorylation at Ser416 by CaM kinase II, no activity with the peptide by CDK5, EC 2.7.11.22, and casein kinase II, EC 2.7.11.26 [86]) (Reversibility: ?) [86] P ADP + phosphorylated tau peptide 408-420 S ATP + tau protein ( phosphorylation at Ser416 by CaM kinase II is high in early stages of brain development [86]; phosphorylation at Ser416 by CaM kinase II is high in early stages of brain development, CaM kinase II is involved in the accumulation of tau in neuronal soma in

18

2.7.11.17

P S P S P S

P S P S

Ca2+/Calmodulin-dependent protein kinase

Alzheimers disease brain [86]; recombinant substrate expressed in Escherichia coli, determination of phosphorylation sites, phosphorylation at Ser416 by CaM kinase II, tau is also a substrate for CDK5, EC 2.7.11.22, and casein kinase II, EC 2.7.11.26 [86]) (Reversibility: ?) [86] ADP + phosphorylated tau protein ATP + tropomyosin ( not [58]) (Reversibility: ?) [58, 61] ADP + phosphotropomyosin ATP + tubulin ( not [6]; rat brain [2]) (Reversibility: ?) [2, 3, 6] ? ATP + vimentin ( specific phosphorylation by CaMKII at Ser82 [82]; specific phosphorylation by CaMKII at Ser82, wild-type vimentin protein and a construct of a vimentin peptide containing Ser82 fused to the NMDA receptor 2B subunit, an interaction partner of CaMKII [82]) (Reversibility: ?) [82] ADP + phosphorylated vimentin ATP + vimentin ( rat brain [2]) (Reversibility: ?) [2] ? Additional information ( substrate specificity [12]; poor or no substrates are kinesin, myosin I, phosvitin, ATP-citrate lyase [5]; cytoskeletal proteins, e.g. vinculin, filamin, fodrin or neurofilament protein [2]; phosphorylase b [6]; no substrates are protamine [5,6]; no substrates are bovine cardiac C-protein, bovine brain fodrin, rabbit skeletal muscle glycogen synthase, phosphorylase B, troponon (I + T + C), actin, tropomyosin, smooth muscle actin, filamin, vinculin, a-actinin, protamine or phosvitin [58]; caldesmon is not a substrate of smoothmuscle myosin light-chain kinase [60]; isozyme of calmodulin-dependent multifunctional protein kinase II in smooth-muscle [62]; involved in neuroplasticity. Mutant caki flies show reduced walking speed in Buridans paradigm [52]; may be important in cell cycle progression [57]; the enzyme is proposed to play a variety of important roles in brain function [19]; protein kinases and protein phosphatases regulate enzyme activities in the cell, overview [9]; substrate specificity and binding structure, the enzyme depends on basic residues for substrate recognition, autoregulation by a pseudosubstrate mechanism, overview [10]; the enzyme performs autophosphorylation [94]; Ca2+ signaling in T-cell activation involves transcriptional activity of MEF-2 and NFAT, which is repressed by Cabin1, activated CaMKIV can overcome the repression by Cabin1, crosstalk between Cabin1 and CaMKIV, dissociation of Cabin1 from MEF-2 by the enzyme requires calmodulin, overview [70]; calmodulin-dependent kinase kinase/calmodulin kinase I activity, not CaMKIV or CaMKII, gates extracellular-signal-regulated kinase-dependent long-term potentiation required for learning and memory, Ras-GRF1 and ERK are also involved, NMDA-dependent activation of ERK, CaMKK pathway regulation, overview [89]; CaM kinase II is strongly phosphorylated by protein kinase A PKA, EC

19

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

2.7.11.11, in electrocyte membranes, the activated CaM kinase II 2fold activates the Ca2+ pump and ATPase in the membranes, overview [80]; CaM kinase II plays a role in diverse cellular processes, overview [65]; CaM kinase II plays a role in diverse cellular processes, the neuronal CaM kinase II is involved in neurotransmitter synthesis and release, modulation of ion cannel activity, cellular transport, cell morphology, regulation of cytoskeleton, and neurite extension, synaptic plasticity, learning and memory, overview, CaM kinase II is involved in memory storage, functional characterization and mechanism, overview, CaMKII is involved in Ca2+ -dependent regulation of tyrosine hydroxylase and tryptophan hydroxylase in catecholamin and serotonin biosynthesis, and regulation of monoamine biosynthesis in the brain, CaMKII is involved in PSD in the postsynaptic space, functional analysis including the ion channel activity regulation, e.g. of the NMDA receptor and its NR2B subunit, the glutamate receptor, and the AMPA receptor, and postsynaptic signaling, overview [65]; CaM-KI and calcium/calmodulin-dependent kinase kinase CaM-KK participate in the control of cell cycle progression in MCF-7 human breast cancer cells, CaM-KK controls the G0-G1 restriction check point [67]; CaM-KI plays a role in cell structure regulation during early embryonic development [69]; CaM-Ks are involved in cell cycle regulation and centrosome replication, as well as in development of cancer via calmodulin activity, overview, CaM-KI is involved in CDK4/cyclin D1 activity in fibroblasts, CaM-KIV induces CREB-dependent transcription, regulation mechanism, overview, CaM-kinase signaling pathways, it plays a role in anti-apoptotic signaling, overview [71]; CaMKIg is involved in Ca2+ signal transduction in the cytoplasmic compartment of certain neuronal populations [84]; CaMKII Ca2+ /calmodulindependently potentiates ATP responses by promoting trafficking of P2X3 receptors, electrical stimulation of dorsal root ganglion neurons or the sciatic nerve enhances the CaMKII-dependent receptor expression in membranes, overview [97]; CaMKII is a critical Ca2+ signaling transducer, CaMKII isozyme have special roles in regulating cardiac function determined by their subcellular localization, nuclear CaMKIIdB plays a key role in hypertrophic gene expression, cytosolic CaMKIIdC can affect excitation-contraction-coupling through phosphorylation of Ca2+ -regulatory proteins and may introduce signals leading to apoptosis, CaMKII is involved in cardiac hypertrophy and heart failure, signaling pathways, overview, CaMK is involved in regulation of various transcription factors and other DNA-binding proteins, overview [68]; CaMKII is a critical Ca2+ signaling transducer, CaMKII isozyme have special roles in regulating cardiac function determined by their subcellular localization, nuclear CaMKIIdB plays a key role in hypertrophic gene expression, cytosolic CaMKIIdC can affect excitation-contraction-coupling through phosphorylation of Ca2+ -regulatory proteins and may introduce signals leading to apoptosis, CaMKII is involved in cardiac hypertrophy, CaMKIIdB expression is increased in heart failure, about 2fold in failing cardiomyopathy, signaling pathways, overview, CaMK is involved in regulation of various

20

2.7.11.17

Ca2+/Calmodulin-dependent protein kinase

transcription factors and other DNA-binding proteins, overview [68]; CaMKII is crucial for cellular and behavioral plasticity, autophosphorylation renders the enzyme independent on Ca2+ and calmodulin, which allows it to act as a molecular memory switch, CaMKII is required for memory formation of the brain in specific neurons, Ca2+ -independent CaMKII mutant T287D in the adult Drosophila melanogaster CNS enhances plasticity and the training of pheromonal cues, mechanism, overview [88]; CaMKII is involved in calcium signaling, synaptic plasticity, learning, and memory, CaMKII activity and expression are altered in the hippocampus of Pb2+ -exposed rats, reaction velocity is reduced by 41% and substrate affinity is increased by 22%, the rats exhibit deficits in hippocampal log-term potentiation and spatial learning [66]; CaMKII is required for gene transcription induced in the hippocampus by contextual fear conditioning, aCaMKII autophosphorylation is required for memory consolidation-specific transcription and formation of long term potentiation and memory, molecular mechanism, overview [94]; CaMKII is reversibly, Ca2+ /calmodulin-independently autophosphorylated at Thr286a and Thr287b with inhibitory effect, inactivated and made sedimentable by acute neuronal excitation in rats in vivo, regulation, overview [85]; CaMKIV regulation, overview, CaMKIV functions as a potent stimulator of Ca2+ -dependent gene expression [78]; CASK in inhibited by the plasma membrane Ca2+ pump 4b/CI, PMCA4b, via direct interaction with the C-terminus of the Ca2+ transporter [75]; components of the Ca2+ /calmodulin-dependent protein kinase cascade, overview [72]; glutamate receptor stimulation induces Ca2+ -dependent CaMKII translocation to synaptic and nonsynaptic sites [90]; isozyme CaMKIId3 is involved in the expression of brain-derive neurotrophic factor, BDNF, in the substantia nigra [87]; the enzyme is regulated by Ca2+ /calmodulin binding and reversible phosphorylation, overview, the autonomous, Ca2+ /calmodulin-independent activity of autophosphorylated Ca2+ /calmodulin-dependent protein kinase IV is required for its role in transcription [79]; the phosphatidylinositollinked dopamine receptor is involved in regulation of CaMK II enzyme activity in the brain [93]; Thr286-autophosphorylated CaMKII is associated with CaMKII-binding proteins densin-180, the N-methyl-daspartate receptor NR2B subunit, and a-actinin-2 in postsynaptic densityenriched rat brain fractions, the proteins influence each other in binding to CaMKII, interaction of binding proteins with CaMKII splicing variants, overview [81]; CaM-K1d performs autophosphorylation in a Ca2+ / calmodulin-dependent manner which has no impact on its kinase activity [72]; CaMKII is a multifunctional enzyme [68]; CaMKII performs autophosphorylation [85]; CaMKII performs autophosphorylation at Thr286 [90]; isozyme-selective CaMKII binding sequence for interaction with ligand proteins, overview [81]; no activity with casein, bovine serum albumin, and light chains of various myosins from Dictyostelium, scallop, Mytilis, and chicken [64]; the enzyme performs Ca2+ /calmodulin-dependent autophosphorylation [96];

21

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

the enzyme performs Ca2+ /calmodulin-dependent autophosphorylation at a Ser residue [92]; the enzyme prefers lysine-rich substrates, no activity with phosvitin and bovine serum albumin, the enzyme performs strictly Ca2+ -dependent autophosphorylation which is influenced by substrates, overview [83]; calmodulin/CaMKII and ANG II regulate surface expression, recycling, and functional activity of ion channel NBCe1 via separate mechanisms, CaMKII activates NBCe1 expression, overview [99]; CaMK activity is required for efficient induction of osteoclast differentiation and bone resorption by receptor activator of nuclear factor kB ligand, RANKL, overview [107]; CaMKI isozymes play distinct roles in hippocampal dendritic growth and neuronal development, overview [116]; CaMKII is a major component of the postsynaptic density of excitatory synapses, and plays a key role in the regulation of synaptic function in the mammalian brain, the unique molecular architecture of the postsynaptic density results in highly selective substrate discrimination by CaMKII, overview [106]; CaMKII is critical in regulating myocyte function with regard to excitation-contraction-relaxation cycles and excitation-transcription coupling [101]; CaMKII is involved in phorbol ester/ionomycin-induced NFkB activation, overview [112]; CaMKII isozymes have distinct cellular localizations and function, overview, release of acetylcholine from dual transmitting sympathetic neurons requires activation of both the p75 receptor and activated CaMKII, model for neurotrophin-dependent modulation of cholinergic transmission, neurotrophins can influence CaMKII signaling by regulating the production of CaMKII protein and/or by changing the level of CaMKII activation, overview [117]; CaMKII kinase modulates PC12 cell neuronal differentiation [109]; CaMKII signaling, overview, CaMKII is essential in the increasing of Ca2+ transient amplitude and production of mechanical contractile recovery from acidosis, two mechanisms, overview [104]; CaMKII substrates CARMA1 and Bcl10 functionally interact and control NF-kB signaling downstream of the T-cell receptor [111]; CpkA and CpkC are involved in pathogenicity while CpkB is redundant, CpkA is required for pycnidium development [113]; isozyme CaMKIId regulates cell proliferation of vascular smooth muscle cells, overview [98]; modulating role of CaMK in excitation-contraction coupling in the heart in response to Ca2+ levels, excitation-contraction coupling can be modulated by CaMKII by phosphorylation of several important Ca2+ regulatory proteins in the heart, overview [103]; N-methyl-d-aspartate-induced neurotoxicity in the rat retina leads to increased levels of phopshorylated CaMKII and susequently of phosphorylated CREB, overview [102]; the enzyme is involved in dendritogenesis in cortical neurons and is required for brain-derived neurotropic factor-stimulated dendritic growth, and regulation of dendritic morphogenesis via the lipid-raft-delineated CL3-STEF-RAc pathway contributing to the development of cortical dendrites, overview [114]; CaMKII performs autophosphorylation, and may also regulate Na+ channels, overview [103]; the enzyme performs autophosphory-

22

2.7.11.17

Ca2+/Calmodulin-dependent protein kinase

lation at Thr286 activating the enzyme activity, and at Thr305/Thr306, which inhibits calmodulin binding and enzyme activation [100]) (Reversibility: ?) [2, 5, 6, 9, 10, 12, 19, 52, 57, 58, 59, 60, 62, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 78, 79, 80, 81, 83, 84, 85, 87, 88, 89, 90, 92, 93, 94, 96, 97, 98, 99, 100, 101, 102, 103, 104, 106, 107, 109, 111, 112, 113, 114, 116, 117] P ? Inhibitors 2-aminopurine [5] 2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylbenzylamine ( i.e. KN-93 [93]; i.e. KN-93, competitive on the Ca2+ /calmodulin binding site, CaMKII- specific inhibitor, blocks activation of the P2X3 receptor in neurons [97]) [93, 97] AC3-I peptide ( i.e. autocamtide-2 inhibitory peptide, inhibits CaMKII [103]) [103] AIP peptide ( a CaMKII inhibitory peptide with the sequence KKALRRQEAVDAL [101]; i.e. autocamtide-2-related inhibitory peptide, comprising 17 amino acids, a CaMKII inhibitory peptide with the sequence KKALRRQEAVDAL [103]) [101, 103] ARRKWQKTGHAVRAIGRLSS ( calmodulin antagonist peptide, IC50: 33.3 nM in H2 O, 10.6 nM in buffer containing 0.1% w/v Tween 80 [12]) [12] BAPTA-AM [82] Ca2+ ( not [5]; reversible, kinetics [6]) [5, 6] calmidazolium ( calmodulin antagonist [71]) [71] chloroquine [5] DTNB [92] EGTA [59, 66] GTP ( in the presence of ATP [61]) [61] heparin [61] K252a ( inhibits CaM-KII [71]) [71] KN-62 ( a Ca2+ /calmodulin-dependent enzyme inhibitor [92]; competitive on the Ca2+ /calmodulin binding site of CaMKII [97]) [70, 71, 92, 97] KN-93 ( CaM-KI and CaMKII, CaMKI inhibition in vivo causes cell cycle arrest in MCF- 7 cells and reduction in cyclin D1 and Rb protein phosphorylation [67]; specific CaM kinase II inhibitor [80]) [66, 67, 68, 71, 80, 86, 95, 104, 106] KN62 ( a CaMKII-specific inhibitor [109]; inhibits CaMKII [103]; reversible inhibition, causes inhibition of osteoclast formation in vivo [107]) [103, 107, 109] KN93 ( binds to the calmodulin-binding site of CaMKII and inhibits its activity [111]; inhibits CaMKII [103]; reversible inhibition of CaMKII [108]; reversible inhibition, causes inhibition of osteoclast formation in vivo [107]) [99, 103, 107, 108, 111, 112]

23

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

N-(6-aminohexyl)-1-naphthalenesulfonamide ( i.e. W7, a calciumcalmodulin inhibitor [109]) [109] PMCA4b ( wild-type PMCA4b inhibits CASK activity, while PMCA4b mutant D672E, containing a point mutation in the ATP binding site, shows only 10% of the wild-type inhibitory potency [75]) [75] phosphatase 2A ( not phosphatase 1 [7]) [7] phosphatidic acid ( at high concentrations, activates at low concentrations [4]) [4] phosphatidylinositol ( strong [4]) [4] protein kinase inhibitor H7 ( weak [3]) [3] quercetin ( at high concentrations [5]) [5] STO-609 ( the CaM-KKa inhibitor STO-609 inhibits activity of the CaM-K1d truncation mutant 1-296 [72]) [72] staurosporine ( at high concentrations [5]) [5] W-13 ( calmodulin antagonist [71]) [71] W-7 ( calmodulin antagonist [71]; a Ca2+ /calmodulin antagonist [92]; no inhibition by calcineurin inhibitor FK506 [70]) [70, 71, 92] W13 ( a calmodulin antagonist [99]) [99] calmodulin antagonist W-7 [56] pea protein peptides ( purified positively charged peptides produced from pea cellular proteins by alkaline protease, i.e. alcalase, are inhibitory for CaMKII in a competitive manner, especially those with a high content of lysine and arginine, which act more in a mixed inhibition type, amino acid compositions of the peptides and IC50 of peptide fractions, overview [91]) [91] peptide AC3-I ( i.e. autocamtide-2 inhibitory peptide, inhibits CaMKII [103]) [103] peptide AIP ( i.e. autocamtide-2-related inhibitory peptide, comprising 17 amino acids, a CaMKII inhibitory peptide with the sequence KKALRRQEAVDAL [103]; i.e. autocamtide-2-related inhibitory peptide, comprising 17 amino acids, a reversible CaMKII inhibitory peptide with the sequence KKALRRQEAVDAL [108]) [103, 108] trifluoperazine dimaleate ( calmodulin antagonist [71]) [71] Additional information ( no inhibition by specific inhibitors of protein kinases A or C and Ca2+ /calmodulin dependent protein kinase [3]; autoinhibitory, in absence of Ca2+ /calmodulin the enzyme shows an open conformation with extensive interactions between the Cterminal autoinhibitory sequence and the kinase core influencing the binding site for ATP [11]; synthesis of peptides behaving as autoregulatory pseudosubstrates, determination of inhibitory potential, sequences of autoregulatory regions of the different enzyme forms, required sequence properties, overview [12]; the enzyme is inhibited by its regulatory subunit masking the active site, autoregulation by a pseudosubstrate mechanism, overview [10]; CaMKII is inactivated by autophosphorylation at Thr305 and Thr306 [65]; CaMKII possesses an autinhibitory domain, the enzyme is regulated by de-/phosphorylation [68]; CaMKII possesses an auto-

24

2.7.11.17

Ca2+/Calmodulin-dependent protein kinase

inhibitory domain, the enzyme is regulated by de-/phosphorylation [68]; CaMKIV contains an autoinhibitory domain which harbors the binding site for Ca2+ and calmodulin [79]; no inhibition by H-7 and PKI [92]; no inhibition by KN-92, redox regulation of CaM-kinases, inhibition mechanisms, overview [71]; R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, i.e. SCH23390, or the PLCb antagonist 1-[6-([17b-methoxyestra-1,3,5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole2,5-dione, i.e. U-73122, inhibit CaMK II transactivation by SKF83959 via the brain phosphatidylinositol-linked dopamine receptor, the transactivation is attenuated by calphostin C or by intracellular calcium chelator BAPTA [93]; the Ca2+ /calmodulin-binding domain overlaps with the autoinhibition domain [74]; Ca2+ binds to the autoregulatory region of the enzyme disrupting autoinhibitory interactions and allowing access to the catalytic site for substrate and ATP [104]; no inhibition of CaMKII by KN92 [107]; the enzyme contains an autoinhibitory region close to the active site, which sterically blocks substrate binding [103]) [3, 10, 11, 12, 65, 68, 71, 74, 79, 92, 93, 103, 104, 107] Cofactors/prosthetic groups 3-phosphoinositide ( enzyme is dependent on [1]) [1] ATP ( dependent on [92]; the ATP-binding site is influenced by the autoinhibitory conformation [11]) [9, 10, 11, 12, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 106, 107, 108, 109, 110, 111, 112, 114, 117] calmodulin ( not [3]; requirement [2, 4, 58, 59, 60, 62]; after autophosphorylation, the enzyme is active in the absence of Ca2+ /calmodulin and even in the presence of EGTA [62]; binding required for activity [9, 10, 11, 12]) [2, 3, 4, 9, 10, 11, 12, 58, 59, 60, 62] Activating compounds 2-amino-6-mercaptopurine ( stimulation [5]) [5] 2-O-tetradecanoyl phorbol 13-acetate ( the activating effect is blocked by EGTA [109]) [109] calmodulin ( required [105, 117]; absolutely dependent on [72]; dependent on [65, 69, 71, 73, 80, 81, 82, 86, 89, 92, 93, 94, 97, 98, 99, 103, 104, 108, 109, 110, 111, 114]; CPK-1 contains a calmodulin-like regulatory apparatus, structural organization, overview [77]; dependent on, activates [84,95]; dependent on, activates at 31000 nM [83]; dependent on, activates the nonphosphorylated CaMKIV, residues F320, N321, D322, D323, N318, N324, N330, and N336 are involved in binding, the autoinhibitory domain harbors the binding site for Ca2+ and calmodulin [79]; dependent on, Ca2+ /calmodulin activate CaMKII prior to autophosphorylation which renders the enzyme independent of Ca2+ /calmodulin [68]; dependent on, Ca2+ /calmodulin-dependent, reversible enzyme clustering by self-association of the recombinant CaMKII,

25

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

which might be hindered by autophosphorylation at Thr286, mechanism, overview [90]; dependent on, intracellular calcium receptor [67]; dependent on, the Ca2+ /calmodulin-binding domain overlaps with the autoinhibition domain [74]; dependent on, transient, tightly regulated Ca2+ /calmodulin-dependent activation requiring phosphorylation at Thr200 by CaMK kinase, the Ca2+ /calmodulin binding-autoinhibitory domain is required for interaction with protein phosphatase PP2A, binding of Ca2+ / CaM and PP2A is exclusive, overview [78]; determination of the calmodulin binding regulatory domain [64]; kinase activity is dependent on [85]; the binding site comprises residues 913-932 with a basic amphiphilic a-helix structure, maximal binding at 105 nM, three different isoforms of calmodulin, CaM1, CaM3, and CaM13, differentially regulate CaMK1, overview, the unphosphorylated CaMK1 is dependent on Ca2+ and calmodulin, while the autophosphorylated enzyme is not [96]; the unphosphorylated CaMK1 is dependent on Ca2+ and calmodulin, while the autophosphorylated enzyme is not [88]; dependent on, activating activity is abolished by calmodulin oxidation, phosphorylation of substrate by CaMKII and CaMKII autophosphorylation at Thr286, calmodulin binding to the enzyme inhibits autophosphorylation at Thr305/Thr306, which leads to enzyme inhibition, overview [100]) [64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 114, 117] isobutylmethylxanthine ( slight stimulation [5]) [5] N-Methyl-d-aspartate ( activates the phosphorylation of synGAP at Ser765 and Ser1123 by CaMKII in cortical neurons [76]) [76] phosphatidic acid ( activating at low concentrations, inhibitory at high concentrations [4]) [4] phosphatidylethanolamine ( activation [4]) [4] phosphatidylserine ( activation, addition leads to 100% phosphorylation of tau2-protein [4]) [4] protamine ( stimulation [5]) [5] ionomycin ( activates both the wild-type and mutant I205K CaMKII [82]; activates nonphosphorylated CaMKIV by increasing intracellular Ca2+ concentration [79]; activates the Ca2+ /calmodulin-activated CaM-K1d further 1.5fold [72]) [70, 72, 78, 79, 82, 90] neurotrophins ( have a regulatory role [117]) [117] phorbol 13,13-dibutyrate ( induces an about 2fold maximum increase in caldesmon phosphorylation [63]) [63] receptor activator of nuclear factor kappa B ligand [107] tubulin ( activation [8]) [8] Additional information ( the enzyme is supposed to be activated by phosphorylation mediated by insulin [7]; after autophosphorylation the enzyme is active in the absence of Ca2+ /calmodulin and even in the presence of EGTA [62]; autoregulation by a pseudosubstrate mechanism, overview [10]; Ras activity can be induced by the nuclear growth factor [9]; 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methyl-phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine,

26

2.7.11.17

Ca2+/Calmodulin-dependent protein kinase

i.e. SKF83959, induces transactivation of CaMK II via the brain phosphatidylinositol-linked dopamine receptor, which is inhibited by SCH23390 or U73122 [93]; activating phosphorylation by calmodulin-dependent kinase kinase is required for CaMKI function in long-term potentiation, and learning and memory [89]; activation mechanism, modeling [77]; Ca2+ /calmodulin-bound CaMKIV is further activated by phosphorylation through Ca2+ /calmodulin-dependent protein kinase kinase CaMKKb, which renders CaMKIV independent on Ca2+ and calmodulin, autonomous activity [79]; CaM kinase II is activated by phosphorylation through PKA, EC 2.7.11.11 [80]; CaM-K Ia is activated in vitro by phosphorylation through kinase CaM-KK at Thr177 independently of Ca2+ and calmodulin [73]; CaM-K1d is activated about 30fold by phosphorylation through the Ca2+ /calmodulin-dependent protein kinase kinase CaM-KKa [72]; CaMKIg1 is activated by the calmodulin-dependent protein kinase kinase, CaMKK, while CaMKIg2 is not [84]; CaMKII is activated by autophosphorylation at Thr286a and Thr287b in the autoinhibition domain [65]; electrical stimulation of dorsal root ganglion neurons or the sciatic nerve enhances the CaMKII activity stimulating the P2X3 receptor, overview [97]; redox regulation of CaM-kinases, overview, CaM-KII and CaM-KIV activation mechanisms, overview [71]; the enzyme is activated by strictly Ca2+ -dependent autophosphorylation [83]; the enzyme is regulated by de-/phosphorylation [68]; Thr178 is localized in the activation loop [74]; transient, tightly regulated Ca2+ /calmodulin-dependent activation requiring phosphorylation at Thr200 by CaMK kinase, the Ca2+ /calmodulin binding-autoinhibitory domain is required for interaction with protein phosphatase PP2A, binding of Ca2+ /CaM and PP2A is exclusive, overview [78]; after Ca2+ /calmodulin-dependent activation CaMKII is further activated by autophosphorylation at Thr287, this activation is retained even after decline of Ca2+ during diastole [103]; brain-derived neurotrophic factor BDNF and nerve growth factor NGF increase the level of activated d-CaMKII but not a-CaMKII, isozyme CaMKIId can be activated by multiple pathways, including via p75 and TrkA, overview [117]; CaMKI activation by phosphorylation through CaMKK, the CaMK kinase [110]; CaMKI and CaMKIV are phosphorylated and activated by Ca2+ /calmodulindependent protein kinase kinases, i.e. CaMKKs [115]; CaMKI is phosphorylated at Thr177 and Thr180 by the Ca2+ /calmodulin-dependent protein kinase kinase, CaMKKa, activating CaMKI, CaMKKK also activates CaMKIV [105]; induction by phorbol 12-myristate 13-acetate PMA/ionomycin [112]; N-methyl-d-aspartate-induced neurotoxicity in the rat retina leads to increased levels of phopshorylated CaMKII and susequently of phosphorylated CREB, overview [102]) [7, 9, 10, 62, 65, 68, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 89, 93, 97, 102, 103, 105, 110, 112, 115, 117] Metals, ions Ca2+ ( required [105, 107, 117]; activates [56];

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requirement [2, 4, 58, 59, 60, 62]; absolutely dependent on [72]; dependent on [65, 67, 69, 71, 73, 81, 82, 86, 93, 94, 97, 98, 99, 103, 108, 110, 111, 114]; not [3]; activity becomes partially independent of Ca2+ after autophosphorylation [37]; the enzyme responds directly to Ca2+ -calmodulin with increased activity [47]; Ca2+ /calmodulin-dependent [1, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57]; autophosphorylation of Ca2+ /calmodulin-dependent protein kinase II converts the enzyme to a Ca2+ -independent form, autophosphorylation site is Thr286 in the a subunit [22]; after autophosphorylation, the enzyme is active in the absence of Ca2+ /calmodulin and even in the presence of EGTA [62]; binding required for activity [9, 10, 11, 12]; dependent on, activates [84, 92, 95]; dependent on, activates the nonphosphorylated CaMKIV, the autoinhibitory domain harbors the binding site for Ca2+ and calmodulin [79]; dependent on, activates, optimal at 0.05 mM [83]; dependent on, activates, the Ca2+ /calmodulin-binding domain overlaps with the autoinhibition domain [74]; dependent on, binding structure and kinetics [77]; dependent on, Ca2+ /calmodulin activate CaMKII prior to autophosphorylation which renders the enzyme independent of Ca2+ /calmodulin [68]; dependent on, Ca2+ /calmodulin-dependent, reversible enzyme clustering by self-association of the recombinant CaMKII, which might be hindered by autophosphorylation at Thr286, mechanism, overview [90]; dependent on, high affinity to [80]; dependent on, transient, tightly regulated Ca2+ /calmodulin-dependent activation requiring phosphorylation at Thr200 by CaMK kinase, the Ca2+ /calmodulin binding-autoinhibitory domain is required for interaction with protein phosphatase PP2A, binding of Ca2+ /CaM and PP2A is exclusive, overview [78]; has a regulatory function for CaMKI activity [89]; kinase activity is dependent on [85]; the unphosphorylated CaMK1 is dependent on Ca2+ and calmodulin, while the autophosphorylated enzyme is not [88,96]; dependent on, activates phosphorylation of substrate by CaMKII and CaMKII autophosphorylation at Thr286 [100]; dependent on, binds to the autoregulatory region of the enzyme disrupting autoinhibitory interactions [104]; dependent on, stimulation of calcium influx by cell depolarization increases Dp71d phosphorylation [109]) [1, 2, 3, 4, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 114, 117] KCl ( KCl-induced cell depolarization stimulates Dp71d phosphorylation [109]) [109] Mg2+ ( activation [5, 59, 61, 62]; dependent on [92]) [5, 59, 61, 62, 64, 65, 66, 67, 69, 70, 71, 72, 73, 76, 77, 78, 79, 80, 81, 82, 83, 84, 86, 89, 90, 91, 92, 93, 94, 95, 97, 99, 101, 102, 106, 107, 108, 109, 110, 111, 112, 117]

28

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Ca2+/Calmodulin-dependent protein kinase

Mn2+ ( activation [5]; partially stimulates [92]) [5, 92] Pb2+ ( CaMKII activity and expression are altered in the hippocampus of Pb2+ -exposed rats, reaction velocity is reduced by 41% and substrate affinity is increased by 22%, the rats exhibit deficits in hippocampal log-term potentiation and spatial learning, the content of CaMKIIb, but not of CaMKIIa, in the cytosolic fraction is reduced [66]) [66] Additional information ( little or no effect by Ni2+ , Ba2+ , Zn2+ , Cu2+ , and Cd2+ [92]) [92] Turnover number (min–1) 2.17 (myelin basic protein) [5] Specific activity (U/mg) 0.00027 ( histone III-S [58]) [58] 0.00054 ( aortic caldesmon [58]) [58] 0.00063 ( synapsin [58]) [58] 0.00067 [8] 0.00069 ( purified enzyme in presence of Ca2+ with substrate histone IIIS [83]) [83] 0.00073 ( autophosphorylation [58]) [58] 0.0035 ( purified enzyme [92]) [92] 0.004 ( recombinant nonphosphorylated, calmodulin-binding-residue mutants [79]) [79] 0.022 [61] 0.035 ( purified recombinant CaM-K1d [72]) [72] 0.8 ( microtubule associated protein 2 as substrate [5]) [5] 0.98 ( purified recombinant CaM-K1d phosphorylated by CaMKKa [72]) [72] 3 ( myelin basic protein as substrate [5]) [5] Additional information [85, 93] Km-Value (mM) 0.00074 (MAP2, isozyme a [65]) [65] 0.00081 (MAP2, isozyme b [65]) [65] 0.0016 (microtubule associated protein 2, epidermal growth factor activated cells [6]) [6] 0.0049 (caldesmon, pH 7.5, 25 C [62]) [62] 0.012 (ATP, pH 7.5, 25 C [62]) [62] 0.013 (ATP, isozyme b [65]) [65] 0.014 (ATP, pH 7.0, 30 C [92]; isozyme a [65]) [65, 92] 0.02 (syntide-2, pH 7.0, 30 C [92]) [92] 0.022 (synthide-2) [96] 0.03 (ATP, epidermal growth factor activated cells [6]) [6] 0.0445 (histone IIIS) [96] 0.063 (autocamptide-2, pH 7.0, 30 C [92]) [92] Additional information ( kinetic parameters, association with caldesmon does not alter enzymatic properties [62]; developmental Pb2+ exposure of rats alters the reaction kinetics of CaMKII in the hippocam-

29

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

pus compared to rats grown in absence of Pb2+ [66]; Ka for calmodulin is 111 nM for isozyme a, and 21 nM for isozyme b [65]; Ka for calmodulin is 8.3 nM [92]; kinetics for binding of calmodulin [79]; reaction and calmodulin binding kinetics [96]) [62, 65, 66, 79, 92, 96] Ki-Value (mM) Additional information ( Ki values of the pseudosubstrates in nano- to micromolar range [12]; inhibition kinetics for positively charged pea protein-derived peptides [91]) [12, 91] pH-Optimum 7 ( assay at [91]) [91] 7.4 ( assay at [78]) [78] 7.5 ( assay at [64, 66, 69, 72, 73, 79, 81, 83, 84, 86, 111]) [64, 66, 69, 72, 73, 79, 81, 83, 84, 86, 111] 7.5-9 [62] 7.6 ( assay at [110]) [110] 8 ( assay at [76]) [76, 92] Additional information ( pI: 4.9 [3]) [3] pH-Range Additional information ( broad range [92]) [92] Temperature optimum ( C) 22 ( assay at [64]) [64] 24 ( assay at [91]) [91] 25 ( assay at [6, 62, 83]) [6, 62, 83] 30 ( assay at [2, 5, 59, 61, 66, 69, 72, 73, 76, 78, 79, 81, 84, 86, 92, 110, 111]) [2, 5, 59, 61, 66, 69, 72, 73, 76, 78, 79, 81, 84, 86, 92, 110, 111]

4 Enzyme Structure Molecular weight 40000 ( rat, growth-factor activated fibroblasts, gel filtration, sucrose density gradient centrifugation [6]) [6] 41340 [47] 42000 ( gel filtration [7]) [7] 71000 ( gel filtration [92]) [92] 130000-140000 [61] 500000-560000 ( brain CaMKII, gel filtration [65]) [65] 519000 ( rat lung, gel filtration, sucrose density gradient centrifugation [2]) [2] 580000 ( rat brain, gel filtration [2]) [2] Additional information ( recombinant CPK-1, gel filtration [77]) [77]

30

2.7.11.17

Ca2+/Calmodulin-dependent protein kinase

Subunits ? ( x * 70000, SDSPAGE [83]; x * 56000, SDS-PAGE [62]; x * 30000, SDS-PAGE [8]; x * 68000 [13]; x * 50000 + x * 60000, rat, SDS-PAGE [4]; x * 51000 + x * 60000, rat, phosphorylated enzyme, SDS-PAGE [2]; x * 43000, rat, SDS-PAGE [5]; x * 65000 + x * 67000 [28]; x * 18735, calculation from nucleotide sequence [30]; x * 42000, calculation from nucleotide sequence [53]; x * 46895, SDS-PAGE [40]; x * 59038, calculation from nucleotide sequence [23]; x * 60200 Da, calculation from nucleotide sequence [56]; x * 51925, calculation from nucleotide sequence [49]; x * 141000, SDS-PAGE [58,59,60]; x * 42519, amino acid sequence calculation [64]; x * 43000, amino acid sequence calculation, x * 45000, SDS-PAGE [69]; x * 43000, CaMKIg2, SDS-PAGE, x * 53000, CaMKIg1, SDS-PAGE [84]; x * 43800, amino acid sequence calculation, x * 45000, SDS-PAGE [69]; x * 52000, isozyme CaMKIId2, SDS-PAGE [98]) [2, 4, 5, 8, 13, 23, 28, 30, 40, 49, 53, 56, 58, 59, 60, 62, 64, 69, 83, 84, 98] dimer ( ab [85]) [85] monomer ( 1 * 69000, SDS-PAGE [92]; CaMKIV and CaMKI [103]) [92, 103] multimer ( CaM-KII is a multimer of 10-12 catalytic subunits due to self-association [71]; CaMKII, hetero- or homomultimer [68]; CaMKII, hetero-or homonultimer [68]; CaMKII, homo-and heteromultimers [103]) [68, 71, 103] octadecamer ( 10 * 54000, a isozyme, + 8 * 60000, b isozyme, CaMKII, SDS-PAGE [65]) [65] oligomer ( CaMKII is a multimeric holoenzyme composed of six to twelve subunits encoded by 4 separate genes [104]) [104] Additional information ( the enzyme has an open, active conformation and a closed, inactive conformation [11]; CaMK1 contains 11 subdomains of the kinase catalytic domain, lacks EF hands for Ca2+ binding, and is structurally similar to the mammalian enzyme [96]; molecular conformation and structure analysis of a and b isozymes [65]; structural analysis of the interaction between a junction region J, the calmodulin-like region, and Ca2+ , overview [77]; multimeric complex formation by CL3 in cortical neurons [114]; the N-terminal part, residues 1290, contains the catalytic site [112]) [11, 65, 77, 96, 112, 114] Posttranslational modification lipoprotein ( the enzyme is modified in two sequential lipidification steps, CAAX prenylation followed by kinase-activity-regulated palmitoylation at C417, C419, C420, and C423, the modifications are essential for CL3 membrane anchoring and targeting of the enzyme into detergent-resistant lipid microdomains or rafts in dendrites, overview [114]) [114] phosphoprotein ( autophosphorylation at Ser19 [12]; phosphorylation at Thr177 in the activation segment leads to activation [11]; activating phosphorylation by

31

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

calmodulin-dependent kinase kinase is required for CaMKI function in longterm potentiation, and learning and memory [89]; Ca2+ /calmodulin-bound CaMKIId is further activated by autophosphorylation at Thr287b/g and Thr286a in the autoinhibitory domain, as well as at Thr306/Thr307b/g and Thr305/Thr306a rendering the enzyme independent of Ca2+ /calmodulin [68]; Ca2+ /calmodulin-bound CaMKIId is further activated by autophosphorylation at Thr287b/g and Thr286a in the autoinhibitory domain, as wellas at Thr306/Thr307b/g and Thr305/Thr306a rendering the enzyme independent of Ca2+ /calmodulin [68]; Ca2+ /calmodulin-bound CaMKIV is further activated by phosphorylation at Thr200 through Ca2+ /calmodulin-dependent protein kinase kinase CaMKKb, which renders CaMKIV independent on Ca2+ and calmodulin, autonomous activity, deactivation by dephosphorylation through PP2A [79]; CaM kinase II is strongly phosphorylated by protein kinase A PKA, EC 2.7.11.11, in electrocyte membranes with simultaneous substantial activation of the Ca2+ pump [80]; CaM-K performs autophosphorylation, CaM-K Ia is activated in vitro by phosphorylation through kinase CaM-KK at Thr177 independently of Ca2+ and calmodulin [73]; CaM-K1d is activated about 30fold by phosphorylation through the Ca2+ /calmodulin-dependent protein kinase kinase CaM-KKa, mechanism, CaM-K1d performs autophosphorylation in a Ca2+ /calmodulin-dependent manner which has no impact on its kinase activity [72]; CaMKIV is phosphorylated and activated by the CaM-K kinase at Thr200, CaM-KI is also phosphorylated by CaM-KK, CaM-kinases II and IV become reversibly autophosphorylated after Ca2+ /calmodulin-dependent activation, which renders the enzyme activity autonomous, CaM-KII is phosphorylated in the pseudosubstrate domain [71]; CaMKI and CaMKII are phosphorylated by the calcium/calmodulin-dependent kinase kinase CaM-KK isozymes, regulatory role, overview [67]; CaMKIg1 is activated by the calmodulindependent protein kinase kinase, CaMKK, while CaMKIg2 is not [84]; CaMKII is activated by autophosphorylation at Thr286a and Thr287b in the autoinhibition domain, CaMKII is inactivated by autophosphorylation at Thr305 and Thr306 [65]; CaMKII is autophosphorylated at Thr286 [66,90]; CaMKII performs activating autophosphorylation [91]; CaMKII performs reversible inhibitory, Ca2+ /calmodulin-independent autophosphorylation at Thr286a and Thr287b [85]; isozyme CaMKIIa is autophosphorylated at Thr286 and Thr287 which allows it to bind to the Cterminal CaMKII-binding site at residues 819-894 of a-actinin-2, to residues 1260-1339 of receptor subunit NR2B, or to residues 1247-1495 of densin-180, overview [81]; the enzyme performs autophosphorylation [94]; the enzyme performs Ca2+ /calmodulin-dependent autophosphorylation at a Ser residue [92]; the enzyme performs Ca2+ /calmodulin-dependent autophosphorylation, which renders the enzyme independent on Ca2+ and calmodulin [88,96]; transient, tightly regulated Ca2+ /calmodulin-dependent activation requiring phosphorylation at Thr200 by CaMK kinase, the Ca2+ / calmodulin binding-autoinhibitory domain is required for interaction with protein phosphatase PP2A, binding of Ca2+ /CaM and PP2A is exclusive, overview [78]; CaMKI activation by phosphorylation through CaMKK, the

32

2.7.11.17

Ca2+/Calmodulin-dependent protein kinase

CaMK kinase [110]; CaMKI is phosphorylated at Thr177 and Thr180 by the Ca2+ /calmodulin-dependent protein kinase kinase, CaMKKa, activating CaMKI, CaMKIV is also a substrate for CaMKKK [105]; CaMKII is autophosphorylated [103]; the enzyme is phosphorylated and activated by Ca2+ /calmodulin-dependent protein kinase kinases, i.e. CaMKKs [115]; the enzyme performs autophosphorylation at Thr286, activating the enzyme, and at Thr305/Thr306 of the calmodulin binding site inhibiting the enzyme [100]) [11, 12, 65, 66, 67, 68, 71, 72, 73, 78, 79, 80, 81, 84, 85, 88, 89, 90, 91, 92, 94, 96, 100, 103, 105, 110, 115] Additional information ( diversity of CaM kinase in Drosophila is generated by alternative splicing of a single gene [38]; at least five alternative splicing variants of b CaMKII [45]; alternative splicing of internal exons may lead to the formation of the two different proteins, CaM kinase Gr and calspermin [29]; four forms of the enzyme generated from a single gene by alternative splicing [39]; CaMK IIb occurred in three splice variants [43]; the enzyme performs activating strictly Ca2+ -dependent autophosphorylation which is influenced by substrates, overview [83]) [29, 38, 39, 43, 45, 83]

5 Isolation/Preparation/Mutation/Application Source/tissue B-lymphocyte ( the enzyme is absent from primary human B lymphocytes but is expressed in Epstein-Barr virus-transformed B-lymphoblastoid cell lines, suggesting that expression of the kinase can be upregulated by an EBV gene products [50]) [43, 50] BBM cell ( receptor activator of nuclear factor kB ligand-differentiated, expression of CaMKI and CaMKIIg [107]) [107] GT1-7 cell ( immortalized GnRH neuron culture [86]) [86] HEK-293 cell [82] HeLa cell [71, 72] JURKAT cell [71] MCF-10A cell ( breast cancer cell line [67]) [67] MCF-7 cell ( breast cancer cell line [67]) [67] P-19 cell ( CaMKII is induced by neural differentiation of the embryonic carcinoma cells [65]) [65] PC-12 cell ( a pheochromocytoma cell line, NGF-induced [109]) [109] Purkinje cell [116] RAW264.7 cell ( receptor activator of nuclear factor kB ligand-differentiated, expression of CaMKI, CaMKIIg and also of CaMKIV at minimum level [107]) [107] T-lymphocyte ( primary [70]; CaMKIV [68]; high expression of CaM-KIV [71]) [68, 70, 71] Thy-1-positive retinal ganglion cell [102] adipose tissue ( very low level [43]) [43]

33

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

adrenal gland [43] aorta ( smooth muscle [61]) [32, 33, 58, 61, 98] bone marrow [107] brain ( forebrain [76]; synaptic junctions [19]; particularly enriched in cerebellar granule cells [28,29]; in adult the gene is expressed almost exclusively in the brain [36]; brains-specific isozymes CaMKII a and CaMKIIb [66]; cortex, soma, Alzheimers disease brain [86]; frontal cortex [93]; high CaM kinase II expression, highly regulated activity in brain development [65]; high CaM kinase II expression, highly regulated activity in brain development, distribution overview [65]; hippocampus and parietal cortex [85]; isozyme CaMKIg, high expression level [74]; soma [86]; two alternative splicing isoforms of CaMKIg, expression patterns in brain regions, such as the olfactory bulb, hippocampal pyramidal cell layer of CA3, central amygdaloid nuclei, ventromedial hypothalamic nucleus, and pineal gland, overview [84]; expression analysis for CaMKI [110]; expression of CaMKI, CaMKII a, b, g and d, and CaMKIV [107]; spatiotemporal expression of four isoforms of CaMKI in brain regions, overview [116]; spatiotemporal expression of four isoforms of CaMKI in brain, isozyme CaMKIb2 is a brain-specific splicing variant, overview [116]) [2, 3, 4, 8, 13, 15, 16, 18, 19, 20, 25, 26, 27, 28, 29, 32, 33, 36, 45, 48, 49, 65, 66, 71, 73, 74, 75, 76, 78, 82, 84, 85, 86, 87, 88, 89, 90, 93, 100, 106, 107, 110, 114, 115, 116, 117] brain stem ( a and b isozymes [65]) [65] breast cancer cell ( differential expression of CaM-KI and CaMKII in cell lines MCF-7 and MCF-10A [67]) [67, 71] cardiac muscle [68] cardiomyocyte ( neonatal and posterior ventricular cardiac myocytes [117]) [104, 117] cell culture ( Jurkat cell [49]) [49] central amygdaloid nucleus [84] central nervous system ( expressed in great quantities in the central nervous system in the late embryonic stage of development [39]; during embryogenesis, larval and pupal life, transcription of caki is restricted almost exclusively to the central nervous system [52]) [39, 52, 85, 87, 88] cerebellar Purkinje cell ( isozyme a [65]) [65] cerebellum ( a and b isozymes, cerebellar nuclei [65]) [65] cerebral cortex ( isozymes CaMKId and CaMKIa [116]) [116] cerebrum [33] chloronema [83] colon [72] diaphragm [33] egg [7] electrocyte [80] embryo ( expressed in great quantities in the central nervous system in the late embryonic stage of development [39]; during

34

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Ca2+/Calmodulin-dependent protein kinase

embryogenesis, larval and pupal life, transcription of caki is restricted almost exclusively to the central nervous system [52]; Camk-2-specific transcripts are first seen in the head section of 12.5-day-old embryos [36]) [36, 39, 52] exocrine pancreas [2] fibroblast ( 1HIRc B cells (overexpressing the human insulin receptor), embryonic cell line 3Y1, both with elevated kinase activity after treatment with mitogens, e.g. insulin or epidermal growth factor [5,6]; CaM-KI [71]) [5, 6, 71] forebrain ( a and b isozymes [65]) [65, 81, 100] ganglion ( nerve ring [2]) [2] gizzard ( smooth muscle [58,59,62,63]) [58, 59, 60, 62, 63] head ( expressed at much higher levels in the fly head than in the body [37,39]; in the adult head, immunohistochemistry reveals Caki protein in the lamina, the neuropil of the medulla, lobula, lobula plate and in the central brain [52]) [37, 39, 52] heart ( d-CaMKII isoform expression pattern in human hearts and changes in this expression pattern in heart failure [46]; CaMKII, no expression of CaMKIV [68]) [2, 33, 46, 68, 101, 103, 104, 108] hepatoma cell [71] hippocampal pyramidal layer [84] hippocampus ( neurons [89]; primary cells [110]; isozymes CaMKII a and CaMKIIb [66]; primary hippocampal neurons [86]; all isozymes, isozyme CaMKIa in pyramidal cell layer and thalamic nuclei [116]) [66, 74, 85, 86, 89, 90, 94, 110, 116] hypothalamus [84] kidney [75] liver ( high activity [75]; moderate expression [43]; CaM-KIV [71]) [43, 71, 72, 75] lung ( low activity [75]) [2, 33, 75] lymphocyte ( very low level [43]) [43, 111] mammary tumor cell [44] muscle ( skeletal muscle [25,33]; aorta smooth muscle [24]) [24, 25, 33, 104] myocardium ( isozyme CaMKIId splicing variants dB and dC [68]) [46, 68] myocyte [103, 108, 117] neuroblastoma cell ( CaMKII is induced by neural differentiation of the embryonic carcinoma cells [65]) [44, 65] neuron ( cortical [76]; hippocampal [110]; CA1 and CA3 hippocampal neurons [74]; CaMKIV [68]; neuronal Ca2+ /calmodulin-dependent protein kinase II is a major component in neurons [65]; predominant expression of CaMKII isozymes gA, gC, d1, and d3 in dopaminergic neurons of substantia nigra [87]; primary hippocampal neurons and immortalized GnRH neurons, i.e. GT1-7 cells [86]; cortical, expression in developing cortex, dendritic

35

Ca2+/Calmodulin-dependent protein kinase

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localization [114]; neonatal mouse superior cervical ganglion neurons, cultured sympathetic neurons express a-, d-, and g-, but not b-CaMKII mRNA [117]; sympathetic [117]) [65, 68, 71, 74, 76, 82, 84, 85, 86, 87, 89, 90, 95, 102, 106, 110, 111, 114, 115, 116, 117] olfactory bulb ( isozymes CaMKId and CaMKIa [116]) [84, 116] oocyte ( high expression level of isozyme CaM-KI LiKb in the neurula stage [69]; the isozymes CaM-KIa is constitutively expressed through embryogenesis leading [69]) [69, 99] osteoclast [107] ovary [72] pancreas [72] pineal gland [84] pituitary gland [43] plasmodium [64] prostate cancer cell [71] prostate gland ( low expression level of CaM-K1d [72]) [72] protonema ( chloronemal cells [83]) [83] retina ( a and b isozymes [65]) [65, 102] skeletal muscle ( low expression level of CaM-K1d [72]; expression of CaMKI isozymes a, b, and d, not of CaMKIV [105]) [2, 72, 105] small intestine [33] spinal cord ( isozyme CaMKIg [116]) [95, 116] spinal ganglion [97] spleen ( very low activity [75]) [2, 13, 27, 72, 75] substantia nigra ( predominant expression of CaMKII isozymes gA, gC, d1, and d3 in dopaminergic neurons [87]) [87] testis ( calspermin mRNA to be predominantly expressed in postmeiotic cells indicating that it may be specific to haploid cells [30]; CaMKIV [68]; high expression level of CaM-K1d [72]; high expression of CaM-KIV [71]) [2, 27, 30, 31, 33, 68, 71, 72] thymus ( low expression level of CaM-K1d [72]) [13, 48, 49, 72] uterus [33] vascular smooth muscle cell ( i.e. VSM cell, aortic, primary, isozymes CaMKIIgB, CaMKIIgC, and CaMKIId2, expression analysis, overview [98]) [98] ventromedial hypothalamic nucleus [84] whole body ( expressed at much higher levels in the fly head than in the body [37,39]) [37, 39] Additional information ( tissue-specific expression of four types of rat calmodulin-dependent protein kinase II mRNAs [33]; no differential tissue distribution of isoforms [38]; CaM kinase II is ubiquitously expressed in tissues [65]; CaM kinase II is ubiquitously expressed in tissues, especially in brain [65]; CaM-K1d tissue expression pattern, no expression in intestine, kidney, placenta, heart,

36

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Ca2+/Calmodulin-dependent protein kinase

and lung [72]; CaMKIIa is associated with CaMKII-binding proteins densin-180, the N-methyl-d-aspartate receptor NR2B subunit, and a-actinin2 in postsynaptic density-enriched rat brain fractions [81]; rats grown with developmental exposure to Pb2+ [66]; tissue distribution of isozymes in the central nervous system [87]; ubiquitous expression of CaMKII [68]; analysis of developmental isozyme expression, overview [116]) [33, 38, 65, 66, 68, 72, 81, 87, 116] Localization Golgi membrane ( anchored, perinuclear Golgi-like membranes [114]) [74, 114] actin filament ( tightly associated [60]) [60] cell soma ( brain [86]; neuron [86]) [86] cytoplasm ( CaMKII isozyme d1-4 in dopaminergic neurons of substantia nigra [87]; isozyme CaMKIId splicing variant dC, CaMKIV [68]) [68, 76, 82, 84, 87, 101] cytosol ( CaM-KIV [71]; isozymes CaMKII a and CaMKIIb, contents of isozymes in membrane and cytosol of Pb2+ treated and untreated rats, overview [66]; isozyme CaMKIId [108]) [2, 6, 65, 66, 71, 92, 103, 108] dendrite ( dendritic raft targeting [114]) [114, 115, 116] endoplasmic reticulum ( perinuclear, a nonsynaptic site [90]) [90] membrane ( anchored [74]; bound, isolated innervated membranes of electrocytes [80]; isozymes CaMKII a and CaMKIIb, contents of isozymes in membrane and cytosol of Pb2+ treated and untreated rats, overview [66]) [66, 74, 80] myofibril ( tightly associated [62]) [62] neurite [86] nucleus ( CaM-KIV predominantly [71]; CaMKII isozyme d1-4 in dopaminergic neurons of substantia nigra [87]; isozyme CaMKIId splicing variant dB, CaMKIV predominantly [68]; CAMKII-mediated phosphorylation modulates the Dp71 nuclear localization [109]) [68, 70, 71, 87, 101, 109] particle-bound ( particulate enzyme shows increased rate of inhibitory autophosphorylation during acute seizure in the brain induced by electroconvulsive treatment [85]) [85] perinuclear space ( endoplasmic reticulum [90]) [90] plasma membrane [74, 75] sarcoplasmic reticulum ( associated [103]) [103, 104] soluble ( soluble enzyme shows decreased rate of inhibitory autophosphorylation during acute seizure in the brain induced by electroconvulsive treatment [85]) [85] synapse ( dendritic CaMKII is dynamically targeted to the synapse [81]) [65, 81, 90] Additional information ( low abundance protein, analogous to kinase of growth factor stimulated cell lines [3]; distribution in hippocampal neurons: CaM kinase II is located in neurites and neuronal soma [86];

37

Ca2+/Calmodulin-dependent protein kinase

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glutamate receptor stimulation induces Ca2+ -dependent CaMKII translocation to synaptic and nonsynaptic sites [90]; subcellular distribution of isozymes a and b, dendritic distribution of mRNA, overview [65]; subcellular distribution of isozymes and splicing variants in substantia nigra [87]; CaMKII isozymes have distinct cellular localizations and function [117]; T-cell receptor engagement redistributes CaMKII to the immune synapse, which is interfered by inhibitor KN93, overview [111]) [3, 65, 86, 87, 90, 111, 117] Purification [58, 59, 60] (recombinant FLAG-tagged CaMKIV from 293A cells by immunoaffinity chromatography) [78] (recombinant FLAG-tagged CaMKIV from 293A cells) [79] [3, 4] (from forebrain by ammonium sulfate fractionation, and calmodulin and phosphate affinity chromatography) [65] (heart or spleen: partial) [2] (insulin stimulated 1HIRc B-cells) [5] (partial: growth-factor stimulated 3Y1-cells) [6] (recombinant GST-tagged CaMKI from Escherichia coli by glutathione affinity chromatography) [110] [4, 8] [61] (recombinant N-terminally His-tagged CPK-1 from Escherichia coli by nickel affinity and ion exchange chromatography, the His-tag is cleaved off) [77] (partial) [2] (644fold from cytosol by ammonium sulfate fractionation, DEAE cellulose ion exchange chromatography, and gel filtration) [92] (partially by preparation of isolated innervated membranes of electrocytes) [80] (native enzyme from chloronemal cells 44fold to near homogeneity by ammoinum sulfate fractionation, DEAE-cellulose ion exchange chromatography, and calmodulin-agarose affinity chromatography in presence of CaCl2 ) [83] [28] [35] [35] (recombinant MsCPK3 protein purified from E. coli) [56] (recombinant GST-tagged wild-type and mutant CaM-K1d from Escherichia coli by glutathione affinity chromatography) [72] (non-tagged recombinant enzyme from Escherichia coli by CaM affinity chromatography and gel filtration, or His-tagged recombinant enzyme by nickel affinity chromatography) [64]

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Crystallization (crystal structure of calcium/calmodulin-dependent protein kinase I in the autoinhibited form) [54] Cloning (CaMKII, DNA and amino acid sequence determination and analysis, gene structure and genomic organization) [65] (CaMKI isozyme expression analysis) [116] (expression of FLAG-tagged CaMKIV in 293A cells) [78] (expression of wild-type and mutant CL3 in COS-7 cells, expression of HA- or GFP-tagged wild-type CL3 in cortical neurons) [114] (expression of wild-type and mutant CaMKI and CaMKIV in cultured neurons) [115] (overexpression of isozyme CaMKIIdC in transgenic mouse myocytes or in rabbit myocytes using adenoviral transfection, affects on Ca2+ influx, Ca2+ current, and inhibition of Ca2+ channel inhibition through phosphorylation, overview) [103] (transient and stable overexpression of isozyme CaMKIId in rabbit and mouse ventricular myocytes leading to a Ca2+ -depdnent shift in voltage dependence of Na+ channel availability, enhanced intermediate inactivation, and slowed recovery from inactivation) [108] (expression in Jurkat cells, co-expression with human CARMA1, T-cell receptor engagement redistributes CaMKII to the immune synapse in an activation-dependent manner) [111] (expression of CaMKII in HEK-293 cells, and expression of CaMKII in cultured neurons using lentiviral transfection, co-expression of protein substrates) [106] (expression of FLAG-tagged CaMKIV in 293A cells) [79] (functional cytoplasmic co-expression of wild-type CaMKII with vimentin-NR2B, a construct of a vimentin peptide containing Ser82 fused to the NMDA receptor 2B subunit, an interaction partner of CaMKII, in HEK-293 cells, translocation of the Vin-NR2B construct to the membrane is regulated by lipid rafts resulting in reduced phosphorylation by CaMKII) [82] (transient co-expression of CaMKIV, MEF-2, and Cabin1 in murine Tcell hybridoma DO11.10, MEF-2 activation of gene transcription is inhibited by Cabin1, the inhibition is reversed by CaMKIV) [70] (CaMKI isozyme expression analysis) [116] (CaMKII isozymes and splicing variants, DNA and amino acid sequence determination and analysis, gene structure and genomic organization of isozyme b) [65] (expression of CaMKII N-terminal catalytic fragment comprising residues 1-290 in Jurkat cells) [112] (expression of CaMKIa in COS-7 cells with localization in the Golgi apparatus and the plasma membrane) [74] (expression of GFP-tagged wild-type and mutant CaMKII in neuronal cultures and in HEK-293 cells, pH-dependent, Ca2+ /calmodulin-dependent, reversible enzyme clustering by self-association of the recombinant CaMKII,

39

Ca2+/Calmodulin-dependent protein kinase

2.7.11.17

which might be hindered by autophosphorylation at Thr286, mechanism, overview) [90] (expression of GST-tagged CaMKI in Escherichia coli) [110] (expression of HA-tagged wild-type CaM-KIa, CaM-K IV, and CaM-K IIa, and CaM-K Ia mutant K49A, and constitutively active CaM-K Ia truncation mutant residues 1-293 in HEK293 cells, Escherichia coli, and Sf9 insect cells) [73] (overexpression of CaMKII isozyme a and truncated mutant CaMKII/ 290 in PC-12 cells) [109] (expression of CPK-1 in Escherichia coli as N-terminally His-tagged enzyme with a thrombin cleavage site) [77] [15] (gene is most likely located within the region of bands q21 to q23 of chromosome 5) [18] [19, 20] [23] (sequence of the cDNA for the a subunit) [26] [27, 28, 30] (organization and analysis of the complete rat calmodulin-dependent protein kinase IV gene) [31] [32] (isolation of cDNA) [33] [35] (bacterial expression) [34] [34, 35] (determination of the complete cDNA sequence of the Camk-2 gene and most of its exon/intron structure, Camk-2 locus is mapped to the proximal region of mouse chromosome 11) [36] [39] (isolation of cDNA) [37] [40] [43] [47] (expressed in Escherichia coli) [49] (isolation and sequencing of cDNA) [48] [52] (characterization of a cDNA clone) [53] (expressed in bacteria as a glutathione S-transferase fusion protein) [55] (expression in COS-7 cells) [13] (expression in Escherichia coli) [56] (expression of the cmk1 cDNA in bacteria and yeast) [57] (CaMKIg1 and CaMKIg2, DNA and amino acid sequence, and genomic structure determination and analysis, expression of FLAG-tagged enzymes in COS-7 cells, hippocampal neurons, and NG108-15 cells in the cytoplasm and neurites, not in the nucleus) [84]

40

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Ca2+/Calmodulin-dependent protein kinase

(isozyme CaM-KI LiKb, DNA and amino acid sequence determination and analysis, overexpression of a constitutively active CaM-KI LiKb mutant inhibits cell division in frog embryos, and causes severe changes in HeLa cell morphology) [69] (isozyme CaM-KIa, DNA and amino acid sequence determination and analysis, overexpression of a constitutively active CaM-KIa mutant inhibits cell division in frog embryos, and causes severe changes in HeLa cell morphology) [69] (construction of a cDNA library, CaMK1 DNA and amino acid sequence determination and analysis, genetic organization, expression of wild-type and mutant CaMK1s in Escherichia coli) [96] (CaM-K1d, DNA and amino acid sequence determination and analysis, expression of GST-tagged wild-type and mutant enzyme in Escherichia coli strain JM109, transient expression of HA-tagged CaM-K1d 1-296 Ca2+ /calmodulin-independent mutant in HeLa and COS-7 cells) [72] (CaMKIg, DNA and amino acid sequence determination and analysis, expression in COS-7 cells) [74] (cNA library construction and screening, DNA and amino acid sequence determination and analsis, expression in Escherichia coli strain BL21(DE3) with or without His-tag) [64] (CaMKIg, DNA and amino acid sequence determination and analysis, expression as GFT-tagged protein in COS-7 cells with localization in the Golgi apparatus and the plasma membrane) [74] (genes CpkA, CpkB, and CpkC, DNA and amino acid sequence determination and analysis, expression analysis, phylogenetic tree) [113] Engineering C417S/C419S/C420S/C423S ( site-directed mutagenesis, mutation of palmitoylation sites [114]) [114] F320D/N321D ( site-directed mutagenesis, the mutation changes the sequence FNDD to DDDD, the mutant shows no binding of calmodulin and increased activity in nonphosphorylated status compared to the wild-type enzyme [79]) [79] I205K ( site-directed mutagenesis, the mutant CaMKII does not undergo self-association in recombinant HEK-293 cells [90]; site-directed mutagenesis, the mutant CaMKII shows reduced activity with vimentin compared to the wild-type enzyme [82]) [82, 90] K42M/T286D ( inactive CaMKII mutant [117]) [117] K50E ( site-directed mutagenesis and truncation mutation constructing mutant K50E 1-295, the mutant isozyme CaM-KIa is constitutively active [69]) [69] K52A ( site-directed mutagenesis, inactive mutant, loss-of-function in embryonic cortical neurons elicits a specific impairment in dendrite morphogenesis [114]) [114] K52E ( site-directed mutagenesis, inactive mutant [116]) [116]

41

Ca2+/Calmodulin-dependent protein kinase

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K52E/I286E/H287D/Q288D/S289D/W303S/F307A ( site-directed mutagenesis of CaMKIa isozyme, the mutant is inactive and unable to bind Ca2+ and calmodulin [116]) [116] K53E ( site-directed mutagenesis and truncation mutation constructing mutant K50E 1-297, the mutant isozyme CaM-KI LiKb is constitutively active [69]) [69] K75E ( site-directed mutagenesis, catalytically inactive CaMKIV mutant [70]) [70] L916R ( site-directed mutagenesis, mutation in the calmodulin binding site residue abolishes the calmodulin binding [96]) [96] R924E/K925E/K926E/K927E ( site-directed mutagenesis, mutations break the basic amphiphilic a-helix structure of the calmodulin binding site, the mutant is not capable of calmodulin binding [96]) [96] T180A ( site-directed mutagenesis, the mutant enzyme shows highly reduced activity compared to the wild-type enzyme, the mutant is phosphorylated and activated by CaM-KKa [72]) [72] T200A ( site-directed mutagenesis, phosphorylation site mutant of CaMKIV, no activation by phosphorylation through CaMKK, no stimulation by ionomycin in absence of Ca2+ and calmodulin [78]; site-directed mutagenesis, the mutant CaMKIV is not phosphorylated by CaMKKb and is thus incapable of developing autonomous activity and control gene transcription, the same effect occurs due to combination of T200A with calmodulin binding site mutations, overview [79]) [78, 79] T286D ( site-directed mutagenesis, the mutant CaMKII exhibits poor self-association in recombinant HEK-293 cells and is impaired in autophosphorylation [90]; site-sirected mutagenesis of a isozyme residue, the mutant is impaired in autophosphorylation and completely in neurite extension [65]; site-sirected mutagenesis of a isozyme residue, the mutant is impaired in autophosphorylation and partially in neurite extension [65]; constitutively active CaMKII mutant [117]) [65, 90, 117] T287D ( site-directed mutagenesis, the Ca2+ -independent mutant expression leads to reduced viability of flies, the toxic effect can be rescued by tetracycline, expression of the mutant in brain mushroom bodies does not affect the immediate memory, overview [88]) [88] W919R ( site-directed mutagenesis, mutation in the calmodulin binding site residue abolishes the calmodulin binding [96]) [96] Additional information ( CaMKI 1-306, is unable to bind Ca2+ -calmodulin and is completely inactive. CaMKI 1-294 does not bind CaM but is fully active in the absence of Ca2+ -calmodulin. CaMKI is phosphorylated on Thr177 and its activity enhances approximately 25-fold by CaMKI kinase in a Ca2+ -calmodulin dependent manner. CaMKI 1-306 is unresponsive to CaMKI kinase, the 1-294 mutant is phosphorylated and activated by CaMKI kinase in both the presence and absence of Ca2+ -CaM although at a faster rate in its presence. Replacement of Thr177 with Ala or Asp prevented both phosphorylation and activation by CaMKI kinase and the latter replacement also leads to partial activation in the absence of CaMKI kinase [47]; CaM-K1d 1-296 truncation mutant is catalytically active

42

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and Ca2+ /calmodulin-independent, lacks the putative autoinhibitory domain and the Ca2+ /calmodulin binding region, the truncation mutant is fully activated by CaM-KKa [72]; CaM-KI inhibition by expression of siRNA causes cell cycle arrest in MCF-7 cells [67]; construction of transgenic mice overexpressing calmodulin, the mutant mice develop severe cardiac hypertrophy and show increased Ca2+ /calmodulin-independent CaMKII activity, overexpression of CaMKIV and CaMKIV knockout also lead to development of cardiac hypertrophy, CaMKIIdB overexpressing transgenic mice do not phosphorylate CREB [68]; deficiency in autophosphorylation in mice leads to impaired upregulation of an associative transcript, the nerve growth factor-inducible gene B messenger RNA, overview [94]; introduction of lentivirus shRNA specific for human CaMKIV into human T-cells and Jurkat cells leads to knockdown of CaMKIV expression [70]; mutation of residues N300, N306, N312, N318, N324, N330, N336, N341, and N347 for determination of residues involved in calmodulin binding, no binding of calmodulin and increased activity compared to the wild-type enzyme by nonphosphorylated mutants of N318, N324, N330, and N336, overview [79]; CaMKII downregulation by CaMKII small interfering RNA in retinal cells [102]; construction of transgenic mice expressing the AIP inhibitory peptide in cardiomyocytes nuclei, the inhibitor affects the nuclear enzyme, but not the cytoplasmic enzyme, which inhibits the translocation of protein HDAC5 from nucleus to cytoplasm, phenotype, overview [101]; disruptions of genes CpkA, CpkB, and CpkC do not affect fungal growth or pathogenicity, but CpkC deficiency leads to delayed lesion development and sporulation during infection, mycelia deficient in CpkA show a phenotype with mycelia lighter in colour, highly reduced sporulation activity, and reduced asexually formed pycnidia, overview [113]; overexpression of CaMKII favors the Dp71d nuclear accumulation [109]; transgenic CaMKIId overexpression prolongs QRS duration and repolarization, i.e. QT intervals, decreases effective refractory periods, and increases the propensity to develop ventricular tachyarrhythmia, overview, CaMKIId enhances steady-state inactivation of transgenic rabbit myocyte sodium current INa, steady-state inactivation, overview [108]) [47, 67, 68, 70, 72, 79, 94, 101, 102, 108, 109, 113] Application medicine ( CaM-kinases act as potential targets in cancer therapy, strategies, overview [71]) [71]

6 Stability Temperature stability 55 ( cytosolic extract, 60 min, inactivation [92]) [92] 80 ( 2 min, inactivation [7]) [7] Organic solvent stability n-propanol ( for extraction and as additive at 5% to the activity assay buffer [83]) [83]

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General stability information , purified enzyme binds tightly to caldesmon, binding is abolished by high concentrations of Mg2+ [62] , purified enzyme preparation is stable to freeze-thawing [60] , activity of the purified enzyme is completely lost upon a freeze-thaw cycle [83] Storage stability , -20 C, in 50% glycerol [61] , 25 C, purified enzyme, increased activity at day 1 to 9, rapid loss within day 10, activity is completely lost upon a freeze-thaw cycle [83]

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[25] Bayer, K.U.; Lohler, J.; Harbers, K.: An alternative, nonkinase product of the brain-specifically expressed Ca2+ /calmodulin-dependent kinase II a isoform gene in skeletal muscle. Mol. Cell. Biol., 16, 29-36 (1996) [26] Hanley, R.M.; Payne, M.E.; Cruzalegui, F.; Christenson, M.A.; Means, A.R.: Sequence of the cDNA for the a subunit of calmodulin kinase II from mouse brain. Nucleic Acids Res., 17, 3992 (1989) [27] Means, A.R.; Cruzalegui, F.; LeMagueresse, B.; Needleman, D.S.; Slaughter, G.R.; Ono, T.: A novel Ca2+ /calmodulin-dependent protein kinase and a male germ cell-specific calmodulin-binding protein are derived from the same gene. Mol. Cell. Biol., 11, 3960-3971 (1991) [28] Ohmstede, C.A.; Jensen, K.F.; Sahyoun, N.E.: Ca2+ /calmodulin-dependent protein kinase enriched in cerebellar granule cells. Identification of a novel neuronal calmodulin-dependent protein kinase. J. Biol. Chem., 264, 5866-5875 (1989) [29] Ohmstede, C.A.; Bland, M.M.; Merrill, B.M.; Sahyoun, N.: Relationship of genes encoding Ca2+ /calmodulin-dependent protein kinase Gr and calspermin: a gene within a gene. Proc. Natl. Acad. Sci. USA, 88, 5784-5788 (1991) [30] Ono, T.; Slaughter, G.R.; Cook, R.G.; Means, A.R.: Molecular cloning sequence and distribution of rat calspermin, a high affinity calmodulinbinding protein. J. Biol. Chem., 264, 2081-2087 (1989) [31] Sun, Z.; Means, R.L.; LeMagueresse, B.; Means, A.R.: Organization and analysis of the complete rat calmodulin-dependent protein kinase IV gene. J. Biol. Chem., 270, 29507-29514 (1995) [32] Schworer, C.M.; Rothblum, L.I.; Thekkumkara, T.J.; Singer, H.A.: Identification of novel isoforms of the d subunit of Ca2+ /calmodulin-dependent protein kinase II. Differential expression in rat brain and aorta. J. Biol. Chem., 268, 14443-14449 (1993) [33] Tobimatsu, T.; Fujisawa, H.: Tissue-specific expression of four types of rat calmodulin-dependent protein kinase II mRNAs. J. Biol. Chem., 264, 17907-17912 (1989) [34] Ohya, Y.; Kawasaki, H.; Suzuki, K.; Londesborough, J.; Anraku, Y.: Two yeast genes encoding calmodulin-dependent protein kinases. Isolation, sequencing and bacterial expressions of CMK1 and CMK2. J. Biol. Chem., 266, 12784-12794 (1991) [35] Pausch, M.H.; Kaim, D.; Kunisawa, R.; Admon, A.; Thorner, J.: Multiple Ca2+ /calmodulin-dependent protein kinase genes in a unicellular eukaryote. EMBO J., 10, 1511-1522 (1991) [36] Karls, U.; Muller, U.; Gilbert, D.J.; Copeland, N.G.; Jenkins, N.A.; Harbers, K.: Structure, expression, and chromosome location of the gene for the b subunit of brain-specific Ca2+ /calmodulin-dependent protein kinase II identified by transgene integration in an embryonic lethal mouse mutant. Mol. Cell. Biol., 12, 3644-3652 (1992) [37] Cho, K.O.; Wall, J.B.; Pugh, P.C.; Ito, M.; Mueller, S.A.; Kennedy, M.B.: The a subunit of type II Ca2+ /calmodulin-dependent protein kinase is highly conserved in Drosophila. Neuron, 7, 439-450 (1991)

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[51] [52] [53] [54] [55] [56]

[57] [58] [59] [60] [61]

[62]

[63]

[64]

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virus (EBV) is induced by the EBV oncogene LMP1. J. Virol., 68, 16971705 (1994) Dimitratos, S.D.; Woods, D.F.; Bryant, P.J.: Camguk, Lin-2, and CASK: novel membrane-associated guanylate kinase homologs that also contain CaM kinase domains. Mech. Dev., 63, 127-130 (1997) Martin, J.R.; Ollo, R.: A new Drosophila Ca2+ /calmodulin-dependent protein kinase (Caki) is localized in the central nervous system and implicated in walking speed. EMBO J., 15, 1865-1876 (1996) Cho, F.S.; Phillips, K.S.; Bogucki, B.; Weaver, T.E.: Characterization of a rat cDNA clone encoding calcium/calmodulin-dependent protein kinase I. Biochim. Biophys. Acta, 1224, 156-160 (1994) Goldberg, J.; Nairn, A.C.; Kuriyan, J.: Structural basis for the autoinhibition of calcium/calmodulin-dependent protein kinase I. Cell, 84, 875-887 (1996) Picciotto, M.R.; Czernik, A.J.; Nairn, A.C.: Calcium/calmodulin-dependent protein kinase I. cDNA cloning and identification of autophosphorylation site. J. Biol. Chem., 268, 26512-26521 (1993) Davletova, S.; Meszaros, T.; Miskolczi, P.; Oberschall, A.; Torok, K.; Magyar, Z.; Dudits, D.; Deak, M.: Auxin and heat shock activation of a novel member of the calmodulin like domain protein kinase gene family in cultured alfalfa cells. J. Exp. Bot., 52, 215-221 (2001) Rasmussen, C.D.: Cloning of a calmodulin kinase I homologue from Schizosaccharomyces pombe. J. Biol. Chem., 275, 685-690 (2000) Scott-Woo, G.C.; Walsh, M.P.: Autophosphorylation of smooth-muscle caldesmon. Biochem. J., 252, 463-472 (1988) Ngai, P.K.; Walsh, M.P.: Inhibition of smooth muscle actin-activated myosin Mg2+ -ATPase activity by caldesmon. J. Biol. Chem., 259, 13656-13659 (1984) Ngai, P.K.; Walsh, M.P.: Properties of caldesmon isolated from chicken gizzard. Biochem. J., 230, 695-707 (1985) Vorotnikov, A.V.; Gusev, N.B.; Hua, S.; Collins, J.H.; Redwood, C.S.; Marston, S.B.: Identification of casein kinase II as a major endogeneous caldesmon kinase in sheep aorta smooth muscle. FEBS Lett., 334, 18-22 (1993) Ikebe, M.; Reardon, S.; Scott-Woo, G.C.; Zhou, Z.; Koda, Y.: Purification and characterization of calmodulin-dependent multifunctional protein kinase from smooth muscle: isolation of caldesmon kinase. Biochemistry, 29, 11242-11248 (1990) Krymsky, M.A.; Chibalina, M.V.; Shirinsky, V.P.; Marston, S.B.; Vorotnikov, A.V.: Evidence against the regulation of caldesmon inhibitory activity by p42/p44erk mitogen-activated protein kinase in vitro and demonstration of another caldesmon kinase in intact gizzard smooth muscle. FEBS Lett., 452, 254-258 (1999) Nakamura, A.; Hanyuda, Y.; Okagaki, T.; Takagi, T.; Kohama, K.: A calmodulin-dependent protein kinase from lower eukaryote Physarum polycephalum. Biochem. Biophys. Res. Commun., 328, 838-844 (2005)

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[78] Anderson, K.A.; Noeldner, P.K.; Reece, K.; Wadzinski, B.E.; Means, A.R.: Regulation and function of the calcium/calmodulin-dependent protein kinase IV/protein serine/threonine phosphatase 2A signaling complex. J. Biol. Chem., 279, 31708-31716 (2004) [79] Chow, F.A.; Anderson, K.A.; Noeldner, P.K.; Means, A.R.: The autonomous activity of calcium/calmodulin-dependent protein kinase IV is required for its role in transcription. J. Biol. Chem., 280, 20530-20538 (2005) [80] Valverde, R.H.; Tortelote, G.G.; Lemos, T.; Mintz, E.; Vieyra, A.: Ca2+ /calmodulin-dependent protein kinase II is an essential mediator in the coordinated regulation of electrocyte Ca2+ -ATPase by calmodulin and protein kinase A. J. Biol. Chem., 280, 30611-30618 (2005) [81] Robison, A.J.; Bass, M.A.; Jiao, Y.; MacMillan, L.B.; Carmody, L.C.; Bartlett, R.K.; Colbran, R.J.: Multivalent interactions of calcium/calmodulin-dependent protein kinase II with the postsynaptic density proteins NR2B, densin-180, and a-actinin-2. J. Biol. Chem., 280, 35329-35336 (2005) [82] Tsui, J.; Inagaki, M.; Schulman, H.: Calcium/calmodulin-dependent protein kinase II (CaMKII) localization acts in concert with substrate targeting to create spatial restriction for phosphorylation. J. Biol. Chem., 280, 9210-9216 (2005) [83] D’Souza, J.S.; Johri, M.M.: Purification and characterization of a Ca2+ -dependent/calmodulin-stimulated protein kinase from moss chloronema cells. J. Biosci., 28, 223-233 (2003) [84] Nishimura, H.; Sakagami, H.; Uezu, A.; Fukunaga, K.; Watanabe, M.; Kondo, H.: Cloning, characterization and expression of two alternatively splicing isoforms of Ca2+ /calmodulin-dependent protein kinase Ig in the rat brain. J. Neurochem., 85, 1216-1227 (2003) [85] Yamagata, Y.; Obata, K.: Ca2+ /calmodulin-dependent protein kinase II is reversibly autophosphorylated, inactivated and made sedimentable by acute neuronal excitation in rats in vivo. J. Neurochem., 91, 745-754 (2004) [86] Yamamoto, H.; Hiragami, Y.; Murayama, M.; Ishizuka, K.; Kawahara, M.; Takashima, A.: Phosphorylation of tau at serine 416 by Ca2+ /calmodulindependent protein kinase II in neuronal soma in brain. J. Neurochem., 94, 1438-1447 (2005) [87] Kamata, A.; Takeuchi, Y.; Fukunaga, K.: Identification of the isoforms of Ca2+ /calmodulin-dependent protein kinase II and expression of brain-derived neurotrophic factor mRNAs in the substantia nigra. J. Neurochem., 96, 195-203 (2006) [88] Mehren, J.E.; Griffith, L.C.: Calcium-independent calcium/calmodulin-dependent protein kinase II in the adult Drosophila CNS enhances the training of pheromonal cues. J. Neurosci., 24, 10584-10593 (2004) [89] Schmitt, J.M.; Guire, E.S.; Saneyoshi, T.; Soderling, T.R.: Calmodulin-dependent kinase kinase/calmodulin kinase I activity gates extracellularregulated kinase-dependent long-term potentiation. J. Neurosci., 25, 1281-1290 (2005) [90] Hudmon, A.; Lebel, E.; Roy, H.; Sik, A.; Schulman, H.; Waxham, M.N.; De Koninck, P.: A mechanism for Ca2+ /calmodulin-dependent protein kinase

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[91] [92] [93]

[94] [95]

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II clustering at synaptic and nonsynaptic sites based on self-association. J. Neurosci., 25, 6971-6983 (2005) Li, H.; Aluko, R.E.: Kinetics of the inhibition of calcium/calmodulin-dependent protein kinase II by pea protein-derived peptides. J. Nutr. Biochem., 16, 656-662 (2005) Dhillon, N.K.; Sharma, S.; Khuller, G.K.: Biochemical characterization of Ca2+ /calmodulin dependent protein kinase from Candida albicans. Mol. Cell. Biochem., 252, 183-191 (2003) Zhen, X.; Goswami, S.; Abdali, S.A.; Gil, M.; Bakshi, K.; Friedman, E.: Regulation of cyclin-dependent kinase 5 and calcium/calmodulin-dependent protein kinase II by phosphatidylinositol-linked dopamine receptor in rat brain. Mol. Pharmacol., 66, 1500-1507 (2004) von Hertzen, L.S.; Giese, K.P.: a-Isoform of Ca2+ /calmodulin-dependent kinase II autophosphorylation is required for memory consolidation-specific transcription. NeuroReport, 16, 1411-1414 (2005) Fang, L.; Wu, J.; Zhang, X.; Lin, Q.; Willis, W.D.: Calcium/calmodulin dependent protein kinase II regulates the phosphorylation of cyclic AMPresponsive element-binding protein of spinal cord in rats following noxious stimulation. Neurosci. Lett., 374, 1-4 (2005) Ma, L.; Liang, S.; Jones, R.L.; Lu, Y.T.: Characterization of a novel calcium/ calmodulin-dependent protein kinase from tobacco. Plant Physiol., 135, 1280-1293 (2004) Xu, G.Y.; Huang, L.Y.: Ca2+ /calmodulin-dependent protein kinase II potentiates ATP responses by promoting trafficking of P2X receptors. Proc. Natl. Acad. Sci. USA, 101, 11868-11873 (2004) House, S.J.; Ginnan, R.G.; Armstrong, S.E.; Singer, H.A.: Calcium/calmodulin-dependent protein kinase II-d isoform regulation of vascular smooth muscle cell proliferation. Am. J. Physiol. Cell Physiol., 292, C22 76-C22 87 (2007) Perry, C.; Le, H.; Grichtchenko, I.I.: ANG II and calmodulin/CaMKII regulate surface expression and functional activity of NBCe1 via separate means. Am. J. Physiol. Renal Physiol., 293, F68-F77 (2007) Robison, A.J.; Winder, D.G.; Colbran, R.J.; Bartlett, R.K.: Oxidation of calmodulin alters activation and regulation of CaMKII. Biochem. Biophys. Res. Commun., 356, 97-101 (2007) Li, B.; Dedman, J.R.; Kaetzel, M.A.: Nuclear Ca2+ /calmodulin-dependent protein kinase II in the murine heart. Biochim. Biophys. Acta, 1763, 1275-1281 (2006) Takeda, H.; Kitaoka, Y.; Hayashi, Y.; Kumai, T.; Munemasa, Y.; Fujino, H.; Kobayashi, S.; Ueno, S.: Calcium/calmodulin-dependent protein kinase II regulates the phosphorylation of CREB in NMDA-induced retinal neurotoxicity. Brain Res., 1184, 306-3015 (2007) Maier, L.S.; Bers, D.M.: Role of Ca2+ /calmodulin-dependent protein kinase (CaMK) in excitation-contraction coupling in the heart. Cardiovasc. Res., 73, 631-640 (2007)

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[104] Mattiazzi, A.; Vittone, L.; Mundina-Weilenmann, C.: Ca2+ /calmodulin-dependent protein kinase: a key component in the contractile recovery from acidosis. Cardiovasc. Res., 73, 648-656 (2007) [105] Witczak, C.A.; Fujii, N.; Hirshman, M.F.; Goodyear, L.J.: Ca2+ /calmodulindependent protein kinase kinase-a regulates skeletal muscle glucose uptake independent of AMP-activated protein kinase and Akt activation. Diabetes, 56, 1403-1409 (2007) [106] Tsui, J.; Malenka, R.C.: Substrate localization creates specificity in calcium/calmodulin-dependent protein kinase II signaling at synapses. J. Biol. Chem., 281, 13794-13804 (2006) [107] Ang, E.S.; Zhang, P.; Steer, J.H.; Tan, J.W.; Yip, K.; Zheng, M.H.; Joyce, D.A.; Xu, J.: Calcium/calmodulin-dependent kinase activity is required for efficient induction of osteoclast differentiation and bone resorption by receptor activator of nuclear factor kappa B ligand (RANKL). J. Cell. Physiol., 212, 787-795 (2007) [108] Wagner, S.; Dybkova, N.; Rasenack, E.C.; Jacobshagen, C.; Fabritz, L.; Kirchhof, P.; Maier, S.K.; Zhang, T.; Hasenfuss, G.; Brown, J.H.; Bers, D.M.; Maier, L.S.: Ca2+ /calmodulin-dependent protein kinase II regulates cardiac Na+ channels. J. Clin. Invest., 116, 3127-3138 (2006) [109] Calderilla-Barbosa, L.; Ortega, A.; Cisneros, B.: Phosphorylation of dystrophin Dp71d by Ca2+ /calmodulin-dependent protein kinase II modulates the Dp71d nuclear localization in PC12 cells. J. Neurochem., 98, 713-722 (2006) [110] Uboha, N.V.; Flajolet, M.; Nairn, A.C.; Picciotto, M.R.: A calcium- and calmodulin-dependent kinase Ia/microtubule affinity regulating kinase 2 signaling cascade mediates calcium-dependent neurite outgrowth. J. Neurosci., 27, 4413-4423 (2007) [111] Ishiguro, K.; Green, T.; Rapley, J.; Wachtel, H.; Giallourakis, C.; Landry, A.; Cao, Z.; Lu, N.; Takafumi, A.; Goto, H.; Daly, M.J.; Xavier, R.J.: Ca2+ /calmodulin-dependent protein kinase II is a modulator of CARMA1mediated NF-kB activation. Mol. Cell. Biol., 26, 5497-5508 (2006) [112] Ishiguro, K.; Ando, T.; Goto, H.; Xavier, R.: Bcl10 is phosphorylated on Ser138 by Ca2+ /calmodulin-dependent protein kinase II. Mol. Immunol., 44, 2095-2100 (2007) [113] Solomon, P.S.; Rybak, K.; Trengove, R.D.; Oliver, R.P.: Investigating the role of calcium/calmodulin-dependent protein kinases in Stagonospora nodorum. Mol. Microbiol., 62, 367-381 (2006) [114] Takemoto-Kimura, S.; Ageta-Ishihara, N.; Nonaka, M.; Adachi-Morishima, A.; Mano, T.; Okamura, M.; Fujii, H.; Fuse, T.; Hoshino, M.; Suzuki, S.; Kojima, M.; Mishina, M.; Okuno, H.; Bito, H.: Regulation of dendritogenesis via a lipid-raft-associated Ca2+ /calmodulin-dependent protein kinase CLICK-III/CaMKIg. Neuron, 54, 755-770 (2007) [115] Kamata, A.; Sakagami, H.; Tokumitsu, H.; Sanda, M.; Owada, Y.; Fukunaga, K.; Kondo, H.: Distinct developmental expression of two isoforms of Ca2+ /calmodulin-dependent protein kinase kinases and their involvement in hippocampal dendritic formation. Neurosci. Lett., 423, 143-148 (2007)

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[116] Kamata, A.; Sakagami, H.; Tokumitsu, H.; Owada, Y.; Fukunaga, K.; Kondo, H.: Spatiotemporal expression of four isoforms of Ca2+ /calmodulindependent protein kinase I in brain and its possible roles in hippocampal dendritic growth. Neurosci. Res., 57, 86-97 (2007) [117] Slonimsky, J.D.; Mattaliano, M.D.; Moon, J.I.; Griffith, L.C.; Birren, S.J.: Role for calcium/calmodulin-dependent protein kinase II in the p75mediated regulation of sympathetic cholinergic transmission. Proc. Natl. Acad. Sci. USA, 103, 2915-2919 (2006)

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1 Nomenclature EC number 2.7.11.18 Systematic name ATP:myosin-light-chain O-phosphotransferase Recommended name myosin-light-chain kinase Synonyms Ca2+ -calmodulin-dependent myosin light chain kinase [102] DNA-dependent protein kinase catalytic subunit [5, 6, 7, 8, 9] EC MLCK [85, 86, 87] MLC kinase [77] MLCK [3, 4, 11, 21, 75, 76, 77, 78, 81, 82, 84, 86, 88, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 106] MLCK-210 [79, 106] MLCK-A [83] Twitchin kinase [3] calcium/calmodulin-dependent myosin light chain kinase cardiac-MLCK [99] endothelial MLCK [88] endothelial cell myosin light chain kinase [86, 87] endothelial myosin light chain kinase [88] kinase, myosin light-chain (phosphorylating) long chain myosin light chain kinase [106] long myosin light chain kinase [80] myosin kinase myosin light chain kinase [6, 8, 9, 11, 12, 13, 17, 18, 21, 22, 23, 24, 77, 78, 79, 82, 86, 87, 90, 91, 92, 93, 94, 96, 97, 98, 99, 100, 101, 103, 104, 105, 106] myosin light chain kinase 2, skeletal/cardiac muscle [2, 5] myosin light chain kinase A [83] myosin light chain kinase, skeletal muscle [16] myosin light chain kinase, smooth muscle [19, 20, 25] myosin light chain kinase, smooth muscle and non-muscle isozymes [1, 10, 11, 12, 13, 14, 15] myosin light chain protein kinase myosin light-chain kinase [95]

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myosine light chain kinase [81, 88] nmMLCK [85, 89] non-muscle myosin light chain kinase [85, 89] short myosin light chain kinase [80] smMLCK [85, 88] smooth muscle myosin light chain kinase [88] smooth-muscle myosin light chain kinase [85] smooth-muscle-myosin-light-chain kinase stretchin-MLCK [66] Additional information ( cf. EC 2.7.11.17 [97, 102]) [35, 97, 102] CAS registry number 51845-53-5

2 Source Organism Gallus gallus (no sequence specified) [19, 32, 36, 41, 45, 46, 47, 50, 51, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 65, 72, 79, 92] Meleagris gallopavo (no sequence specified) [32, 38, 42, 43, 44, 47, 49, 52, 53, 56] Cavia porcellus (no sequence specified) [56] Drosophila melanogaster (no sequence specified) [66] mammalia (no sequence specified) [3] eukaryota (no sequence specified) [4] Mus musculus (no sequence specified) [78, 88, 90, 91, 94, 98, 106] Homo sapiens (no sequence specified) [21, 30, 38, 43, 44, 56, 57, 73, 77, 80, 81, 82, 85, 86, 87, 88, 89, 92, 99, 100, 103] Rattus norvegicus (no sequence specified) [19, 40, 44, 56, 65, 76, 94, 96, 101, 105] Sus scrofa (no sequence specified) [39, 44, 69] Bos taurus (no sequence specified) [19, 21, 31, 32, 33, 34, 35, 36, 37, 44, 47, 56, 57, 75, 95] Oryctolagus cuniculus (no sequence specified) [19, 26, 27, 28, 29, 44, 45, 47, 68, 70, 71, 80, 89, 93, 97] Ovis aries (no sequence specified) [38] Dictyostelium discoideum (no sequence specified) [83] Canis familiaris (no sequence specified) [56] Lytechinus pictus (no sequence specified) [104] Oncorhynchus mykiss (no sequence specified) [67] Limulus sp. (no sequence specified) [48] Danio rerio (no sequence specified) [99] Oryctolagus cuniculus (UNIPROT accession number: P07313) [5, 6, 7, 8, 9] Gallus gallus (UNIPROT accession number: P11799) [10, 11, 12, 13, 14, 15]

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Rattus norvegicus (UNIPROT accession number: P20689) [16] Dictyostelium discoideum (UNIPROT accession number: P25323) [17, 18] Oryctolagus cuniculus (UNIPROT accession number: P29294) [19, 20] Homo sapiens (UNIPROT accession number: Q15746) [1, 21, 22, 23, 24, 74, 102] Bos taurus (UNIPROT accession number: Q28824) [25] Homo sapiens (UNIPROT accession number: Q9H1R3) [2, 5, 102] Oryctolagus cuniculus (UNIPROT accession number: P07131) [5, 6, 7] Homo sapiens (UNIPROT accession number: Q5MYA0) [84] Homo sapiens (UNIPROT accession number: Q5MY99) [84]

3 Reaction and Specificity Catalyzed reaction ATP + [myosin light chain] = ADP + [myosin light chain] phosphate Reaction type phospho group transfer Natural substrates and products S ATP + [myosin II regulatory light chain] ( involved in many cellular cytoskeletal functions [81]) (Reversibility: ?) [81] P ADP + [myosin II regulatory light chain] phosphate S ATP + [myosin light chain 2a] ( MLC phosphorylation plays a regulatory role in inotropic response to a1 -adrenergic stimulation in the heart, enzyme inhibition causes heart failure in ventricular trabeculae [77]) (Reversibility: ?) [77] P ADP + [myosin light chain 2a] phosphate S ATP + [myosin light chain] ( activation of the enzyme is a key regulatory step in the modulation of endothelial permeability, central to parthogenesis of inflammatory lung disease is disruption of the endothelial barrier function [88]; enzyme is regulating cytoskeletal rearrangement and cell motility [82]; the endothelial isozyme is a mutifunctional contractile effector involved in vascular barrier regulation, leukocyte diapedesis, apoptosis, and angiogenesis [87]; the multifunctional regulatory enzyme stimulates smooth muscle myosin ATPase activity by binding to the myosin heads without phosphorylating the myosin light chain, kinetics, overview [75]; the non-muscle myosin light chain kinase is involved in regulation of hepatic functions in response to intra- and extracellular signals [89]) (Reversibility: ?) [75, 80, 82, 85, 86, 87, 88, 89] P ADP + [myosin light chain] phosphate S ATP + light chain myosin II ( cardiac-MLCK is essential for normal cardiac development and function in zebrafish embryos, deletion of the gene encoding cardiac-MLCK is lethal for embryos [99]; causes endothelial contraction [95]; cytokine-induced epithelial barrier dysfunction can be mediated by increased MLCK expres-

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P S P S

P S

P S

Myosin-light-chain kinas

sion and subsequent myosin II regulatory light chain phosphorylation, the enzyme is involved in the inflammatory bowel disease [103]; MLC phosphorylation increases muscle contraction and plays a prominent role in skeletal muscle force potentiation of fast-twitch type IIb but not type I or IIa fibers, overview [97]; MLCK plays a key role in the control of MLC-phosphorylation status, and it modulates barrier function through its regulation of intracellular contractile machinery, overview, endothelial mechanism of MLC-dependent barrier injury in burns, overview [106]; myosin II activation is essential for stress fiber and focal adhesion formation, and is implicated in integrin-mediated signaling events [98]; regulatory myosin chain, in thick filaments, isozyme L-MLCK plays a role in cytoskeleton organization [93]; roles of MLCK and ROCK on myosin II activation, overview, a global, MLCK-dependent increase in myosin II cortical contractility accompanies the metaphase-anaphase transition in sea urchin eggs, overview [104]; the enzyme is important in regulation of shape, adhesion and migration of fibrosarcoma cells, overview [91]) (Reversibility: ?) [91, 93, 95, 97, 98, 99, 101, 103, 104, 106] ADP + phosphorylated light chain myosin II ATP + myosin IIB (Reversibility: ?) [92] ADP + phosphorylated myosin IIB ATP + myosin light chain ( phosphorylation of myosin light chains by myosin light chain kinase is a key event in agonist-mediated endothelial cell gap formation and vascular permeability [21]; the enzyme phosphorylates the 18000 Da Dictyostelium myosin regulatory light chain [18]) (Reversibility: ?) [3, 4, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25] ADP + phosphorylated myosin light chain ATP + myosin light chain ( involved in myosin phosphorylation and enzyme secretion [40]; obligatory step in development of active tension in smooth muscle [37]; involved in muscle contractility and motility of nonmuscle cells [56]; involved in regulation of actin-myosin contractile activity in adrenal medulla [31]; event in initiation of smoothmuscle contraction [19]; inhibition of actin-myosin ineraction [59, 60]) (Reversibility: ?) [18, 19, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 59, 60] ADP + myosin light chain phosphate Additional information ( the differentiationdependent enzyme splice variant MLCK1 regulates epithelial tight junction permeability, the endothelial isozyme is responsible for Na+ -glucose cotransport-induced tight junction regulation [84]; the enzyme activity is cell cycle regulated with a decrease in activity during mitosis due to phosphorylation, inhibition of enzyme phosphorylation during mitosis leads to microtubule defects, overview [80]; the enzyme interacts with macrophage migration inhibition factor MIF in endothelium which may be important for the regulation of both non-muscle cytoskeletal dynamics as well as pathobiological vascular events involving the enzyme [87]; the

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enzyme is a potential cytoskeleton integrator through its unique N-terminal domain, the enzyme binds tubulin and actin, and is involved in microtubule/microfilament association [79]; the enzyme is involved, probably via microfilament assembly, in sperm chromatin-induced cortical reorganization during oocyte maturation to a polarized egg [78]; the enzyme mediates eosinophil chemotaxis in a mitogen-activated protein kinase-dependent manner [82]; the enzyme plays an important role in TNFa-dependent induction of NFkB activity, mechanism [86]; Human T cell leukemia virus 1-infected lymphocytes can cause a breakdown of the blood-brain barrier inducing an increase in paracellular endothelial permeability and transcellular migration, this disruption is associated with tight junction disorganization between endothelial cells and altered tight junction proteinexpression involving the enzyme MLCK, enzyme inhibition prevents the changes in endothelial cells, overview [100]; increased MLCK activity accompanies increases in MLC expression, overview [103]; infection of brain endothelial cells with Haemophilus somnus causes alterations in brain endothelial cell and blood-brain barrier integrity and causes inflammation involving the enzyme, which acts in rapid cytoskeletal rearrangement, overview [95]; inhibition of MLCK results in spherical cells and marked impairment of adhesion and migration of fibrosarcoma cells, overview [91]; inhibition of the enzyme retards the growth of mammary cancer cells [94]; inhibition of the enzyme retards the growth of prostate cancer cells [94]; MLCK is probably involved in development of diabetic nephropathy, overview [96]; regulation of the MLCK promoters and gene expression involving myocardin, model, overview [90]; the enzyme binds to thin filaments with high affinity, myofilament binding by Ig-like modules is blocked by disassembling of the filaments, overview [93]; the enzyme is a key regulator of various forms of cell motility involving actin and myosin II [92]; the enzyme is not a regulator of synaptic vesicle trafficking during repetitive exocytosis in cultured hippocampal neurons, overview [101]; the enzyme negatively regulates synaptic plasticity and fear learning in the lateral nucleus of the amygdala, the enzyme is involved in memory aquisition, rather than in posttraining consolidation of memory, the enzyme may help to prevent aquisition of irrelevant fears, thus enzyme deficiency or defects can lead to pathological fear learning, overview [105]; the myosin light chain kinase plays a role in the regulation of epithelial cell survival, and in the generation of pro-survival signals in both untransformed and transformed epithelial cells, apoptosis following inhibition of myosin II activation by MLCK is probably meditated through the death receptor pathway, overview [98]; ventricular/cardiac muscle isozyme cardiac-MLCK, which is involved in the development of human cardiomyopathy, is an important structural protein that affects physiologic cardiac sarcomere formation and heart development, the cardiac MLCK regulates sarcomere assembly in the vertebrate heart, overview [99]) (Reversibility: ?) [78, 79, 80, 82, 84, 86, 87, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 103, 105] P ?

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Substrates and products S ATP + BpaKKRAARATSNVFA ( Bpa is the photoreactive amino acid p-benzoylphenylalanine [68]) (Reversibility: ?) [68] P ADP + ? S ATP + H-KKRAARATSNVFA-NH2 ( peptide substrate [82]) (Reversibility: ?) [82] P ADP + ? S ATP + KKRAARATSNVFA (Reversibility: ?) [68] P ADP + ? S ATP + Lys-Lys-Arg-Ala-Ala-Arg-Ala-Thr-Ser-Asn-Val-Phe-Ala (Reversibility: ?) [41] P ADP + ? S ATP + Lys-Lys-Arg-Pro-Gln-Arg-Ala-Thr-Ser-Asn-Val-Phe-Ser (Reversibility: ?) [51] P ADP + ? S ATP + TRPC5 channel ( Ca2+ /calmodulin-dependent myosin light chain kinase is essential for activation of plasma membrane TRPC5 channels, responsible for Ca2+ influx, from Drosophila melanogaster expressed in HEK-293 cells, phosphorylation sites are Ser698, Ser775, and Thr700, mutational analysis [102]) (Reversibility: ?) [102] P ADP + phosphorylated TRPC5 channel S ATP + [myosin II light chain] ( from Dictyostelium discoideum, activated enzyme [83]) (Reversibility: ?) [83] P ADP + [myosin II lihght chain] phosphate S ATP + [myosin II regulatory light chain] ( involved in many cellular cytoskeletal functions [81]) (Reversibility: ?) [81] P ADP + [myosin II regulatory light chain] phosphate S ATP + [myosin light chain 2a] ( MLC phosphorylation plays a regulatory role in inotropic response to a1 -adrenergic stimulation in the heart, enzyme inhibition causes heart failure in ventricular trabeculae [77]) (Reversibility: ?) [77] P ADP + [myosin light chain 2a] phosphate S ATP + [myosin light chain] ( activation of the enzyme is a key regulatory step in the modulation of endothelial permeability, central to parthogenesis of inflammatory lung disease is disruption of the endothelial barrier function [88]; enzyme is regulating cytoskeletal rearrangement and cell motility [82]; the endothelial isozyme is a mutifunctional contractile effector involved in vascular barrier regulation, leukocyte diapedesis, apoptosis, and angiogenesis [87]; the multifunctional regulatory enzyme stimulates smooth muscle myosin ATPase activity by binding to the myosin heads without phosphorylating the myosin light chain, kinetics, overview [75]; the non-muscle myosin light chain kinase is involved in regulation of hepatic functions in response to intra- and extracellular signals [89]; activated phosphorylated enzyme [82, 85, 86, 87]) (Reversibility: ?) [75, 80, 82, 85, 86, 87, 88, 89] P ADP + [myosin light chain] phosphate

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S ATP + kemptamide ( i.e. peptide KKRPQRATSNVFS-NH2, activated enzyme [83]) (Reversibility: ?) [35, 83] P ADP + kemptamide phosphate S ATP + light chain myosin II ( cardiac-MLCK is essential for normal cardiac development and function in zebrafish embryos, deletion of the gene encoding cardiac-MLCK is lethal for embryos [99]; causes endothelial contraction [95]; cytokine-induced epithelial barrier dysfunction can be mediated by increased MLCK expression and subsequent myosin II regulatory light chain phosphorylation, the enzyme is involved in the inflammatory bowel disease [103]; MLC phosphorylation increases muscle contraction and plays a prominent role in skeletal muscle force potentiation of fast-twitch type IIb but not type I or IIa fibers, overview [97]; MLCK plays a key role in the control of MLC-phosphorylation status, and it modulates barrier function through its regulation of intracellular contractile machinery, overview, endothelial mechanism of MLC-dependent barrier injury in burns, overview [106]; myosin II activation is essential for stress fiber and focal adhesion formation, and is implicated in integrin-mediated signaling events [98]; regulatory myosin chain, in thick filaments, isozyme L-MLCK plays a role in cytoskeleton organization [93]; roles of MLCK and ROCK on myosin II activation, overview, a global, MLCK-dependent increase in myosin II cortical contractility accompanies the metaphase-anaphase transition in sea urchin eggs, overview [104]; the enzyme is important in regulation of shape, adhesion and migration of fibrosarcoma cells, overview [91]; phosphorylation at Ser19 [104]; regulatory myosin chain [97]; regulatory myosin chain, phosphorylation at Ser18 and Thr19 on the N-terminus [91,93]; regulatory myosin light chain [103]; the cardiac-specific substrate cardiac-MLCKis phosphorylated by the cardiac-specific isozyme MLC2v [99]; the cardiacspecific substrate MLC2v is phosphorylated by the cardiac-specific isozyme cardiac-MLCK [99]) (Reversibility: ?) [91, 93, 95, 97, 98, 99, 101, 103, 104, 106] P ADP + phosphorylated light chain myosin II S ATP + myosin II ( from Dictyostelium discoideum, activated enzyme [83]) (Reversibility: ?) [83] P ADP + myosin II phosphate S ATP + myosin IIB (Reversibility: ?) [92] P ADP + phosphorylated myosin IIB S ATP + myosin light chain ( acceptor substrates are myosin light chains of smooth muscle myosin [42, 43, 47, 51, 52, 53]; no substrates are myosin heavy chain and phosvitin [18, 30, 33, 39, 56]; no substrate is protamine [30, 39]; acceptor substrates are myosin light chains of skeletal muscle [26, 27, 28, 31, 33, 35, 42, 43, 44, 45, 56]; acceptor substrates are myosin light chains of cardiac muscle [27, 33, 34, 42, 43, 44, 45]; no substrates are actin and tropomyosin [48]; transfers

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the g-phosphate of ATP to a Ser-residue of myosin light chain [43]; no substrate is histone 2-A [18, 30, 33, 36, 38, 40, 42, 48]; ITP, GTP, CTP or UTP cannot replace ATP [27]; acceptor substrates are myosin light chains of non-muscle myosin [56]; not specific for 22 kDa and 15 kDa light chain [27, 56]; no substrate is casein [18, 26, 27, 30, 33, 35, 36, 38, 39, 42, 47, 48, 56]; no substrates are 15 kDa and 22 kDa light-chain or heavy-chain fractions of myosin from white skeletal muscle [27]; phosphorylation sites: Thr-residues in smooth muscle and pancreas myosin light chain [35, 40, 44]; phosphorylation sites: Ser-residues in smooth and skeletal muscle [44]; acceptor substrates are myosin light chains of adrenal medullary myosin [31]; no substrate is histone 2 b [35, 48]; no substrate is troponin [26, 27, 56]; no substrate is histone H1 [48]; highly specific for regulatory or P-lightchain [26, 27, 33, 35, 39, 44, 45]; highly specific for 18 kDa light chain [26, 27, 33, 35, 39, 40]; specific for 18.5 kDa Dictyostelium or 19 kDa skeletal muscle light chain [44]; no substrate is synapsin [35, 40]; 1 mol phosphate per mol light chain in skeletal muscle [31, 45, 48]; no substrate is phosphorylase kinase [33, 39, 42, 56]; acceptor substrates are myosin light chains of smooth muscle [19, 27, 30, 33, 35, 36, 45, 47, 51, 53, 56]; no substrate is molluscan adductor myosin [27]; specific for 20 kDa light chain [26, 27, 30, 31, 33, 35, 39, 40, 42, 43, 44, 45, 48, 53]; phosphorylation sites: Ser-19 and Thr-18 in smooth muscle myosin light chain [44]; no substrates are myelin basic protein, glycogen synthase, tubulin, microtubule-associated protein 2, kemptide and peptide pp60src [35]; not 16 kDa light chain [18, 31, 43]; no substrate is histone V-S [30, 36, 42]; acceptor substrates are myosin light chains of Ml3-myosin rabbit muscle [26]; no substrate is phosphorylase b [18, 26, 27, 30, 31, 33, 35, 36, 38, 39, 42, 47, 56]; no substrate is histone III-S from thymus [27]; kinase from skeletal muscle with broader specificity than smooth muscle kinase [56]; involved in myosin phosphorylation and enzyme secretion [40]; obligatory step in development of active tension in smooth muscle [37]; involved in muscle contractility and motility of non-muscle cells [56]; involved in regulation of actin-myosin contractile activity in adrenal medulla [31]; event in initiation of smooth-muscle contraction [19]; inhibition of actin-myosin ineraction [59,60]) (Reversibility: ?) [18, 19, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 59, 60]

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P ADP + myosin light chain phosphate [18, 19, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52] S ATP + myosin light chain ( phosphorylation of myosin light chains by myosin light chain kinase is a key event in agonist-mediated endothelial cell gap formation and vascular permeability [21]; the enzyme phosphorylates the 18000 Da Dictyostelium myosin regulatory light chain [18]) (Reversibility: ?) [3, 4, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25] P ADP + phosphorylated myosin light chain S ATP + myosin regulatory light chain (Reversibility: ?) [71] P ? S ATP + protein ( intramolecular autophosphorylation activates the enzyme [18]) (Reversibility: ?) [18] P ADP + phosphoprotein S ATP + telokin ( telokin may modulate enzyme activity in vivo [62]) (Reversibility: ?) [62] P ADP + ? S Additional information ( substrate specificity [4]; the enzyme possesses ATPase activity [33]; skeletal, gizzard smooth and cardiac enzymes perform intramolecular autophosphorylation in the absence of acceptor substrate [18,56]; no intramolecular autophosphorylation in the absence of acceptor substrate [39,48]; the differentiation-dependent enzyme splice variant MLCK1 regulates epithelial tight junction permeability, the endothelial isozyme is responsible for Na+ -glucose cotransport-induced tight junction regulation [84]; the enzyme activity is cell cycle regulated with a decrease in activity during mitosis due to phosphorylation, inhibition of enzyme phosphorylation during mitosis leads to microtubule defects, overview [80]; the enzyme interacts with macrophage migration inhibition factor MIF in endothelium which may be important for the regulation of both non-muscle cytoskeletal dynamics as well as pathobiological vascular events involving the enzyme [87]; the enzyme is a potential cytoskeleton integrator through its unique Nterminal domain, the enzyme binds tubulin and actin, and is involved in microtubule/microfilament association [79]; the enzyme is involved, probably via microfilament assembly, in sperm chromatin-induced cortical reorganization during oocyte maturation to a polarized egg [78]; the enzyme mediates eosinophil chemotaxis in a mitogen-activated protein kinase-dependent manner [82]; the enzyme plays an important role in TNFa-dependent induction of NFkB activity, mechanism [86]; substrate specificity and binding structure, the enzyme depends on basic residues for substrate recognition, autoregulation by a pseudosubstrate mechanism, overview [3]; Human T cell leukemia virus 1-infected lymphocytes can cause a breakdown of the blood-brain barrier inducing an increase in paracellular endothelial permeability and transcellular migration, this disruption is associated with tight junction disorga-

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nization between endothelial cells and altered tight junction proteinexpression involving the enzyme MLCK, enzyme inhibition prevents the changes in endothelial cells, overview [100]; increased MLCK activity accompanies increases in MLC expression, overview [103]; infection of brain endothelial cells with Haemophilus somnus causes alterations in brain endothelial cell and blood-brain barrier integrity and causes inflammation involving the enzyme, which acts in rapid cytoskeletal rearrangement, overview [95]; inhibition of MLCK results in spherical cells and marked impairment of adhesion and migration of fibrosarcoma cells, overview [91]; inhibition of the enzyme retards the growth of mammary cancer cells [94]; inhibition of the enzyme retards the growth of prostate cancer cells [94]; MLCK is probably involved in development of diabetic nephropathy, overview [96]; regulation of the MLCK promoters and gene expression involving myocardin, model, overview [90]; the enzyme binds to thin filaments with high affinity, myofilament binding by Ig-like modules is blocked by disassembling of the filaments, overview [93]; the enzyme is a key regulator of various forms of cell motility involving actin and myosin II [92]; the enzyme is not a regulator of synaptic vesicle trafficking during repetitive exocytosis in cultured hippocampal neurons, overview [101]; the enzyme negatively regulates synaptic plasticity and fear learning in the lateral nucleus of the amygdala, the enzyme is involved in memory aquisitoion, rather than in posttraining consolidation of memory, the enzyme may help to prevent aquisition of irrelevant fears, thus enzyme deficiency or defects can lead to pathological fear learning, overview [105]; the myosin light chain kinase plays a role in the regulation of epithelial cell survival, and in the generation of pro-survival signals in both untransformed and transformed epithelial cells, apoptosis following inhibition of myosin II activation by MLCK is probably meditated through the death receptor pathway, overview [98]; ventricular/cardiac muscle isozyme cardiacMLCK, which is involved in the development of human cardiomyopathy, is an important structural protein that affects physiologic cardiac sarcomere formation and heart development, the cardiac MLCK regulates sarcomere assembly in the vertebrate heart, overview [99]; MLCK in the plasma membrane distribution of TRPC5 channels, overview [102]) (Reversibility: ?) [3, 4, 18, 33, 39, 48, 56, 78, 79, 80, 82, 84, 86, 87, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 105] P ? Inhibitors (+)-catechin ( IC50: 0.44 mM [50]) [50] (-)-epicatechin ( IC50: 0.32 mM [50]) [50] 1,12-diaminododecane ( IC50: 0.063 mM [55]) [55] 1,4-diaminoanthraquinone ( IC50: 0.018 mM [41]) [41] 1-hexadecylpyridinium bromide ( IC50: 0.049 mM [55]) [55]

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11-(3-chloro-6-immino-6H-pyridazin-1-yl)-undecanoic acid (6-phenyl-pyridazin-3-yl)-amide ( highly specific inhibitor, competitive to ATP binding [88]) [88] 2,2’-dihydroxychalcone [50] 3’,4’,5’-tri-O-methyltricetin [50] 3’,4’-dihydroxyflavone ( IC50: 0.262 mM [50]) [50] 3,3’,4’-trihydroxyflavone ( IC50: 0.001 mM [50]) [50] 5,4’-dihydroxyflavone ( IC50: 0.024 mM [50]) [50] 5,7-dihydroxyflavone ( IC50: 0.043 mM [50]) [50] 7,8,3’,4’-tetrahydroxyflavone ( IC50: 0.02 mM [50]) [50] 7-O-methylapigenin [50] AKKLSKDRMAAYMARRK ( synthetic peptide, analog of inhibitory region of myosin light chain kinase [49]) [49] AKKLSKDRMKKYMA ( synthetic peptide, analog of inhibitory region of myosin light chain kinase [49]) [49] AKKLSKDRMKKYMAAAA ( synthetic peptide, analog of inhibitory region of myosin light chain kinase [49]) [49] AKKLSKDRMKKYMARR ( synthetic peptide, analog of inhibitory region of myosin light chain kinase [49]) [49] AKKLSKDRMKKYMARRK ( synthetic peptide, analog of inhibitory region of myosin light chain kinase [49]) [49] AKKLSKDRMKKYMARRKWQKTG ( synthetic peptide, analog of inhibitory region of myosin light chain kinase [49]) [49] ARRKWQKTGHAVRAIGRLSS [69] ATP ( free form, strong, not in the presence of excess Mg2+ [27]) [27] amiloride [53] apigenin ( IC50: 0.023 mM [50]) [50] arachidonic acid [52] Ca2+ ( at higher free concentrations, 0.4-3 mM, independent of Mg2+ or pH-value [31]) [31] calmodulin-binding protein from bovine cardiac muscle [34] chalcone [50] d-sphingosine ( IC50: 0.006 mM [55]) [55] dihydroquercetin ( IC50: 0.08 mM [50]) [50] dihydrosphingosine ( erythro- and threo-dihydrosphingosine, IC50: 0.008 mM [55]) [55] dimethyldioctadecylammonium bromide ( IC50: 0.008 mM [55]) [55] EGTA ( strong [27]) [26, 27, 30, 31, 32] gossypol [50] H1152 ( low inhibition [104]) [104] hexadecyltrimethylammonium bromide ( IC50: 0.011 mM [55]) [55] histone 2A [18] increasing ionic strength ( up to 0.4 M NaCl, weak [27]; above 0.1 M KCl [18]) [18, 27, 33] isoliquiritigenin [50]

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KCl [28] KDRMKKYMARR ( synthetic peptide, analog of inhibitory region of myosin light chain kinase [49]) [49] KT5926 ( i.e. (8R,9S,11S)-(-)-9-hydroxy-9-methoxycarbonyl-8methyl-14-n-propoxy-2,3,9,10-tetrahydro-8,11-epoxy,1H,8H,11H-2,7b,11atriazadeibenzo[a,g]cycloocta[cde]triden-1-one, specific inhibitor [88]) [88] kaempferol ( i.e. 3,5,7-trihydroxy-2-(4-hydroxyphenyl)-1-benzopyran-4-one, IC50: 0.00045 mM [37]; IC50: 0.004 mM [50]) [37, 50] LSKDRMKKYMARRKWQK ( synthetic peptide, analog of inhibitory region of myosin light chain kinase [49]) [49] linoleic acid [52] luteolin ( IC50: 0.026 mM [50]) [50] ML-7 ( specific inhibitor [86]; calmodulin/enzyme-specific inhibitor, inhibits cell attachment to extracellular substrate in vivo, attenuates the activation of GTP-binding protein Rac and cell migration [76]; i.e. 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine HCl, specific inhibitor [88]; specific inhibitor, inhibits activation by eotaxin [82]; specifically inhibits the enzyme and prevents sperm chromatin-induced cortical reorganization in eggs in vivo [78]; strong specific inhibition [77]; 40-60% inhibition in vivo [91]; a specific inhibitor, in vivo the inhibitor enhances the short-term and long-term memory, when applied before fear conditioning, but not immediately afterwards, the inhibitor has no effet on memory retrieval and behaviour when the training stimuli are presented in a non-associative manner [105]; inhibition of MLCK induces apoptosis in adherent cells and disrupts cell-cell adhesion [98]; specific inhibitor of MLCK, has a chemopreventive effect in an in vitro mouse mammary organ culture model, in vivo the inhibitor retards the growth of mammary tumours, acts as an adjuvant to etoposide stimulating its ability to prevent growth of established tomours, overview [94]; specific inhibitor of MLCK, in vivo the inhibitor retards the growth of prostate tumours, acts as an adjuvant to etoposide stimulating its ability to prevent growth of established tomours, overview [94]; specificity, overview, ML-7 changes action potential amplitude and voltage-gated Ca2+ channel current nonspecifically, but does not affect calcimycin-induced release and vesicle readily releasable pool RRP recovery after depletion [101]) [67, 76, 77, 78, 82, 86, 88, 91, 94, 95, 98, 100, 101, 104, 105] ML-9 ( impairs the plasma membrane localization of TRPC5 channels [102]; inhibition of MLCK induces apoptosis in adherent cells and disrupts cell-cell adhesion [98]) [98, 102] MLCK pepitde ( complete inhibition [104]) [104] MS-347a ( from Aspergillus sp. KY52178, structurally related to sydowinin B, irreversible, inhibition of calmodulin-dependent and independent activity, IC50: 0.0092 mM [54]) [54] morin ( IC50: 0.028 mM [50]) [50] myricetin ( IC50: 0.006 mM [50]) [50] N-alkyl-N,N-dimethyl-3-ammonio-1-propanesulfonates ( zwittergents 3-14 and 16 [55]) [55]

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N-methyloctadecylamine ( IC50: 0.01 mM [55]) [55] NaCl [28] naphthalene sulfonamide derivatives [47] octadecylamine ( IC50: 0.011 mM [55]) [55] okanin [50] oleic acid [52] peptide 18 ( i.e. H-RKKYKYRRK-NH2, specifically inhibits the enzyme and prevents sperm chromatin-induced cortical reorganization in eggs in vivo [78]) [78] phosphate ( up to 0.1 M, weak [27]) [27] phosphorylation ( at 2 sites [47]) [44, 47] quercetin ( IC50: 0.006 mM [50]) [50] RRKWQKTGHAVRAIGRL [69] RRKYQKTGHAVRAIGRL [69] Rho GDI [104] rutin ( IC50: 0.32 mM [50]) [50] SKDRMKKYMARRKWQKTGHAVRAI ( autoregulatory pseudosubstrate sequence of smooth muscle enzyme, residues 787-810 [4]) [4] SQRLLKKYLMKRRWKKNFIAVSAA ( autoregulatory pseudosubstrate sequence of the skeletal muscle enzyme, residues 570-593 [4]) [4] sodium dodecylsulfate ( IC50: 0.049 mM [55]) [55] sodium octadecylsulfate ( IC50: 0.043 mM [55]) [55] sodium tetradecylsulfate ( IC50: 0.038 mM [55]) [55] tetradecyltrimethylammonium bromide ( IC50: 0.011 mM [55]) [55] trifluoperazine [47] W-7 ( calmodulin/enzyme-specific inhibitor, attenuates cell migration in vivo [76]; 40-60% inhibition in vivo [91]) [76, 91] wortmannin ( complete inhibition at 0.01 mM [77]; i.e. MS54, IC50: 0.0019 mM, irreversible, highly selective, kinetics, high concentrations of ATP protect [51]) [51, 77] Y-27632 ( 40-60% inhibition in vivo [91]) [91] acylcarnitin ( weak [55]) [55] alizarin ( IC50: 0.014 mM [41]) [41] alkylamine ( long and straight chain, most effective with chain length C-13 to C-18 [55]) [55] alkyltrimethylammonium halide [55] anthraflavic acid ( IC50: 0.037 mM [41]) [41] anthrarufin [41] blebbistatin ( complete inhibition at 0.1 mM [104]) [104] cAMP-dependent protein kinase ( phosphorylates light chain myosin kinase leading to decreased affinity from calmodulin [32, 35, 39]) [32, 35, 39] chrysazine ( IC50: 0.02 mM [41]) [41] chrysophanic acid [41] cytasters ( low inhibition [104]) [104] decylamine ( IC50: 0.2 mM [55]) [55] dihydroapigenin ( IC50: 0.17 mM [50]) [50]

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dihydrofisetin ( IC50: 0.18 mM [50]) [50] dihydroluteolin [50] dioctylamine ( IC50: 0.055 mM [55]) [55] dodecylamine ( IC50: 0.083 mM [55]) [55] dodecyltrimethylammonium bromide ( IC50: 0.078 mM [55]) [55] emodin ( IC50: 0.008 mM [41]) [41] fisetin ( IC50: 0.005 mM [50]) [50] galangin ( IC50: 0.02 mM [50]) [50] hesperidin [50] hexadecylamine ( IC50: 0.016 mM [55]) [55] hydroxyflavone ( IC50: 0.32 mM [50]) [50] kaempferid ( IC50: 0.008 mM [50]) [50] lauroylcholine iodide ( IC50: 0.12 mM [55]) [55] merocyanine dye (C16 ) ( IC50: 0.040 mM [55]) [55] merocyanine dye (CH3 ) [55] mitoxanthrone ( IC50: 0.002 mM [41]) [41] myristoylcarnitine chloride [55] myristoylcholine iodide ( IC50: 0.02 mM [55]) [55] oleylamine ( IC50: 0.006 mM [55]) [55] p21-activated kinase 1 [67] palmitoylcarnitine chloride [55] palmitoylcholine iodide ( IC50: 0.014 mM [55]) [55] protein kinase inhibitor PKI [3] pseudobabtisin [50] purpurin ( IC50: 0.025 mM [41]) [41] quercetagetin ( IC50: 0.026 mM [50]) [50] quercetrin ( IC50: 0.137 mM [50]) [50] quinalizarin ( IC50: 0.053 mM [41]) [41] quinizarin ( IC50: 0.026 mM [41]) [41] sodium alkylsulfate [55] stearoylcarnitine chloride [55] stearoylcholine iodide ( IC50: 0.013 mM [55]) [55] tetradecylamine ( IC50: 0.012 mM [55]) [55] tricetin ( IC50: 0.012 mM [50]) [50] tridecylamine ( IC50: 0.019 mM [55]) [55] unsaturated fatty acids ( irreversible by Ca2+ /calmodulin [52]) [52] Additional information ( autoregulatory domain extends from Asn780 to Arg808. The peptide Leu774 to Ser787 does not inhibit smMLCK, peptides of similar or shorter length from the pseudosubstrate region, Ser787 to Val807, are potent inhibitors [12]; the enzyme is regulated by an autoinhibitory domain [17]; structural requirements of autoinhibition of myosin light chain kinase [49]; no inhibition by 3,5-cAMP [26,27]; inhibition by autophosphorylation [59]; no inhibition by epicatechin, pseudobabtisin, 4-dimethylaminobenzaldehyde [50]; no inhibition by diacylglycerol, phosphatidylserine [52]; no inhibition by AMP [27]; residues 283-288 function as an autoinhibitory domain, autoinhibition is fully relieved by Thr166 phosphorylation [83];

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synthesis of peptides behaving as pseudosubstrates, determination of inhibitory potential [4]; the enzyme is inhibited by its regulatory subunit masking the active site, autoregulation by a pseudosubstrate mechanism, protein substrate-pseudosubstrate interactions, overview [3]; no inhibition by nocodazone [104]; no inhibition in vivo by Y-27632 [98]) [3, 4, 12, 17, 26, 27, 49, 50, 52, 59, 83, 98, 104] Cofactors/prosthetic groups ATP ( residues A27, A29, A32, and A31 are involved in binding [85]) [3, 4, 75, 76, 77, 79, 80, 81, 82, 83, 85, 86, 87, 88, 89, 91, 92, 93, 95, 97, 98, 99, 101, 102, 103, 104, 105, 106] calmodulin ( dependent on [80, 81]; not [18]; requirement [19, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56]; trypsin or chymotrypsin digested smooth muscle enzyme is independent of Ca2+ /calmodulin [44, 46, 47, 56]; aged enzyme loses Ca2+ /calmodulin sensitivity by proteolysis [31]; only active as ternary complex of calmodulin, Ca2+ and kinase: activation is initiated by binding of Ca2+ to calmodulin [33]; calmodulin in presence of Ca2+ abolishes the inhibition of actin-myosin interaction [59, 60, 61]; optimal ratio of enzyme to calmodulin for telokin phosphorylation is 1:4 [62]; lower affinity for Ca2+ /caldesmon after phosphorylation by cAMP-dependent protein kinase, Ka: 0.0000006 mM [39]; 1:1 stoichiometric complex in the presence of Ca2+ [47, 56]; binding site I at residue 1002-1022, binding site II at residues 26-42, complex formation with Ca2+ [75]) [18, 19, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 59, 60, 61, 62, 63, 65, 69, 70, 75, 76, 79, 80, 81, 85, 86, 87, 89] Activating compounds autophosphorylation ( activation [18]; no activation [39,48]) [18, 39, 48] calmodulin ( a calmodulin-sensitive MLCK isozyme [97]; activates, dependent on [102]) [97, 102, 106] F-actin ( binding via the DFRXXL motifs in the N-terminal region of isozymes S-MLCK and L-MLCK, the latter also uses the six Ig-like modules in its N-terminal extension for binding, the first two of which are minimally required for microfilament binding, overview [93]) [93] phosphorylation ( no activation [48]; activation, smooth muscle enzyme, not bovine cardiac enzyme [33]) [33, 48] TNFa ( stimulates endothelial isozyme activity in endothelium, and increases EC MLCK interaction with macrophage migration inhibition factor MIF [87]) [87] thrombin ( stimulates endothelial isozyme activity in endothelium, and increases EC MLCK interaction with macrophage migration inhibition factor MIF [87]) [87] eotaxin ( activates the enzyme 4fold, induces enzyme phosphorylation [82]) [82]

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interleukin 1 ( i.e IL-1, activates enzyme activity in endothelial cells [100]) [100] isoprenaline ( 80% activation at up to 0.01 mM [77]) [77] phenylephrine ( 80% activation at up to 0.1 mM [77]) [77] tumor necrosis factor-a ( i.e TNF-a, activates enzyme activity in endothelial cells [100]) [100] Additional information ( no activation by mild proteolysis [33]; no activation by cGMP [18]; no activation by Ca2+ plus b-lactoglobulin, cytochrome c, troponin C or parvalbumin [31]; no activation by phosphatidylserine [39]; no activation by cAMP [18,26,27,31,39]; 140fold activation through phosphorylation at Thr166 [83]; autoregulation by a pseudosubstrate mechanism, overview [3]; the endothelial isozyme EC MLCK contains a unique N-terminal sequence which is a target for upregulation by signaling cascade components such as p60src [87]; the enzyme is activated by phosphorylation through mitogen activated protein kinase MAPK [78]; electric stimulation of intact skeletal muscles activate the enzyme activity, overview [97]; myocardin, a cardiac SAP, SAF-A/B, acinus, PIAS, domain-containing protein, is important in regulation of enzyme expression, overview, induction of enzyme expression by the thyrotroph embryonic factor binding to the the CArG box of the promoter, TEF [90]; tumor necrosis factor-a induces enzyme activity in vivo [95]) [3, 18, 26, 27, 31, 33, 39, 78, 83, 87, 90, 95, 97] Metals, ions Ca2+ ( activates [89]; dependent on [80, 81, 97]; not [18]; calcium/calmodulin regulation [18]; Ca2+ /calmodulin-dependent [6,8,19]; inhibits at higher free concentrations [31]; Ca2+ in presence of calmodulin abolishes the inhibition of actin-myosin interaction [59, 60, 61]; KM : 0.0025 mM [40]; requirement, only in combination with calmodulin [31]; effect depends on Mg2+ concentration [27]; Km -value: 0.0003 [39]; aged enzyme loses Ca2+ /calmodulin sensitivity by proteolysis [31]; complex formation with calmodulin [75]; activates, dependent on [102]) [6, 8, 18, 19, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 59, 60, 61, 62, 63, 69, 70, 75, 80, 81, 82, 89, 97, 102] calcium ( calcium-binding protein [10]) [10] Mg2+ ( requirement, varies with ATP-concentration, MgATP2- is the active substrate [27]; Km -value: 2 mM [35]) [3, 4, 18, 27, 31, 33, 35, 81, 82, 83, 91, 92, 93, 95, 97, 98, 99, 101, 102, 103, 104, 105, 106] Turnover number (min–1) 5.17 (myosin light chain, 23-25 C, pH 7.5 [30]) [30] 16 (myosin light chain, 25 C, pH 7.6, isolated [28]) [28] 19 (myosin light chain, 25 C, pH 7.6, bound to myosin [28]) [28] 88 (myosin light chain, 25 C, pH 7.6, isolated, freshly prepared [28]) [28]

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Specific activity (U/mg) 0.00615 [18] 0.3 [26] 0.47 [40] 1.8 ( myosin light chain, isolated [35]) [35, 44] 2.51 ( myosin light chain, in native myosin [35]) [35] 3.1 [30] 5.4 ( rabbit uterine myosine [38]) [38] 6 [42, 43, 44] 6.1 [32] 7.7 ( turkey gizzard myosine [38]) [38] 7.9 [36, 39, 44] 8.1 [32] 13 ( BpaKKRAARATSNVFA as substrate [68]) [68] 18.5 [34] 19.9 ( KKRAARATSNVFA as substrate [68]) [68] 24 ( skeletal muscle [28,44]) [28, 44] 25 [27] 33 [45] Additional information ( 1280 pmol/min/pmol [70]; quantification of enzyme activity using a Ca2+ /calmodulin-dependent fluorescent biosensor MLCK in vitro or in vivo, overview [81]) [70, 81, 91, 96, 98] Km-Value (mM) 0.000002 (calmodulin, 30 C, pH 6.8 [35]; 30 C, pH 7.5 [40]) [35, 40] 0.004 (Dictyostelium myosin, 22 C, pH 7.5 [18]) [18] 0.004 (myosin, myosin from Dictyostelium [18]) [18] 0.005 (myosin light chain, 24 C, pH 7.3 [42]) [42, 43] 0.005-0.0095 (myosin light chain, 30 C, pH 7.2 [36,37]) [19, 36, 37, 45] 0.0067 (myosin regulatory light chain, pH 7, M968P [71]) [71] 0.0075 (BpaKKRAARATSNVFA, 25 C, pH 7, Bpa is the photoreactive amino acid p-benzoylphenylalanine [68]) [68] 0.0084 (KKRAARATSNVFA, 25 C, pH 7 [68]) [68] 0.011 (myosin regulatory light chain, pH 7, A986P [71]) [71] 0.011-0.02 (myosin light chain, 30 C, pH 7 [34]) [34] 0.014 (myosin regulatory light chain, pH 7, wild type [71]) [71] 0.0156 (Limulus myosin light chain, 25 C, pH 7.5 [48]) [48] 0.018 (myosin light chain, 23-25 C, pH 7.5 [30]; 30 C, pH 7.5 [40]) [30, 40] 0.019 (myosin light chain, 25 C, pH 7.6, bound to myosin [28]) [28] 0.02-0.027 (turkey gizzard myosin light chain, 30 C, pH 7 [39]; 30 C, pH 6.8 [35]; 30 C, pH 7.6, ATP [31]) [31, 35, 39] 0.04 (turkey gizzard myosin light chain, pH 7.5, myometrium enzyme [38]) [38]

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0.05 (ATP, 24 C, pH 7.3 [42]) [42, 43] 0.05-0.063 (bovine cardiac muscle myosin light chain) [45] 0.05-0.063 (isolated myosin light chain, 25 C, pH 7.6 [28]) [28] 0.073 (ATP, 30 C, pH 7.5 [40]) [40] 0.075 (ATP) [37] 0.094-0.096 (skeletal muscle myosin light chain) [45] 0.1-0.2 (rabbit white skeletal muscle myosin P-light chain, 27 C, pH 7.6 [27]) [27] 0.11 (kemptamide, 30 C, pH 6.8 [35]) [35] 0.121 (ATP, 23-25 C, pH 7.5 [30]) [30] 0.167 (ATP) [45] 0.175 (ATP, 30 C, pH 8 [33]) [33] 0.22 (ATP, 30 C, pH 7 [34]) [34] 0.224 (ATP) [45] Additional information ( in the presence of wortmannin [51]; kinetic constants for enzymes from various sources with different myosin light chains as substrates [56]) [51, 56] Ki-Value (mM) Additional information ( Ki values of the pseudosubstrates in nanoto micromolar range [4]) [4] pH-Optimum 6.5 [27] 7 ( assay at [81,82]) [81, 82] 7-8 [26] 7.5 ( assay at [83,91,93]) [83, 91, 93] 7.8-8 [47] 8.1 [33] pH-Range 5.7-8.2 ( about half-maximal activity at pH 5.7 and 8.2, with a small shoulder of 77% of maximal activity at 7-7.5 [27]) [27] 6.3-9.2 ( about half-maximal activity at pH 6.3 and 9.2 [28]) [28] 6.8-8.8 ( about half-maximal activity at pH 6.8 and about 75% of maximal activity at pH 8.8 [33]) [33] Temperature optimum ( C) 22 ( assay at [18,38]) [18, 38] 23-25 ( assay at [30]) [30] 24 ( assay at [42]) [42] 25 ( assay at [26,27,28]) [26, 27, 28] 28 ( assay at [51,54]) [51, 54] 30 ( assay at [26, 33, 34, 35, 40, 50, 82, 83, 93]) [26, 33, 34, 35, 40, 50, 82, 83, 93] 37 ( assay at [85,91]) [85, 91]

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4 Enzyme Structure Molecular weight 34000 ( gel filtration [18]) [18] 37000 ( PAGE, 2 forms of myosin light chain kinase [48]) [48] 39000 ( PAGE, 2 forms of myosin light chain kinase [48]) [48] 77000 ( gel filtration [27]) [27] 85000 ( gel filtration [33]) [33] 103000 ( sedimentation equilibrium method [28]) [28] 108000 ( smooth muscle isozyme [88]) [88] 108000-125000 ( short myosin light chain kinase [80]) [80] 124000 ( sedimentation equilibrium centrifugation [42,43,56]) [42, 43, 56] 125700 ( calculated from sequence of DNA [19]) [19] 127000 ( sucrose density gradient centrifugation [35]) [35] 130000 ( gel filtration [42]) [42] 130000-150000 ( smooth muscle isozyme [88]) [88] 150000 ( gel filtration and sedimentation studies [31]) [31, 82] 155000 [25] 210000 ( endothelial isozyme [88]; long myosin light chain kinase [80]) [79, 80, 88] 211000 ( deduced from nucleotide sequence [21]) [21] 214000 ( endothelial isozyme [88]) [88] 926000 ( deduced from nucleotide sequence, stretchin-MLCK [66]) [66] Additional information ( amino acid sequence of an active fragment of rabbit skeletal muscle myosin light chain kinase [8]; amino acid sequence of rabbit skeletal muscle myosin light chain kinase [9]; different molecular weights may be due to high sensitivity to proteolysis during purification [56]; amino acid composition of rabbit [28]; relative masses of various animal skeletal muscle enzymes [56]) [8, 9, 28, 32, 42, 47, 56] Subunits ? ( SDS-PAGE [38]; x * 160000, SDS-PAGE [36]; x * 105000, SDS-PAGE [30]; x * 135000, SDS-PAGE [36]; x * 94000, SDS-PAGE [34]; x * 130000, SDS-PAGE [39]; x * 92000, SDS-PAGE [26]; x * 152000, SDS-PAGE [35]; x * 136000, SDSPAGE, enzyme from smooth muscle [19]; x * 138000, SDS-PAGE [40]; x * 152000, SDS-PAGE, recombinant enzyme [19]; x * 155000, SDS-PAGE [19]; x * 214000, SDS-PAGE, from endothelium [57]; x * 190000, recombinant Ca2+ /calmodulin-dependent fluorescent biosensor MLCK, SDS-PAGE [81]; x * 190000, recombinant enzyme mutant MLCK1745, SDS-PAGE, x * 210000, wild-type enzyme and mutant MLCKATPdel, SDS-PAGE [85]) [19, 26, 30, 34, 35, 36, 38, 39, 40, 57, 81, 85] monomer ( 1 * 130000, SDS-PAGE [32, 42, 43, 56]; 1 * 34000, SDS-PAGE [18]; 1 * 77000, SDS-PAGE [27];

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1 * 85000, SDS-PAGE [33]; 1 * 94000, SDS-PAGE [28]; 1 * 214000, SDS-PAGE, endothelial enzyme [21]; 1 * 37000, SDS-PAGE 2 forms of myosin light chain kinase [48]; 1 * 39000, SDS-PAGE, 2 forms of myosin light chain kinase [48]) [18, 21, 27, 28, 32, 33, 40, 42, 43, 48, 56] Additional information ( the carboxyl terminus of the smooth muscle myosin light chain kinase is expressed as an independent protein, telokin [20]; gel electrophoresis in various buffers gives different molecular weights [28]; multienzyme complex with smooth muscle myosin light chain phosphatase [64]; skeletal muscle myosin light chain kinases from different species share more identity than skeletal muscle and smooth muscle myosin light chain kinases from the same species [46]; skeletal muscle enzyme structure: overall asymmetric shape, globular head and tail region [47]; the high molecular weight endothelial enzyme is stably associated to a complex containing p60src and 80000 cortactin [73]; different molecular weights may be due to high sensitivity to proteolysis during purification [56]; MLCK-210 contains an additional actin-binding domain at the Nterminus [79]; the endothelial isozyme EC MLCK contains a unique Nterminal sequence which is a target for upregulation by signaling cascade components such as p60src, EC MLCK splice variants doamin structure [87]; the endothelial isozyme possesses a catalytic domain including the actin-binding domain and the calmodulin binding domain, like the smooth muscle isozyme, but also a protein-protein interaction domain including SH2 and SH3 domains [88]) [20, 28, 46, 47, 56, 64, 73, 79, 87, 88] Posttranslational modification phosphoprotein ( diffential phosphorylation by Aurora B on serine residues during interphase and mitosis has regulatory function, phosphorylation sites for Aurora B on the enzyme, overview [80]; diffential phosphorylation by Aurora B on serine residues, e.g. in the enzymes IgG domain, during interphase and mitosis has regulatory function, phosphorylation sites for Aurora B on the enzyme, overview [80]; eotaxin induces enzyme phosphorylation by serine/threonine protein kinases e.g. by MAP kinases ERK1/2 and p38 at Thr43, phosphorylation is required for activation of the enzyme [82]; the enzyme is 140fold activated through phosphorylation at Thr166 by a recombinant constitutively active Ca2+ /calmodulin-dependent protein kinase kinase, the enzyme performs autophosphorylation at Thr289, subsequent to Thr166 phosphorylation by the protein kinase kinase, and at several serine residues, leading to release of the autoinhibitory domain from the catalytic core, identification of phosphorylation sites [83]; the enzyme is phosphorylated and activated by mitogen activated protein kinase MAPK [78]) [78, 80, 82, 83]

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5 Isolation/Preparation/Mutation/Application Source/tissue CACO-2 cell ( endothelial cell, 2 isozymes MLCK1 and MLCK2 [84]) [84] CMEC/D3 cell ( a cerebral microvascular endothelial cell line [100]) [100] HT-1080 cell ( a fibrosarcoma cell line [91]) [91] HeLa cell [80] Kupffer cell ( myofibroblast-like stellate cell line, previously called Ito cells, lipocytes, or fat-storing cells [76]) [76] Mat-Ly-Lu cell ( a prostate cancer cell line [94]) [94] Mm5MT cell ( a mammary adenocarcinoma cell line [94]) [94] T-lymphocyte [100] adrenal medulla ( medulla [31]; not rat [19]) [19, 31] amygdala ( lateral [105]) [105] aorta ( thoracic [37]) [19, 37, 79] atrium [77] bladder [38] brain [35, 44, 69, 95, 100, 101, 105] brain endothelium cell line ( a SV40-infected endothelial cell line [95]) [95] breast [58] cardiac muscle ( myocardium [33]) [26, 33, 34, 56, 102] cardiomyocyte ( from embryos, in myofibril precursors and sarcomeric Z-lines, co-localization with myosin IIB [92]) [92] central nervous system [95] colon ( epithelium [103]) [103] egg ( polarized, arrested in MII [78]; at the equator of dividing cells [104]) [78, 104] embryo ( fibroblasts [13]) [13, 99] endothelial cell ( brain [95]) [85, 86, 95, 100] endothelium ( endothelial isozyme EC MLCK [87]; specific isozyme [88]) [21, 57, 73, 84, 87, 88] enterocyte ( well differentiated cells, isozyme MLCK1 [84]) [84] eosinophil [82] epithelial cell [98] epithelium [103] fibroblast ( from embryo [13]) [13] gizzard ( pregnant sheep myometrium, turkey and chicken gizzard enzyme are immunologically related [38]; rat pancreatic and turkey gizzard enzyme are immunologically related [41]) [32, 36, 38, 41, 42, 44, 47, 49, 50, 51, 52, 56, 59, 60, 61, 62, 63, 64, 65] heart ( left ventricle tissue, MLCK occurs in a cross-striated pattern overlapping with the distribution of a-actin [92]; specific cardiac/

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ventricular isozyme cardiac-MLCK [99]; specific cardiac/ventricular isozyme cardiac-MLCK encoded by gene MLCK3, expression analysis in healthy hearts and hearts from patients with heart failure [99]) [77, 92, 99] hepatocyte [89] hippocampus ( cultured hippocampal neurons [101]) [23, 101] ileum ( ileal epithelial MLCK expression is mildly upregulated in inactive inflammatory bowel disease, and highly upregulated in active IBD [103]) [103] intestine ( epithelium, expression of MLVK is upregulated by inflammatory bowel disease [103]) [84, 103] jejunum [84] kidney ( not rat [19]; expression analysis of MLCK in healthy and streptozotocin-induced diabetic rats, expression in glomerulus, renal tubule and glomerular arteriolar, glomerulus expression is increased in diabetic rats, overview [96]) [19, 67, 96] leukocyte ( polymorphonuclear and alveolar [29]) [29] liver ( not rat [19]; distribution analysis [89]) [19, 89] muscle ( skeletal muscle [6,8,9,16]; smooth muscle [11]; telokin, the carboxyl terminus of the smooth muscle myosin light chain kinase which is expressed as an independent protein, is expressed in some smooth muscle tissues but not in aortic smooth muscle or in any non-muscle tissues [20]; striated, a distinct MLCK isozyme [92]) [6, 8, 9, 11, 12, 16, 19, 20, 92] myocardium ( adult, MLCK occurs in a cross-striated pattern overlapping with the distribution of a-actin [92]) [92, 99] myometrium ( pregnant sheep myometrium, turkey and chicken gizzard enzyme are immunologically related [38]) [38, 39, 44] neuron ( cultured hippocampal neurons [101]) [101] oocyte [78] pancreas ( rat pancreatic and turkey gizzard enzyme are immunologically related [40]) [40, 44] platelet [30, 43, 44, 56] rumen [32] skeletal muscle ( pectoralis muscle [45]; red and white [56]; back and hindlegs [44]) [3, 4, 26, 27, 28, 44, 45, 46, 56, 58, 68, 97, 102] skin [65] smooth muscle ( arterial [36, 44]; uterus, trachea, aorta, ileum, gizzard [19]; specific isozyme [88]; long isozyme L-MLCK and short isozyme S-MLCK [93]; specific smooth muscle isozyme smMLCK encoded by gene MLCK2 [99]) [3, 4, 19, 36, 44, 46, 47, 56, 58, 59, 60, 63, 64, 65, 69, 71, 75, 81, 88, 90, 93, 99, 102] stomach [25, 38, 47] telson ( muscle [48]) [48] thyroid gland [56] trachea [38]

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uterus ( not rat [19]) [19] vascular endothelial cell ( the long isoform of MLCK, MLCK-210, is the predominant isoform expressed in vascular endothelial cells [106]) [106] Additional information ( the human MLCK gene yields multiple nonmuscle MLCK isoforms by alternative splicing of its transcribed mRNA precursor with differential distribution of these isoforms in various human tissues and cells [22]; myosin light chain kinases in smooth muscle and non-muscle tissues are the same protein [19]; expression profile of isozyme MLCK1 [84]; expression profile of isozymes MLCK1 and MLCK2 [84]; subcellular localization [104]; tissue dependent MLCK expression analysis of 26 inflammatory bowel disease patients [103]; tissue distribution analysis, overview [99]; two isozymes: the endothelial, long or nonmuscle 220-kDa MLCK and a short, smooth muscle 130-kDa MLCK, mechanism of regulation of tissue-specific mylk gene expression, overview [90]) [19, 22, 84, 90, 99, 103, 104] Localization actin filament ( F-actin-associated along cellular stress fibres [36]) [36] actomyosin ( associated [30]) [30] axon [101] cytoskeleton [92] cytosol [91] microtubule ( astral [104]) [104] myofibril ( associated [32,42,43,44]) [32, 42, 43, 44, 92] perinuclear space ( isozyme MLCK2 [84]) [84] sarcoplasm [26, 27] soluble [33, 35, 39, 40] synapse ( of lateral amygdala [105]) [105] Additional information ( isozyme MLCK1 is predominantly located in the perijunctional actomyosin ring in villus enterocytes [84]; peripherally in hepatocytes, rarely in cytoplasm [89]; subcellular localization study of MLCK in embryonic cardiomyocytes, overview [92]) [84, 89, 92] Purification [45, 46, 58, 59, 60, 61, 62, 64] (purified to homogeneity from a number of vertebrate muscles and partially purified from non-muscle tissues) [56] [32, 43, 44] (affinity chromatography on calmodulin-Sepharose) [42] (purified to homogeneity from a number of vertebrate muscles and partially purified from non-muscle tissues) [56] (purified to homogeneity from a number of vertebrate muscles and partially purified from non-muscle tissues) [56] [44] (partial, affinity chromatography on calmodulin-Sepharose) [30]

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(partially from eosinophils) [82] (purified to homogeneity from a number of vertebrate muscles and partially purified from non-muscle tissues) [56] (recombinant GFP-fusion enzyme from HeLa cells) [80] (recombinant GST-fusion isozyme EC MLCK by affinity chromatgraphy) [87] (recombinant wild-type and mutant enzymes from transfected bovine endothelial cells) [86] (partial) [40, 44] (purified to homogeneity from a number of vertebrate muscles and partially purified from non-muscle tissues) [56] [39] [44] (purified to homogeneity from a number of vertebrate muscles and partially purified from non-muscle tissues) [56] (recombinant GST-tagged C-terminal enzyme fragment by glutathione affinity chromatography) [75] [27, 29, 44, 45] (affinity chromatography on calmodulin-Sepharose) [28] (partial) [26] (recombinant His-tagged wild-type and mutant isozymes from Escherichia coli strain Bl21(DE3) by nickel affinity chromatograpyh) [93] [38] (purified to homogeneity from a number of vertebrate muscles and partially purified from non-muscle tissues) [56] [48] [17, 18] Crystallization (twitchin kinase, bilobal structure analysis) [3] (isolution structure of a calmodulin-target peptide complex by multidimensional NMR) [7] Cloning (expression in BL21(DE3) cells as GFP fusion protein) [72] (expression of His6-tagged MLCK-210 nad His-tagged N452-MLCK in Escherichia coli, expression of GFP-tagged MLCK-210 and GFP-tagged N452-MLCK in CV-1 African green monkey kidney cells) [79] (skeletal muscle enzyme) [46] (transient expression as GFP fusion protein in A7r5, HeLa, NIH3T3 or COS-7 cells) [72] (expression of wild-type and dominant-negative MLCK in untransformed and Ras-transformed MCF-10A cells) [98] (gene mylk1, located on chromosome 16, contains at least 31 exons, DNA and amino acid sequence determination and analysis, genetic structure and regulation, the serum response factor myocardin plays a central role in regulating mylk1 gene expression, a highly conserved CArG element within 130kDa MLCK intron 1 is important for promoter activity binding activation

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factors like myocardin, homebox proteins, GATA family members, and the thyrotroph embryonic factor, regulation model, overview) [90] (DNA sequence determination and analysis, overexpression in Escherichia coli strain XL-1 Blue) [89] (expression as His-tagged protein) [73] (expression of GFP-tagged enzyme in HeLa cells) [80] (expression of calmodulin-independent mutant MLCK1745 and of MLVKATPdel mutant in African green monkey kidney CV1 fibroblasts as V5-epitope- and His-tagged proteins) [85] (expression of calmodulin-independent mutant MLCK1745, lacking the C-terminal part including the autoinhibitory domain, and the myosin- and the calmodulin-binding sites, and of MLVKATPdel mutant with a defective ATP-binding site in bovine pulmonary artery endothelial cells BPAEC as V5epitope-tagged proteins) [86] (expression of epitope-tagged endothelial isozyme in endothelial cells, expression of GST-fusion isozyme EC MLCK in bacteria, expression of endothelial iszyme EC MLCK and macrophage migration inhibition factor MIF in the yeast two-hybrid system, overview) [87] (genes MYLK2 and MYLK3, DNA and amino acid sequence determination and analysis, expression analysis in heart, sequence comparisons) [99] (stable expression of a constructed Ca2+ /calmodulin-dependent fluorescent biosensor MLCK in HEK-293 cells) [81] (expression of a C-terminal enzyme fragment comprising residues 8601176 as GST-fusion protein in Escherichia coli strain Bl21(DE3), the GST-tag slightly reduces the activity of the recombinant enzyme fragment compared to the untagged fragment) [75] (expression in A7r5 rat thoracic aorta smooth muscle cells as GFP-fusion protein) [70] (expression in COS-7 african green monkey kidney cells) [71] (expression in COS-cells) [19] (expression in Sf9 insect cells) [68] (expression in transgenic mice, expression in COS cells) [97] (expression of the long isozyme l-MLCK in murine NIH3T3 cells, expression of GFP-tagged wild-type and mutant isozymes in COS-7 cells and as His-tagged proteins in Escherichia coli strain BL21(DE3)) [93] (genes MYLK2 and MYLK3, DNA and amino acid sequence determination and analysis, expression analysis in heart) [99] (cDNA, expressed in COS cells) [6] [15] (domain organization of chicken gizzard myosin light chain kinase deduced from a cloned cDNA) [11] (isolation of cDNA) [16] (the full-length enzyme as well as a truncated form lacking the putative auto-inhibitory domain are expressed in bacterial cells) [17] (expression in COS cells) [19] (telokin, the carboxyl terminus of the smooth muscle myosin light chain kinase which is expressed as an independent protein) [20]

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[21, 23] (DNA and amino acid sequence determination and analysis, expressionin HEK-293 cells, co-expression with TRPC5 from Drosophila melanogaster) [102] (isolation of cDNA) [25] [5] (DNA and amino acid sequence determination and analysis, expressionin HEK-293 cells, co-expression with TRPC5 from Drosophila melanogaster) [102] (DNA sequence determination and analysis of splicing variant 1 of long endothelial enzyme, large scale expression of endothelial isozyme MLCK1 in Spodoptera frugiperda Sf9 cells via Baculovirus transfection system) [84] (DNA sequence determination and analysis of splicing variant 2 of long endothelial enzyme, large scale expression of endothelial isozyme MLCK2 in Spodoptera frugiperda Sf9 cells via Baculovirus transfection system) [84] Engineering A27F/A29R/A31R/A32F ( mutant enzyme with defective ATP binding site, mutant leads to nearly unaltered MLC phosphorylation activity and altered morphology in transfected CV1 cells [85]) [85] A983P ( dramatic increase in Ca2+ required for half-maximal activity [71]) [71] A986P ( significantly increase in Ca2+ required for half-maximal activity, slightly decreased KM for regulatory light chain [71]) [71] M968P ( 10% Ca2+ /calmodulin independent activity of total activity, decreased KM for regulatory light chain [71]) [71] Additional information ( serial carboxyterminal deletions of the regulatory and catalytic domains are constructed and expressed in COS cells. The truncated kinases have no detectable myosin light chain kinase activity [6]; deletion of DRFXXL motifs leads to a worse binding to actin filaments especially in the presence of Mg2+ [72]; construction of an enzyme mutant MLCK1745 which lacks the C-terminal amino acids including the autoinhibitory domain, and the myosin- and the calmodulin-binding sites, the MLCK1745 mutant increases the TNFa response to upregulate NFkB activity in transfected endothelial cells, MLCKATPdel mutant enzyme with defective ATP binding site inhibits TNFa-induced NFkB-activation activity in transfected endothelial cells [86]; construction of an enzyme mutant MLCK1745 which lacks the C-terminal amino acids including the autoinhibitory domain, and the myosin- and the calmodulin-binding sites, the MLCK1745 mutation leads to increased growth rates of transfected CV1 fibroblasts and an increase in basal level MLC phosphorylation compared to untransfected cells, stress fiber formation is unaffected by the mutation [85]; construction of eMLCK or smMLCK knockout mutant mice by genetic or chemical methods, overview [88]; silencing of MLCK1 via specific siRNA increases transepithelial resistance in Caco-2 cells [84]; construction of a dominant-negative MLCK mutant [98]; construction of transgenic mice that express an skeletal muscle-

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MLCK, i.e. skMLCK, CaM biosensor in skeletal muscle to determine whether skMLCK or calmodulin is limiting to twitch force potentiation. Three transgenic mouse lines exhibited up to 22-fold increases in skMLCK protein expression in fast-twitch extensor digitorum longus muscle containing type IIa and IIb fibers, with comparable expressions in slow-twitch soleus muscle containing type I and IIa fibers, overview [97]; construction of truncation mutants of long and short MLCKs [93]; expression of a dominant-negative mutant of MLCK inhibits the TRPC5 channel activity, revealing an essential role of MLCK in maintaining TRPC5 channel activity [102]; knockdown of cardiac-MLCK by specific siRNAs decreases cardiac-MLCK phosphorylation and impairs epinephrine-induced activation of sarcomere reassembly, knockdown of z-cardiac-MLCK expression using morpholino antisense oligonucleotides results in dilated cardiac ventricles and immature sarcomere structures [99]; long isozyme MLCK-210-deficient mice display a significantly improved survival with a greatly attenuated microvascular hyperpermeability response to albumin and fluid [106]) [6, 72, 84, 85, 86, 88, 93, 97, 98, 99, 102, 106] Application medicine ( therapeutic inhibition via specific chemical inhibitors of endothelial isozyme, i.e. 11-(3-chloro-6-immino-6H-pyridazin-1-yl)-undecanoic acid (6-phenyl-pyridazin-3-yl)-amide, represents an important new target for the treatment of inflammatory lung disease with less side effects than other therapies [88]; long isozyme MLCK-210 is a potential therapeutic target in the treatment of burn edema [106]) [88, 106]

6 Stability pH-Stability 5 ( rapid inactivation below [27,28]; 30-60 min, about 50% loss of activity [33]) [27, 28, 33] 6.3-8 ( stable in 10% sucrose [27]) [27] General stability information , EGTA prevents Ca2+ -dependent proteolysis during initial purification [42] , MgCl2 is critical for kinase extraction from myofibrils [42] , glycerol and Tween 40 stabilize [35] , protease inhibitors with broad specificity and glycerol stabilize during initial purification, unstable to further purification [31] , unstable upon lyophilization [28, 35] , repeated freeze-thawing decreases activity [43, 44] , protease inhibitors stabilize during purification [38, 40, 43] Storage stability , -30 C, 30% loss of activity within 3 weeks [42] , -70 C, at least 6 months [42]

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, -70 C, 1% bovine serum albumin, more than 2 months [40] , -20 C, quite unstable on storage [39] , -20 C, in 5% w/v sucrose, several weeks [44] , proteolysis occurs even on storage at -80 C, myometrium enzyme [38]

References [1] Boeckmann, B.; Bairoch, A.; Apweiler, R.; Blatter, M.C.; Estreicher, A.; Gasteiger, E.; Martin M.J.; Michoud, K.; O’Donovan, C.; Phan, I.; Pilbout, S.; Schneider, M.: The SWISS-PROT protein knowledgebase and its supplement TrEMBL. Nucleic Acids Res., 31, 365-370 (2003) [2] Deloukas, P.; Matthews, L.H.; Ashurst, J.; Burton, J.; Gilbert, J.G.; et al.: The DNA sequence and comparative analysis of human chromosome 20. Nature, 414, 865-871 (2001) [3] Kemp, B.E.; Parker, M.W.; Hu, S.; Tiganis, T.; House, C.: Substrate and pseudosubstrate interactions with protein kinases: determinants of specificity. Trends Biochem. Sci., 19, 440-444 (1994) [4] Kemp, B.E.; Pearson, R.B.; House, M.: Pseudosubstrate-based peptide inhibitors. Methods Enzymol., 201, 287-304 (1991) [5] Davis, J.S.; Hassanzadeh, S.; Winitsky, S.; Lin, H.; Satorius, C.; Vemuri, R.; Aletras, A.H.; Wen, H.; Epstein, N.D.: The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation. Cell, 107, 631-641 (2001) [6] Herring, B.P.; Stull, J.T.; Gallagher, P.J.: Domain characterization of rabbit skeletal muscle myosin light chain kinase. J. Biol. Chem., 265, 1724-1730 (1990) [7] Ikura, M.; Clore, G.M.; Gronenborn, A.M.; Zhu, G.; Klee, C.B.; Bax, A.: Solution structure of a calmodulin-target peptide complex by multidimensional NMR. Science, 256, 632-638 (1992) [8] Takio, K.; Blumenthal, D.K.; Edelman, A.M.; Walsh, K.A.; Krebs, E.G.; Titani, K.: Amino acid sequence of an active fragment of rabbit skeletal muscle myosin light chain kinase. Biochemistry, 24, 6028-6037 (1985) [9] Takio, K.; Blumenthal, D.K.; Walsh, K.A.; Titani, K.; Krebs, E.G.: Amino acid sequence of rabbit skeletal muscle myosin light chain kinase. Biochemistry, 25, 8049-8057 (1986) [10] Collinge, M.; Matrisian, P.E.; Zimmer, W.E.; Shattuck, R.L.; Lukas, T.J.; Van Eldik, L.J.; Watterson, D.M.: Structure and expression of a calcium-binding protein gene contained within a calmodulin-regulated protein kinase gene. Mol. Cell. Biol., 12, 2359-2371 (1992) [11] Guerriero, V., Jr.; Russo, M.A.; Olson, N.J.; Putkey, J.A.; Means, A.R.: Domain organization of chicken gizzard myosin light chain kinase deduced from a cloned cDNA. Biochemistry, 25, 8372-8381 (1986) [12] Olson, N.J.; Pearson, R.B.; Needleman, D.S.; Hurwitz, M.Y.; Kemp, B.E.; Means, A.R.: Regulatory and structural motifs of chicken gizzard myosin light chain kinase. Proc. Natl. Acad. Sci. USA, 87, 2284-2288 (1990)

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[96] Zhu, H.; Zhang, X.; Zuo, L.; Zhou, Q.; Gui, S.; Wei, W.; Wang, Y.: Expression of myosin light chain kinase in kidney of streptozotocin-induced diabetic rats. Int. J. Mol. Sci., 7, 510-518 (2006) [97] Ryder, J.W.; Lau, K.S.; Kamm, K.E.; Stull, J.T.: Enhanced skeletal muscle contraction with myosin light chain phosphorylation by a calmodulinsensing kinase. J. Biol. Chem., 282, 20447-20454 (2007) [98] Connell, L.E.; Helfman, D.M.: Myosin light chain kinase plays a role in the regulation of epithelial cell survival. J. Cell Sci., 119, 2269-2281 (2006) [99] Seguchi, O.; Takashima, S.; Yamazaki, S.; Asakura, M.; Asano, Y.; Shintani, Y.; Wakeno, M.; Minamino, T.; Kondo, H.; Furukawa, H.; Nakamaru, K.; Naito, A.; Takahashi, T.; Ohtsuka, T.; Kawakami, K.; Isomura, T.; Kitamura, S.; Tomoike, H.; Mochizuki, N.; Kitakaze, M.: A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart. J. Clin. Invest., 117, 2812-2824 (2007) [100] Afonso, P.V.; Ozden, S.; Prevost, M.C.; Schmitt, C.; Seilhean, D.; Weksler, B.; Couraud, P.O.; Gessain, A.; Romero, I.A.; Ceccaldi, P.E.: Human bloodbrain barrier disruption by retroviral-infected lymphocytes: role of myosin light chain kinase in endothelial tight-junction disorganization. J. Immunol., 179, 2576-2583 (2007) [101] Tokuoka, H.; Goda, Y.: Myosin light chain kinase is not a regulator of synaptic vesicle trafficking during repetitive exocytosis in cultured hippocampal neurons. J. Neurosci., 26, 11606-11614 (2006) [102] Shimizu, S.; Yoshida, T.; Wakamori, M.; Ishii, M.; Okada, T.; Takahashi, M.; Seto, M.; Sakurada, K.; Kiuchi, Y.; Mori, Y.: Ca2+ -calmodulin-dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK293 cells. J. Physiol., 570, 219-235 (2006) [103] Blair, S.A.; Kane, S.V.; Clayburgh, D.R.; Turner, J.R.: Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease. Lab. Invest., 86, 191-201 (2006) [104] Lucero, A.; Stack, C.; Bresnick, A.R.; Shuster, C.B.: A global, myosin light chain kinase-dependent increase in myosin II contractility accompanies the metaphase-anaphase transition in sea urchin eggs. Mol. Biol. Cell, 17, 4093-4104 (2006) [105] Lamprecht, R.; Margulies, D.S.; Farb, C.R.; Hou, M.; Johnson, L.R.; LeDoux, J.E.: Myosin light chain kinase regulates synaptic plasticity and fear learning in the lateral amygdala. Neuroscience, 139, 821-829 (2006) [106] Reynoso, R.; Perrin, R.M.; Breslin, J.W.; Daines, D.A.; Watson, K.D.; Watterson, D.M.; Wu, M.H.; Yuan, S.: A role for long chain myosin light chain kinase (MLCK-210) in microvascular hyperpermeability during severe burns. Shock, 28, 589-595 (2007)

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Phosphorylase kinase

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1 Nomenclature EC number 2.7.11.19 Systematic name ATP:phosphorylase-b phosphotransferase Recommended name phosphorylase kinase Synonyms DphK-g [23] GPK [90] glycogen phosphorylase kinase KPI-2 kinase [99] PSK-C3 PhK [3, 5, 88, 89, 91, 92, 93, 94, 95, 98, 100, 101, 102] phosphorylase b kinase [88, 92] SkM Phk [88] dephosphophosphorylase kinase glycogen phosphorylase b kinase [90] kinase kinase/phosphatase/inhibitor-2 [99] kinase, phosphorylase (phosphorylating) phosphorylase B kinase GAMMA catalytic chain [23] phosphorylase B kinase g catalytic chain, skeletal muscle isoform [6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 22] phosphorylase B kinase g catalytic chain, testis/liver [21] phosphorylase B kinase g catalytic chain, testis/liver isoform [15, 18, 19, 20, 24] phosphorylase kinase [1] phosphorylase kinase-b [97] transmembrane Ser/Thr kinase KPI-2 [99] Additional information ( formerly EC 2.7.1.38 [91]) [91] CAS registry number 9001-88-1

89

Phosphorylase kinase

2.7.11.19

2 Source Organism



















Gallus gallus (no sequence specified) [34, 64, 66, 75] Cavia porcellus (no sequence specified) [34] Mammalia (no sequence specified) [2, 3] eukaryota (no sequence specified) [1, 5] Mus musculus (no sequence specified) [4,34,39,80,83,92] Homo sapiens (no sequence specified) [4,87,97,99,100] Rattus norvegicus (no sequence specified) [34,38,43,48,61,76] Saccharomyces cerevisiae (no sequence specified) ( cDNA fragment coding for peptide Ala21-Ser538 of the full-length MT1-MMP [34, 52]) [34, 52] Bos taurus (no sequence specified) [34,40,54,56] Oryctolagus cuniculus (no sequence specified) [4, 7, 11, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 46, 47, 49, 50, 51, 53, 55, 56, 57, 58, 60, 62, 63, 65, 67, 68, 69, 70, 71, 72, 73, 74, 77, 78, 79, 81, 82, 84, 85, 86, 88, 91, 92, 93, 94, 95, 96, 98, 101, 102] Calliphoridae (no sequence specified) ( alkB4 gene from Rhodococcus Q15 [39]) [39] Canis familiaris (no sequence specified) [26] Squalus acanthias (no sequence specified) [34, 39, 42] Rana temporaria (no sequence specified) [90] Scorpaena porcus (no sequence specified) [90] Hyalophora cecropia (no sequence specified) [59] Oryctolagus cuniculus (UNIPROT accession number: P00518) [6, 7, 8, 9, 10, 11] Mus musculus (UNIPROT accession number: P07934) [12, 13, 14] Rattus norvegicus (UNIPROT accession number: P13286) [16, 17] Homo sapiens (UNIPROT accession number: P15735) [15, 18, 19, 20] Rattus norvegicus (UNIPROT accession number: P31325) [21] Homo sapiens (UNIPROT accession number: Q16816) [22, 89] Mus musculus (UNIPROT accession number: Q9DB30) [24] Drosophila melanogaster (UNIPROT accession number: Q9VYV7) [23] Rattus norvegicus (UNIPROT accession number: Q64649) [88] Homo sapiens (UNIPROT accession number: P46020) [89]

3 Reaction and Specificity Catalyzed reaction 2 ATP + phosphorylase b = 2 ADP + phosphorylase a ( mechanism [46,72,78]; catalytic aspartate residue [3]) Reaction type phospho group transfer

90

2.7.11.19

Phosphorylase kinase

Natural substrates and products S ATP + Ca2+ -ATPase ( activation of Ca2+ -transporting ATPase, EC 3.6.1.3, accelerating the Ca2+ transport in the sarcoplasmic reticulum of muscle, regulatory role, effect of the enzyme on Ca2+ transport and enzyme kinetics [90]; activation of Ca2+ -transporting ATPase, EC 3.6.3.8, accelerating the Ca2+ transport in the sarcoplasmic reticulum of muscle, regulatory role, effect of the enzyme on Ca2+ transport and enzyme kinetics [90]) (Reversibility: ?) [90] P ADP + phospho-Ca2+ -ATPase S ATP + a protein (Reversibility: ?) [1, 2, 4] P ADP + a phosphoprotein S ATP + glycogen phosphorylase ( conversion to an AMP-independent form, key enzyme of neural and hormonal control of glycogen metabolism [53]) (Reversibility: ?) [53] P ? S ATP + glycogen phosphorylase b (Reversibility: ?) [96, 98, 102] P ADP + phosphorylated glycogen phosphorylase b S ATP + glycogen phosphorylase b ( activation of glycogen phosphorylase b, EC 2.4.1.1, accelerating the glycogenolysis in muscle, regulatory role [90]; activation of glycogen phosphorylase which acts as a Ca2+ -dependent blood glucose sensor liberating glucose from glycogen as needed, involved in regulation of the glycogen phosphorylase [87]; key enzyme in conversion of glycogen to glucose in skeletal muscle, regulation of enzyme activity during apoptosis, overview [92]; regulatory enzyme in the activation cascade of glycogenolysis [94]) (Reversibility: ?) [87, 90, 92, 93, 94] P ADP + glycogen phosphorylase a S ATP + glycogen synthase ( key enzyme of neural and hormonal control of glycogen metabolism [53]; decreases activity of this substrate [43]; conversion to a glucose 6-phosphate dependent form [53,55]) (Reversibility: ?) [43, 53, 55] P ? S ATP + phosphorylase b (Reversibility: ?) [99] P ADP + phosphorylated phosphorylase b S ATP + phosphorylase b ( i.e. EC 2.4.1.1 or glycogen phosphorylase [53,78]; involved in glycogenolysis [34]; stimulates glycogenolysis in skeletal muscle [43]; regulates conversion of inactive phosphorylase b into active phosphorylase a [43,78]; vital process for short term energy supply to the cell, located at an interface between signalling and metabolic pathway [78]; involved in glycogen metabolism regulation [25]; key enzyme of neural and hormonal control of glycogen metabolism [53]) (Reversibility: ?) [25, 34, 43, 53, 78] P ? S ATP + phosphorylase b ( the enzyme interacts with glycogen and phosphorylase b [91]) (Reversibility: ?) [3, 4, 5, 89, 91] P ADP + phosphorylase a

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Phosphorylase kinase

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S ATP + protein ( in the presence of Ca2+ /calmodulin, the isoform PhK-g T of the catalytic subunit is able to efficiently phosphorylate glycogen phosphorylase and convert it from an inactive to an active form [21]) (Reversibility: ?) [21] P ATP + phosphoprotein S Additional information ( key enzyme in glycogen metabolism [16]; enzyme is required in early embryonic processes, such as gastrulation and mesoderm formation [23]; mutations in PHKG2, the catalytic g subunit, are associated with an increased cirrhosis risk [18]; modeling of glycogen phosphorylase regulation by Ca2+ -oscillations, and dephosphorylation and phosphorylation involving the enzyme and a phosphatase, overview [87]; muscle-specific enzyme deficiency causes glycogen storage disease [89]; protein kinases and protein phosphatases regulate enzyme activities in the cell, overview [1]; correlation of gene transcriptional processing and catalytic regulation of PhK subunits, overview [100]; hormonal regulation of KPI-2, kinase KPI-2 reveals reactivity with cystic fibrosis transmembrane conductance regulator and phosphorylase [99]; interaction of flavin adenine dinucleotide, FAD, with rabbit skeletal muscle phosphorylase kinase, FAD prevents the formation of the enzyme-glycogen complex in a cooperative manner, but exerts practically no effect on the phosphorylase kinase activity, the complex of glycogen metabolism enzymes in protein-glycogen particles may function as a flavin depot in skeletal muscle [96]; key enzyme in regulating glycogenolytic flux in skeletal muscle in response to changing energy demands, phosphorylase kinase associates with the cytoskeletal organizing protein Cdc42-interacting protein 4, CIP4, in vivo in skeletal muscle, the cognate binding domain on CIP4 lies between residues 398 and 545, the interaction is independent of the SH3 domain [95]; phosphorylase-b kinase deficient patients, suffering glycogen storage disease GSD IXa, show an accumulation of fat in the liver that resolves with aging, overview [97]; the enzyme complex regulates glycogenolysis [98]) (Reversibility: ?) [1, 16, 18, 23, 87, 89, 95, 96, 97, 98, 99, 100] P ? Substrates and products S ATP + Ca2+ -ATPase ( activation of Ca2+ -transporting ATPase, EC 3.6.1.3, accelerating the Ca2+ transport in the sarcoplasmic reticulum of muscle, regulatory role, effect of the enzyme on Ca2+ transport and enzyme kinetics [90]; activation of Ca2+ -transporting ATPase, EC 3.6.3.8, accelerating the Ca2+ transport in the sarcoplasmic reticulum of muscle, regulatory role, effect of the enzyme on Ca2+ transport and enzyme kinetics [90]) (Reversibility: ?) [90] P ADP + phospho-Ca2+ -ATPase S ATP + Ca2+ -dependent transport ATPase ( rabbit [34]) (Reversibility: ?) [34] P ?

92

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Phosphorylase kinase

S ATP + Lys-Arg-Glu-Gln-Ile-Ser-Val-Arg-Gly-Leu (Reversibility: ?) [82] P ADP + Lys-Arg-Glu-Gln-Ile-(phospho)Ser-Val-Arg-Gly-Leu [82] S ATP + Lys-Arg-Lys-Gln-Ile-Ser-Val-Arg-Gly-Leu (Reversibility: ?) [82] P ADP + Lys-Arg-Lys-Gln-Ile-(phospho)Ser-Val-Arg-Gly-Leu [82] S ATP + Lys-Arg-Lys-Gln-Ile-Ser-Val-Asp (Reversibility: ?) [83] P ? S ATP + Lys-Arg-Lys-Gln-Ile-Ser-Val-Asp-Gly-Ile (Reversibility: ?) [83] P ? S ATP + Lys-Arg-Lys-Glu-Ile-Ser-Val-Arg-Gly-Leu (Reversibility: ?) [82] P ADP + Lys-Arg-Lys-Glu-Ile-(phospho)Ser-Val-Arg-Gly-Leu [82] S ATP + Lys-Glu-Lys-Gln-Ile-Ser-Val-Arg-Gly-Leu (Reversibility: ?) [82] P ADP + Lys-Glu-Lys-Gln-Ile-(phospho)Ser-Val-Arg-Gly-Leu [82] S ATP + Lys-Pro-Val-Thr-Arg-Glu-Ile-Ser-Ile-Arg-NH2 ( i.e. S-peptide [83]) (Reversibility: ?) [83] P ? S ATP + Ser-Asp-Gln-Glu-Lys-Arg-Lys-Gln-Ile-Ser-Val-Asp (Reversibility: ?) [83] P ? S ATP + Ser-Asp-Gln-Glu-Lys-Arg-Lys-Gln-Ile-Ser-Val-Asp-Gly-Ile ( i.e. phosphorylase b peptide (5-18) [83]) (Reversibility: ?) [83] P ? S ATP + a protein ( the phosphorylase kinase phosphorylates proteins and proteolytic fragments thereof, phosphorylation of multiple residues in the substrate sequence by mammary gland casein kinase [2]) (Reversibility: ?) [1, 2, 4, 5] P ADP + a phosphoprotein S ATP + agd subunit complex ( autophosphorylation, by incorporation of phosphate into a subunit [46]) (Reversibility: ?) [46] P ADP + activated agd subunit complex [46] S ATP + casein ( not [38,41,42,64]; very poor substrate [48]; rabbit [34]; k-casein [58,67]) (Reversibility: ?) [34, 38, 41, 42, 48, 58, 64, 67] P ? S ATP + glycogen S peptide ( synthetic peptide corresponding to residues 5-18 of its convertible region [98]) (Reversibility: ?) [98] P ADP + phosphorylated glycogen S peptide S ATP + glycogen phosphorylase ( conversion to an AMP-independent form, key enzyme of neural and hormonal control of glycogen metabolism [53]) (Reversibility: ?) [53] P ? S ATP + glycogen phosphorylase b ( the hexadecameric enzyme complex that catalyzes the phosphorylation and activation of glycogen phosphorylase b [102]) (Reversibility: ?) [96, 98, 102]

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Phosphorylase kinase

2.7.11.19

P ADP + phosphorylated glycogen phosphorylase b S ATP + glycogen phosphorylase b ( activation of glycogen phosphorylase b, EC 2.4.1.1, accelerating the glycogenolysis in muscle, regulatory role [90]; activation of glycogen phosphorylase which acts as a Ca2+ -dependent blood glucose sensor liberating glucose from glycogen as needed, involved in regulation of the glycogen phosphorylase [87]; key enzyme in conversion of glycogen to glucose in skeletal muscle, regulation of enzyme activity during apoptosis, overview [92]; regulatory enzyme in the activation cascade of glycogenolysis [94]) (Reversibility: ?) [87, 90, 92, 93, 94] P ADP + glycogen phosphorylase a S ATP + glycogen synthase ( key enzyme of neural and hormonal control of glycogen metabolism [53]; decreases activity of this substrate [43]; conversion to a glucose 6-phosphate dependent form [53,55]) (Reversibility: ?) [43, 53, 55] P ? S ATP + glycogen synthase ( rabbit phosphorylase kinase [34]; inactivation of skeletal muscle glycogen synthase in the presence or absence of EGTA [38]; glycogen synthase a [55]; phosphorylatable residue: Ser-7 [34,53,55]; at high concentration, from yeast [52]; at high concentration, from rabbit skeletal muscle [38,48]; at the same rate as phosphorylase b [55]) (Reversibility: ?) [34, 38, 43, 48, 52, 53, 55, 58] P ADP + phosphoglycogen synthase S ATP + histone H1 (Reversibility: ?) [58] P ? S ATP + liver dephosphophosphorylase (Reversibility: ?) [26, 37] P ? S ATP + melittin (Reversibility: ?) [79] P ADP + phosphomelittin [79] S ATP + modified phosphorylase b ( modification at AMP-site [32]) (Reversibility: ?) [32] P ? S ATP + myelin basic protein (Reversibility: ?) [67] P ? S ATP + myosin light chain kinase ( rabbit [39]) (Reversibility: ?) [39] P ? S ATP + nonactivated phosphorylase kinase ( not [64]; in the presence of Mg2+ and Ca2+ [59]; presumably only in vitro [34]; i.e. autophosphorylation and autoactivation [34,37,41,42,44,50,60]; phosphorylation sites [83]; ATP can be replaced by dATP or adenosine 5-(3-thiotriphosphate) with 50% and 10% efficiency, respectively [42]; phosphorylates a and b, not g or d subunits [60]) (Reversibility: ?) [34, 37, 41, 42, 44, 50, 58, 59, 60, 64, 66, 83]

94

2.7.11.19

Phosphorylase kinase

P ADP + activated phosphorylase kinase [34, 37, 41, 42, 44, 50] S ATP + peptides derived from glycogen synthase ( rabbit, overview [34]) (Reversibility: ?) [34] P ? S ATP + phosphorylase b ( i.e. EC 2.4.1.1 or glycogen phosphorylase [53,78]; involved in glycogenolysis [34]; stimulates glycogenolysis in skeletal muscle [43]; regulates conversion of inactive phosphorylase b into active phosphorylase a [43,78]; vital process for short term energy supply to the cell, located at an interface between signalling and metabolic pathway [78]; involved in glycogen metabolism regulation [25]; key enzyme of neural and hormonal control of glycogen metabolism [53]) (Reversibility: ?) [25, 34, 43, 53, 78] P ? S ATP + phosphorylase b ( r [33]; best substrate [48, 58]; yeast [52]; yeast (not) [58]; i.e. EC 2.4.1.1 or glycogen phosphorylase [37, 44, 53, 78]; liver (rat) [48]; cosubstrate: MgATP complex [7, 11, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86]; main reaction [34]; liver [48,76]; binding studies with immobilized substrate [86]; phosphorylase b from heart [26]; incorporation of terminal phosphate of ATP into phosphorylase b [37]; phosphorylation site: Ser-14 [34, 55, 83]; phosphorylation site located 14 residues from amino terminal [53]; dogfish [42]; rabbit skeletal muscle [26, 37, 38, 42, 48, 52, 58, 59, 60, 64, 66, 77, 80, 82, 83, 86]; human, rat [58]; ATP can be replaced by 8-azido-ATP and its 2,3-dialdehyde derivative, not by any other natural nucleotide triphosphate [34]; the enzyme interacts with glycogen and phosphorylase b [91]) (Reversibility: ?) [3, 4, 5, 7, 11, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 89, 91] P ADP + phosphorylase a [39] S ATP + phosphorylase b ( KPI-2 reacts with Ser residues either preceded by or followed by Pro residues, does not strictly require an adjacent Pro residue [99]) (Reversibility: ?) [99] P ADP + phosphorylated phosphorylase b S ATP + protein ( in the presence of Ca2+ /calmodulin, the isoform PhK-g T of the catalytic subunit is able to efficiently phosphorylate glycogen phosphorylase and convert it from an inactive to an active form [21]) (Reversibility: ?) [21] P ATP + phosphoprotein

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Phosphorylase kinase

2.7.11.19

S ATP + sarcolemmal Na+ ,K+ ATPase ( rabbit [34]) (Reversibility: ?) [34] P ? S ATP + sarcolemmal protein (Reversibility: ?) [58] P ? S ATP + sarcoplasmic protein (Reversibility: ?) [58] P ? S ATP + synthetic pentadecapeptide ( from amino-terminal of glycogen synthase, i.e. Pro-Leu-Ser-Arg-Thr-Leu-Ser-Val-Ser-Ser-LeuPro-Gly-Leu-Glu [47]) (Reversibility: ?) [47] P ? S ATP + synthetic peptides derived from glycogen synthase ( overview, phosphorylation at the same site as glycogen synthase [58]) (Reversibility: ?) [58] P ? S ATP + synthetic peptides derived from phosphorylase b ( overview [34, 39, 58]; rabbit [34]) (Reversibility: ?) [34, 39, 58] P ? S ATP + synthetic tetradecapeptide ( i.e. Ser-Asp-GlnGlu-Lys-Arg-Lys-Gln-Ile-Ser-Val-Arg-Gly-Leu [42, 47, 58, 72, 77]; phosphorylation site: Ser between Ile and Val [42]; substrate for holoenzyme and for catalytic g subunit [72]; from amino-terminal of phosphorylase b [41]) (Reversibility: ?) [41, 42, 47, 58, 72, 77] P ? S ATP + troponin I ( phosphorylation site [34,83]; phosphorylation site (Thr-residue) [34]; not rabbit or dogfish troponin I [42]; rabbit phosphorylase kinase [34]) (Reversibility: ?) [34, 42, 44, 50, 58, 83] P ADP + phosphotroponin I S ATP + troponin T ( not rabbit or dogfish troponin T [42]) (Reversibility: ?) [42, 58, 67] P ADP + phosphotroponin T [58, 67] S GTP + phosphorylase b ( not [34,40,42,56]; cosubstrate: Mg-UTP complex [52]; not (dogfish) [42]) (Reversibility: ?) [34, 40, 42, 52, 56] P GDP + phosphorylase a S UTP + phosphorylase b ( not [34,40,42,56]; cosubstrate: Mg-UTP complex [52]; not (dogfish) [42]) (Reversibility: ?) [34, 40, 42, 52, 56] P UDP + phosphorylase a S Additional information ( specificity [58]; substrate specificity [4]; troponin (whole complex), histone IIAS [64]; creatine phosphate, phosphoenolpyruvate, actin, parvalbumin, protamin, dogfish or rabbit myosin, adenosine 5-(3-methyltriphosphate), 5-adenylylimidodiphosphate (dogfish) [42]; ITP, CTP (dogfish) [40,42,56]; histone V-S

96

2.7.11.19

Phosphorylase kinase

[48]; no substrates are phosphorylase kinase g subunit [41]; Lys-Gln-Ile-Ser-Val-Arg, Ser-Asp-Gln-Glu-Lys-Arg-Lys-Gln-Gly-Ser-GlyArg-Gly-Leu, Lys-Gln-Ile-Thr-Val-Arg, Arg-Lys-Gln-Ile-Thr-Val-Arg [58]; histone H2B [38]; histone II-A [42,48]; phosvitin [42,48,64]; gd complex catalyzes EGTA-insensitive phosphorylation of holoenzyme [34]; no spontaneous or MnSO4 -induced dephosphorylation of activated enzyme [38]; polylysine, polyarginine [60]; key enzyme in glycogen metabolism [16]; enzyme is required in early embryonic processes, such as gastrulation and mesoderm formation [23]; mutations in PHKG2, the catalytic g subunit, are associated with an increased cirrhosis risk [18]; modeling of glycogen phosphorylase regulation by Ca2+ -oscillations, and dephosphorylation and phosphorylation involving the enzyme and a phosphatase, overview [87]; muscle-specific enzyme deficiency causes glycogen storage disease [89]; protein kinases and protein phosphatases regulate enzyme activities in the cell, overview [1]; poor activity on free amino acids, consensus sequence of PhK is R-XXS/ TF-F [5]; substrate specificity, the enzyme depends on basic residues for substrate recognition, overview, the residues at the substrate phosphorylation site greatly influence the enzyme activity, autoregulation by a pseudosubstrate mechanism, overview [2]; the enzyme performs autophosphorylation [88]; correlation of gene transcriptional processing and catalytic regulation of PhK subunits, overview [100]; hormonal regulation of KPI-2, kinase KPI-2 reveals reactivity with cystic fibrosis transmembrane conductance regulator and phosphorylase [99]; interaction of flavin adenine dinucleotide, FAD, with rabbit skeletal muscle phosphorylase kinase, FAD prevents the formation of the enzymeglycogen complex in a cooperative manner, but exerts practically no effect on the phosphorylase kinase activity, the complex of glycogen metabolism enzymes in protein-glycogen particles may function as a flavin depot in skeletal muscle [96]; key enzyme in regulating glycogenolytic flux in skeletal muscle in response to changing energy demands, phosphorylase kinase associates with the cytoskeletal organizing protein Cdc42-interacting protein 4, CIP4, in vivo in skeletal muscle, the cognate binding domain on CIP4 lies between residues 398 and 545, the interaction is independent of the SH3 domain [95]; phosphorylase-b kinase deficient patients, suffering glycogen storage disease GSD IXa, show an accumulation of fat in the liver that resolves with aging, overview [97]; the enzyme complex regulates glycogenolysis [98]; subunit PhKa is autophosphorylated [98]) (Reversibility: ?) [1, 2, 4, 5, 16, 18, 23, 34, 38, 40, 41, 42, 48, 56, 58, 60, 64, 87, 88, 89, 95, 96, 97, 98, 99, 100] P ? Inhibitors (D)-Arg-(D)-Leu-(D)-Ser-(D)-Leu ( Ser-Asp-Gln-Glu-Lys-ArgLys-Gln-Ile-Ser-Val-Arg-Gly-Leu as substrate [58]) [58] (D)-Leu-(D)-Ser-(D)-Leu-(D)-Arg [58]

97

Phosphorylase kinase

2.7.11.19

(D)-Leu-(D)-Ser-(D)-Tyr-(D)-Arg-(D)-Arg-(D)-Tyr-(D)-Ser-(D)-Leu

[58] (NH4 )2 SO4 ( above 0.2 M, stimulates at 0.05-0.1 M [37]) [37] 1,2-dimethoxyethane ( above 10% v/v, stimulates below [46]) [46] 5’-adenylylimidodiphosphate ( substrate-directed dead end inhibitor [72]) [72] ADP ( gd subunit complex [46]; g subunit [67]) [46, 67] ATP ( total inhibition if ATP concentration exceeds that of divalent cation (i.e. Mg2+ ) [27]; total inhibition if ATP concentration exceeds that of divalent cation [40]; otherwise activating [27,40]; free ATP, reversible [61]) [27, 40, 61] actin ( inhibits activation of subunit g-troponin C or subunit gcalmodulin complexes [77]) [77] antibodies to d subunit of phosphorylase kinase [43] antibodies to rabbit phosphorylase kinase ( rabbit [34]) [34] antibodies to rat testis calmodulin ( calmodulin or troponin (the latter at high concentrations) reverses [43]) [43] Arg-Lys-Gln-Ile-Thr-Val-Arg ( synthetic peptides as substrate [58]) [58] betaine ( stimulates enzyme self-association and interaction with glycogen, prevents complex formation with phosphorylase b [91]) [91] Ca2+ ( inhibition in millimolar, activation in micromolar range [49]) [49] calcineurin ( i.e. calmodulin-binding protein, blocks activation by calmodulin [53]) [53] calmodulin ( inhibits cAMP-dependent protein kinase mediated activation of phosphorylase kinase, kinetics [69]) [69] DTNB ( only gradual loss of activity after more than 10 min, pH-dependent [30]) [30, 39] EDTA ( Ca2+ restores [28,42]; Ca2+ and Mg2+ partially protect [44]; less effective than EGTA [28]) [28, 42, 44] EGTA ( strong [28,40,42]; not [41]; partial [48,59]; kinetics [37]; Ca2+ restores [34,37,40,42,46]; irreversible upon prolonged incubation (liver enzyme) [37]; effect on kinetic parameters [46]; autophosphorylation [60]; Ca2+ and Mg2+ partially protect [44]; influence on helical structure [51]; together with trifluoperazime additive effect [47]; agd and gd subunit complexes less sensitive than holoenzyme [46]; nonactivated enzyme, more effective than EDTA [28]) [28, 34, 36, 37, 38, 40, 41, 42, 44, 45, 46, 47, 48, 51, 59, 60, 64] GTP ( gd subunit complex [46]; weak, with ATP as substrate [40]) [40, 46] glucose ( less effective than glucose 6-phosphate, pH 8.2 [27]) [27] glucose 6-phosphate ( not (gd subunit complex) [46]; pH 8.2 [27]; Mg2+ protects, phosphorylase b as substrate, me-

98

2.7.11.19

Phosphorylase kinase

chanism, kinetics [32]; no inhibition with modified phosphorylase b or a tetradecapeptide as substrate [32]) [27, 32, 39, 46] heparin ( depending on pH it inhibits or activates nonactivated enzyme [27]) [27] hexametaphosphate ( pH 8.2 [27]) [27] histone VIIS ( gd subunit complex [46]) [46] ITP ( weak, with ATP as substrate [40]; not (gd subunit complex) [46]) [40, 46] Ile-Ser-Val-Arg-Gly ( Ser-Asp-Gln-Glu-Lys-Arg-Lys-Gln-Ile-SerVal-Arg-Gly-Leu as substrate [58]) [58] K252a ( microbial broth product, highly selective [71]) [71] KCl ( not [37]) [37, 39] LLRDPYALRSVRHLIDNCAFRL ( autoregulatory pseudosubstrate sequence of the g subunit, residues 336-357 [4]) [4] Lys-Pro-Val-Thr-Arg-Glu-Ile-Val-Ile-Arg-NH2 ( i.e. V-peptide [83]) [83] melittin ( model calmodulin-binding peptide, mechanism, kinetic, phosphorylase b as substrate [79]) [79] Mg2+ ( not [52]; in excess of ATP [38,74]; free Mg2+ , only activated enzyme, reversible [61]; nonactivated and activated enzyme [38]) [38, 52, 61, 74] MgADP- ( product inhibition [72]) [72] Mn2+ ( free Mn2+ [46,61,67]) [46, 61, 67] monospecific antibodies against a, b and g subunits ( mechanism, kinetic, anti-b subunit reverses inhibition by anti-a at pH 6.8 [65]) [65] NH4 Cl ( inhibits A1 and A2 activities by lowering of vmax, not A0 [49]) [49, 50] NaCl ( 0.1 M [37]) [37] phenothiazin ( blocks activation by extrinsic calmodulin [34]) [34] phosphorylase b ( high concentration [64]) [64] phosphotetradecapeptide ( product inhibition [72]) [72] poly-l-lysine ( strong, activated and nonactivated enzyme, stimulates autophosphorylation [60]) [60] polyaspartic acid ( pH 8.2 [27,39]) [27, 39] proline ( inhibits enzyme self-association and interaction with glycogen and phosphorylase b [91]) [91] protamine ( pH 8.2 [27,39]) [27, 39] protein phosphatase ( type I, reverses autoactivation [73]; rabbit (not dogfish) kinase [42]) [42, 73] quercetin ( ATP does not reverse [64]) [64] Ser-Asp-Gln-Glu-Lys-Arg-Lys-Gln-Ile-Asp-Val-Arg-Gly-Leu ( substrate-directed dead end inhibitor [72]) [72] staurosporine [71] synthetic peptide PhK13 ( derived from g subunit region, residues 302-326 [7]; kinetic [7,82]; calmodulin reverses [82]; synergistic with PhK5 [7]) [7, 82]

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Phosphorylase kinase

2.7.11.19

synthetic peptide PhK5 ( kinetic [7,82]; calmodulin reverses [82]; derived from g subunit region, residues 342-366 [7]; synergistic with PhK13 [7]) [7, 82] trifluoperazine ( nonspecific inactivation, at high concentrations, together with EGTA additive effect [47]; prevents activation by troponin C [53]) [47, 53] trimethylamine N-oxide ( stimulates enzyme self-association and interaction with glycogen, prevents complex formation with phosphorylase b [91]) [91] UTP ( weak, gd subunit complex [46]) [46] VIRDPYALPPLRRLIDAYAFRI ( autoregulatory pseudosubstrate sequence of the g subunit, residues 333-354 [4]) [4] VIRDPYALRPLRRLIDAYAFRI ( autoregulatory pseudosubstrate sequence of the g subunit, residues 332-353 [4]) [4] Zn2+ [27] Additional information ( regions of the g-subunit represented by PhK5 and PhK13 work in concert as regulatory subdomains that transduce Ca2+ -induced conformational changes in the dsubunit to the catalytic g-subunit through a pseudosubstrate autoinhibitory mechanism [7]; phosphorylase kinase a and b subunits suppress catalytic activity of g subunit in holoenzyme [68]; g subunit with autoinhibitory domains [7,82]; no inhibition by troponin (rabbit) [34]; no inhibition by UDPglucose [27,39]; no inhibition by spermidine, spermine, F- [27]; no inhibition by glucose 1-phosphate (gd subunit complex) [27,39,46]; no inhibition by diethyldithiocarbamic acid, 2,2-dipyridyl [28]; inhibition study with modified g subunit [82]; no inhibition by CTP, caffeine, cAMP, cGMP, IMP, glucose 6phosphate (gd subunit complex) [46]; no inhibition by cAMP-binding protein [52,73]; after treatment of differentiated C2C12 muscle myoblasts with apoptosis inducers staurosporine, N,N,N,N-tetrakis(2-pyridylmethyl)ethylenediamine, doxorubicin, or UV radiation the enzyme a-subunit disappears [92]; autoregulation by a pseudosubstrate mechanism, overview [2]; effect of molecular crowding, osmolytes inhibit complex formation with substrate phosphorylase b [91]; synthesis of peptides behaving as pseudosubstrates, determination of inhibitory potential [4]; FAD prevents the formation of the enzyme-glycogen complex in a cooperative manner, but exerts practically no effect on the phosphorylase kinase activity, in the presence of 1 M trimethylamine-N-oxide, FAD has an inhibitory effect on self-association of phosphorylase kinase [96]; KPI-2 is inhibited in living cells by addition of nerve growth factor or serum [99]) [2, 4, 7, 27, 28, 34, 39, 46, 52, 68, 73, 82, 91, 92, 96, 99] Cofactors/prosthetic groups 2’-deoxy-ADP ( activation, can replace ADP [81]) [81] ADP ( activation [27, 34]; stimulates phosphorylase conversion and autophosphorylation, 8 mol ADP per mol (abgd)4 [34]; kinetics, 8 binding sites per

100

2.7.11.19

Phosphorylase kinase

hexadecamer [81]; allosteric effector [34,81]; can partially replace ATP in the activation of nonactivated enzyme [27]) [27,34,81] ATP ( dependent on [5]; by autophosphorylation or protein kinase phosphorylation [34]; not alone, only in the presence of Mg2+ or Mn2+ [34]; activation of nonactivated enzyme by phosphorylation of subunits A and B, not C [27, 31]; by phosphorylation of subunits a, b not g [34]) [1, 2, 3, 4, 5, 27, 31, 34, 87, 88, 89, 90, 91, 92, 93, 94, 96, 98, 99, 101, 102] calmodulin ( requirement [34,43,47,53]; allosteric effector [34]; no additional activation [54]; additional activation [55,64,80]; activation of recombinant g subunit at pH 6.8, slightly at pH 8.2 [80]; calmodulin containing enzyme i.e. tightly bound d subunit [34,43,47,53]; calmodulin containing enzyme in the absence of Ca2+ [53]; no activation of phosphorylated or proteolytically modified enzyme by d-subunit [55]; activation of nonactivated enzyme and agd subunit complex [47]; in the presence of Ca2+ : 1 mol extrinsic calmodulin per mol abgd rabbit enzyme [34]; interacts with a subunit [47]; tightly bound molecule interacts with additional calmodulin in the presence of Ca2+ [53]; in the presence of Ca2+ phosphorylase kinase binds a second molecule calmodulin (i.e. d subunit) producing additional activation [43]; no activation of bovine red skeletal muscle or rabbit cardiac enzymes [34]; Ca2+ -dependent binding, identical with the d subunit [88]; encoded by 3 different genes CALM1-3 [89]; identical with the d subunit [92,93,94]; mediates Ca2+ -sensitivity of the enzyme, calmodulin is identical with the d-subunit [87]) [34,43,47,53,54,55,64,80,87,88,89,92,93,94] Activating compounds 1,2-dimethoxyethane ( activation, 10% v/v, stimulates phosphorylase kinase and agd (not gd) subunit complex [46]) [46] adenosine 3’,5’-monophosphate ( i.e. 3’,5’-cAMP, activation of nonactivated enzyme, not alone, only in the presence of Mg2+ or Mn2+ [27]; cAMP mediated activation [38]; no enhancement or inhibition of this activation by various nucleotides and other compounds, overview [27]; cf. catalytic subunit of cAMP-dependent protein kinase [34]) [27, 34, 38, 40] adenosine 3’-phosphate 5’-phosphosulfate ( activation, can replace ADP to some extent [81]) [81] adenosine 5’-phosphosulfate ( activation, can replace ADP to some extent [81]) [81] artificial thin filaments ( activation, made by mixing actin, tropomyosin and troponin complex [43]) [43] betaine ( stimulates enzyme self-association and interaction with glycogen, prevents complex formation with phosphorylase b [91]) [91]

101

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Ca2+ -dependent protease ( proteolytic activation of nonactivated enzyme [27,34]; i.e. kinase-activating factor [27,28]; ir [34]; or Ca2+ activating factor [34]) [27, 28, 34] Ca2+ /calmodulin ( the phosphorylase kinase is activated by both cAMP-dependent protein kinase and Ca2+ /calmodulin [1]) [1] calmodulin ( influences the conformational substates of the subunits, overview [101]) [101] casein protein kinase ( activation of nonactivated enzyme [34]) [34] catalytic subunit of cAMP-dependent protein kinase ( not [42]; activation of nonactivated enzyme [34,39,40,43,46,48,50,54,55,56,58,66,69]; at low Mg2+ -concentration, 2 phosphorylation sites, one Ser residue on a and b subunit each [43]; ATP cannot be replaced by 5-AMP, 3-AMP, 2,3AMP, CMP, CDP, CTP, UMP, UDP, UTP, GMP, GDP, GTP, IMP, IDP, ITP [34]; or agd subunit complex [46]; and b [49,55,56]; a [49,55]; by phosphorylation of a [40,56]; Mn2+ stimulates [58]; activation by enhancing vmax selectively for A2 activity [49]; kinetics [69]; subunits, in the presence of ATP and Mg2+ [34,58]; and b (not g) [40]) [34, 39, 40, 42, 43, 46, 48, 49, 50, 54, 55, 56, 58, 66, 69] catalytic subunit of cGMP-dependent protein kinase ( not [43]; activation of nonactivated enzyme [34]) [34, 43] chymotrypsin ( proteolytic activation of nonactivated enzyme [34,55,66]; by limited proteolysis of a subunit, not g or d subunits [55]) [34, 55, 66] glycogen ( activation [27, 34, 39, 46, 54, 86]; allosteric effector, mechanism [34]; increases apparent affinity for phosphorylase b [86]; pH-dependent [27]; effect on nonactivated and activated enzyme [54]; stimulates phosphorylase kinase and agd (not gd) subunit complex [46]; no significant effect on dogfish enzyme [42]) [27, 34, 39, 42, 46, 54, 86] heparin ( activation [27,39,46]; pHdependent [27,39]; stimulates only holoenzyme, not subunit complexes [46]) [27, 39, 46] papain ( proteolytic activation of nonactivated enzyme [34]) [34] poly-l-arginine ( strong, phosphorylase kinase as substrate, i.e. autophosphorylation [60]) [60] poly-l-lysine ( strong, only with phosphorylase kinase as substrate, i.e. autophosphorylation, inhibits activity of activated and nonactivated enzyme with other substrates [60]) [60] proteases ( proteolytic activation of nonactivated enzyme, mechanism [34]) [34, 39]

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protein kinases ( not [42]; activation of nonactivated enzyme, phosphorylation sites, mechanism [34]; not (liver enzyme) [37]) [34, 37, 42] trimethylamine N-oxide ( stimulates enzyme self-association and interaction with glycogen, prevents complex formation with phosphorylase b [91]) [91] troponin ( i.e. complex of troponin C, I and T, activation, as effective as troponin C, forms complex with b subunit [53]) [53] troponin C ( activation [34, 43, 53]; presumably key event in vivo, coupling glycogenolysis and muscle contraction [43]; can replace extrinsic calmodulin [43,53]) [34, 43, 53] trypsin ( at low concentration [27]; proteolytic activation of nonactivated enzyme [27, 28, 29, 34, 39, 43, 47, 49, 54, 55, 64, 66]; accompanied by loss of absolute requirement for Ca2+ , activates holoenzyme and agd subunit complex, not gd complex [43]; strong, by limited proteolysis of a and b subunits (not g) [39,55]; strong, by limited proteolysis of a and b subunits [39,43,55]; increase of pH 6.8 activity, not pH 8.2 activity [54]; vmax enhancement of all three activities of the kinase: A0, A1 and A2 [49]; strong, by limited proteolysis of a and b subunits or d subunits [55]) [27, 28, 29, 34, 39, 43, 47, 49, 54, 55, 64, 66] caspase-3 ( selective in vitro cleavage of the regulatory a-subunit increasing the enzyme activity 2fold [92]) [92] Additional information ( hexadecamer of (abgd)4 with variable degree of activity depending on pH, metal ions, allosteric effectors, covalent modifications, etc. [78]; or autophosphorylation [31, 34, 39, 50]; adenine, adenosine, 5-AMP, 2,5ADP, 3,5-ADP, adenosine 2:3cyclic phosphate 5-monophosphate, a,b-methylene-ADP, adenosine 2-phosphate 5-phosphosulfate, adenosine 5-diphosphoglucose, adenosine 5-diphosphoribose, ADP-3-diphosphate, adenylylimidodiphosphate, diadenosine diphosphate [81]; phosphorylation by protein kinases [27, 31, 34, 39, 49]; the nonactivated enzyme (i.e. dephospho-enzyme) [34]; glucose 6-phosphate, UDPglucose, dogfish myosin, actin, tropomyosin, rabbit glycogen synthase [42]; no activation of nonactivated enzyme by renin (with or without Ca2+ ), thrombin (with or without Ca2+ ), phospholipase D from Clostridium perfringens or phospholipase from Crotalus adamanteus [28]; poly-aspartic acid, hexametaphosphate, yeast nucleic acid, at pH 6.8 [27]; no stimulation of autophosphorylation by poly-l-alanine, poly-l-asparagine, putrescine, spermidine or spermine [60]; no autoactivation [64]; No activation by substrates of phosphorylase b reaction, i.e. AMP or glucose 1-phosphate [27, 42]; allosteric effectors, overview [34]; parvalbumin [42, 43]; the nonactivated enzyme is activated either by limited proteolysis [27, 28, 29, 31, 34, 39, 43, 47, 49, 50, 54, 55, 64, 66]; three separate activities can be characterized by their response to Ca2+ , Mg2+ , NH4 Cl and pH: A0, A1 and

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A2 [49,50]; activation segment structure [3]; autoregulation by a pseudosubstrate mechanism, overview [2]; effect of molecular crowding [91]; location of an allosteric activation switch in the multisubunit phosphorylase kinase complex, overview [98]) [2, 3, 27, 28, 29, 31, 34, 39, 42, 43, 47, 49, 50, 54, 55, 60, 64, 66, 78, 81, 91, 98] Metals, ions (NH4 )2 SO4 ( activation, 0.05-0.1 M, inhibits above 0.2 M [37]) [37] Ba2+ ( activation, can replace Ca2+ with 60% efficiency [28]; activation, can replace Ca2+ with 26% efficiency [42]) [28, 42] Ca2+ ( requirement [34, 39, 40, 42, 56, 59, 64]; dependent on [94]; not [25]; phosphorylase kinase is a Ca2+ -regulated, multisubunit enzyme that contains calmodulin as an integral subunit, the g-subunit of skeletal muscle phosphorylase kinase contains two noncontiguous domains that act in concert to bind calmodulin [8]; activation, 0.0001-0.001 mM, inhibits above 0.001 mM [48]; irreversible activation of nonactivated kinase by preincubation together with a separate kinase-activating factor independent of cAMP, kinetics [28]; binding studies [35]; required for efficient substrate binding of active and nonactivated enzyme and for maximal catalysis of active enzyme [38]; isolated d-subunit from rabbit has 4 Ca2+ -binding sites of which 2 are lost at high ionic strength and 2 Mg2+ / Ca2+ -binding sites that can bind either ion, treatment of gd-subunit complex with EGTA with following centrifugation leads to Ca2+ -independent catalytic activity [34]; synergism with Mg2+ [34,44,45]; stabilization, no absolute requirement for catalytic subunit g2 [41]; 12 mol Ca2+ per mol (abgd)4 [35]; d-subunit confers Ca2+ -sensitivity to the phosphorylase kinase reaction [43]; allosteric mechanism [34]; Ca2+ -independent activity: A0 [49,50]; stimulates autophosphorylation in micromolar range at pH 6.8, inhibits at millimolar range [50]; requirement (trypsin activation leads to loss of absolute requirement) [43]; required for activity and activation [34,50]; stimulates phosphorylase b binding to enzyme, but to a considerable lesser extent than Mg2+ [86]; activates, binding structure modeling, Ca2+ -binding induces structural perturbation of the subunits and promotes redistribution of density throughout the lobes and bridges of the enzyme structure [93]; activates, dependent on, required for binding of calmodulin [88]; Ca2+ -sensitivity of the enzyme is mediated by the d-subunit which is identical with calmodulin [87]; dependent on, induces enzyme selfassociation and increases interaction with glycogen [91]; activates, the four integral d subunits of the phosphorylase kinase complex are identical to calmodulin and confer Ca2+ sensitivity to the enzyme, but bind independently of Ca2+ , Ca2+ influences the conformational substates of the subunits, overview [101]; is an obligatory allosteric activator absolutely required by the enzyme, Ca2+ activates PhK by binding to its nondissociable calmodulin subunits, it couples the cascade activation of glycogenolysis with muscle

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contraction, enzyme surface electrostatic properties of solvent accessible charged and polar groups are altered upon the binding of Ca2+ ions [102]; required for complex formation [96]) [8, 25, 28, 33, 34, 35, 37, 38, 39, 40, 41, 42, 43, 44, 45, 48, 49, 50, 53, 55, 56, 57, 58, 59, 61, 64, 85, 86, 87, 88, 91, 92, 93, 94, 96, 98, 101, 102] calcium ( dependent on [11]) [11] Cd2+ ( can partially substitue Mg2+ [5]) [5] Co2+ ( not [28]; activation, can replace Ca2+ with 10% efficiency [42]; can partially substitue Mg2+ [5]) [5, 28, 42] Fe3+ ( not [28]; activation, can replace Ca2+ with 10% efficiency [42]) [28, 42] Li+ ( activation [39, 42]; can replace Ca2+ with 10% efficiency [42]; LiBr [39]) [39, 42] Mg2+ ( requirement [7, 11, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86]; not [28]; 10 mM [46, 61]; can replace Mn2+ [25]; free Mg2+ inhibits activated enzyme [61]; free Mg2+ stimulates (nonactivated enzyme) [61]; enzyme catalyzes its own phosphorylation (i.e. a and b subunits, not gd subunit complex) in the presence of MgATP2- and Ca2+ [34]; effect of Mg2+ on Ca2+ -binding properties of nonactivated enzyme at pH 6.8 [35]; synergism with Ca2+ [34, 44, 45]; Mg2+ added in excess of ATP concentration stimulates [34]; greatly enhances affinity for phosphorylase b [86]; allosteric effector, rabbit d-subunit has two Mg2+ /Ca2+ -binding sites that can bind either ion [34]; major role of Mg2+ : cosubstrate in Mg2+ -ATP complex [7, 11, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86]; required for activity phosphorylation by (cAMP-dependent protein kinase) [34, 45, 48, 58, 61]; required for activity and activation (by autophosphorylation) [48]; dependent on, induces enzyme self-association and increases interaction with glycogen [91]; dependent on, Mg2+ is the physiologic metal ion, other divalent cations are able to support nucleotide binding, but only Mn2+ , Co2+ , and Cd2+ can substitute Mg2+ in supporting the catalytic activity [5]; required for complex formation and activity [96]) [1, 2, 3, 4, 5, 7, 11, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 91, 92, 94, 96, 98, 99, 101, 102] Mn2+ ( requirement [25, 26, 27, 28, 40, 42, 46, 86]; activation [58]; can substitute for Mg2+ [27, 46]; stimulates activation by catalytic subunit of cAMP-dependent protein kinase [58]; can replace Ca2+ with 15% efficiency [42]; can substitute for Ca2+ [28]; free Mn2+ inhibits [46]; at equimolar concentration of

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metal ion and ATP Mn2+ more effective than Mg2+ [46]; enhances enzyme/phosphorylase b interaction more effectively [86]; optimal at ATP:Mg ratio of 1:1 [25,46]; can substitute for Mg2+ (less effective) [40]; can partially substitue Mg2+ [5]) [5, 25, 26, 27, 28, 40, 42, 46, 58, 86] phosphate ( contains 7.18-19 mol per mol (abgd)4 depending on phosphorylation status [34]; agd complex undergoes autophosphorylation: up to 4.2 mol phosphate/mol complex incorporated into a subunit [46]; 20 mol/mol holoenzyme, phosphate content of subunits [62]; requirement, phosphate containing enzyme [7, 11, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86]; nonactivated enzyme is activated by phosphorylation [34]; gd subunit complex cannot phosphorylate itself but phosphorylates and activates native enzyme, even in the presence of EGTA or protein kinase inhibitor [46]; a and b subunits are phosphorylated by protein kinases or autophosphorylation [55,56]) [7, 11, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86] Sr2+ ( activation, can replace Ca2+ with 60% efficiency [28]; activation, can replace Ca2+ with 45% efficiency [42]) [28, 42] Additional information ( three separate activities can be characterized by their response to Ca2+ , Mg2+ , NH4 Cl and pH: A0, A1 and A2 [49,50]; synopsis of activity by Ca2+ /Mg2+ and phosphorylation [78]; no activation by Cu2+ , Cd2+ , Sn2+ , Al3+ [42]; Fe2+ , Zn2+ or Ni2+ [28,42]) [28, 42, 49, 50, 78] Turnover number (min–1) 0.0983 (melittin) [79] 23.6 (tetradecapeptide) [79] 57.1 (phosphorylase b) [79] 91.4 (phosphorylase b, nonactivated enzyme [46]) [46] 99 (phosphorylase b, agd subunit complex [46]) [46] 104 (phosphorylase b, gd subunit complex [46]) [46] Specific activity (U/mg) 0.426 [48] 0.53 [64] 1.1 [69] 2.8 ( dogfish [42]) [42] 3.68 [40, 56] 4 ( pH 8.2 [35]) [35] 8.3 [54] 10.2 [55] 10.9 ( truncated form of phosphorylase kinase g subunit [83]) [83] 16.4 ( hind limb [66]) [66]

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19.6 ( brest [66]) [66] Additional information ( activity of purified native and recombinant enzymes and subunit subcomplexes at different pH [88]) [25, 27, 38, 52, 88, 99] Km-Value (mM) 0.002-0.0025 (phosphorylase b, in the presence of glycogen [66]) [66] 0.0098 (melittin) [79] 0.01 (phosphorylase b, pH 7.5, in the presence of glycogen [27]) [27] 0.014 (phosphorylase b, recombinant g subunit, pH 6.8 [80,83]) [80, 83] 0.015-0.017 (phosphorylase b, bovine heart [56]; activated enzyme, pH 8.2 [27]) [27, 56] 0.017-0.027 (MgATP2-, autophosphorylation [34]) [34] 0.018 (ATP, phosphorylase b, truncated form of phosphorylase kinase g subunit [84]) [52, 84] 0.019-0.02 (phosphorylase b, pH 7, activated enzyme [34]) [34, 66] 0.025 (ATP, proteolytic fragment of phosphorylase kinase [37]) [37] 0.0276 (phosphorylase b, holoenzyme [79]) [79] 0.03-0.037 (ATP, pH 8.5 [27,34]; phosphorylase b [27, 28, 34, 80, 83]; activated enzyme, pH 7.5 [27, 28, 34]; recombinant g subunit, pH 8.2 [80, 83]) [27, 28, 34, 37, 80, 83] 0.04 (phosphorylase b, before activation, pH 8.2 [27]) [27] 0.044-0.08 (phosphorylase b, holoenzyme [84]) [84] 0.05 (ATP) [76] 0.07 (MgATP2-, activated rabbit skeletal muscle enzyme, pH 8.2 [38]; ATP (+ melittin) [79]) [38, 79] 0.07-0.24 (phosphorylase b) [34] 0.08 (MgATP2-, pH 8.2, g subunit or holoenzyme [67]; ATP (+ tetrapeptide) [79]; phosphorylase b, activated enzyme [46]; activated rabbit skeletal muscle enzyme, pH 6 [38]) [38, 46, 67, 79] 0.0824 (phosphorylase b, g subunit [79]) [79] 0.084 (phosphorylase b, from rabbit, pH 8.2, dogfish enzyme [42]) [42] 0.094 (phosphorylase b, pH 8.2, gd subunit complex [46]) [46] 0.098 (MgATP2-, pH 8.2, g subunit or holoenzyme [67]) [67] 0.1 (MgATP2-, nonactivated rabbit skeletal muscle enzyme, pH 6 [38]; dogfish phosphorylase b, pH 8.2, dogfish enzyme [42]) [38, 42] 0.11 (phosphorylase b, pH 8.2, agd subunit complex [46]) [46] 0.12 (phosphorylase b, pH 7.5 [27]) [27] 0.125 (phosphorylase b, before activation, pH 7.5 [27]) [27] 0.14 (phosphorylase b, before activation, pH 7.5 [28]) [28]

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0.14-0.22 (ATP, at different phosphorylase b concentrations [40]) [40] 0.19 (phosphorylase b, nonactivated enzyme, pH 8.2 [83]) [83] 0.2 (ATP, Ser-Asp-Gln-Glu-Lys-Arg-Lys-Gln-Ile-Ser-Val-Asp, LysArg-Lys-Gln-Ile-Ser-Val-Asp, nonactivated enzyme, pH 8.2 [83]) [66, 83] 0.2-2.3 (peptides, from phosphorylase b, synthetic [58]) [58] 0.21 (S-peptide, recombinant g subunit, pH 8.2 [83]) [83] 0.22 (ATP, bovine heart [56]; S-peptide, activated enzyme, pH 6.8 [83]; pH 8.2, nonactivated enzyme [46]) [46, 56, 83] 0.24 (ATP, nonactivated enzyme, pH 7.5 [27]) [27] 0.25 (phosphorylase b, pH 7.6 [27,34]; pH 8.2, nonactivated enzyme [46]) [27, 34, 46] 0.27 (phosphorylase b, nonactivated enzyme [58]) [58] 0.28 (S-peptide, recombinant g subunit, pH 6.8 [83]) [83] 0.3085 (tetradecapeptide) [79] 0.37 (phosphorylase b, nonactivated enzyme, pH 7 [34]) [34] 0.38 (ATP, activated enzyme, pH 7.5 [27]) [27] 0.4 (ATP) [55] 0.45 (ATP) [64] 0.47 (tetradecapeptide) [72] 0.5 (ATP, pH 8.2, agd subunit complex [46]) [46] 0.6 (GTP) [52] 0.7-3.5 (peptides, from glycogen synthase, synthetic [58]) [58] 0.9-1 (Lys-Arg-Lys-Gln-Ile-Ser-Val-Asp-Gly-Ile, pH 8.2 [83]) [83] 0.95 (ATP, pH 8.2, gd subunit complex [46]) [46] 1.2 (Ser-Asp-Gln-Glu-Lys-Arg-Lys-Gln-Ile-Ser-Val-Asp-Gly-Ile, nonactivated enzyme, pH 8.2 [83]) [83] 1.4 (UTP) [52] 2 (Ser-Asp-Gln-Glu-Lys-Arg-Lys-Gln-Ile-Ser-Val-Asp, activated enzyme, pH 8.2 [83]) [83] 3.5 (Ser-Asp-Gln-Glu-Lys-Arg-Lys-Gln-Ile-Ser-Val-Asp-Gly-Ile, activated enzyme, pH 8.2 [83]) [83] Additional information ( kinetic studies [34]; pH-dependence of kinetic parameters [27,39]; kinetic properties, overview [34,39]; influence on kinetic parameters, glycogen decreases Km -values for phosphorylase b [54]; kinetic data for phosphorylase b [34,39,58]; kinetic parameters of catalytically active g subunit at pH 6.8 and 8.5 [41]; effects of holoenzyme dissociation [34]; kinetic parameters for different enzyme forms [67]; kinetic properties of covalently modified and nonmodified phosphorylase kinase [49]; effect of isolated d subunit on kinetic parameters of nonactivated holoenzyme and agd complex [47]; influence of anti-subunit antibodies [65]; kinetic data of holoenzyme and catalytically active proteolytic fragment [37]; kinetic data for peptides derived from glycogen synthase [34,58]; kinetic properties of subunit complexes at pH 6.8 and 8.5 [46]; influence of Ca2+ [76]; kinetic parameters for recombinant wild-type g

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subunit and its mutant form [83]; random kinetic mechanism, reaction order can be influenced by the sort of substrate [5]; kinetics of phosphorylase kinase-glycogen complex formation [96]) [5, 27, 34, 37, 38, 39, 41, 46, 47, 49, 54, 58, 59, 64, 65, 67, 76, 83, 96] Ki-Value (mM) Additional information ( Ki values of the pseudosubstrates in nano- to micromolar range [4]) [4] pH-Optimum 6 ( nonactivated enzyme [38]) [38] 6.8 ( assay at [91,92,94,96]; enzyme assay at pH 6.8 [89]; assay at, substrate glycogen phosphorylase b [98]) [89, 91, 92, 94, 96, 98] 6.8-7 ( assay at [101]) [101] 7 ( liver enzyme [37]; nonactivated enzyme [48]; above, activated enzyme [38]) [37, 38, 48] 7.4 ( assay at [99]) [99] 7.6 ( above, nonactivated rabbit enzyme [34]) [34] 8 [52] 8.2 ( enzyme assay at pH 8.2 [89]) [89] 8.3 ( assay at, substrate glycogen S peptide [98]) [98] 8.5 [42, 66] 8.8 [25, 40] 9.3 [64] 9.5 ( muscle enzyme [37]) [37] Additional information ( pI: 5.77 (nonactivated rabbit enzyme) [30,39]; pH 6.8/8.2 activity ratios: 0.58 [64]; nonactivated kinase activity ratios at pH 6.8/8.2: between 0.01-0.05, activated kinase activity ratio: about 0.6 [30]; 0.3-0.5 [66]; activated enzyme has a higher pH-optimum than nonactivated enzyme [76]; pH-activity profiles of agd and gd subunit complexes [51]; 0.5-0.6 (g subunit) [67]; nonactivated enzyme has only low activity at pH 6.8 [54]; influence of activation by protein kinase on pH-activity profile [48]; activity ratios pH 6.8/8.2 of nonactivated enzyme: 0.07 (in the presence of 0.05-0.07 M Ca2+ ) and 0.23 (after calmodulin addition) [55]; activity ratios at pH 6.8/8.2: 0.01-0.02 (phosphorylase kinase a), 0.36 (phosphorylase kinase sa), 0.67 (phosphorylase kinase a) [33]; pH-dependence of partial activities A1 and A2 [49]; enzyme assay at pH 6.8 and pH 8.2 [89]) [27, 30, 33, 39, 48, 49, 51, 54, 55, 64, 66, 67, 76, 89] pH-Range 6-11.5 ( about half-maximal activity at pH 6 and 11.5, liver enzyme [37]) [37] 6.2-7.6 ( about half-maximal activity at pH 6.2 and 7.6, nonactivated enzyme [48]) [48] 6.2-8 ( progressive increase of activity, about half-maximal activity at pH 7.4 [66]) [66]

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6.2-8.8 ( progressive increase of activity [40]) [40] 6.2-9.3 ( progressive increase of activity from 10% to 100% of maximal activity, with half-maximal activity at pH 7 [64]) [64] 6.2-9.5 ( about half-maximal activity at pH 6.2 and about 70% of maximal activity at pH 9.5 [41]) [41] 6.5-8.5 ( progressive increase of activity, biphasic with dogfish phosphorylase b as substrate: then about half-maximal activity at pH 7.2-7.6 (dogfish activated enzyme) [42]) [42] 6.6-9.1 ( about half-maximal activity at pH 6.6 and 9.1, activity increases up to pH 8, sharp drop above 9 [25]) [25] 6.8-8.5 ( about half-maximal activity at pH 6.8 and maximal activity at pH 8.5, activated rabbit enzyme [42]) [42] 7.2-9 ( 70% of maximal activity at pH 7.2 and and 9 [52]) [52] 8.1-8.5 ( about half-maximal activity at pH 8.1 and maximal activity at pH 8.5, nonactivated rabbit enzyme [42]) [42] 9-10 ( about half-maximal activity at pH 9 and 10, muscle enzyme [37]) [37] Additional information ( activity of purified native and recombinant enzymes and subunit subcomplexes at different pH, the latter show higher activity at pH 6.8, while the native enzyme shows higher activity at pH 8.2 [88]) [88] Temperature optimum ( C) 20 ( assay at [91]) [91] 22 ( assay at room temperature [101]) [101] 26 ( assay at [96]) [96] 30 ( assay at [7, 25, 27, 28, 37, 38, 40, 41, 42, 48, 49, 50, 51, 52, 54, 55, 56, 57, 58, 59, 60, 61, 63, 64, 67, 68, 69, 71, 77, 79, 82, 83, 84, 85, 92, 94, 98, 99]; autophosphorylation reaction at [88]) [7, 25, 27, 28, 37, 38, 40, 41, 42, 48, 49, 50, 51, 52, 54, 55, 56, 57, 58, 59, 60, 61, 63, 64, 67, 68, 69, 71, 77, 79, 82, 83, 84, 85, 88, 92, 94, 98, 99] 37 ( assay at [26]) [26] Additional information ( reaction and conformation temperature dependence, overview [102]) [102]

4 Enzyme Structure Molecular weight 29000 ( gel filtration [52]) [52] 86000 ( catalytically active gg subunit complex, gel filtration [41]) [41] 205000 ( trypsinized or chymotrypsinized enzyme form, gel filtration [74]) [74] 243000 ( agd complex, gel filtration [51]) [51] 1000000 [76]

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1220000 ( HPLC gel filtration [62]) [62] 1260000 ( gel filtration [74]) [74] 1300000 ( gel filtration [38,48]; rabbit, gel filtration [37]; gel filtration or sedimentation velocity analysis [42]; sucrose density gradient centrifugation [40]) [37, 38, 40, 42, 48, 93, 94] 1320000 ( gel filtration [66,75]) [66, 75] 1330000 ( analytical ultracentrifugation [30,34,39]; rabbit, nonactivated enzyme [30,34]) [30, 34, 39] Additional information ( amino acid composition [30,39]; mechanism and structure [78]; amino acid sequence in regulatory domain of g subunit [83]; MW of trypsinized enzyme [54]; enzyme aggregates to high polymeric forms which arise as artifacts during isolation procedure due to sensitivity to high hydrostatic pressure, e.g. during sucrose density gradient centrifugation at very high angular velocities [30]) [30, 39, 54, 78, 83] Subunits ? ( x * 44673, calculation from amino acid sequence [11]) [11] dimer ( 2 * 45000, rabbit, catalytically active gg subunit, SDSPAGE [41]) [41] hexadecamer ( a4 b4 g4d4 , a and b subunits are regulatory, d is calmodulin, and the g subunit is catalytic [16]; 4 * 118000145000 + 4 * 108000-128000 + 4 * 44673 + 4 * 16680, (abgd)4 , rabbit, SDSPAGE, 2 isozymes that differ in size of the largest subunit (a: 118000-145000 and a: 133000-140000) [34]; 4 * 145000 + 4 * 130000 + 4 * 45000 + 4 * 17000, (abgd)4 , rabbit, SDS-PAGE [53,55]; 4 * 134000 + 4 * 125000 + 4 * 48000 + 4 * ?, (abgd)4 , SDS-PAGE, the forth subunit is comigrating with calmodulin [40]; 2 major isozymes in muscle: (abgd)4 and (abgd)4 [56]; 4 * 140000 + 4 * 130000 + 4 * 46000 + 4 * 18000, (abgd)4 , SDS-PAGE [54]; (abgd)4 [88,92,93,94]; a4 b4 g4d4 [87]; tertiary and secondary structure of PhK measured in presence or absence of Ca2+ , conformational changes induced by Ca2+ , surface electrostatic properties of solvent accessible charged and polar groups are altered upon the binding of Ca2+ ions, overview [102]) [16, 34, 40, 53, 54, 55, 56, 87, 88, 92, 93, 94, 102] oligomer [89, 91] tetramer ( 2 * 69000 + 2 * 44000, proteolytic form, SDS-PAGE [74]; the enzyme forms a (abgd)4 complex, location of an allosteric activation switch in the multisubunit phosphorylase kinase complex, overview [98]) [74, 98] Additional information ( subunit composition of a4 b4 g4d4 , in which the a and b subunits are regulatory, d is calmodulin, and the g subunit is catalytic [16]; composed of 3 regulatory and 1 catalytic subunit [73]; molecular interaction and subunit structure [47]; the d subunit is firmly bound to holoenzyme whereas d subunit (i.e. calmodulin) is bound only in the presence of Ca2+ [43]; g subunit is not identical with rabbit skeletal muscle g subunit [66]; subunit a in isozymes that occur primarily in cells relying

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on glycolytic activity and a in tissues with higher oxidative than glycolytic activity [34]; g subunit [11,78]; a and b subunits are regulatory subunits controlled by phosphorylation and proteolysis, Ca2+ -sensitivity is conferred to d subunit [84]; spatial arrangement of subunits [34,39]; the catalytic g subunit contains a kinase domain and a calmodulin binding domain [84]; homology with catalytic subunit of cAMP dependent protein kinase [11]; structure/function relationships of subunits [78]; chicken g and a subunits compared to that of rabbit red muscle enzyme [75]; the d subunit is very similar to calmodulin but a tightly bound integral component of holoenzyme [34]; partial amino acid composition of subunits [31]; d subunits [36,51]; a [70]; amino acid composition of a [51,62,65]; amino acid sequence of a, b [70,78]; g [51,62,65]; b [62,65]; calmodulin is identical with the d subunit [92]; calmodulin is identical with the d subunit, determination and analysis of enzyme three-dimensional structure with a resolution of 25 A by cryoelectron microscopy [94]; calmodulin is identical with the d subunit, X-ray light-scattering structure modeling of unactivated enzyme or enzyme after structural changes induced by Ca2+ binding, structure analysis, overview [93]; phosphorylase kinase is a multisubunit protein kinase with molecular weight above 1000000 Da [5]; self-association is induced by Mg2+ and Ca2+ , kinetics [91]; the d subunit is identical with calmodulin [87,88]; the enzyme has an open, active conformation and a closed, inactive conformation [3]; conformational substates of PhK subunit bound or unbound to calmodulin and Ca2+ , overview [101]) [3, 5, 11, 16, 31, 34, 36, 39, 43, 47, 51, 62, 65, 66, 70, 73, 75, 78, 84, 87, 88, 91, 92, 93, 94, 101] Posttranslational modification phosphoprotein ( autophosphorylation, the site often depends more on structure than on primary sequence [2]; regulation by de-/phosphorylation performed by cAMP-dependent protein kinase, EC 2.7.11.11 [88]; the phosphorylase kinase is activated by cAMP-dependent protein kinase [1]; subunit PhKa is autophosphorylated [98]) [1, 2, 88, 98] proteolytic modification ( specific cleavage of caspase-3 at a specific cleavage site within the a-subunit at residue 46 in the sequence DWMD*G [92]; specific cleavage of caspase-3 at a specific cleavage site within the a-subunit in vivo [92]) [92] Additional information ( the native and the recombinant enzyme performs autophosphorylation of its a and b subunits [88]) [88]

5 Isolation/Preparation/Mutation/Application Source/tissue C2C12 cell ( differentiated muscle myoblasts [92]) [92] adipose tissue [100]

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adrenal gland [100] bladder [100] blood [89, 100] bone [100] bone marrow [100] brain [100] breast [100] cardiac muscle [34, 39, 40, 54, 56] cartilage [100] cell culture ( HeLa cells [15]) [15] cervix [100] colon [100] connective tissue [100] eye [100] fat body ( pupae [59]) [59] femoral muscle [90] flight muscle [39] gizzard smooth muscle [34, 64] head ( neck [100]) [100] heart [12, 100] hepatocyte [87] intestine [100] kidney [100] liver [34, 37, 38, 39, 48, 61, 73, 74, 76, 87, 97, 100] lung [100] lymph node [100] lymphocyte [100] mammary gland [100] mouth [100] muscle ( skeletal muscle [10,12]; soleus muscle [17]; muscle isoform [89]) [8, 10, 12, 14, 17, 89] myoblast ( muscle cells [92]) [92, 95] myotube [95] nasopharynx [100] nerve [100] ovary [100] pancreas [100] pituitary gland [100] placenta [100] prostate gland [100] psoas [98, 101, 102] salivary gland [100] skeletal muscle [7, 11, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 46, 47, 51, 53, 55, 56, 57, 58, 60, 62, 65, 66, 67, 68, 69, 70, 71, 72, 75, 77, 80, 81, 84, 85, 86, 88, 90, 91, 92, 93, 94, 95, 96, 100, 102] skin [100]

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small intestine [100] spinal muscle [90] spleen [100] stomach [100] testis [19, 21, 100] thymus [100] thyroid gland [100] tongue ( papillary [100]) [100] trachea [100] uterus [100] Additional information ( tissue distribution in dogfish [42]; isozyme distribution in different tissues [39,56]; PhK shows a wide tissue distribution, expression of subunits, overview [100]) [39, 42, 56, 100] Localization cytosol [25, 37, 38, 40, 42, 52] glycogen particle ( organelle-like particles [78]; due to protein-protein interactions in glycogen particles the proteins behave differently from those in cytosol [78]; together with other enzymes of glycogen metabolism linked together on glycogen particles [43]) [34, 43, 55, 78] membrane ( of sarcoplasmic reticulum [90]; KPI-2 is a transmembrane protein [99]) [90, 99] sarcoplasmic reticulum [34, 39, 90] soluble [25, 37, 38, 40, 42, 52] Purification (to near homogeneity) [64, 66] (recombinant g-subunit, as expressed in Sf-9 cells) [80] (recombinant c-Myc-/His6-tagged full-length KPI-2 from Sf9 cells by nickel affinity and ion exchange chromatography, and gel filtration) [99] (partial) [38] (to near homogeneity from glycogen-rich pellet, from 1000 rats) [48] (partial) [52] (heart) [56] (nonactivated enzyme) [54] (to near homogeneity) [40, 54] [11, 30, 62, 67, 92, 93] (2 isozymes separable by calmodulin affinity chromatography) [34] (active g subunit from inactive form by reverse-phase HPLC)) [85] (a, a’ and b subunits by preparative SDS-PAGE) [70] (as in vivo activated phosphorylase sa) [33] (as nonactivated enzyme) [27] (by affinity chromatography on calmodulin-Sepharose 4B) [47] (catalytic subunit (i.e. g subunit, from holoenzyme by dissociation)) [41] (catalytic subunit as expressed in Escherichia coli) [84]

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(catalytically active agd complexes) [47, 51] (catalytically active gd complexes) [47] (catalytically active proteolytic product of holoenzyme) [37] (d subunit) [36] (from protein-glycogen complex) [55] (from skeletal muscle) [91] (homogenous a, b and g subunits) [65] (isolation of denatured subunits) [34] (isolation of denatured subunits (from nonactivated enzyme)) [68] (liver) [37] (native and proteolytically generated enzyme forms) [74] (native enzyme from psoas muscle) [98] (native enzyme from skeletal muscle by anion exchange chromatography to homogeneity) [96] (native enzyme from skeletal muscle, recombinant enzyme subunit subcomplexes from Sf9 insect cells) [88] (overview) [34, 39] (partial) [25, 28] (to near homogeneity) [37, 55] (to near homogeneity (phosphorylase b is a persistent contaminant)) [27] (heart) [26] [42] (from sarcoplasmic reticular membranes of femoral muscle) [90] (from sarcoplasmic reticular membranes of spinal muscle) [90] (recombinant holoenzyme and enzyme subunit subcomplexes from Sf9 insect cells) [88] Crystallization (crystallization of PhK in active conformation) [3] (rabbit muscle phosphorylase kinase catalytic domain of catalytic subunit, i.e. Phkgtrnc, in the presence of Mg-ATP, X-ray data) [84] (crystal structures of the catalytic core, residues 1-298, of the g-subunit, the binary complex with Mn2+ /b-g-imidoadenosine 5’-triphosphate to a resolution of 2.6 A and the binary complex with Mg2+ /ADP to a resolution of 3.0 A) [10] (structure of a truncated form of the g-subunit of phosphorylase kinase in a ternary complex with a non-hydrolysable ATP analogue, adenylylimidodiphosphate, and a heptapeptide substrate related in sequence to both the natural substrate and to the optimal peptide substrate) [9] Cloning (mouse catalytic g subunit, Baculovirus-directed expression in Sf9 insect cells) [80] (PhK isozymes, DNA sequence and genomic localization determination and analysis, genetic organization, the genes encoding the a, b, and g subunits of PhK undergo extensive transcriptional processing, e.g. exon 6 of

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PhKG1 is a 3’ composite terminal exon due to the presence of weak polyadenylation and cleavage site in intron 6) [100] (expression of c-Myc-/His6-tagged full-length KPI-2 and minimal kinase fold, residues 137-407 plus an additional C-terminal segment in HEK-293 cells and in Spodoptera frugiperda Sf9 cells using the baculovirus transfection system) [99] (cooverexpression with the b subunit of the rabbit enzyme with the rat holoenzyme and rat agd and gd subunit complexes in Spodoptera frugiperda Sf9 cells via the baculovirus infection system, resulting in formation of subunit subcomplexes, overview) [88] (rabbit muscle phosphorylase kinase catalytic domain of catalytic subunit, expressed in Escherichia coli) [84] (two hybrid rabbit DNA library screening using the yeast strain EGY48 and a C-terminal fragment of isozyme PhKa, expression of the enzyme and interaction partners in C2C12 cells) [95] (two-hybrid plasmid construction of fusions containing the PhK b subunit and its deletion mutants and expression in a yeast two-hybrid system) [98] (isolation and sequence analysis of a cDNA clone encoding the entire catalytic subunit) [6] (isolation of cDNA clones for the catalytic g subunit of mouse muscle phosphorylase kinase) [13] (nucleotide sequence of cDNA encoding the catalytic subunit) [17] [15, 19] (PhK-g T isoform of phosphorylase kinase catalytic subunit) [21] (DNA sequence determination and structural analysis, genetic organization, the subunits of the muscle isozyme are encoded by different genes, subunit g is encoded by gene PHKG1, genes PHKA1, PHKB1, PHKG1, CALM1, CALM2, and CALM3 are involved, relation to several pseudogenes) [89] (cDNA sequence and predicted primary structure of the g M subunit) [22] (subcloning of subunits in Escherichia coli, overexpression of the soluble holoenzyme and of soluble trimeric agd and dimeric gd subunit subcomplexes, as well as coexpression with the b subunit of the rabbit enzyme also resulting in subunit complex formation, in Spodoptera frugiperda Sf9 cells via the baculovirus infection system) [88] (DNA sequence determination and structural analysis, genetic organization, the subunits of the muscle isozyme are encoded by different genes, subunit a is encoded by gene PHKA1, genes PHKA1, PHKB1, PHKG1, CALM1, CALM2, and CALM3 are involved, relation to several pseudogenes) [89] Engineering D299V ( naturally occurring mutation in gene PHKB, encoding subunit b, missense mutation leads to enzyme deficiency in vivo [89]) [89]

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Q657K ( naturally occurring heterozygous single amino acid replacement in gene PHKB, might not be significant for enzyme deficiency disease, patient shows low enzyme activity [89]) [89] Y770C ( naturally occurring heterozygous single amino acid replacement in gene PHKB, might not be significant for enzyme deficiency disease, patient shows low enzyme activity [89]) [89] Additional information ( a B2 repeat insertion generates alternate structures of the mouse muscle g-phosphorylase kinase gene [14]; regulatory enzyme of glycogen metabolism, mutations in the testis/liver isoform of the phosphorylase kinase g subunit cause autosomal liver glycogenosis. Mutation V106E, G189E and D215N are responsible for autosomal form of Phk deficiency [20]; construction of PhKb subunit deletion mutants [98]) [14, 20, 98]

6 Stability pH-Stability 6 ( below, rapid irreversible inactivation [42]) [42] Temperature stability 20 ( 2 mg enzyme/ml, trypsin-activated enzyme, with or without ATP, 4 h stable [29]) [29] 30 ( at least 30 min [37]) [37] 37 ( 50% loss of nonactivated enzyme activity within 15 min, 50% loss of agd subunit complex activity within 7 min, 90% loss of gd subunit complex activity within 5 min [47]) [47] 40 ( t1=2 : 3 min, in 10% ethylene glycol, pH 8 [37]) [37] 45 ( t1=2 : 1 min, in 10% ethylene glycol, pH 8 [37]) [37] General stability information , 5%, w/v, glycerol stabilizes [52] , About 70% loss of activity during centrifugation for 5 h on a glycerol density gradient [37] , d-Subunit remains tightly bound to agd subunit complex even in the presence of 8 M urea [47] , Effects of protein concentration, buffer and ATP on stability and dissociation behaviour of trypsin-activated enzyme [29] , In the presence of ATP nonactivated enzyme does not dissociate into catalytically active subunits as trypsin-activated enzyme does [29] , Inactive g subunit after reverse-phase HPLC can be reactivated by dilution into ice-cold, pH 8.2, Ca2+ /calmodulin containing buffer [85] , Incubation of nonactivated enzyme with 100 mM ATP at 0 C dissociates the 23 S enzyme to active 7.5 S and 14 S subunits, with LiBr it produces 5 S subunits [41] , Nonactivated or protein kinase-activated enzyme stable in the cold, not trypsin-activated enzyme [29]

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, Rabbit muscle enzyme is subject to pressure denaturation leading to the formation of polydisperse aggregates [39] , Unstable in the presence of Mg2+ [27] , With strong tendency to aggregate, unstable in high concentrations of ammonium sulfate for prolonged periods [55] , isoelectric focusing inactivates [30] , Ca2+ -free enzyme is unstable [42] , Rapid irreversible inactivation during desalting by gel filtration or dialysis at ionic strength below 0.1, sucrose, glycerol, salts, SH-compounds or reagents does not stabilize, glycogen, glucose, glucose 1-phosphate, glucose 6-phosphate, mono-, di- and trinucleotides or divalent metal ions and protease inhibitors do not protect [42] , Tends to aggregate upon standing [42] , unstable in dilute solutions [29, 38] Storage stability , -20 C, in 0.25 M sucrose, 0.1 M Tris-HCl, 0.5 mM DTT, pH 7.4, 50% glycerol, several weeks [38] , -70 C, in 20 mM triethanolamine-HCl, pH 7.5, 20% v/v glycerol, 1 mM DTT, 0.02% NaN3 , stable [48] , -70 C, several months [40] , Frozen in liquid N2 , in 50 mM b-glycerophosphate, pH 7, 2 mM EDTA, 1 mM DTT, 10% sucrose, stable [54] , -20 C, in 50 mM sodium glycerophosphate, 0.1% v/v 2-mercaptoethanol, pH 7, 2 mM EDTA, 50% v/v glycerol, at least 1 year [55] , -20 C, partially purified, at least 2 months [25] , -25 C, in 50% ethylene glycol, at least 1 month [37] , 0-4 C, in 5-20% glycerol, 70% loss of activity within 5 h, more rapid inactivation in 5-20% sucrose [37] , 0 C, 2 mg enzyme/ml, trypsin-activated enzyme, with or without ATP, 30% loss of activity within 4 h [29] , 0 C, in 10% ethylene glycol, at least 1 week [37] , 20 C, 2 mg enzyme/ml, trypsin-activated enzyme, with or without ATP, 4 h [29] , frozen, at least 6 months [27] , -15 C, 3 mg dogfish enzyme/ml, in 0.1 M glycerophosphate, 2 mM EDTA, pH 7, 0.3 M NaCl or in 0.1 M glycerophosphate, 2 mM EDTA, 10% sucrose, 1 mM ATP, pH 7, 1 mM DTT, about 50% loss of activity within 1 week [42] , -15 C, partially purified dogfish enzyme, lyophilized, almost indefinitely [42]

References [1] Hunter, T.: Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell, 80, 225-236 (1995)

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[2] Kemp, B.E.; Parker, M.W.; Hu, S.; Tiganis, T.; House, C.: Substrate and pseudosubstrate interactions with protein kinases: determinants of specificity. Trends Biochem. Sci., 19, 440-444 (1994) [3] Johnson, L.N.; Noble, M.E.M.; Owen, D.J.: Active and inactive protein kinases: structural basis for regulation. Cell, 85, 149-158 (1996) [4] Kemp, B.E.; Pearson, R.B.; House, M.: Pseudosubstrate-based peptide inhibitors. Methods Enzymol., 201, 287-304 (1991) [5] Adams, J.A.: Kinetic and catalytic mechanisms of protein kinases. Chem. Rev., 101, 2271-2290 (2001) [6] da Cruz e Silva, E.F.; Cohen, P.T.: Isolation and sequence analysis of a cDNA clone encoding the entire catalytic subunit of phosphorylase kinase. FEBS Lett., 220, 36-42 (1987) [7] Dasgupta, M.; Blumenthal, D.K.: Characterization of the regulatory domain of the g-subunit of phosphorylase kinase. The two noncontiguous calmodulin-binding subdomains are also autoinhibitory. J. Biol. Chem., 270, 22283-22289 (1995) [8] Dasgupta, M.; Honeycutt, T.; Blumenthal, D.K.: The g-subunit of skeletal muscle phosphorylase kinase contains two noncontiguous domains that act in concert to bind calmodulin. J. Biol. Chem., 264, 17156-17163 (1989) [9] Lowe, E.D.; Noble, M.E.; Skamnaki, V.T.; Oikonomakos, N.G.; Owen, D.J.; Johnson, L.N.: The crystal structure of a phosphorylase kinase peptide substrate complex: kinase substrate recognition. EMBO J., 16, 6646-6658 (1997) [10] Owen, D.J.; Noble, M.E.; Garman, E.F.; Papageorgiou, A.C.; Johnson, L.N.: Two structures of the catalytic domain of phosphorylase kinase: an active protein kinase complexed with substrate analogue and product. Structure, 3, 467-482 (1995) [11] Reimann, E.M.; Titani, K.; Ericsson, L.H.; Wade, R.D.; Fischer, E.H.; Walsh, K.A.: Homology of the g subunit of phosphorylase b kinase with cAMP-dependent protein kinase. Biochemistry, 23, 4185-4192 (1984) [12] Bender, P.K.; Emerson, C.P., Jr.: Skeletal muscle phosphorylase kinase catalytic subunit mRNAs are expressed in heart tissue but not in liver. J. Biol. Chem., 262, 8799-8805 (1987) [13] Chamberlain, J.S.; VanTuinen, P.; Reeves, A.A.; Philip, B.A.; Caskey, C.T.: Isolation of cDNA clones for the catalytic g subunit of mouse muscle phosphorylase kinase: expression of mRNA in normal and mutant Phk mice. Proc. Natl. Acad. Sci. USA, 84, 2886-2890 (1987) [14] Maichele, A.J.; Farwell, N.J.; Chamberlain, J.S.: A B2 repeat insertion generates alternate structures of the mouse muscle g-phosphorylase kinase gene. Genomics, 16, 139-149 (1993) [15] Hanks, S.K.: Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family. Proc. Natl. Acad. Sci. USA, 84, 388-392 (1987) [16] Cawley, K.C.; Akita, C.G.; Angelos, K.L.; Walsh, D.A.: Characterization of the gene for rat phosphorylase kinase catalytic subunit. J. Biol. Chem., 268, 1194-1200 (1993)

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[17] Cawley, K.C.; Ramachandran, C.; Gorin, F.A.; Walsh, D.A.: Nucleotide sequence of cDNA encoding the catalytic subunit of phosphorylase kinase from rat soleus muscle. Nucleic Acids Res., 16, 2355-2356 (1988) [18] Burwinkel, B.; Shiomi, S.; Al Zaben, A.; Kilimann, M.W.: Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis. Hum. Mol. Genet., 7, 149-154 (1998) [19] Hanks, S.K.: Messenger ribonucleic acid encoding an apparent isoform of phosphorylase kinase catalytic subunit is abundant in the adult testis. Mol. Endocrinol., 3, 110-116 (1989) [20] Maichele, A.J.; Burwinkel, B.; Maire, I.; Sovik, O.; Kilimann, M.W.: Mutations in the testis/liver isoform of the phosphorylase kinase g subunit (PHKG2) cause autosomal liver glycogenosis in the gsd rat and in humans. Nat. Genet., 14, 337-340 (1996) [21] Calalb, M.B.; Fox, D.T.; Hanks, S.K.: Molecular cloning and enzymatic analysis of the rat homolog of “PhK-g T,“ an isoform of phosphorylase kinase catalytic subunit. J. Biol. Chem., 267, 1455-1463 (1992) [22] Wehner, M.; Kilimann, M.W.: Human cDNA encoding the muscle isoform of the phosphorylase kinase g subunit (PHKG1). Hum. Genet., 96, 616-618 (1995) [23] Bahri, S.M.; Chia, W.: DPhK-g, a putative Drosophila kinase with homology to vertebrate phosphorylase kinase g subunits: molecular characterisation of the gene and phenotypic analysis of loss of function mutants. Mol. Gen. Genet., 245, 588-597 (1994) [24] Kawai, J.; Shinagawa, A.; Shibata, K.; Yoshino, M.; Itoh, M.; et al.: Functional annotation of a full-length mouse cDNA collection. Nature, 409, 685-690 (2001) [25] Krebs, E.G.; Fischer, E.H.: Phosphorylase b-to-a converting enzyme of rabbit skeletal muscle. Biochim. Biophys. Acta, 20, 150-157 (1956) [26] Rall, T.W.; Wosilait, W.D.; Sutherland, E.W.: Interconversion of phosphorylase a and phosphorylase b from dog heart muscle. Biochim. Biophys. Acta, 20, 69-76 (1956) [27] Krebs, E.G.; Love, D.S.; Bratvold, G.E.; Trayser, K.A.; Meyer, W.L.; Fischer, E.H.: Purification and properties of rabbit skeletal muscle phosphorylase b kinase. Biochemistry, 3, 1022-1033 (1964) [28] Meyer, W.L.; Fischer, E.H.; Krebs, E.G.: Activation of skeletal muscle phosphorylase b kinase by calcium ion. Biochemistry, 3, 1033-1039 (1964) [29] Graves, D.J.; Hayakawa, T.; Horvitz, R.A.; Beckman, E.; Krebs, E.G.: Studies on the subunit structure of trypsin-activated phosphorylase kinase. Biochemistry, 12, 580-585 (1973) [30] Hayakawa, T.; Perkins, J.P.; Walsh, D.A.; Krebs, E.G.: Physiochemical properties of rabbit skeletal muscle phosphorylase kinase. Biochemistry, 12, 567-573 (1973) [31] Hayakawa, T.; Perkins, J.P.; Krebs, E.G.: Studies of the subunit structure of rabbit skeletal muscle phosphorylase kinase. Biochemistry, 12, 574-580 (1973) [32] Tu, J.I, Graves, D.J.: Inhibition of the phosphorylase kinase catalyzed reaction by glucose-6-P. Biochem. Biophys. Res. Commun., 53, 59-65 (1973)

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[33] Yeoman, S.J.; Cohen, P.: The hormonal control of activity of skeletal muscle phosphorylase kinase. Phosphorylation of the enzyme at two sites in vivo in response to adrenalin. Eur. J. Biochem., 51, 93-104 (1975) [34] Pickett-Gies, C.A.; Walsh, D.A.: Phosphorylase kinase. The Enzymes, 3rd. Ed. (Boyer, P.D., Krebs, E.G., eds.), 17, 395-456 (1986) [35] Kilimann, M.; Heilmeyer, L.M.G.: The effect of Mg2+ on the Ca2+ -binding properties of non-activated phosphorylase kinase. Eur. J. Biochem., 73, 191-197 (1977) [36] Cohen, P.; Burchell, A.; Foulkes, J.G.; Cohen, P.T.W.; Vanaman, T.C.; Nairn, A.C.: Identification of the Ca2+ -dependent modulator protein as the fourth subunit of rabbit skeletal muscle phosphorylase kinase. FEBS Lett., 92, 287-293 (1978) [37] Sakai, K.; Matsumura, S.; Okimura, Y.; Yamamura, H.; Nishizuka, Y.: Liver glycogen phosphorylase kinase. Partial purification and characterization. J. Biol. Chem., 254, 6631-6637 (1979) [38] Vandenheede, J.R.; De Wulf, H.; Merlevede, W.: Liver phosphorylase b kinase. Cyclic-AMP-mediated activation and properties of the partially purified rat-liver enzyme. Eur. J. Biochem., 101, 51-58 (1979) [39] Carlson, G.M.; Bechtel, P.J.; Graves, D.J.: Chemical and regulatory properties of phosphorylase kinase and cyclic AMP-dependent protein kinase. Adv. Enzymol. Relat. Areas Mol. Biol., 50, 41-115 (1979) [40] Cooper, R.H.; Sul, H.S.; McCullough, T.E.; Walsh, D.: Purification and properties of the cardiac isoenzyme of phosphorylase kinase. J. Biol. Chem., 255, 11794-11801 (1980) [41] Skuster, J.R.; Chan, K.F.J.; Graves, D.J.: Isolation and properties of the catalytically active g subunit of phosphorylase b kinase. J. Biol. Chem., 255, 2203-2210 (1980) [42] Pocinwong, S.; Blum, H.; Malencik, D.; Fisher, E.H.: Phosphorylase kinase from dogfish skeletal muscle. Purification and properties. Biochemistry, 20, 7219-7226 (1981) [43] Cohen, P.; Klee, C.B.; Picton, C.; Shenolikar, S.: Calcium control of muscle phosphorylase kinase through the combined action of calmodulin and troponin. Ann. N.Y. Acad. Sci., 356, 151-161 (1980) [44] King, M.M.; Carslon, G.M.: Synergistic effect of Ca2+ and Mg2+ in promoting an activity of phosphorylase kinase that is insensitive to ethylene glycol bis(b-aminoethyl ether)-N,N-tetraacetic acid. Arch. Biochem. Biophys., 209, 517-523 (1981) [45] King, M.M.; Carslon, G.M.: Synergistic activation by Ca2+ and Mg2+ as the primary cause for hysteresis in the phosphorylase kinase reactions. J. Biol. Chem., 256, 11058-11064 (1981) [46] Chan, K.F.J.; Graves, D.J.: Rabbit skeletal muscle phosphorylase kinase. Catalytic and regulatory properties of the active a g d and g d complexes. J. Biol. Chem., 257, 5948-5955 (1982) [47] Chan, K.F.J.; Graves, D.J.: Rabbit skeletal muscle phosphorylase kinase. Interactions between subunits and influence of calmodulin on different complexes. J. Biol. Chem., 257, 5956-5961 (1982)

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[48] Chrisman, T.D.; Jordan, J.E.; Exton, J.H.: Purification of rat liver phosphorylase kinase. J. Biol. Chem., 257, 10798-10804 (1982) [49] Kilimann, M.W.; Heilmeyer, L.M.G.: Multiple activities on phosphorylase kinase. 1. Characterization of three partial activities by their response to calcium ion, magnesium ion, pH, and ammonium chloride and effect of activation by phosphorylation and proteolysis. Biochemistry, 21, 17271734 (1982) [50] Kilimann, M.W.; Heilmeyer, L.M.G.: Multiple activities on phosphorylase kinase. 2. Different specificities toward the protein substrates phosphorylase b, troponin, and phosphorylase kinase. Biochemistry, 21, 1735-1739 (1982) [51] Chan, K.F.J.; Graves, D.J.: Isolation and physicochemical properties of active complexes of rabbit muscle phosphorylase kinase. J. Biol. Chem., 257, 5939-5947 (1982) [52] Pohlig, G.; Wingender-Drissen, R.; Becker, J.U.: Characterization of phosphorylase kinase activities in yeast. Biochem. Biophys. Res. Commun., 114, 331-338 (1983) [53] Picton, C.; Shenolikar, S.; Grand, R.; Cohen, P.: Calmodulin as an integral subunit of phosphorylase kinase from rabbit skeletal muscle. Methods Enzymol., 102, 219-227 (1983) [54] Killilea, S.D.; Ky, N.M.: Purification and partial characterization of bovine heart phosphorylase kinase. Arch. Biochem. Biophys., 221, 333-342 (1983) [55] Cohen, P.: Phosphorylase kinase from rabbit skeletal muscle. Methods Enzymol., 99, 243-250 (1983) [56] Sul, H.S.; Dirden, B.; Angelos, K.L.; Hallenbeck, P.; Walsh, D.: Cardiac phosphorylase kinase: preparation and properties. Methods Enzymol., 99, 250-259 (1983) [57] Chan, K.F.J.; Graves, D.J.: Separation of the subunits of muscle phosphorylase kinase. Methods Enzymol., 99, 259-267 (1983) [58] Graves, D.J.: Use of peptide substrates to study the specificity of phosphorylase kinase phosphorylation. Methods Enzymol., 99, 268-278 (1983) [59] Ashida, M.; Wyatt, G.R.: Properties and activation of phosphorylase kinase from silkmoth fat body. Insect Biochem., 9, 403-409 (1979) [60] Negami, A.; Sakai, K.; Kobayashi, T.; Tabuchi, H.; Nakamura, S.; Yamamura, H.: Two diverse effects of poly(L-lysine) on rabbit skeletal muscle phosphorylase kinase: stimulation of autophosphorylation and inhibition of its activity. FEBS Lett., 166, 335-338 (1984) [61] Chrisman, T.D.; Sobo, G.E.; Exton, J.H.: The Mg2+ requirements of nonactivated and activated rat liver phosphorylase kinase. Inhibition of the activated form by free Mg2+ . FEBS Lett., 167, 295-300 (1984) [62] Crabb, J.W.; Heilmeyer, L.M.G.: High performance liquid chromatography purification and structural characterization of the subunits of rabbit muscle phosphorylase kinase. J. Biol. Chem., 259, 6346-6350 (1984) [63] Srivastava, A.K.: Inhibition of phosphorylase kinase, and tyrosine protein kinase activities by quercetin. Biochem. Biophys. Res. Commun., 131, 1-5 (1985)

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[64] Nikolaropoulos, S.; Sotiroudis, T.G.: Phosphorylase kinase from chicken gizzard. Partial purification and characterization. Eur. J. Biochem., 151, 467-473 (1985) [65] Jennissen, H.P.; Petersen-von Gehr, J.K.H.; Botzet, G.: Activation and inhibition of phosphorylase kinase by monospecific antibodies against preparatively isolated a, b and g subunits. Eur. J. Biochem., 147, 619-630 (1985) [66] Andreeva, I.E.; Livanova, N.B.; Eronina, T.B.; Silonova, G.V.; Poglazov, B.F.: Phosphorylase kinase from chicken skeletal muscle. Quaternary structure, regulatory properties and partial proteolysis. Eur. J. Biochem., 158, 99-106 (1986) [67] Kee, S.M.; Graves, D.J.: Properties of the g subunit of phosphorylase kinase. J. Biol. Chem., 262, 9448-9453 (1987) [68] Paudel, H.K.; Carlson, G.M.: Inhibition of the catalytic subunit of phosphorylase kinase by its a/b subunits. J. Biol. Chem., 262, 11912-11915 (1987) [69] Cox, D.E.; Meinke, M.H.; Edstrom, R.D.: Mechanism of calmodulin inhibition of cAMP-dependent protein kinase activation of phosphorylation kinase. Arch. Biochem. Biophys., 259, 350-362 (1987) [70] Crabb, J.W.; Harris, W.R.; Johnson, C.M.; Sotiroudis, T.G.; Kuhn, C.C.; Heilmeyer, L.M.G.: Electrophoretic purification of the a and b subunits of phosphorylase kinase and evidence in support of the deduced amino acid sequences. Electrophoresis, 11, 133-140 (1990) [71] Elliott, L.H.; Wilkinson, S.E.; Sedgwick, A.D.; Hill, C.H.; Lawton, G.; Davis, P.D.; Nixon, J.S.: K252a is a potent and selective inhibitor of phosphorylase kinase. Biochem. Biophys. Res. Commun., 171, 148-154 (1990) [72] Farrar, Y.J.K.; Carlson, G.M.: Kinetic characterization of the calmodulinactivated catalytic subunit of phosphorylase kinase. Biochemistry, 30, 10274-10279 (1991) [73] Beleta, J.; Benedicto, P.; Gella, F.J.: Regulatory properties of rabbit liver phosphorylase kinase. Int. J. Biochem., 22, 453-460 (1990) [74] Beleta, J.; Benedicto, P.; Aymerich, P.; Gella, F.J.: Purification and characterization of native and proteolytic forms of rabbit liver phosphorylase kinase. Int. J. Biochem., 22, 443-451 (1990) [75] Eronina, T.B.; Andreeva, I.E.; Livanova, N.B.; Silonova, G.V.; Poglazov, B.F.: Regulatory properties and quaternary structure of chicken skeletal muscle phosphorylase kinase. Biol. Zentralbl., 107, 39-43 (1988) [76] Doorneweerd, D.D.; Tan, A.W.H.; Nuttall, F.Q.: Liver phosphorylase kinase: characterization of two interconvertible forms and partial purification of phosphorylase kinase a. Mol. Cell. Biochem., 47, 45-53 (1982) [77] Paudel, H.K.; Carlson, G.M.: Functional and structural similarities between the inhibitory region of troponin I coded by exon VII and the calmodulin-binding regulatory region of the catalytic subunit of phosphorylase kinase. Proc. Natl. Acad. Sci. USA, 87, 7285-7289 (1990) [78] Heilmeyer, L.M.G.: Molecular basis of signal integration in phosphorylase kinase. Biochim. Biophys. Acta, 1094, 168-174 (1991)

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[79] Paudel, H.K.; Xu, Y.H.; Jarrett, H.W.; Carlson, G.M.: The model calmodulin-binding peptide melittin inhibits phosphorylase kinase by interacting with its catalytic center. Biochemistry, 32, 11865-11872 (1993) [80] Lanciotti, R.A.; Bender, P.K.: Baculovirus-directed expression of the gsubunit of phosphorylase kinase: purification and calmodulin dependence. Biochem. J., 299, 183-189 (1994) [81] Cheng, A.; Fitzgerald, T.J.; Carlson, G.M.: Adenosine 5-diphosphate as an allosteric effector of phosphorylase kinase from rabbit skeletal muscle. J. Biol. Chem., 260, 2535-2542 (1985) [82] Huang, C.Y.F.; Yuan, C.J.; Blumenthal, D.K.; Graves, D.J.: Identification of the substrate and pseudosubstrate binding sites of phosphorylase kinase g-subunit. J. Biol. Chem., 270, 7183-7188 (1995) [83] Lanciotti, R.A.; Bender, P.K.: The g subunit of phosphorylase kinase contains a pseudosubstrate sequence. Eur. J. Biochem., 230, 139-145 (1995) [84] Owen, D.J.; Papageorgiou, A.C.; Garman, E.F.; Noble, M.E.M.; Johnson, L.N.: Expression, purification and crystallisation of phosphorylase kinase catalytic domain. J. Mol. Biol., 246, 374-381 (1995) [85] Kee, S.M.; Graves, D.J.: Isolation and properties of the active g subunit of phosphorylase kinase. J. Biol. Chem., 261, 4732-4737 (1986) [86] Xu, Y.H.; Wilkinson, D.A.; Carlson, G.M.: Divalent cations but not other activators enhance phosphorylase kinases affinity for glycogen phosphorylase. Biochemistry, 35, 5014-5021 (1996) [87] Rozi, A.; Jia, Y.: A theoretical study of effects of cytosolic Ca2+ oscillations on activation of glycogen phosphorylase. Biophys. Chem., 106, 193-202 (2003) [88] Kumar, P.; Brushia, R.J.; Hoye, E.; Walsh, D.A.: Baculovirus-mediated overexpression of the phosphorylase b kinase holoenzyme and a g d and g d subcomplexes. Biochemistry, 43, 10247-10254 (2004) [89] Burwinkel, B.; Hu, B.; Schroers, A.; Clemens, P.R.; Moses, S.W.; Shin, Y.S.; Pongratz, D.; Vorgerd, M.; Kilimann, M.W.: Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases. Eur. J. Hum. Genet., 11, 516-526 (2003) [90] Shmelev, V.K.; Serebrenikova, T.P.; Nesterov, V.P.: Role of glycogen phosphorylase kinase in regulation of Ca2+ -ATPase of sarcoplasmic reticulum of the common frog Rana temporaria. J. Evol. Biochem. Physiol., 40, 98101 (2004) [91] Chebotareva, N.A.; Andreeva, I.E.; Makeeva, V.F.; Livanova, N.B.; Kurganov, B.I.: Effect of molecular crowding on self-association of phosphorylase kinase and its interaction with phosphorylase b and glycogen. J. Mol. Recognit., 17, 426-432 (2004) [92] Hilder, T.L.; Carlson, G.M.; Haystead, T.A.; Krebs, E.G.; Graves, L.M.: Caspase-3 dependent cleavage and activation of skeletal muscle phosphorylase b kinase. Mol. Cell. Biochem., 275, 233-242 (2005) [93] Priddy, T.S.; MacDonald, B.A.; Heller, W.T.; Nadeau, O.W.; Trewhella, J.; Carlson, G.M.: Ca2+ -induced structural changes in phosphorylase kinase

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[94] [95]

[96]

[97]

[98]

[99]

[100] [101] [102]

Phosphorylase kinase

detected by small-angle X-ray scattering. Protein Sci., 14, 1039-1048 (2005) Nadeau, O.W.; Gogol, E.P.; Carlson, G.M.: Cryoelectron microscopy reveals new features in the three-dimensional structure of phosphorylase kinase. Protein Sci., 14, 914-920 (2005) Archila, S.; King, M.A.; Carlson, G.M.; Rice, N.A.: The cytoskeletal organizing protein Cdc42-interacting protein 4 associates with phosphorylase kinase in skeletal muscle. Biochem. Biophys. Res. Commun., 345, 15921599 (2006) Makeeva, V.F.; Chebotareva, N.A.; Andreeva, I.E.; Livanova, N.B.; Kurganov, B.I.: Interaction of phosphorylase kinase from rabbit skeletal muscle with flavin adenine dinucleotide. Biochemistry (Moscow), 71, 652-657 (2006) Sijens, P.E.; Smit, G.P.; Borgdorff, M.A.; Kappert, P.; Oudkerk, M.: Multiple voxel 1H MR spectroscopy of phosphorylase-b kinase deficient patients (GSD IXa) showing an accumulation of fat in the liver that resolves with aging. J. Hepatol., 45, 851-855 (2006) Nadeau, O.W.; Anderson, D.W.; Yang, Q.; Artigues, A.; Paschall, J.E.; Wyckoff, G.J.; McClintock, J.L.; Carlson, G.M.: Evidence for the location of the allosteric activation switch in the multisubunit phosphorylase kinase complex from mass spectrometric identification of chemically crosslinked peptides. J. Mol. Biol., 365, 1429-1445 (2007) Wang, H.; Brautigan, D.L.: Peptide microarray analysis of substrate specificity of the transmembrane Ser/Thr kinase KPI-2 reveals reactivity with cystic fibrosis transmembrane conductance regulator and phosphorylase. Mol. Cell. Proteomics, 5, 2124-2130 (2006) Winchester, J.S.; Rouchka, E.C.; Rowland, N.S.; Rice, N.A.: In silico characterization of phosphorylase kinase: evidence for an alternate intronic polyadenylation site in PHKG1. Mol. Genet. Metab., 92, 234-242 (2007) Priddy, T.S.; Price, E.S.; Johnson, C.K.; Carlson, G.M.: Single molecule analyses of the conformational substates of calmodulin bound to the phosphorylase kinase complex. Protein Sci., 16, 1017-1023 (2007) Priddy, T.S.; Middaugh, C.R.; Carlson, G.M.: Electrostatic changes in phosphorylase kinase induced by its obligatory allosteric activator Ca2+ . Protein Sci., 16, 517-527 (2007)

125

Elongation factor 2 kinase

2.7.11.20

1 Nomenclature EC number 2.7.11.20 Systematic name ATP:[elongation factor 2] phosphotransferase Recommended name elongation factor 2 kinase Synonyms GCN2 [9] eEF-2 kinase [4, 5, 10, 12] eEF2 kinase [6, 8, 11] eEF2-kinase [7] eEF2K [6] elongation factor 2 kinase [1, 2] eukaryotic elongation factor 2 kinase [4, 5, 8, 10, 11, 12] eukaryotic elongation factor-2 kinase [5] eukaryotic translation initiation factor 2a kinase [9] CAS registry number 116283-83-1

2 Source Organism





Homo sapiens (no sequence specified) [4, 5, 6, 7, 8, 11, 12] Rattus norvegicus (no sequence specified) [3, 5, 8] Saccharomyces cerevisiae (no sequence specified) [9] Aplysia californica (no sequence specified) [10] Homo sapiens (UNIPROT accession number: O00418) [1] Caenorhabditis elegans (UNIPROT accession number: O01991) [1] Mus musculus (UNIPROT accession number: O08796) [1] Rattus norvegicus (UNIPROT accession number: P70531) [1,2]

3 Reaction and Specificity Catalyzed reaction ATP + [elongation factor 2] = ADP + [elongation factor 2] phosphate

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Reaction type phospho group transfer Natural substrates and products S ATP + [elongation factor 2] ( elongation factor 2 regulates the translation elongation through mTOR, p38, and MEK pathways, and is modulated through protein phosphatase 2A, overview [3]; enzyme regulation by de-/phosphorylation, overview [8]; enzyme regulation via de-/phosphorylations, especially at Ser78, involving several kinases is dependent on the cellular amino acid status, enzyme regulation, overview [12]; phosphorylation at Thr56 [11]; phosphorylation at Thr57 inhibits the elongation factor 2 and blocks translational elongation, enzyme activity is regulated by rampamycin, 5-hydroxytryptamine, and serotonin, regulation mechanism [10]) (Reversibility: ?) [3, 4, 5, 7, 8, 10, 11, 12] P ADP + [elongation factor 2]phosphate S ATP + [elongation factor 3] (Reversibility: ?) [9] P ADP + [elongation factor 3]phosphate S ATP + [elongation translation factor 2] (Reversibility: ?) [6] P ADP + [elongation translation factor 2]phosphate S ATP + [eukaryotic translation initiation factor 2a] ( GCN2 mediates translational control of gene expressionin amino acid-starved cells by phosphorylation of the eukaryotic translation initiation factor 2a associated to polyribosome and the regulatory GCN1-GCN20 complex, overview [9]) (Reversibility: ?) [9] P ADP + [eukaryotic translation initiation factor 2a]phosphate S Additional information ( SCH66336, a farnesyltransferase inhibitor, induces rapid phosphorylation and inhibition of eukaryotic translation elongation factor 2 in head and squamous cell carcinoma cells leading to growth inhibition in the cancer cells, the inhibitor functions independently of the signaling cascade involving the eEF2 kinase and its activators phosphorylated p70S6K and phosphorylated MEK [6]; the enzyme expression and activity is increased in several forms of malignancy and human cancer, non-specific inhibitors of the enzyme cause cell death [4]; the enzyme regulates protein synthesis in skeletal muscle [11]; translation regulation mechanism [9]; unphosphorylated elongation factor 2 promotes translational elongation, phosphorylation by the eEF2-kinase inhibits it, eEF2-kinase phosphorylated elongation factor 2 is further phosphorylated by cAMP-dependent protein kinase, EC 2.7.11.11, upon forskolin treatment leading to inhibition of elongation of cyclin D3 in T-lymphocytes, overview [7]) (Reversibility: ?) [4, 6, 7, 9, 11] P ? Substrates and products S ATP + [elongation factor 2] ( elongation factor 2 regulates the translation elongation through mTOR, p38, and MEK pathways, and is modulated through protein phosphatase 2A, overview [3]; enzyme regulation by de-/phosphorylation, overview [8]; enzyme regulation

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P S P S P S

P S P S

P

2.7.11.20

via de-/phosphorylations, especially at Ser78, involving several kinases is dependent on the cellular amino acid status, enzyme regulation, overview [12]; phosphorylation at Thr56 [3,11]; phosphorylation at Thr57 inhibits the elongation factor 2 and blocks translational elongation, enzyme activity is regulated by rampamycin, 5-hydroxytryptamine, and serotonin, regulation mechanism [10]; phosphorylation at Thr57 inhibits the elongation factor 2 [10]) (Reversibility: ?) [3, 4, 5, 7, 8, 10, 11, 12] ADP + [elongation factor 2]phosphate ATP + [elongation factor 3] (Reversibility: ?) [9] ADP + [elongation factor 3]phosphate ATP + [elongation translation factor 2] (Reversibility: ?) [6] ADP + [elongation translation factor 2]phosphate ATP + [eukaryotic translation initiation factor 2a] ( GCN2 mediates translational control of gene expressionin amino acid-starved cells by phosphorylation of the eukaryotic translation initiation factor 2a associated to polyribosome and the regulatory GCN1-GCN20 complex, overview [9]) (Reversibility: ?) [9] ADP + [eukaryotic translation initiation factor 2a]phosphate ATP + a protein (Reversibility: ?) [1, 2] ADP + a phosphoprotein Additional information ( SCH66336, a farnesyltransferase inhibitor, induces rapid phosphorylation and inhibition of eukaryotic translation elongation factor 2 in head and squamous cell carcinoma cells leading to growth inhibition in the cancer cells, the inhibitor functions independently of the signaling cascade involving the eEF2 kinase and its activators phosphorylated p70S6K and phosphorylated MEK [6]; the enzyme expression and activity is increased in several forms of malignancy and human cancer, non-specific inhibitors of the enzyme cause cell death [4]; the enzyme regulates protein synthesis in skeletal muscle [11]; translation regulation mechanism [9]; unphosphorylated elongation factor 2 promotes translational elongation, phosphorylation by the eEF2-kinase inhibits it, eEF2-kinase phosphorylated elongation factor 2 is further phosphorylated by cAMP-dependent protein kinase, EC 2.7.11.11, upon forskolin treatment leading to inhibition of elongation of cyclin D3 in T-lymphocytes, overview [7]) (Reversibility: ?) [4, 6, 7, 9, 11] ?

Inhibitors carbachol ( a secretagogue, increases elongation rates, and decreases elongation factor 2 phosphorylation [3]) [3] cholecystokinin ( a secretagogue, increases elongation rates, increases phosphorylation of eEF2 kinase, and decreases elongation factor 2 phosphorylation reversed by rapamycin, PD98059, calyculin, or SB202190 [3]) [3] NH125 ( an imidazolium histidine kinase inhibitor also inhibits the eukaryotic eEF-2 kinase enzyme in vitro and in vivo, IC50 is 60 nM, de-

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creases viability of cancer cell lines with IC50S of 0.0007 to 0.0048 mM, overview [4]) [4] serotonin ( inhibits the enzyme in synaptosomes and in isolated neurites, antagonizes rapamycin/5-hydroxytryptamine, mechanism [10]) [10] TS2 ( 1,3-selenazine derivative [7]) [7] TS4 ( 1,3-selenazine derivative [7]) [7] bombesin ( a secretagogue, increases elongation rates, and decreases elongation factor 2 phosphorylation [3]) [3] phorbol ester PMA [3] Additional information ( inhibition of elongation factor 2 phosphorylation by the eEF2-kinase prevents the forskolin-induced down-regulation of cyclin D3 elongation [7]; no effect by CPT-cAMP and A23187 [3]; non-specific inhibitors of the enzyme cause cell death [4]) [3, 4, 7] Cofactors/prosthetic groups ATP [3,4,5,6,7,8,9,10,11,12] Activating compounds 2-deoxy-d-glucose [8] 5-amino-4-imidazolecarboxyamide riboside [8] calmodulin ( dependent on [8,12]; completely dependent on [8]; strong activation, activation in response to exercise in skeletal muscle [11]) [4, 8, 11, 12] GCN1-GCN20 ( positive effectors, uncharged tRNAs activate GCN2 requiring direct interaction with both the GCN1-GCN20 regulatory complex and ribosomes [9]) [9] PD98059 ( reverses activation of the elongation factor 2 by dephosphorylation through cholecystokinin [3]) [3] rapamycin ( increases the binding of calmodulin to the enzyme [12]; reverses activation of the elongation factor 2 by dephosphorylation through cholecystokinin [3]) [3, 8, 12] SB202190 ( reverses activation of the elongation factor 2 by dephosphorylation through cholecystokinin [3]) [3] calyculin ( reverses activation of the elongation factor 2 by dephosphorylation through cholecystokinin [3]) [3] carbonyl cyanide 3-chlorophenylhydrazone [8] mTOR ( mediates the insulin-induced activation of Ser78 phosphorylation, insulin-dependent decrease of eEF2 phosphorylation is blocked by rapamycin [12]) [12] phosphorylated MEK ( activates the enzyme [6]) [6] phosphorylated p70S6K ( activates the enzyme [6]) [6] rapamycin/5-hydroxytryptamine ( rapamycin activates the enzyme in neuron and antagonizes serotonin mediated by 5-hydroxytryptamine, rapamycin alone has no effect, but increases with 5-hydroxytryptamine the dephosphorylation of the eukaryotic elongation factor 2, 5-hydroxytryptamine decreases the phosphorylation of the eukaryotic elongation factor 2 at Thr57 in a rapamycin-sensitive manner, mechanism [10]) [10]

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uncharged tRNAs ( activate GCN2 requiring direct interaction with both the GCN1-GCN20 regulatory complex and ribosomes [9]) [9] Additional information ( 90 min continuous exercise rapidly increases eukaryotic elongation factor 2 phosphorylation 5-7fold within 1 minute in skeletal muscle of male humans, activation does not function by covalent mechanisms but by allosteric mechanisms involving Ca2+ signaling via calmodulin [11]; ATP depletion activates the enzyme [8]; ATP depletion activates the enzyme in cardiomyocytes [8]; no effect by CPTcAMP and A23187 [3]; the eEF3-like domain has an effector function in GCN2 activation [9]) [3, 8, 9, 11] Metals, ions Ca2+ ( dependent on [12]; Ca2+ -dependent elongation factor 2 phosphorylation and inhibition blocks the elongation in translation, rapamycin/5-hydroxytryptamine increase the dephosphorylation [10]; completely dependent on, activates [8]; dependent on, activates [8]; strong activation, activation in response to exercise in skeletal muscle [11]) [4, 8, 10, 11, 12] Mg2+ [4, 8, 12] pH-Optimum 7 ( assay at [8]) [8] 7.5 ( assay at [4,12]) [4, 12] Temperature optimum ( C) 30 ( assay at [4,8,12]) [4, 8, 12]

4 Enzyme Structure Subunits ? ( x * 81499, calculation from nucleotide sequence [2]) [2] Additional information ( recombinant GST-tagged enzyme peptide mapping [8]) [8] Posttranslational modification phosphoprotein ( phosphorylation at Ser366 inhibits the enzyme, mediated by cholecystokinin [3]; the eEF2 kinase is activated by phosphorylation through AMPK, phosphorylation sites of the eEF2 kinase are Ser366, Ser398, and Ser78, the phosphorylation of the latter is regulated by insulin in an mTOR protein-dependent manner, Ser78 is no target for the kinase S6K1 [12]; the enzyme performs autophosphorylation, stimulation of AMP-activated protein kinase, EC 2.7.11.11, by AMP leads to activation of the enzyme and to its phosphorylation at Ser398 in the regulatory domain, other phosphorylation sites of the enzyme are Ser78, Ser359, Ser377, and Ser366 [8]; the enzyme performs autophosphorylation, stimulation of AMP-activated protein kinase, EC 2.7.11.11, by AMP leads to activation of the wild-type and mutant enzyme and to its phosphorylation at Ser398 in the regulatory domain, other phosphorylation sites of the enzyme

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are Ser78, Ser359, Ser377, and Ser366, the latter is phosphorylated by kinases S6K1 and p90RSK inhibiting the enzyme [8]) [3, 8, 12] Additional information ( the enzyme is ubiquitinated in vivo, ubiquitination and turnover is increased by inhibition of heat shock protein 90, enzyme degradation involves the proteasome [5]) [5]

5 Isolation/Preparation/Mutation/Application Source/tissue A-172 cell ( glioblastoma cell line [4]) [4] A-2780 cell ( ovarian carcinoma cell line [4,5]) [4, 5] HeLa cell ( cervical carcinoma cell line [4]) [4] JURKAT cell [7] KB cell ( oral epidermoid carcinoma cell line [8]) [8] MCF-7 cell ( breast carcinoma cell line [4]; breastcancer cell line [5]) [4, 5] MDA-1186 cell ( cancer cell line [6]) [6] MDA-886 cell ( cancer cell line [6]) [6] OVCAR-3 cell ( ovarian carcinoma cell line [4]) [4] PC-3 cell ( prostate carcinoma cell line [4]) [4] T-98G cell ( glioblastoma cell line [4]; glioma cell line [5]) [4, 5] T-lymphocyte ( at the level of elongation [7]) [7] TR-146 cell ( cancer cell line [6]) [6] U-138MG cell ( glioblastoma cell line [4]) [4] U-87MG cell ( glioblastoma cell line [4]) [4] UMSCC-14B cell ( cancer cell line [6]) [6] UMSCC-17B cell ( cancer cell line [6]) [6] UMSCC-21A cell ( cancer cell line [6]) [6] UMSCC-22A cell ( cancer cell line [6]) [6] UMSCC-38 cell ( cancer cell line [6]) [6] cardiac myocyte ( ventricle [8]) [8] glioma cell line ( C-6 cell, half-life of the enzyme is 6 h [5]) [5] heart ventricle [8] neuron [10] pancreas [3] pancreatic acinar cell [3] skeletal muscle [11] squamous cell carcinoma cell ( cell lines of head and neck cancer [6]) [6] Additional information ( the enzyme expression and activity is increased in several forms of malignancy [4]) [4] Localization synaptosome [10]

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Elongation factor 2 kinase

2.7.11.20

Purification (recombinant GST-tagged wild-type and FLAG-tagged mutant enzymes from Escherichia coli) [8] Cloning (expression of GST-tagged enzyme in Escherichia coli) [12] (expression of GST-tagged wild-type enzyme and of a FLAG-tagged mutant enzyme in Escherichia coli) [8] (overexpression of the enzyme in glioma T98-G cells causes a 10fold increased resistance to inhibitor NH125) [4] [1] [1] [1] [1, 2] Engineering S398A ( site-directed mutagenesis, mutation of a phosphorylation site, no phosphorylation by AMPK, altered regulation by phosphorylation compared to the wild-type enzyme [8]) [8] S78A ( site-directed mutagenesis, mutation of a phosphorylation site, altered regulation by phosphorylation compared to the wild-type enzyme, but the mutation does not influence AMPK [8]) [8] Additional information ( construction of GCN1 and GCN2 mutants with mutations in the domain structures that are involved in interaction between the GCNs, the elongation factors, and the polyribosome, overview [9]; the eEF2 kinase level is higher in PDK1-lacking cells, constitutive phosphorylation at Ser78 of the eEF2 kinase occurs in TSC2-deficient cells [12]) [9, 12] Application pharmacology ( the enzyme is a target for development of anticancer drugs [4]) [4]

6 Stability General stability information , in vivo half-life of the enzyme is 6 h, proteasome inhibitor MG132 prolonged the half-life of the enzyme to more than 24 h [5]

References [1] Ryazanov, A.G.; Ward, M.D.; Mendola, C.E.; Pavur, K.S.; Dorovkov, M.V.; Wiedmann, M.; Erdjument-Bromage, H.; Tempst, P.; Parmer, T.G.; Prostko, C.R.; Germino, F.J.; Hait, W.N.: Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase. Proc. Natl. Acad. Sci. USA, 94, 4884-4889 (1997)

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[2] Redpath, N.T.; Price, N.T.; Proud, C.G.: Cloning and expression of cDNA encoding protein synthesis elongation factor-2 kinase. J. Biol. Chem., 271, 17547-17554 (1996) [3] Sans, M.D.; Xie, Q.; Williams, J.A.: Regulation of translation elongation and phosphorylation of eEF2 in rat pancreatic acini. Biochem. Biophys. Res. Commun., 319, 144-151 (2004) [4] Arora, S.; Yang, J.M.; Kinzy, T.G.; Utsumi, R.; Okamoto, T.; Kitayama, T.; Ortiz, P.A.; Hait, W.N.: Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines. Cancer Res., 63, 6894-6899 (2003) [5] Arora, S.; Yang, J.M.; Hait, W.N.: Identification of the ubiquitin-proteasome pathway in the regulation of the stability of eukaryotic elongation factor-2 kinase. Cancer Res., 65, 3806-3810 (2005) [6] Ren, H.; Tai, S.K.; Khuri, F.; Chu, Z.; Mao, L.: Farnesyltransferase inhibitor SCH66336 induces rapid phosphorylation of eukaryotic translation elongation factor 2 in head and neck squamous cell carcinoma cells. Cancer Res., 65, 5841-5847 (2005) [7] Gutzkow, K.B.; Lahne, H.U.; Naderi, S.; Torgersen, K.M.; Skalhegg, B.; Koketsu, M.; Uehara, Y.; Blomhoff, H.K.: Cyclic AMP inhibits translation of cyclin D3 in T lymphocytes at the level of elongation by inducing eEF2phosphorylation. Cell. Signal., 15, 871-881 (2003) [8] Browne, G.J.; Finn, S.G.; Proud, C.G.: Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398. J. Biol. Chem., 279, 1222012231 (2004) [9] Sattlegger, E.; Hinnebusch, A.G.: Polyribosome binding by GCN1 is required for full activation of eukaryotic translation initiation factor 2{a} kinase GCN2 during amino acid starvation. J. Biol. Chem., 280, 16514-16521 (2005) [10] Carroll, M.; Warren, O.; Fan, X.; Sossin, W.S.: 5-HT stimulates eEF2 dephosphorylation in a rapamycin-sensitive manner in Aplysia neurites. J. Neurochem., 90, 1464-1476 (2004) [11] Rose, A.J.; Broholm, C.; Kiillerich, K.; Finn, S.G.; Proud, C.G.; Rider, M.H.; Richter, E.A.; Kiens, B.: Exercise rapidly increases eukaryotic elongation factor 2 phosphorylation in skeletal muscle of men. J. Physiol., 569, 223228 (2005) [12] Browne, G.J.; Proud, C.G.: A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol. Cell. Biol., 24, 2986-2997 (2004)

133

Polo kinase

2.7.11.21

1 Nomenclature EC number 2.7.11.21 Systematic name ATP:protein phosphotransferase (spindle-pole-dependent) Recommended name polo kinase Synonyms Cdc5 [24, 42, 46, 49] Cdc5p [41] FGF-inducible kinase Fnk [3] PLK [34, 41, 46] Plk1 [25, 27, 28, 30, 35, 36, 37, 38, 43, 46, 47] Plk2 [26, 46] Plk3 [32, 46] Plo1 [33, 39, 40, 44, 46] Plx1 [28, 29, 31, 46, 48] polo kinase [29] polo-like kinase 1 [25, 27, 28, 29, 31, 35, 36, 37, 38, 47, 48] Prk [6, 7] proliferation-related kinase SMK/PLK-AKIN kinase [21] Sak [21] cell cycle protein kinase CDC5/MSD2 [9] cytokine-inducible serine/threonine-protein kinase [3, 4, 5, 6, 7, 8] polo related kinase [16] polo-like kinase [34, 39, 41, 46, 49] polo-like kinase 3 [32] polo-like kinase PLK-1 [10] polo-like kinase-1 [30, 43] polo-like kinase-2 [26] protein kinase polo [1, 14] serine/threonine-protein kinase PLK [15, 16, 17, 18, 20] serine/threonine-protein kinase SNK [19, 23] serine/threonine-protein kinase plk-1 [10, 11, 12] serine/threonine-protein kinase plk-2 [22] serine/threonine-protein kinase plk-3 [11]

134

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Polo kinase

serine/threonine-protein kinase plo1 [2, 13] Additional information ( the enzyme belongs to the family of pololike kinases [25]) [25] CAS registry number 149433-93-2 (Polo kinase)

2 Source Organism Drosophila melanogaster (no sequence specified) [29, 45, 46] Homo sapiens (no sequence specified) [26, 27, 28, 30, 32, 34, 35, 36, 37, 38, 46] Sus scrofa (no sequence specified) [25] Saccharomyces cerevisiae (no sequence specified) [24, 42, 46, 49] Xenopus laevis (no sequence specified) [28,29,31,46,48] Schizosaccharomyces pombe (no sequence specified) [33,39,40,44,46] Candida albicans (no sequence specified) [41] Mus musculus (UNIPROT accession number: Q60806) [3,4] Homo sapiens (UNIPROT accession number: Q9H4B4) [5,6,7,8] Saccharomyces cerevisiae (UNIPROT accession number: P32562) [9] Caenorhabditis elegans (UNIPROT accession number: P34331) [10, 11, 12] Schizosaccharomyces pombe (UNIPROT accession number: P50528) [2, 13] Drosophila melanogaster (UNIPROT accession number: P52304) [1, 14] Homo sapiens (UNIPROT accession number: P53350) [15, 16, 17, 18, 47] Mus musculus (UNIPROT accession number: P53351) [19] Mus musculus (UNIPROT accession number: Q07832) [16, 18, 20] Caenorhabditis elegans (UNIPROT accession number: Q20845) [11] Mus musculus (UNIPROT accession number: Q64702) [21] Caenorhabditis elegans (UNIPROT accession number: Q9N2L7) [22] Rattus norvegicus (UNIPROT accession number: Q9R012) [23] Rattus norvegicus (UNIPROT accession number: Q07832) [43]

3 Reaction and Specificity Catalyzed reaction ATP + a protein = ADP + a phosphoprotein ( consensus sequence of Plk1 is D/E-X-S/T-hydrophobic amino acid-X-D/E, X can be any amino acid, with neighbouring phosphorylation sequence l-Q-S-V-l-E being phosphorylated at the serine residue [28,46]; the Plk consensus sequence is D/E-X-S/Thydrophobic amino acid-X-D/E with X being any amino acid [34])

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Natural substrates and products S ATP + 20S proteasome ( phosphorylation by Plk1 enhances the proteolytic activity [46]) (Reversibility: ?) [46] P ADP + phosphorylated S20 proteasome S ATP + 3F3/2 kinase ( the enzyme creates the 3F3/2 kinase phosphoepitope on mitotic kinetichores, depletion of enzyme in M phase cell extract leads to loss of 3F3/2 kinase activity [28]) (Reversibility: ?) [28] P ADP + phosphorylated 3F3/2 kinase S ATP + 85 kDa microtubule-associated protein ( protein is released from microtubules after phosphorylation [45]) (Reversibility: ?) [45] P ADP + phosphorylated 85 kDa microtubule-associated protein S ATP + Cdc25C ( phosphorylation by Plk1 on Ser198 in a nuclear export signal sequence promoting its nuclear translocation, inhibition of Cdc25 activation resulting in a delay in Cdc2 activation [46]) (Reversibility: ?) [46] P ADP + phosphorylated Cdc25C S ATP + Chk2 ( phosphorylation at Thr68 [46]) (Reversibility: ?) [35, 46] P ADP + phosphorylated Chk2 S ATP + Emi2 ( CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit, in response to increased free Ca2+ levels CaMKII acts as a priming kinase mediating the interaction between Emi2 and Plx1 polo box domain via phosphorylation at a specific motif [48]) (Reversibility: ?) [48] P ADP + phosphorylated Emi2 S ATP + MEI-S332 protein ( phosphorylation/polo box binding is required for chromosomal dissociation of MEI-S332 [29]; substrate is a protein essential in meiosis for maintaining cohesion at centromers until sister chromatids separate at the metaphase II/anaphase II transition, phosphorylation by polo kinase removes the protein from centromeres and antagonizes the MEI-S332 function, MEI-S332 phosphorylation by polo kinase is essential for viability of the cells [29]) (Reversibility: ?) [29] P ADP + phosphorylated MEI-S332 protein S ATP + Mad3 ( phosphorylation of Mad3 isozymes at 5 serine residues, S222, S380, S466, S504, and especially at S268, during spindle checkpoint activation, Mad3 is an inhibitor of Cdc20/APC ubiquitin ligase, overview [24]) (Reversibility: ?) [24] P ADP + phosphorylated Mad3 S ATP + Mid1p ( required for positioning of division sites in cytokinesis [46]) (Reversibility: ?) [46] P ADP + phosphorylated Mid1p S ATP + Myt1 ( phosphorylation of Myt1 during M phase [34]) (Reversibility: ?) [34]

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P ADP + phosphorylated Myt1 S ATP + NudC ( i.e. nuclear distribution protein C, Plk1 phosphorylates Ser274 and Ser326 [46]) (Reversibility: ?) [46] P ADP + phosphorylated kinesin-like protein 2 S ATP + Pin1 ( Plk1-mediated phosphorylation at Ser65 stabilizes Pin1 by inhibiting its ubiquitination in cells [37]) (Reversibility: ?) [37] P ADP + phosphorylated Pin1 S ATP + TRF1 ( the cell-cycle-dependent TRF1 recruitment to telomere chromatin is regulated by the enzyme, TRF1 binds the telomere via the telomeric repeats, process overview [31]) (Reversibility: ?) [31] P ADP + phosphorylated TRF1 S ATP + abnormal spindle pole protein ( i.e. abnormal spindle pole protein, activation of abnormal spindle pole protein by phosphorylation [45]) (Reversibility: ?) [45] P ADP + phosphorylated abnormal spindle pole protein S ATP + b-tubulin ( the enzyme is required for b-tubulin recruitment to the centrosome [45]) (Reversibility: ?) [45] P ADP + phosphorylated b-tubulin S ATP + claspin ( Plx1 is involved in alleviating DNA replication checkpoint response by inactivation of claspin through phosphorylation [46]) (Reversibility: ?) [46] P ADP + phosphorylated claspin S ATP + cohesin ( phosphorylation by Cdc5 required for removal of cohesin from chromosomes [46]) (Reversibility: ?) [46] P ADP + phosphorylated cohesin S ATP + cyclin B ( phosphorylation at S126, S128, S133, and S147 for nuclear translocation of cyclin B [46]) (Reversibility: ?) [46] P ADP + phosphorylated cyclin B S ATP + cyclin B1 ( phosphorylation at S101, not at S113 in the cytoplasmic retention sequence [46]) (Reversibility: ?) [46] P ADP + phosphorylated cyclin B S ATP + giantin (Reversibility: ?) [32] P ADP + phosphorylated giantin S ATP + kinesin-like protein 2 ( Plk1, essential for cytokinesis [46]) (Reversibility: ?) [46] P ADP + phosphorylated kinesin-like protein 2 S ATP + p125 ( peptide fragment of DNA polymerase d, phosphorylation at Ser60 by Plk3 [46]) (Reversibility: ?) [46] P ADP + phosphorylated p125 S ATP + p53 ( Plk1 binds tumor suppressor p53, dependent on DNA-binding to the specific DNA binding domain within residues 102292 of p53, and inhibits its transactivation activity [36]) (Reversibility: ?) [36, 46] P ADP + phosphorylated p53 ( Plk3, Plk1 inhibits tumor suppressor p53 transactivating activity in lung carcinoma cells [46]) S Additional information ( the enzyme may be involved in the early signaling events re-

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quired for growth factor-stimulated cell cycle progression [4]; playing an important role in regulating the onset and/or progression of mitosis in mammalian cells [8]; the enzyme is involved in regulating M phase functions during the cell cycle. Prks role in mitosis is at least partly mediated through direct regulation of Cdc25C [7]; expression appears to be down-regulated in lung carcinomas [6]; has two functions, one during the entry of cells into the cell cycle and a second during mitosis of cycling cells [3]; required for nuclear envelope breakdown and the completion of meiosis [10]; required for the initiation of chromosomal DNA replication in Saccharomyces cerevisiae and interaction with the CDC7 protein kinase [9]; normal bipolar spindles with polyploid complements of chromosomes, bipolar spindles in which one pole can be unusually broad, and monopolar spindles [14]; the enzyme is regulated dynamically with synaptic plasticity [23]; mutation in polo leads to a variety of abnormal mitoses in Drosophila larval neuroblasts. These include otherwise normal looking mitotic spindles upon which chromosomes appear overcondensed [14]; expression of PLK mRNA appeared to be strongly correlated with the mitotic activity of cells [15]; cell cycle- and terminal differentiation-associated regulation [18]; enzyme is involved in cell proliferation, expression is associated with mitotic and meiotic cell division [21]; Plk1 is likely to function in cell cycle progression [17]; the enzyme is required to form a bipolar spindle, the actin ring, and septum, can drive septum formation in G1 and G2 cells [13]; Cdc5 plays a role in chromosomes segregation during meiosis I, it is required for phosphorylation and removal of cohesin from chromosomes, it is required for sister-kinetochore orientation with associated Mam1 protein, mechanism, overview [49]; Chk2 phosphorylation at Thr68 is enhanced by overexpression of Plk1 in vivo [35]; cytokinetic actomyosin ring formation and septation in fission yeast are dependent on the full recruitment of the polo-like kinase PLO1 to the spindle pole body, regulated by Mad2, and a functional spindle assembly checkpoint which requires an intact microtubule cytoskeleton, overview [39]; physical and functional interactions between polo kinase and the spindle pole component Cut12 regulate mitotic commitment by feedback control of the MPF complex, overview [33]; Plk1 depletion induces apoptosis in cancer cells and stabilizes p53 tumor-suppressor protein [47]; Plk1 inhibits Wee1 inactivation resulting in a delay in Cdc2 activation, the enzyme is pivotal in cell division as a regulator of cell cycle checkpoints in mitotic progression, modeling of major Plk metabolism pathways, spindle checkpoint machinery, overview [46]; Plk1 is important in activation and regulation of spindle assembly during mitosis [24]; Plk1 is involved in regulating centrosome maturation, mitotic entry, sister chromatid cohesion, the anaphase-promoting complex/cyclosome, and cytokinesis, as well as in chromosome orientation, detailed overview of physiological functions of the enzyme [27]; Plk1 is involved in the regulation of M-phase of the cell cycle and might also be involved in tumorigenesis [36]; Plk3 is involved in

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regulating Golgi fragmentation during the cell cycle [32]; polo kinase Cdc5 is involved as part of the FEAR network, i.e. fourteen early anaphase release network, and of MEN network, i.e. mitotic exit network, in controlling protein phosphatase Cdc14 localization and activity, the enzyme induces phosphorylation of Cdc14 and Cfi1/Net1 by activating the networks, overview [42]; polo-like kinase 1 creates the tension-sensing 3F3/2 phosphoepitope and modulates the association of spindle-checkpoint proteins at kinetochores [28]; polo-like kinase 1 creates the tension-sensing 3F3/2 phosphoepitope and modulates the association of spindle-checkpoint proteins at kinetochores, the enzyme is required for association of Cdc20 to kinetochores [28]; the enzyme is a mitotic kinase and is required for centrosome maturation at mitotic M-phase entry in order to recruit the g-tubulin ring complex and activate abnormal spindle pole protein, Asp, the enzyme is involved in mitotic networks and cytokinesis, e.g. in spermatogenesis, overview, functional modeling of polo kinase in mitotic phases [45]; the enzyme is essential for Ca2+ induced meiotic exit of fertilized eggs after arrest in metaphase II before fertilization [48]; the enzyme is involved in regulation of centriole duplication cycle by protein phosphorylation [26]; the enzyme is involved in regulation of cytokinesis and microtubule polymerization modulation during oocyte meiotic maturation, fertilization and early embryonic mitosis [25,43]; the enzyme is involved in regulation of Nek2-induced centrosome separation after DNA damage [38]; the enzyme is involved in spindle formation and septation playing an important role in cell cycle regulation [40]; the enzyme is pivotal in cell division as a regulator of cell cycle checkpoints in mitotic progression, Cdc5 is part of mitotic networks, e.g. the fourteen early anaphase release network FEAR for Cdc14 release, overview [46]; the enzyme is pivotal in cell division as a regulator of cell cycle checkpoints in mitotic progression, mechanism [46]; the enzyme is pivotal in cell division as a regulator of cell cycle checkpoints in mitotic progression, Plo1 is involved in cytokinesis [46]; the enzyme is pivotal in cell division as a regulator of cell cycle checkpoints in mitotic progression, regulation of cytokinesis, overview [46]; the enzyme plays an essential role in promoting mitosis and cytokinesis, the kinase activity is regulated by the conserved Cterminal polo box domain which acts as both an autoinhibitory domain and a subcellular localization domain, structure analysis [30]; the enzyme recruitment to the spindle pole body influences the balance between Cdc25 and Wee1 activities on mitosis-promoting factor, MPF [44]; the polo-loke kinase activates cyclase-dependent hyphal-like growth acting like a switch between yeast and hyphal growth forms, mechanism, overview [41]) (Reversibility: ?) [3, 4, 6, 7, 8, 9, 10, 13, 14, 15, 17, 18, 21, 23, 24, 25, 26, 27, 28, 30, 32, 33, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49] P ?

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Substrates and products S ATP + 20S proteasome ( phosphorylation by Plk1 enhances the proteolytic activity [46]) (Reversibility: ?) [46] P ADP + phosphorylated S20 proteasome S ATP + 3F3/2 kinase ( the enzyme creates the 3F3/2 kinase phosphoepitope on mitotic kinetichores, depletion of enzyme in M phase cell extract leads to loss of 3F3/2 kinase activity [28]; purified recombinant Plk1 or M phase cell extract, phosphoepitope mapping reveals that the 3F3/2 kinase phosphoepitope overlaps the enzyme consensus phosphorylation seqence, overview [28]) (Reversibility: ?) [28] P ADP + phosphorylated 3F3/2 kinase S ATP + 85 kDa microtubule-associated protein ( protein is released from microtubules after phosphorylation [45]) (Reversibility: ?) [45] P ADP + phosphorylated 85 kDa microtubule-associated protein S ATP + Cdc25C ( phosphorylation by Plk1 on Ser198 in a nuclear export signal sequence promoting its nuclear translocation, inhibition of Cdc25 activation resulting in a delay in Cdc2 activation [46]; Plk3 activity in vitro, phosphorylation by Plk1 on Ser198 [46]) (Reversibility: ?) [46] P ADP + phosphorylated Cdc25C S ATP + Chk2 ( phosphorylation at Thr68 [46]; substrate is a protein kinase, phosphorylated by Plk1 at Ser28, Thr68, and Thr26 in vitro [35]) (Reversibility: ?) [35, 46] P ADP + phosphorylated Chk2 S ATP + Emi2 ( CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit, in response to increased free Ca2+ levels CaMKII acts as a priming kinase mediating the interaction between Emi2 and Plx1 polo box domain via phosphorylation at a specific motif [48]; Emi2, i.e. XErp1, is a cytostatic factor [48]) (Reversibility: ?) [48] P ADP + phosphorylated Emi2 S ATP + MEI-S332 protein ( phosphorylation/polo box binding is required for chromosomal dissociation of MEI-S332 [29]; substrate is a protein essential in meiosis for maintaining cohesion at centromers until sister chromatids separate at the metaphase II/anaphase II transition, phosphorylation by polo kinase removes the protein from centromeres and antagonizes the MEI-S332 function, MEI-S332 phosphorylation by polo kinase is essential for viability of the cells [29]; enzyme requires residues T331 and possibly in combination with S234 for activity, no activity with MEI-S332 protein mutants T331A and S234A/T331A [29]; enzyme requires residues T331 and possibly in combination with S234 for activity, no activity with MEI-S332 protein mutants T331A and S234A/T331A in S2 cells [29]) (Reversibility: ?) [29] P ADP + phosphorylated MEI- S332 protein S ATP + Mad3 ( phosphorylation of Mad3 isozymes at 5 serine residues, S222, S380, S466, S504, and especially at S268, during spindle

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P S P S

P S P S

P S P S

P S

P S P S P S P S P S

Polo kinase

checkpoint activation, Mad3 is an inhibitor of Cdc20/APC ubiquitin ligase, overview [24]; recombinant HA-tagged wild-type and mutant Mad3 substrate proteins, the activity with mutants in which phosphorylation site Ser is replaced by Ala is highly reduced, Mad3 is a homologue to the human BubR1 protein [24]) (Reversibility: ?) [24] ADP + phosphorylated Mad3 ATP + Mid1p ( required for positioning of division sites in cytokinesis [46]) (Reversibility: ?) [46] ADP + phosphorylated Mid1p ATP + Myt1 ( phosphorylation of Myt1 during M phase [34]; i.e. membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, no activity with a Myt1 mutant in which the 4 C-terminal phosphorylation sites are mutated to alanine [34]) (Reversibility: ?) [34] ADP + phosphorylated Myt1 ATP + NudC ( i.e. nuclear distribution protein C, Plk1 phosphorylates Ser274 and Ser326 [46]) (Reversibility: ?) [46] ADP + phosphorylated kinesin-like protein 2 ATP + Pin1 ( Plk1-mediated phosphorylation at Ser65 stabilizes Pin1 by inhibiting its ubiquitination in cells [37]; recombinant isomerase Pin1 expressed in Escherichia coli, phosphorylation at Ser65, wild-type and truncated mutant Pin1 comprising residues 1-70 [37]) (Reversibility: ?) [37] ADP + phosphorylated Pin1 ATP + Plk1 polo box 1-derived peptide ( synthetic substrate [37]) (Reversibility: ?) [37] ADP + phosphorylated Plk1 polo box 1-derived peptide ATP + TRF1 ( the cell-cycle-dependent TRF1 recruitment to telomere chromatin is regulated by the enzyme, TRF1 binds the telomere via the telomeric repeats, process overview [31]; endogenous TRF1 associated to telomeres during mitosis, phosphorylation by Plx1 in vitro [31]) (Reversibility: ?) [31] ADP + phosphorylated TRF1 ATP + abnormal spindle pole protein ( i.e. abnormal spindle pole protein, activation of abnormal spindle pole protein by phosphorylation [45]) (Reversibility: ?) [45] ADP + phosphorylated abnormal spindle pole protein ATP + a-casein ( high activity of wild-type enzyme [26]) (Reversibility: ?) [26, 32] ADP + phosphorylated a-casein ATP + b-tubulin ( the enzyme is required for b-tubulin recruitment to the centrosome [45]) (Reversibility: ?) [45] ADP + phosphorylated b-tubulin ATP + casein (Reversibility: ?) [38] ADP + phosphorylated casein ATP + casein (Reversibility: ?) [8] ATP + phosphorylated casein ATP + casein (Reversibility: ?) [9]

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P ADP + phosphocasein S ATP + claspin ( Plx1 is involved in alleviating DNA replication checkpoint response by inactivation of claspin through phosphorylation [46]; checkpoint protein, interaction and phosphorylation at Thr906 and Ser934 [46]) (Reversibility: ?) [46] P ADP + phosphorylated claspin S ATP + cohesin ( phosphorylation by Cdc5 required for removal of cohesin from chromosomes [46]; phosphorylation adjacent to the cleavage site of Scc1 by Cdc5 [46]) (Reversibility: ?) [46] P ADP + phosphorylated cohesin S ATP + cyclin B ( phosphorylation at S126, S128, S133, and S147 for nuclear translocation of cyclin B [46]; no phosphorylation of cyclin B1 [46]) (Reversibility: ?) [46] P ADP + phosphorylated cyclin B S ATP + cyclin B1 ( phosphorylation at S101, not at S113 in the cytoplasmic retention sequence [46]) (Reversibility: ?) [46] P ADP + phosphorylated cyclin B S ATP + giantin (Reversibility: ?) [32] P ADP + phosphorylated giantin S ATP + histone H1 kinase ( activation [33]) (Reversibility: ?) [33] P ADP + phosphorylated histone H1 kinase S ATP + kinesin-like protein 2 ( Plk1, essential for cytokinesis [46]; Plk1 [46]) (Reversibility: ?) [46] P ADP + phosphorylated kinesin-like protein 2 S ATP + p125 ( peptide fragment of DNA polymerase d, phosphorylation at Ser60 by Plk3 [46]; peptide fragment of DNA polymerase d, phosphorylation at Ser60 by Plk3, wild-type and mutant GST-tagged or His6-tagged Plk3 [46]) (Reversibility: ?) [46] P ADP + phosphorylated p125 S ATP + p53 ( Plk1 binds tumor suppressor p53, dependent on DNA-binding to the specific DNA binding domain within residues 102292 of p53, and inhibits its transactivation activity [36]; phosphorylation at Ser20 [36]; Plk3 phosphorylates S20 in vitro, Plk1 inhibits p53 by phosphorylation [46]) (Reversibility: ?) [36, 46] P ADP + phosphorylated p53 ( Plk3, Plk1 inhibits tumor suppressor p53 transactivating activity in lung carcinoma cells [46]) S Additional information ( no phosphorylation of histone H1 [8]; the enzyme may be involved in the early signaling events required for growth factor-stimulated cell cycle progression [4]; playing an important role in regulating the onset and/or progression of mitosis in mammalian cells [8]; the enzyme is involved in regulating M phase functions during the cell cycle. Prks role in mitosis is at least partly mediated through direct regulation of Cdc25C [7]; expression appears to be down-regulated in lung carcinomas [6]; has two functions, one during the entry of cells into the cell cycle and a second during mitosis of cycling cells [3]; required for nuclear envelope breakdown and the completion of meiosis [10]; re-

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quired for the initiation of chromosomal DNA replication in Saccharomyces cerevisiae and interaction with the CDC7 protein kinase [9]; normal bipolar spindles with polyploid complements of chromosomes, bipolar spindles in which one pole can be unusually broad, and monopolar spindles [14]; the enzyme is regulated dynamically with synaptic plasticity [23]; mutation in polo leads to a variety of abnormal mitoses in Drosophila larval neuroblasts. These include otherwise normal looking mitotic spindles upon which chromosomes appear overcondensed [14]; expression of PLK mRNA appeared to be strongly correlated with the mitotic activity of cells [15]; cell cycle- and terminal differentiation-associated regulation [18]; enzyme is involved in cell proliferation, expression is associated with mitotic and meiotic cell division [21]; Plk1 is likely to function in cell cycle progression [17]; the enzyme is required to form a bipolar spindle, the actin ring, and septum, can drive septum formation in G1 and G2 cells [13]; Cdc5 plays a role in chromosomes segregation during meiosis I, it is required for phosphorylation and removal of cohesin from chromosomes, it is required for sister-kinetochore orientation with associated Mam1 protein, mechanism, overview [49]; Chk2 phosphorylation at Thr68 is enhanced by overexpression of Plk1 in vivo [35]; cytokinetic actomyosin ring formation and septation in fission yeast are dependent on the full recruitment of the polo-like kinase PLO1 to the spindle pole body, regulated by Mad2, and a functional spindle assembly checkpoint which requires an intact microtubule cytoskeleton, overview [39]; physical and functional interactions between polo kinase and the spindle pole component Cut12 regulate mitotic commitment by feedback control of the MPF complex, overview [33]; Plk1 depletion induces apoptosis in cancer cells and stabilizes p53 tumor-suppressor protein [47]; Plk1 inhibits Wee1 inactivation resulting in a delay in Cdc2 activation, the enzyme is pivotal in cell division as a regulator of cell cycle checkpoints in mitotic progression, modeling of major Plk metabolism pathways, spindle checkpoint machinery, overview [46]; Plk1 is important in activation and regulation of spindle assembly during mitosis [24]; Plk1 is involved in regulating centrosome maturation, mitotic entry, sister chromatid cohesion, the anaphase-promoting complex/cyclosome, and cytokinesis, as well as in chromosome orientation, detailed overview of physiological functions of the enzyme [27]; Plk1 is involved in the regulation of M-phase of the cell cycle and might also be involved in tumorigenesis [36]; Plk3 is involved in regulating Golgi fragmentation during the cell cycle [32]; polo kinase Cdc5 is involved as part of the FEAR network, i.e. fourteen early anaphase release network, and of MEN network, i.e. mitotic exit network, in controlling protein phosphatase Cdc14 localization and activity, the enzyme induces phosphorylation of Cdc14 and Cfi1/Net1 by activating the networks, overview [42]; polo-like kinase 1 creates the tension-sensing 3F3/2 phosphoepitope and modulates the association of spindle-checkpoint proteins at kinetochores [28]; polo-like kinase 1 creates the tension-sensing 3F3/2 phosphoepitope and modulates the association of spindle-checkpoint pro-

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teins at kinetochores, the enzym is required for association of Cdc20 to kinetochores [28]; the enzyme is a mitotic kinase and is required for centrosome maturation at mitotic M-phase entry in order to recruit the gtubulin ring complex and activate abnormal spindle pole protein, Asp, the enzyme is involved in mitotic networks and cytokinesis, e.g. in spermatogenesis, overview, functional modeling of polo kinase in mitotic phases [45]; the enzyme is essential for Ca2+ -induced meiotic exit of fertilized eggs after arrest in metaphase II before fertilization [48]; the enzyme is involved in regulation of centriole duplication cycle by protein phosphorylation [26]; the enzyme is involved in regulation of cytokinesis and microtubule polymerization modulation during oocyte meiotic maturation, fertilization and early embryonic mitosis [25,43]; the enzyme is involved in regulation of Nek2-induced centrosome separation after DNA damage [38]; the enzyme is involved in spindle formation and septation playing an important role in cell cycle regulation [40]; the enzyme is pivotal in cell division as a regulator of cell cycle checkpoints in mitotic progression, Cdc5 is part of mitotic networks, e.g. the fourteen early anaphase release network FEAR for Cdc14 release, overview [46]; the enzyme is pivotal in cell division as a regulator of cell cycle checkpoints in mitotic progression, mechanism [46]; the enzyme is pivotal in cell division as a regulator of cell cycle checkpoints in mitotic progression, Plo1 is involved in cytokinesis [46]; the enzyme is pivotal in cell division as a regulator of cell cycle checkpoints in mitotic progression, regulation of cytokinesis, overview [46]; the enzyme plays an essential role in promoting mitosis and cytokinesis, the kinase activity is regulated by the conserved C-terminal polo box domain which acts as both an autoinhibitory domain and a subcellular localization domain, structure analysis [30]; the enzyme recruitment to the spindle pole body influences the balance between Cdc25 and Wee1 activities on mitosis-promoting factor, MPF [44]; the polo-loke kinase activates cyclase-dependent hyphal-like growth acting like a switch between yeast and hyphal growth forms, mechanism, overview [41]; determination of enzyme consensus sequence [34]; Plk1 interacts with the 20S and the 26S proteasomes, Plk3 interacts with DNA polymerase d and Plk1 with the Golgi specific protein GRASP65 [46]; the enzyme interacts with diverse proteins via its poloboxes, overview [40]; the enzyme interacts with DNA polymerase d [46]; the protein phosphatase 1 is no substrate of Plk1 [38]) (Reversibility: ?) [3, 4, 6, 7, 8, 9, 10, 13, 14, 15, 17, 18, 21, 23, 24, 25, 26, 27, 28, 30, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49] P ? Inhibitors ataxia-telangiectasia mutant ( i.e. ATM, inhibits p53 phosphorylation by Plk1 in vivo [36]) [36] Additional information ( in vivo inhibition of Plk1 by DNA damage is ATM- or ATR-dependent [38]; Plk1 activity is inhibited upon DNA damage involving ATM or ATR, caffeine blocks the inhibition [46];

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Plk1 depletion in HeLa Plk RNAi cells by Aurora B inhibitor hesperadin, enzyme depletion delays entry into mitosis and arrest in prometaphase activating the spindle checkpoint [27]; Plk1 expression is decreased during ciplatin-induced apoptosis while p53 is stabilized [36]; the enzyme activity is inhibited upon DNA damage [46]; the kinase activity is regulated by the conserved C-terminal polo box domain which acts as both an autoinhibitory domain and a subcellular localization domain [30]) [27, 30, 36, 38, 46] Cofactors/prosthetic groups ATP [24,26,28,29,31,32,34,35,36,37,38,45,46,48] Activating compounds Additional information ( expression of Plk2 is rapidly induced by X-ray irradiation and is partly mediated by p53 [46]; in vivo enzyme activity is dependent on Cut12 [33]; Plk2 is activated in vivo near the G1- to S-phase transition of the cell cycle [26]) [26, 33, 46] Metals, ions KCl [38] Mg2+ [26, 28, 32, 36, 38, 48] Mn2+ [24, 26, 32] Specific activity (U/mg) Additional information ( activity of wild-type and mutant GSTtagged or His6-tagged Plk3 with p125 [46]) [46] pH-Optimum 7.4 ( assay at [32,48]) [32, 48] 7.5 ( assay at [24,26,28]) [24, 26, 28] Temperature optimum ( C) 25 ( assay at [33]) [33] 30 ( assay at [24,26,38,48]) [24, 26, 38, 48] 37 ( assay at [32,37]) [32, 37]

4 Enzyme Structure Subunits ? ( x * 70000, about, SDS-PAGE [32]) [32] Additional information ( Plo1 is a component of the spindle pole body, assembly at spindle checkpoint, mechanism, recruitment of Plo1 to the complex is inhibited by Mad2, overview [39]; the enzyme contains 3 different polo box motifs in the non-catalytic region that are involved in protein protein interactions in the mitotic spindle formation process [40]) [39, 40]

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Posttranslational modification phosphoprotein ( Plo1 is phosphorylated at Ser402 in the stress response pathway, mechanism, phosphorylation is required for recruitment to the interphase spindle pole body and mitotic entry for cell tip growth and cell division, Plo1 phosphorylation is increased at elevated temperature [44]; the enzyme is phosphorylated by Chk2 [46]) [44, 46]

5 Isolation/Preparation/Mutation/Application Source/tissue 293T cell [37] A-549 cell [32] CFPAC-1 cell [28] HeLa cell [26, 27, 28, 34, 38] HeLa-S3 cell [37] KE-37 cell ( leukemic cell line [26]) [26] LLC-PK cell [28] NIH-3T3 cell [37] SCHNEIDER-2 cell ( embryonic cell line [29]) [29] SH-SY5Y cell ( neuroblastoma cell [36]) [36] T-cell ( primary, when activated by phytohemagglutinin, a high level of PLK transcripts results within 2-3 days. In some cases, addition of interleukin 2 to these cells increases the expression of PLK mRNA further [15]) [15] U2-OS cell [26, 38] cell culture [28] colon [15] egg [28, 29, 31, 46, 48] embryo ( early [43]) [10, 21, 25, 43, 45] fibroblast [26] larva [14, 45] lung cancer cell ( expression appears to be down-regulated in lung carcinomas [6]; Plk1 [46]) [6, 46] macrophage ( transition of monocytes from peripheral blood to matrix bound macrophages is accompanied by increasing levels of Fnk with time in culture [5]) [5] neuroblast [14] neuroblastoma [36] olfactory mucosa [21] oocyte ( maturing, after activation [43]) [10, 25, 43] ovary ( during embryonic development, the mRNA is expressed in all tissues examined, whereas in adult tissues, expression is limited to thymus and ovaries [16]) [16] placenta [15] respiratory mucosa [21]

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thymus ( during embryonic development, the mRNA is expressed in all tissues examined, whereas in adult tissues, expression is limited to thymus and ovaries [16]) [16] thyroid cell ( Plk2 [46]) [46] Additional information ( during embryonic development, the mRNA is expressed in all tissues examined, whereas in adult tissues, expression is limited to thymus and ovaries [16]; no PLK transcripts are found in normal adult lung, brain, heart, liver, kidney, skeletal muscle, and pancreas, resting peripheral lymphocytes do not express the gene at all. Primary cultures of human peripheral macrophages, which are not dividing under the culture conditions applied, showed very little or no PLK mRN [15]; enzyme quantity is stable during meiotic maturation [25,43]) [15, 16, 25, 43] Localization Golgi apparatus ( localization of Plk3 with Golgi fragments during mitosis, overview [32]; Plk1, Plk3 during interphase, binding via phosphorylated Nir2 [46]) [32, 46] centrosome ( associated with Hsp90 [45]; Plk2 interaction with the centrosome is independent on enzyme kinase activity [26]; primarily, during interphase [46]) [26, 27, 30, 35, 45, 46] chromatin ( unseparated [41]) [41] chromosome ( polo kinase undergoes cell cycle-dependent changes in its distribution. It is predominantly cytoplasmic during interphase, it becomes associated with condensed chromosomes toward the end of prophase, and it remains associated with chromosomes until telophase, whereupon it becomes cytoplasmic [14]) [14] cytoplasm ( polo kinase undergoes cell cycle-dependent changes in its distribution. It is predominantly cytoplasmic during interphase, it becomes associated with condensed chromosomes toward the end of prophase, and it remains associated with chromosomes until telophase, whereupon it becomes cytoplasmic [14]; in fertilized eggs between female and male pronuclei at microtubules [43]) [14, 43, 45, 46] germinal vesicle ( accumulation of Plk1 in germinal vesicle stage oocytes [25,43]) [25, 43] kinetochore [24, 27, 28, 30, 45, 49] microtubule ( enzyme is located at and required for microtubule assembly [43]) [25, 43] mitotic spindle ( during mitosis [46]) [46] nucleolus [42] nucleoplasm ( nucleocytoplasmic space of mitotic cells [27]) [27] nucleus ( the nuclear localization sequence is 48RSRRRYVRGR57 [36]) [36, 41, 49] pronucleus ( after fertilization, female and male [25]) [25] spindle ( central [30]; co-localization at the central spindle with Pavarotti, a kinesin-related motor protein [46]; mid [27]; mid zone of the central spindle [45]; middle region,

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at anaphase-telophase I and anaphase-telophase II stages [25,43]; spindle pole body [39,40,44]; unseparated [41]) [24, 25, 27, 28, 30, 39, 40, 41, 43, 44, 45, 46] spindle microtubule [25] spindle pole ( after germinal vesicle breakdown, at metaphase I stage, and in MII spindle pole [25,43]) [25, 27, 28, 33, 43, 45] spindle pole body ( recruitment to [46]; unseparated [41]) [41, 46] Additional information ( intracellular localization of wildtype and mutant enzymes, overview [40]; localization changes with embryonal development, colchicine inhibits spindle pole localization of the enzyme, taxol treatment leads to localization in the cytoplasm [25]; localization changes with embryonal development, e.g. throughout the division plane during cytokinesis, subcellular localization analysis, overview, colchicine inhibits spindle pole localization of the enzyme, taxol treatment leads to localization in the cytoplasm [43]; localization of the enzyme is dependent on cell cycle stage [28]; the enzyme co-localizes with the protein kinase Chk2 [35]; the kinase activity is regulated by the conserved Cterminal polo box domain which acts as both an autoinhibitory domain and a subcellular localization domain [30]) [25, 28, 30, 35, 40, 43] Purification (recombinant GST-tagged Plk1 from Spodoptera frugiperda Sf9 cells) [37] (recombinant HA-tagged Plk from HeLa cells by immunoprecipitation) [34] (recombinant His6-tagged wild-type and mutant Plk3 from HeLa cells) [32] (recombinant selenomethionine-labeled GST-tagged Plk1 from Escherichia coli by glutathione affinity chromatography, the GST-tag is cleaved off, recombinant His-tagged Plk1 from Sf9 insect cells by nickel affinity chromatography) [30] Crystallization (purified untagged recombinant selenomethionine-labeled enzyme comprising residues 367-603, cleavage through subtilisin, sitting drop vapour diffusion method, 4 C, 0.001 ml of protein solution containing 10 mg/ml protein is mixed with 0.001 ml mother liquor containing 5-10% v/v PEG 4000, 0.1 M sodium citrate, pH 6.0, and 0.1 M ammonium acetate, formation of needlelike crystals that do not diffract, co-crystallization with the synthesized phosphopeptide MQSpTPL is suitable for crystallization giving crystals within 2-3 days by sitting drop vapour diffusion from 1-10% PEG 20000, 0.1 M MES, pH 6.5, at room temperature, X-ray diffraction structure determination and analysis at 2.2-2.3 A resolution, complex formation between enzyme and phosphopeptide via residues W414, L490, H538, and K540) [30]

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Cloning (developmental expression analysis of the highly conserved enzyme) [45] (expression of GST-tagged Plx1 in S2 cells, co-expression with GFPtagged MEI-S332) [29] (DNA sequence determination, transient expression of FLAG-tagged wild-type and mutant enzymes in 293T cells, co-expression witg GFP, overexpression induces wild-type protein kinase Chk2 phosphorylation, but does not increase phosphorylation of Chk2 mutant T68A) [35] (expression in U2OS cells) [38] (expression of FLAG-tagged Plk1 in COS-7 cells, co-expression of Plk1 and p53 in p53-deficient lung carcinoma H1299 cells greatly decreases the p53-mediated recombinant transcription, this effect does not appear with co-expression of kinase-defective K82M Plk1) [36] (expression of GFP-tagged enzyme in HeLa cells and LLCPK cells) [28] (expression of GST-tagged Plk1 in Escherichia coli strain B834(DE3) strain as selenomethionine-labeled enzyme, expression of His-tagged Plk1 in Spodoptera frugiperda Sf9 cells using the baculovirus system) [30] (expression of HA-tagged Plk in HeLa cells, co-expression of His-tagged Plk with wild-type and mutant Myt1) [34] (expression of His6-tagged wild-type and mutant Plk3 in HeLa cells) [32] (expression of wild-type and K111R mutant enzyme in CHO cells, overexpression of HA-tagged wild-type and mutant Plk2 in U2OS cells) [26] (expression of wild-type and mutant GST-tagged or His6-tagged Plk3) [46] (stable expression of Plk1 and transfection with hairpin shRNA in HeLa cells, expression of GST-tagged Plk1 in Spodoptera frugiperda Sf9 cells) [37] (expression of CDC5 fused to the Met3 promoter intergrated in the LEU2 locus of a yeast strain carrying a allele of CDC5) [24] (overexpression of mutant K69R in a checkpoint-defective mad2-deletion strain, two-hybrid expression of wild-type and mutant enzymes with diverse protein partners for interaction study, overview) [40] (Fnk as fusion protein with GFP expressed in COS cells) [5] (expressed through the baculoviral vector system) [8] [14] [15] (determination of nucleotide sequence of cDNA) [18] (expression in Escherichia coli) [17] (expression of Plk1 in HeLa cells, DU145 cells, T98G cells, and in GM05849 cells) [47] [16, 20] (isolation of cDNA) [21]

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Engineering D181N ( site-directed mutagenesis, mutation of the kinase domain, no complementation by plo1 [40]) [40] D181R ( site-directed mutagenesis, mutation of the kinase domain, no complementation by plo1 [40]) [40] D623A/H624A/K625A ( site-directed mutagenesis, mutation of polo box 3, mutant strain shows reduced mitotic activity, no complementation by plo1 [40]) [40] E139K ( site-directed mutagenesis, mutation in the kinase domain, mutant enzyme is fully active with histone H1 kinase [33]) [33] E193V ( site-directed mutagenesis, mutation of the kinase domain, no complementation by plo1 [40]) [40] F518A/N519A ( site-directed mutagenesis, mutation of polo box 1, mutant strain shows reduced mitotic activity [40]) [40] G505A ( site-directed mutagenesis, mutation of polo box 1, mutant strain shows reduced mitotic activity [40]) [40] K111R ( site-directed mutagenesis, kinase inactive mutant, overexpression blocks the centriole duplication and arrests the cells in S-phase [26]) [26] K52R ( site-directed mutagenesis, kinase-defective mutant [32]) [32] K69R ( site-directed mutagenesis, mutation of the kinase domain, mutant is catalytically inactive, no complementation by plo1 [40]) [40] K82M ( site-directed mutagenesis, kinase-defective mutant [36]; site-directed mutagenesis, kinase-defective Plk1 mutant [37]) [36, 37] L577A ( site-directed mutagenesis, mutation of polo box 2, mutant strain shows reduced mitotic activity [40]) [40] S402A ( site-directed mutagenesis, no phosphorylation of the mutant by the stress response machinery, leading to delay in cell tip growth and cell division [44]) [44] T197V ( site-directed mutagenesis, mutation of the kinase domain, no complementation by plo1 [40]) [40] T210D ( site-directed mutagenesis, constitutively active mutant, overrides the irradiation-induced DNA damage and inhibition of centrosome separation in contrast to the wild-type enzyme [38]; site-directed mutagenesis, hyperactive Plk1 mutant, shows reduced activity with truncated Pin1 compared to the wild-tpe Plk1 [37]) [37, 38] T82A ( site-directed mutagenesis [35]) [35] W49F ( site-directed mutagenesis, mutation of polo box 1, mutant strain shows reduced mitotic activity [40]) [40] Y506A/Q507A/L508A ( site-directed mutagenesis, mutation of polo box 1, mutant strain shows reduced mitotic activity, no complementation by plo1 [40]) [40] Additional information ( constructed mutant cells deficient in Cdc5p are blocked early in nuclear division with very short spindles and unseparated chromatin, the cell cycle defective mutants show also formation of hyphal-like filaments under yeast growth conditions [41]; construction of an kinase-active deletion mutant lacking 32 amino acids of te N-

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terminus [32]; construction of C-terminal deletions, the deletion mutants comprise residues 1-633, 1-583, and 1-483, no complementation of the mutants by plo1 [40]; construction of Plk1 deletion mutants comprising residues 1-480, 1-330, or 1-408, deletion mutant 1-330 shows no kinase activity [35]; down-regulation of Plk1 by expression of hairpin shRNA results in increased Pin1 ubiquitination and to down-regulation of pin 1 levels during mitosis [37]; enzyme depletion using the vector-based small interfering RNA technique, Plk1 depletion leads to highly inhibited cell proliferation, decreased viability, and results in cell-cycle arrest with 4 n DNA content, formation of dumbbell-like chromatin structure due to impaired sister chromatin separation, induction of apoptosis, the apoptotic effect is reversible by co-transfection of murine Plk1 [47]; enzyme inhibition by expression of siRNA or inhibition of enzyme expression in HeLa cells reducing the the level of 3F3/2 phosphoepitope and inhibiting normal kinetochore association, overview [28]; generation of temperature-sensitive mutants of Plo1 which are inactivated at 35 C for 4 h, Plo1 activity is abolished in Cut12 loss-of-function mutant cells, but is increased in Cut12 gain-of-function mutant cells [33]; in mutant cells in which the Cdc5 promoter is exchanged for the Clb2 promoter, the enzyme is degradated during G1 phase and is absent in meiosis, Cdc5-depleted cells progress through premeiotic S phase and enter metaphase I but arrest in metaphase I, mechanism [49]; inhibition of p53 phosphorylation by Plk3 via siRNA transfection [46]; male homozygous polo mutant flies die in the third instar larval stage, heterozygous mutants show affected centromer dissociation of MEI-S332, but not association resulting in chromosome segragation defects [29]; mutant phenotype analysis [45]; overexpression of Cdc5 leads to Cdc14 release from the nucleolus in S-phase-arrested cells [42]; overexpression of dominant negative Plk2 mtant results in abolished centriole duplication in fibroblasts and in U2OS2 cells [26]; overexpression of mutant or wild-type Cdc5 results in multinucleated cells, Cdc5 overexpression overrides checkpoint-induced cell cycle arrest, Cdc5-defective mutant protein suppresses a Rad53 checkpoint defect [46]; overexpression of Plo1 results in formation of multiple septa without nuclear division [46]; Plk1 depletion by siRNA transfection combined with Nek2 overexpression in U2OS cells [38]) [26, 28, 29, 32, 33, 35, 37, 38, 40, 41, 42, 45, 46, 47, 49]

6 Stability General stability information , association with Hsp90 at the centrosome stabilizes the enzyme [45]

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References [1] Adams, M.D.; Celniker, S.E.; Holt, R.A.; Evans, C.A.; Gocayne, J.D.; et al.: The genome sequence of Drosophila melanogaster. Science, 287, 2185-2195 (2000) [2] Wood, V.; Gwilliam, R.; Rajandream, M.A.; Lyne, M.; Lyne, R.; et al.: The genome sequence of Schizosaccharomyces pombe. Nature, 415, 871-880 (2002) [3] Chase, D.; Feng, Y.; Hanshew, B.; Winkles, J.A.; Longo, D.L.; Ferris, D.K.: Expression and phosphorylation of fibroblast-growth-factor-inducible kinase (Fnk) during cell-cycle progression. Biochem. J., 333, 655-660 (1998) [4] Donohue, P.J.; Alberts, G.F.; Guo, Y.; Winkles, J.A.: Identification by targeted differential display of an immediate early gene encoding a putative serine/ threonine kinase. J. Biol. Chem., 270, 10351-10357 (1995) [5] Holtrich, U.; Wolf, G.; Yuan, J.; Bereiter-Hahn, J.; Karn, T.; Weiler, M.; Kauselmann, G.; Rehli, M.; Andreesen, R.; Kaufmann, M.; Kuhl, D.; Strebhardt, K.: Adhesion induced expression of the serine/threonine kinase Fnk in human macrophages. Oncogene, 19, 4832-4839 (2000) [6] Li, B.; Ouyang, B.; Pan, H.; Reissmann, P.T.; Slamon, D.J.; Arceci, R.; Lu, L.; Dai, W.: Prk, a cytokine-inducible human protein serine/threonine kinase whose expression appears to be down-regulated in lung carcinomas. J. Biol. Chem., 271, 19402-19408 (1996) [7] Ouyang, B.; Li, W.; Pan, H.; Meadows, J.; Hoffmann, I.; Dai, W.: The physical association and phosphorylation of Cdc25C protein phosphatase by Prk. Oncogene, 18, 6029-6036 (1999) [8] Ouyang, B.; Pan, H.; Lu, L.; Li, J.; Stambrook, P.; Li, B.; Dai, W.: Human Prk is a conserved protein serine/threonine kinase involved in regulating M phase functions. J. Biol. Chem., 272, 28646-28651 (1997) [9] Kitada, K.; Johnson, A.L.; Johnston, L.H.; Sugino, A.: A multicopy suppressor gene of the Saccharomyces cerevisiae G1 cell cycle mutant gene dbf4 encodes a protein kinase and is identified as CDC5. Mol. Cell. Biol., 13, 4445-4457 (1993) [10] Chase, D.; Serafinas, C.; Ashcroft, N.; Kosinski, M.; Longo, D.; Ferris, D.K.; Golden, A.: The polo-like kinase PLK-1 is required for nuclear envelope breakdown and the completion of meiosis in Caenorhabditis elegans. Genesis, 26, 26-41 (2000) [11] Ouyang, B.; Wang, Y.; Wei, D.: Caenorhabditis elegans contains structural homologs of human prk and plk. DNA Seq., 10, 109-113 (1999) [12] Wilson, R.; Ainscough, R.; Anderson, K.; Baynes, C.; Berks, M.; Bonfield, J.; Burton, J.; Connell, M.; Copsey, T.; Cooper, J.; et al.: 2.2 Mb of contiguous nucleotide sequence from chromosome III of C. elegans. Nature, 368, 32-38 (1994) [13] Ohkura, H.; Hagan, I.M.; Glover, D.M.: The conserved Schizosaccharomyces pombe kinase plo1, required to form a bipolar spindle, the actin ring, and septum, can drive septum formation in G1 and G2 cells. Genes Dev., 9, 1059-1073 (1995)

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[14] Llamazares, S.; Moreira, A.; Tavares, A.; et al.: Polo encodes a protein kinase homolog required for mitosis in Drosophila. Genes Dev., 5, 2153-2165 (1991) [15] Holtrich, U.; Wolf, G.; Brauninger, A.; Karn, T.; Bohme, B.; RubsamenWaigmann, H.; Strebhardt, K.: Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors. Proc. Natl. Acad. Sci. USA, 91, 1736-1740 (1994) [16] Hamanaka, R.; Maloid, S.; Smith, M.R.; O’Connell, C.D.; Longo, D.L.; Ferris, D.K.: Cloning and characterization of human and murine homologues of the Drosophila polo serine-threonine kinase. Cell Growth Differ., 5, 249257 (1994) [17] Golsteyn, R.M.; Schultz, S.J.; Bartek, J.; Ziemiecki, A.; Ried, T.; Nigg, E.A.: Cell cycle analysis and chromosomal localization of human Plk1, a putative homologue of the mitotic kinases Drosophila polo and Saccharomyces cerevisiae Cdc5. J. Cell Sci., 107, 1509-1517 (1994) [18] Lake, R.J.; Jelinek, W.R.: Cell cycle- and terminal differentiation-associated regulation of the mouse mRNA encoding a conserved mitotic protein kinase. Mol. Cell. Biol., 13, 7793-7801 (1993) [19] Simmons, D.L.; Neel, B.G.; Stevens, R.; Evett, G.; Erikson, R.L.: Identification of an early-growth-response gene encoding a novel putative protein kinase. Mol. Cell. Biol., 12, 4164-4169 (1992) [20] Clay, F.J.; McEwen, S.J.; Bertoncello, I.; Wilks, A.F.; Dunn, A.R.: Identification and cloning of a protein kinase-encoding mouse gene, Plk, related to the polo gene of Drosophila. Proc. Natl. Acad. Sci. USA, 90, 4882-4886 (1993) [21] Fode, C.; Motro, B.; Yousefi, S.; Heffernan, M.; Dennis, J.W.: Sak, a murine protein-serine/threonine kinase that is related to the Drosophila polo kinase and involved in cell proliferation. Proc. Natl. Acad. Sci. USA, 91, 6388-6392 (1994) [22] Chase, D.; Golden, A.; Heidecker, G.; Ferris, D.K.: Caenorhabditis elegans contains a third polo-like kinase gene. DNA Seq., 11, 327-334 (2000) [23] Kauselmann, G.; Weiler, M.; Wulff, P.; Jessberger, S.; Konietzko, U.; Scafidi, J.; Staubli, U.; Bereiter-Hahn, J.; Strebhardt, K.; Kuhl, D.: The polo-like protein kinases Fnk and Snk associate with a Ca2+ - and integrin-binding protein and are regulated dynamically with synaptic plasticity. EMBO J., 18, 5528-5539 (1999) [24] Rancati, G.; Crispo, V.; Lucchini, G.; Piatti, S.: Mad3/BubR1 phosphorylation during spindle checkpoint activation depends on both Polo and Aurora kinases in budding yeast. Cell Cycle, 4, 972-980 (2005) [25] Yao, L.J.; Fan, H.Y.; Tong, C.; Chen, D.Y.; Schatten, H.; Sun, Q.Y.: Polo-like kinase-1 in porcine oocyte meiotic maturation, fertilization and early embryonic mitosis. Cell. Mol. Biol., 49, 399-405 (2003) [26] Warnke, S.; Kemmler, S.; Hames, R.S.; Tsai, H.L.; Hoffmann-Rohrer, U.; Fry, A.M.; Hoffmann, I.: Polo-like kinase-2 is required for centriole duplication in mammalian cells. Curr. Biol., 14, 1200-1207 (2004)

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[27] Sumara, I.; Gimenez-Abian, J.F.; Gerlich, D.; Hirota, T.; Kraft, C.; de la Torre, C.; Ellenberg, J.; Peters, J.M.: Roles of polo-like kinase 1 in the assembly of functional mitotic spindles. Curr. Biol., 14, 1712-1722 (2004) [28] Ahonen, L.J.; Kallio, M.J.; Daum, J.R.; Bolton, M.; Manke, I.A.; Yaffe, M.B.; Stukenberg, P.T.; Gorbsky, G.J.: Polo-like kinase 1 creates the tension-sensing 3F3/2 phosphoepitope and modulates the association of spindle-checkpoint proteins at kinetochores. Curr. Biol., 15, 1078-1089 (2005) [29] Clarke, A.S.; Tang, T.T.; Ooi, D.L.; Orr-Weaver, T.L.: POLO kinase regulates the Drosophila centromere cohesion protein MEI-S332. Dev. Cell, 8, 53-64 (2005) [30] Cheng, K.Y.; Lowe, E.D.; Sinclair, J.; Nigg, E.A.; Johnson, L.N.: The crystal structure of the human polo-like kinase-1 polo box domain and its phospho-peptide complex. EMBO J., 22, 5757-5768 (2003) [31] Nishiyama, A.; Muraki, K.; Saito, M.; Ohsumi, K.; Kishimoto, T.; Ishikawa, F.: Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase. EMBO J., 25, 575-584 (2006) [32] Ruan, Q.; Wang, Q.; Xie, S.; Fang, Y.; Darzynkiewicz, Z.; Guan, K.; JhanwarUniyal, M.; Dai, W.: Polo-like kinase 3 is Golgi localized and involved in regulating Golgi fragmentation during the cell cycle. Exp. Cell Res., 294, 51-59 (2004) [33] MacIver, F.H.; Tanaka, K.; Robertson, A.M.; Hagan, I.M.: Physical and functional interactions between polo kinase and the spindle pole component Cut12 regulate mitotic commitment in S. pombe. Genes Dev., 17, 15071523 (2003) [34] Nakajima, H.; Toyoshima-Morimoto, F.; Taniguchi, E.; Nishida, E.: Identification of a consensus motif for Plk (Polo-like kinase) phosphorylation reveals Myt1 as a Plk1 substrate. J. Biol. Chem., 278, 25277-25280 (2003) [35] Tsvetkov, L.; Xu, X.; Li, J.; Stern, D.F.: Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody. J. Biol. Chem., 278, 84688475 (2003) [36] Ando, K.; Ozaki, T.; Yamamoto, H.; Furuya, K.; Hosoda, M.; Hayashi, S.; Fukuzawa, M.; Nakagawara, A.: Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. J. Biol. Chem., 279, 25549-25561 (2004) [37] Eckerdt, F.; Yuan, J.; Saxena, K.; Martin, B.; Kappel, S.; Lindenau, C.; Kramer, A.; Naumann, S.; Daum, S.; Fischer, G.; Dikic, I.; Kaufmann, M.; Strebhardt, K.: Polo-like kinase 1-mediated phosphorylation stabilizes Pin1 by inhibiting its ubiquitination in human cells. J. Biol. Chem., 280, 3657536583 (2005) [38] Zhang, W.; Fletcher, L.; Muschel, R.J.: The role of polo-like kinase 1 in the inhibition of centrosome separation after ionizing radiation. J. Biol. Chem., 280, 42994-42999 (2005) [39] Mulvihill, D.P.; Hyams, J.S.: Cytokinetic actomyosin ring formation and septation in fission yeast are dependent on the full recruitment of the polo-like kinase PLO1 to the spindle pole body and a functional spindle assembly checkpoint. J. Cell Sci., 115, 3575-3586 (2002)

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[40] Reynolds, N.; Ohkura, H.: Polo boxes form a single functional domain that mediates interactions with multiple proteins in fission yeast polo kinase. J. Cell Sci., 116, 1377-1387 (2003) [41] Bachewich, C.; Thomas, D.Y.; Whiteway, M.: Depletion of a polo-like kinase in Candida albicans activates cyclase-dependent hyphal-like growth. Mol. Biol. Cell, 14, 2163-2180 (2003) [42] Visintin, R.; Stegmeier, F.; Amon, A.: The role of the polo kinase Cdc5 in controlling Cdc14 localization. Mol. Biol. Cell, 14, 4486-4498 (2003) [43] Fan, H.Y.; Tong, C.; Teng, C.B.; Lian, L.; Li, S.W.; Yang, Z.M.; Chen, D.Y.; Schatten, H.; Sun, Q.Y.: Characterization of polo-like kinase-1 in rat oocytes and early embryos implies its functional roles in the regulation of meiotic maturation, fertilization, and cleavage. Mol. Reprod. Dev., 65, 318-329 (2003) [44] Petersen, J.; Hagan, I.M.: Polo kinase links the stress pathway to cell cycle control and tip growth in fission yeast. Nature, 435, 507-512 (2005) [45] Glover, D.M.: Polo kinase and progression through M phase in Drosophila: a perspective from the spindle poles. Oncogene, 24, 230-237 (2005) [46] Xie, S.; Xie, B.; Lee, M.Y.; Dai, W.: Regulation of cell cycle checkpoints by polo-like kinases. Oncogene, 24, 277-286 (2005) [47] Liu, X.; Erikson, R.L.: Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc. Natl. Acad. Sci. USA, 100, 5789-5794 (2003) [48] Hansen, D.V.; Tung, J.J.; Jackson, P.K.: CaMKII and Polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. Proc. Natl. Acad. Sci. USA, 103, 608-613 (2006) [49] Lee, B.H.; Amon, A.: Role of polo-like kinase CDC5 in programming meiosis I chromosome segregation. Science, 300, 482-486 (2003)

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1 Nomenclature EC number 2.7.11.22 Systematic name ATP:cyclin phosphotransferase Recommended name cyclin-dependent kinase Synonyms A-type cyclin-dependent kinase [198] B-type cyclin-dependent kinase [200] CAK [4, 7] CDC2 kinase [45] CDC2-like serine/threonine-protein kinase CRP [87] CDC2a [64] CDC2dT ( a variant of human CDC2, that lacks 171 nucleotides corresponding to 57 amino acids, which compose most of the T-loop [33]) [33] CDK [5, 162, 167, 168, 171, 172, 178, 186, 188, 201, 203] CDK11p110 [165] CDK2 [6, 7, 8, 155, 169, 171, 174, 175, 176, 179, 180, 182, 185, 190, 195, 197, 205] CDK2L [21] CDK4 [1, 39, 163, 164, 176, 179, 185] CDK5 homolog [101] CDK5/p25 [159] CDK9 [114, 175] CDKA [200] CDKA,1 [199] CDKA1 [177] CDKB [200] CDKB1 [177] CDKB1,1 [196] CDKF,1 [197] CRK4 protein kinase [128, 130] CTD kinase a subunit [131] Cdc2 [194] Cdc28p-Chlp kinase [189]

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Cdc2p complex [24] Cdk-A [198] Cdk1 [171, 175, 178, 180, 181, 187, 192, 194, 195] Cdk1/cyclin B1 kinase [187] Cdk5 [105, 118, 156, 158, 159, 166, 173, 175, 181, 183, 191, 193, 194, 195, 202] Cdk5-p35 [184] Cyclin-dependent kinase pef1 Eph-related receptor protein tyrosine kinase [3] G2-specific protein kinase NIMA [152, 153, 154] G2-specific protein kinase nim-1 [154] K-cyclin/cdk6 kinase [182] K35 [104] MO15/CDK7 [112] Mcm1p [189] NIMA protein kinase [153, 154] PCTAIRE 2 [20] PCTAIRE-3 [132] PHO85 [47, 48] PHO85 homolog PHOA [172] PHOB [172] PISSLRE [139] PITALRE [117] PITSLRE ( formerly [165]) [165] PK5 [178] Prk1 protein kinase [19] R2 [201] STK9 [15] cdc2 PK [4] cdc2-related kinase [11, 88, 89] cdc28p [161] cdc2MsB [135] cdc42p [161] cdk6 [1, 181, 182, 185, 204] cdk7 ( subunit of the transcription/DNA repair factor TFIIH [107]) [4, 107, 175] cell division control protein 2 [9, 24, 25, 26, 27, 28, 29, 119, 123] cell division control protein 2 cognate [13, 60] cell division control protein 2 homolog [33, 34, 35, 36, 37, 38, 44, 45, 54, 86, 88, 93, 102, 124, 137, 147] cell division control protein 2 homolog 1 [61, 62, 92] cell division control protein 2 homolog 2 [61, 62, 92, 135] cell division control protein 2 homolog 3 [92] cell division control protein 2 homolog A [63, 64, 65, 66, 141, 149] cell division control protein 2 homolog B [64, 65, 149] cell division control protein 2 homolog C [141]

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Cyclin-dependent kinase

2.7.11.22

cell division control protein 2 homolog D [141] cell division control protein 28 [22, 23, 94, 95, 96] cell division cycle 2-related protein kinase 7 [146] cell division protein kinase 10 [138, 139, 140] cell division protein kinase 2 [21, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 99, 103, 143, 144] cell division protein kinase 2 homolog [55, 56, 57, 58, 59, 60, 133] cell division protein kinase 2 homolog CRK1 [136] cell division protein kinase 3 [121] cell division protein kinase 4 [3, 10, 39, 40, 41, 42, 43, 81, 82, 83, 90] cell division protein kinase 5 [81, 105, 106, 118, 121, 125, 126, 127] cell division protein kinase 5 homolog [17, 101] cell division protein kinase 6 [121, 122] cell division protein kinase 7 [50, 51, 81, 107, 108, 109, 110, 111, 112, 113, 120, 128, 129] cell division protein kinase 9 [114, 115, 116] cyclin A/Cdk2 [190] cyclin activating kinase [7] cyclin dependent kinase 2 [7] cyclin-dependent kinase 11p110 [165] cyclin-dependent kinase 11p58 [170] cyclin-dependent kinase 2 [174, 176, 179] cyclin-dependent kinase 4 [90, 163, 164, 176, 179] cyclin-dependent kinase 5 [105, 118, 158, 160, 183, 191, 193, 194, 202] cyclin-dependent kinase 5-p35 [184] cyclin-dependent kinase 5/p39 [156] cyclin-dependent kinase 6 [181, 204] cyclin-dependent kinase 8 [104] cyclin-dependent kinase A [198] cyclin-dependent kinase activating kinase [4] cyclin-dependent kinase-2 [8, 205] cyclin-dependent kinase-5 [159, 173] galactosyltransferase associated protein kinase p58/GTA [52, 67, 100] glycogen synthase kinase-3ab [160] kinase Cdk6 [122] male germ cell-associated kinase [49] meiosis induction protein kinase IME2/SME1 [84, 85] meiotic mRNA stability protein kinase UME5 [148] mrk [178] negative regulator of the PHO system [46, 47, 48, 148] p25-Cdk5 kinase complex [157] p34cdc2 [133] p34cdc2 homologue [54]

158

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Cyclin-dependent kinase

p34cdc2 protein kinase [26, 123] p40MO15 [51, 110] p58clk-1 protein kinase [52, 53] protein kinase csk1 [9, 91] serine/threonine kinase p [15] serine/threonine protein kinase PCTAIRE-3 [121] serine/threonine protein kinase PITSLRE [17] serine/threonine protein kinase SGV1 [14] serine/threonine-protein kinase ALS2CR7 [145] serine/threonine-protein kinase CAK1 [150, 151] serine/threonine-protein kinase KIN28 [12, 30, 31, 32] serine/threonine-protein kinase KKIALRE [121] serine/threonine-protein kinase MAK [49, 134] serine/threonine-protein kinase MHK [97, 98] serine/threonine-protein kinase PCTAIRE-1 [121, 132] serine/threonine-protein kinase PCTAIRE-2 [20, 121] serine/threonine-protein kinase PCTAIRE-3 [20, 132] serine/threonine-protein kinase pef1 [18] serine/threonine-protein kinase prk1 [9, 19] Additional information ( CDK5 is a unique member of the CDK family, see also EC 2.7.11.26 [159]; see also EC 2.7.11.1 and EC 2.7.11.22 [160]; see also EC 2.7.11.26 [156, 157, 158, 160]; the enzyme belongs to the CDK family [159]; the enzyme belongs to the PITSLRE kinase family [170]) [156, 157, 158, 159, 160, 170] CAS registry number 150428-23-2

2 Source Organism







Gallus gallus (no sequence specified) [193] Drosophila melanogaster (no sequence specified) [166] mammalia (no sequence specified) [5] eukaryota (no sequence specified) [1, 4, 7, 8, 167] Mus musculus (no sequence specified) [156, 159, 160, 166, 168, 173, 183, 194, 202] Homo sapiens (no sequence specified) [6, 155, 157, 160, 162, 163, 164, 166, 168, 169, 170, 171, 174, 176, 178, 179, 180, 181, 182, 186, 187, 188, 190, 194, 195, 203, 204, 205] Rattus norvegicus (no sequence specified) [158, 166, 168, 173, 184, 185, 191, 194] Sus scrofa (no sequence specified) [166] Saccharomyces cerevisiae (no sequence specified) [161,166,189,192] Aspergillus nidulans (no sequence specified) [172] Zea mays (no sequence specified) [198]

159

Cyclin-dependent kinase

2.7.11.22

Arabidopsis thaliana (no sequence specified) ( NarG, a subunit [199]) [196, 197, 199] Canis familiaris (no sequence specified) [166] Xenopus laevis (no sequence specified) [171] Caenorhabditis elegans (no sequence specified) [166] Plasmodium falciparum (no sequence specified) [178] Oryza sativa (no sequence specified) [201] Cercopithecus aethiops (no sequence specified) [175] Loligo pealei (no sequence specified) [166] Danio rerio (no sequence specified) [166] Marthasterias glacialis (no sequence specified) [180] Drosophila melanogaster (UNIPROT accession number: Q9VPC0) [2, 13, 17] Saccharomyces cerevisiae (UNIPROT accession number: P23293) [14, 16, 148] Homo sapiens (UNIPROT accession number: O76039) [15] Schizosaccharomyces pombe (UNIPROT accession number: O74456) [9, 18] Schizosaccharomyces pombe (UNIPROT accession number: O13958) [9, 19] Rattus norvegicus (UNIPROT accession number: O35831) [20] Rattus norvegicus (UNIPROT accession number: O35832) [20] Cricetulus griseus (UNIPROT accession number: O55076) [21] Saccharomyces cerevisiae (UNIPROT accession number: P00546) [22, 23] Schizosaccharomyces pombe (UNIPROT accession number: P04551) [9, 24, 25, 26, 27, 28, 29] Saccharomyces cerevisiae (UNIPROT accession number: P06242) [12, 30, 31, 32] Homo sapiens (UNIPROT accession number: P06493) [33, 34, 35] Mus musculus (UNIPROT accession number: P11440) [36, 37, 38] Homo sapiens (UNIPROT accession number: P11802) [10, 39, 40, 41, 42, 43] Gallus gallus (UNIPROT accession number: P13863) [44, 45] Saccharomyces cerevisiae (UNIPROT accession number: P17157) [46, 47, 48, 148] Rattus norvegicus (UNIPROT accession number: P20793) [49] Homo sapiens (UNIPROT accession number: P20794) [49] Xenopus laevis (UNIPROT accession number: P20911) [50, 51] Homo sapiens (UNIPROT accession number: P21127) [52, 53] Zea mays (UNIPROT accession number: P23111) [54] Xenopus laevis (UNIPROT accession number: P23437) [55, 56, 57, 58, 59, 60] Drosophila melanogaster (UNIPROT accession number: P23573) [13, 60] Xenopus laevis (UNIPROT accession number: P24033) [61, 62] Arabidopsis thaliana (UNIPROT accession number: P24100) [63, 64, 65, 66, 149]

160

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Cyclin-dependent kinase

Mus musculus (UNIPROT accession number: P24788) [67] Homo sapiens (UNIPROT accession number: P24941) [68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80] Arabidopsis thaliana (UNIPROT accession number: P25859) [64, 65, 149] Mus musculus (UNIPROT accession number: P30285) [3,81,82,83] Saccharomyces cerevisiae (UNIPROT accession number: P32581) [84,85] Dictyostelium discoideum (UNIPROT accession number: P34112) [86] Dictyostelium discoideum (UNIPROT accession number: P34117) [87] Caenorhabditis elegans (UNIPROT accession number: P34556) [11, 88, 89] Rattus norvegicus (UNIPROT accession number: P35426) [90] Xenopus laevis (UNIPROT accession number: P35567) [61,62] Schizosaccharomyces pombe (UNIPROT accession number: P36615) [9, 91] Trypanosoma brucei brucei (UNIPROT accession number: P38973) [92] Saccharomyces cerevisiae (UNIPROT accession number: P39073) [148] Rattus norvegicus (UNIPROT accession number: P39951) [93] Candida albicans (UNIPROT accession number: P43063) [94,95,96] Arabidopsis thaliana (UNIPROT accession number: P43294) [97,98] Carassius auratus (UNIPROT accession number: P43450) [99] Rattus norvegicus (UNIPROT accession number: P46892) [100] Drosophila melanogaster (UNIPROT accession number: P48609) [17, 101] Bos taurus (UNIPROT accession number: P48734) [102] Mesocricetus auratus (UNIPROT accession number: P48963) [103] Homo sapiens (UNIPROT accession number: P49336) [104] Mus musculus (UNIPROT accession number: P49615) [81,105,106] Homo sapiens (UNIPROT accession number: P50613) [107, 108, 109, 110, 111, 112, 113] Homo sapiens (UNIPROT accession number: P50750) [114,115,116,117] Xenopus laevis (UNIPROT accession number: P51166) [118] Ajellomyces capsulata (UNIPROT accession number: P54119) [119] Trypanosoma brucei brucei (UNIPROT accession number: P54665) [92] Trypanosoma brucei brucei (UNIPROT accession number: P54666) [92] Dictyostelium discoideum (UNIPROT accession number: P54685) [120] Homo sapiens (UNIPROT accession number: Q00526) [121] Homo sapiens (UNIPROT accession number: Q00532) [121] Homo sapiens (UNIPROT accession number: Q00534) [121,122] Homo sapiens (UNIPROT accession number: Q00535) [121] Homo sapiens (UNIPROT accession number: Q00536) [121] Homo sapiens (UNIPROT accession number: Q00537) [121] Emericella nidulans (UNIPROT accession number: Q00646) [123] Crithidia fasciculata (UNIPROT accession number: Q01917) [124] Bos taurus (UNIPROT accession number: Q02399) [125] Rattus norvegicus (UNIPROT accession number: Q03114) [126,127] Mus musculus (UNIPROT accession number: Q03147) [3,81,128,129,130]

161

Cyclin-dependent kinase

















2.7.11.22

Saccharomyces cerevisiae (UNIPROT accession number: Q03957) [131] Mus musculus (UNIPROT accession number: Q04735) [132] Entamoeba histolytica (UNIPROT accession number: Q04770) [133] Mus musculus (UNIPROT accession number: Q04859) [134] Mus musculus (UNIPROT accession number: Q04899) [132] Medicago sativa (UNIPROT accession number: Q05006) [135] Leishmania mexicana (UNIPROT accession number: Q07002) [136] Homo sapiens (UNIPROT accession number: Q07002) [121] Plasmodium falciparum (UNIPROT accession number: Q07785) [137] Homo sapiens (UNIPROT accession number: Q15131) [138,139,140] Antirrhinum majus (UNIPROT accession number: Q38772) [141] Antirrhinum majus (UNIPROT accession number: Q38774) [141] Antirrhinum majus (UNIPROT accession number: Q38775) [141] Vigna aconitifolia (UNIPROT accession number: Q41639) [142] Rattus norvegicus (UNIPROT accession number: Q63699) [143, 144] Homo sapiens (UNIPROT accession number: Q96Q40) [145] Homo sapiens (UNIPROT accession number: Q9NYV4) [146] Rana dybowskii (UNIPROT accession number: Q9W739) [147] Saccharomyces cerevisiae (UNIPROT accession number: P43568) [150, 151] Emericella nidulans (UNIPROT accession number: P11837) [152, 153, 154] Neurospora crassa (UNIPROT accession number: P48479) [154] Ostreococcus tauri (no sequence specified) [200] Helianthus tuberosus (UNIPROT accession number: Q8GVD8) [177] Helianthus tuberosus (UNIPROT accession number: Q8GVD7) [177] Homo sapiens (UNIPROT accession number: U04816) [165]

3 Reaction and Specificity Catalyzed reaction ATP + a protein = ADP + a phosphoprotein ( reaction mechanism [8]; activation involves the activation loop, a polypeptide region outside the active site cleft, which is reversibly phosphorylated at a Thr residue, phosphorylation leads to enzyme inhibition [7]; catalytic aspartate residue [6]; active site amino acid sequences of PK5 and mrk [178]) Reaction type phospho group transfer Natural substrates and products S ATP + Cdc20 ( Cdk phosphorylation affects interaction of Cdc20 with Mad2 and the anaphase-promoting complex-cyclosome in HeLa cells [171]; substrate of Cdk1, rather than of Cdk2 [171]) (Reversibility: ?) [171] P ADP + phosphorylated Cdc20

162

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Cyclin-dependent kinase

S ATP + Cprk ( i.e. Cdk5/p35-regulated kinase [166]) (Reversibility: ?) [166] P ADP + phosphorylated Cprk S ATP + ErbB2 ( phosphorylation of the neuregulin receptor by Cdk5 is involved in regulation of neuregulin [166]) (Reversibility: ?) [166] P ADP + phosphorylated ErbB2 S ATP + ErbB3 ( phosphorylation of the neuregulin receptor by Cdk5 is involved in regulation of neuregulin [166]) (Reversibility: ?) [166] P ADP + phosphorylated ErbB3 S ATP + Fkh2p ( phosphorylation of forkhead transcription factor Fkh2p is part of regulation of cell cycle-specific gene expression, e.g. of the CLB2 cluster, Fkh2p phosphorylation by Cdc28p is regulated by complex formation with Mcm1p and Ndd1p, and phosphorylation, overview [189]) (Reversibility: ?) [189] P ADP + phosphorylated Fkh2p S ATP + MAP1B ( reaction in growth cones is important for stability of microtubules [193]) (Reversibility: ?) [193] P ADP + phosphorylated MAP1B S ATP + MEK1 ( Cdk5 regulates the ERK1/2 pathway through phosphorylation of MEK1, overview [166]) (Reversibility: ?) [166] P ADP + phosphorylated MEk1 S ATP + Munc-18 ( involved in regulation of exocytosis involving SNARE proteins, Munc-18 is required for mediating secretory responsesoverview [166]) (Reversibility: ?) [166] P ADP + phosphorylated Munc-18 S ATP + NF-H ( neurofilament protein that correlates neurit outgrowth, phosphorylation at the KSP repeats, regulated by the myelin-associate glycoprotein [166]; neurofilament protein, phosphorylation at the KSP repeats, regulated by the myelin-associate glycoprotein [166]) (Reversibility: ?) [166] P ADP + phosphorylated NF-H S ATP + NF-M ( neurofilament protein, phosphorylation at the KSP repeats, regulated by the myelin-associate glycoprotein [166]) (Reversibility: ?) [166] P ADP + phosphorylated NF-M S ATP + NR1 receptor ( involved in synaptic transmission, overview [166]) (Reversibility: ?) [166] P ADP + phosphorylated NR1 receptor S ATP + NR2 receptor ( involved in synaptic transmission, phosphorylation of Ser1232 on the A subunit upregulates NMCAR activity, overview [166]) (Reversibility: ?) [166] P ADP + phosphorylated NR2 receptor

163

Cyclin-dependent kinase

2.7.11.22

S ATP + SCR-1 ( Cdk2-cyclin A, phosphorylation at Lys5 regulates SCR-1 interaction with the progesterone receptor [190]) (Reversibility: ?) [190] P ADP + phosphorylated SCR-1 S ATP + STAT3 ( specific phosphorylation at Ser727 by CDK5-p35, CDK5 is involved in regulation of the signal transducer and transcription activator STAT3 in brain and muscle [202]) (Reversibility: ?) [202] P ADP + phosphorylated STAT3 S ATP + T-cell protein tyrosine phosphatase ( phosphorylation of the two splicing varaints TC45 and TC48 at Ser304 in a cell cycle-dependent manner, optimally in mitosis, overview [162]) (Reversibility: ?) [162] P ADP + phosphorylated T-cell protein tyrosine phosphatase S ATP + VGCC ( a voltage-dependent calcium channel, phosphorylation within the intracellular loop of the channel inhibiting interaction with SNARE proteins, SNAP-25, and synaptotagmin I required for neurotransmitter release, overview [166]) (Reversibility: ?) [166] P ADP + phosphorylated NR1 receptor S ATP + Varicella-Zoster virus IE63 protein ( phosphorylation at Ser224 by CDK1 in vivo is required for correct localization of the virus protein, e.g. in the host cytoplasm during latency, S224A mutation leads to inhibition of phosphorylation and exclusive localization of IE63 protein in the nucleus [175]) (Reversibility: ?) [175] P ADP + phosphorylated Varicella-Zoster virus IE63 protein S ATP + Wee1A ( phosphorylation at S123, S53, and S121 promotes binding of Wee1A by b-TrCP, the b-transducin repeat-containing protein, which is the substrate recognition component of the ubiquitin ligase, leading to proteasomal degradation of Wee1A, overview [203]) (Reversibility: ?) [203] P ADP + phosphorylated Wee1A S ATP + [tau protein] ( substrate of CDK5 in the central nervous system, see also EC 2.7.11.26, tau hyperphosphorylation is involved in neurodegeneration and Alzheimers disease, tau protein phosphorylation by CDK5 is involved in apoptosis in cortical cells [159]) (Reversibility: ?) [159] P ADP + [O-phospho-tau protein] S ATP + [tau-protein] ( activity in organisms with mutated APP and tau, not in wild-type, overview [160]; cdk5 associated with p25, cdk5 substrate in brain [157]; hyperphosphorylation of tau by CDK5 is involved in apoptosis and neurodegeneration in Alzheimers disease, overview [159]; tau is microtubule-associated, phopshorylation at T231 by CDK5 causes its release into the cytoplasm [158]) (Reversibility: ?) [157, 158, 159, 160] P ADP + O-phospho-[tau-protein] S ATP + [tau-protein] ( cdk5 substrate in brain, cdk5 associated with p39, tau is a microtubule-associated and developmentally regulated protein involved in axonal development in neurons, tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its

164

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P S P S P S

P S P S P S P S

P S P S P S

P S

P S

P

Cyclin-dependent kinase

affinity for microtubules, reaction of EC 2.7.11.26 [156]) (Reversibility: ?) [156] ADP + O-phospho -[tau-protein] ATP + a protein (Reversibility: ?) [1, 4, 5, 6, 7, 8, 161] ADP + a phosphoprotein ATP + axonal cytoskeleton protein ( regulated by integrin a1 b1 [166]) (Reversibility: ?) [166] ADP + phosphorylated axonal cytoskeleton protein ATP + c-Jun N-terminal kinase 3 ( i.e. JNK3, phosphorylation inhibits JNK3 and leads to reduced phosphorylation of c-jun and to reduced apoptosis [166]) (Reversibility: ?) [166] ADP + phosphorylated c-Jun N-terminal kinase 3 ATP + cyclin-dependent kinase (Reversibility: ?) [151] ADP + phosphorylated cyclin-dependent kinase ATP + dephosphin ( Cdk5 regulates endocytosis involving dephosphin activity, overview [166]) (Reversibility: ?) [166] ADP + phosphorylated dephosphin ATP + dopamine ( phosphorylation by cdk5 [191]) (Reversibility: ?) [191] ADP + phosphorylated dopamine ATP + dopamine and cAMP-regulated phosphoprotein ( i.e. DARPP-32, phosphorylation by cdk5 at Thr75 and Thr34 [191]) (Reversibility: ?) [191] ADP + phosphorylated dopamine and cAMP-regulated phosphoprotein ATP + histone H1 ( substrate of Cdk-A/cyclin D2 [198]) (Reversibility: ?) [198] ADP + phosphorylated histone H1 ATP + neuregulin receptor ErbB2 ( phosphorylation at Ser1176 by Cdk5 [173]) (Reversibility: ?) [173] ADP + phosphorylated neuregulin receptor ErbB2 ATP + neuregulin receptor ErbB3 ( phosphorylation at Thr871 and Ser11 20 by Cdk5 [173]; phosphorylation at Thr871 and Ser1120 in the consensus sequence RSRSPR by Cdk5, Cdk5 associates with Erb3 in vivo [173]) (Reversibility: ?) [173] ADP + phosphorylated neuregulin receptor ErbB3 ATP + pocket protein p107 ( hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis [168]) (Reversibility: ?) [168] ADP + phosphorylated pocket protein 107 ATP + pocket protein p130 ( hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis [168]) (Reversibility: ?) [168] ADP + phosphorylated pocket protein 130

165

Cyclin-dependent kinase

2.7.11.22

S ATP + progesterone receptor ( cyclin-dependent kinase activity is required for progesterone receptor PR function, the phosphorylation of the receptor protein has little effect, but cyclin A/Cdk2 acts as a progesterone receptor coactivator via stimulation of PR transcription, Cdk2-cyclin A is PR-dependently recruited to the PR promoter binding to cyclin A, mechanism involving SCR-1 and regulation, overview [190]) (Reversibility: ?) [190] P ADP + phosphorylated progesterone receptor S ATP + protein ( NIMA is a cell cycle regulated protein kinase required, in addition to p34cdc2/cyclin B, for initiation of mitosis. NIMA accumulates when cells are arrested in G2 and is degraded as cells traverse mitosis. NIMA degradation during mitosis is required for correct mitotic progression in Aspergillus nidulans [153]) (Reversibility: ?) [153] P ADP + phosphoprotein S ATP + retinoblastoma protein ( i.e. Rb protein [163, 182, 185]; i.e. Rb protein, hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis [168]; phosphorylation by CDK4/cyclin D at one site, or by CDK2/cyclin E or A at multiple sites in the cell cycle G1 phase [176]) (Reversibility: ?) [163, 168, 176, 182, 185] P ADP + phosphorylated retinoblastoma protein S ATP + retinoblastoma-related protein ( i.e. RBR, substrate of Cdk-A/cyclin D2 [198]) (Reversibility: ?) [198] P ADP + phosphorylated retinoblastoma-related protein S ATP + tau protein ( cdk5 substrate in brain, Cdk5-p25 or Cdk5-p35 [194]; hyperactivated Cdk5-p25 [166]) (Reversibility: ?) [166, 19] P ADP + phosphorylated tau protein S Additional information ( the gene coding for the enzyme is a candidate for the following disorders: Nance-Horan syndrome, oral-facial-digital syndrome type 1, and nonsyndromic sensorineural deafness [15]; enzyme is required for initiation of meiosis and sporulation [85]; enzyme may play a role in the regulation of plant growth and development [98]; enzyme is required for mitosis [93]; CDK4 amplification might contribute to oncogenesis [43]; the cdc2 protein kinase plays a role in transcriptional regulation [38]; mutation of CDK4 can create a tumor-specific antigen and can disrupt the cell-cycle regulation exerted by the tumor suppressor p16INK4a [42]; CDK9 is the catalytic subunit of a general RNA polymerase II elongation factor termed p-TEFb which is targeted by the human immunodeficiency virus Tat protein to activate elongation of the integrated proviral genome [114,115]; enzyme is required for M phase in meiotic and mitotic cell divisions, but not for S

166

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phase [88]; enzyme is involved in Dictyostelium differentiation rather than growth [87]; control point in cell cycle [135]; the enzyme is a component of maturation-promoting factor [147]; proper regulation of p58 protein kinase is essential for normal cell cycle progression in these cells [53]; PISSLRE could be involved in processes distinct from cell proliferation [140]; negative regulatory factors of the PHO system [47]; enzyme plays a central role in control of the mitotic cell cycle [65]; human K35-cyclin C might be functionally associated with the mammalian transcription apparatus, perhaps involved in relaying growth-regulatory signals [104]; enzyme is required both for entry into S phase and mitosis [58]; enzyme is required for both the G1-S and G2-M transitions during mitotic growth, and also for the second meiotic nuclear division [26]; potential function in sensory cells [134]; the enzyme is required during both G1 and G2 phases of the cell division cycle [28]; enzyme may have a critical function during normal embryonic development and continues to be expressed in differentiated adult tissues [67]; key component of the eukaryotic cell cycle, which is required for G1 to S-phase transition and for entry into mitosis [66]; enzyme is involved in signal transduction process of pattern formation in the hindbrain [3]; Kin28 may be a cyclin dependent kinase which is required for cell proliferation [31]; enzyme is required for induction of meiosis [84]; enzyme plays an important role in spermatogenesis [49]; TFIIH is a multisubunit complex, containing ATPase, helicases, and kinase subunit of TFIIH. In mitosis the CDK7 subunit of TFIIH and the largest subunit of RNAPII become hyperphosphorylated. MPF-induced phosphorylation of CDK7 results in inhibition of the TFIIH-associated kinase and transcription activities [108]; enzyme may be involved in controlling aspects of the cell cycle which are linked to the differentiation of the parasite during its complex life cycle [92]; csk1 may encode a protein kinase physically associated with mcs2 or alternatively may function as an upstream activator of the mcs2-associated kinase [91]; enzyme is involved in negative regulation of meiotic maturation of Xenopus oocytes [51]; Cdk2 protein might be required for entry into the S phase of the cell cycle in FRTL-Tc cells [143]; CDK4 gene is a melanoma-predisposing gene [39]; enzyme is involved in controlling aspects of the cell cycle which are linked to the differentiation of the parasite during its complex life cycle [92]; cdk7 is a subunit of the transcription/DNA repair factor TFIIH, cdk7 may phosphorylate the carboxyterminal domain of RNA pol II in the absence of promoter opening [107]; can properly regulate the cell cycle [89]; abnormal phosphorylation of tau in dividing cells leads to its accumulation in the cytosol as microtubule-free form, Cdk5 is involved in neurodegenerative mechanisms [157]; CDK5-dependent clustering of endoplasmic reticulum ER and mitochondria during ceramide-mediated neuronal death: neurotoxic calcium transfer from ER to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau, inhibition of the pro-

167

Cyclin-dependent kinase

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cess leads to cell death [158]; naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of mutants leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2 -terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of mutants leads to age-dependent memory deficits [160]; naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of organisms with Alzheimers disease leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2 -terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of patients suffering from Alzheimers disease leads to age-dependent memory deficits [160]; regulation mechanisms, overview [4]; CDK is involved in control of cell differentiation and organogenesis [201]; Cdk-A/cyclin D2 is involved in DNA replication progress and cell proliferation [198]; CDK-cyclins and CDK inhibitory proteins are involved in the cell cycle regulation and of vascular cell proliferation and migration, as well as in the control of neointimal thickening, modeling, overview [168]; Cdk1/cyclin B is induced in cells with dysregulated cell cycle, e.g. after infection with the human cytomegalovirus, regulation mechanisms, overview [187]; CDK11p110 is involved in transcription and RNA processing [165]; CDK11p58 interacts with the histone acetyltransferase HBO1 in vitro and in vivo, CDK11p58 acts as a regulator of HBO1 activity in eukaryotic transcription [170]; CDK4 governs cell cycle progression through the G1 phase, CDK2 is involved in all cell cycle phases, overview [176]; Cdk5 is crucial for stability of axons and growth cones in retina, overview [193]; Cdk5 is involved in neuronal migration and phosphorylation of neurofilaments and cytoskeletal proteins [166]; Cdk5 regulates Akt activation and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway, null mutants show lower phosphatidylinositol 3-kinase activity, Cdk5-p35 mediates neuroprotection [173]; Cdk5 regulation, overview, Cdk5 is involved in neuronal migration and phosphorylation of neurofilaments and cytoskeletal proteins, and is critical for neuronal survival, deregulation of Cdk5 occurs in neurodegeneration [166]; Cdk5 regulation, overview, Cdk5 is involved in neuronal migration and phosphorylation of neurofilaments and cytoskeletal proteins, deregulation of Cdk5 occurs in neurodegeneration [166]; Cdk5 regulation, overview, Cdk5 regulates endocytosis through association with amphiphysin and dynamin, Cdk5 is involved in neuronal migration and phosphorylation of neurofilaments and cytoskeletal proteins, deregulation of Cdk5 occurs in neurodegeneration [166]; Cdk5-p35 is negatively regulated by interaction with membranes in brain and liver, mechanism [184]; CDK6/cyclin D1 enhances the transition of cells through the G1 phase of the cell cycle, CDK6 without bound cyclin D1 associates with the androgen receptor

168

2.7.11.22

Cyclin-dependent kinase

AR and enhances, independently of its kinase activity, its transcriptional activity in presence of dihydrotestosterone in prostate cancer cells, this stimulation is highly exaggerated with AR mutant T877A found in prostate cancer, thus CDK6 is probably important for prostate cancer development, CDK6 is no essential for stimulation of AR, overview [204]; CDKA1 is involved in cell cycle regulation and dormancy [177]; CDKB and CDKA are regulated through phosphorylation and cyclins A and B during the cll cycle, regulation overview [200]; CDKB1 is involved in cell cycle regulation and dormancy [177]; Cdks are cell cycle regulating enzymes, Cdk1 phosphorylates the anaphase-promoting complex-cyclosome during mitosis, which is a prerequisite for its activity but reduces the anaphase-promoting complex-cyclosome interaction with Cdc20 involving Mad2, the spindle checkpoint requires cyclin-dependent kinase activity, inhibition of Cdk overrides checkpoint-dependent arrest in eggs increasing the interaction of the anaphase-promoting complex-cyclosome with Cdc20, regulation overview [171]; Cdks are cell cycle regulating enzymes, the spindle checkpoint requires cyclin-dependent kinase activity, regulation overview [171]; CDKs are cell cycle-related enzymes, CDK5 activity increases 1.6fold within 5 weeks during neuronal cell differentiation induced by retinoic acid, while the activity of CDK1 and CDK2 decreases by 14.4fold, overview [195]; constitutitve activation of CDK2-cyclin E leads to G1/S deregulation and tumor progression [174]; cyclin-dependent kinase activity is required for apoptotic death involving the retinoblastoma protein but not inclusion formation in cortical neurons after proteasomal inhibition, Cdk2, Cdk4, and Cdk6 promote the apoptosis induced by lactacystin and other proteasome inhibitors, expression of a defective retinoblastoma protein is neuroprotective [185]; determination of cyclin specificity of Cdk1 during cell cycle using mutant Cdk1-as1 with an enlarged ATP binding site, overview [192]; herpes simplex virus type 1 ICP0 directs the degradation of cellular proteins associated with nuclear structures called ND10 by transactivation of promoters and gene expression involving cdks, overview, virus replication, of HSV-1, HSV-2, HMCV, and varicella-zoster virus, is inhibited by inhibition of cdks by inhibiting specific steps or activities of viral regulatory proteins, thus cdks have broad and pleiotropic effects on virus replication, overview [186]; multisite phosphorylation and network dynamics of cyclin-dependent kinase signaling in the eukaryotic cell cycle, determination of the importance of phosphorylations of regulatory proteins in the cell cycle and biological network, CDK regulation involving positive feedback by Cdc25, Wee1, and CAK, mathematical modeling, overview [167]; p34SEI- 1 is involved in regulation of CDK4-cyclin D2 activity [164]; plant-specific cyclin-dependent kinase CDKB1,1 and transcription factor E2Fa-DPa control the balance of mitotically dividing and endoreduplicating cells in Arabidopsis thaliana, CDKB1,1 is required to inhibit the endocycle and promote the ectopic cell divisions triggered by E2Fa-DPa, regulation model [196]; the CDKs are involved in regulation of cell cycle and neuronal differentiation [194];

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Cyclin-dependent kinase

2.7.11.22

the CDKs are involved in regulation of cell cycle and neuronal differentiation, cleavage of p35 to p25 occurs in neurons undergoing induced cell death and in brains exposed to ischaemia [194]; the CDKs PHOA is involved in modulation of differentiation in response to environmental conditions, including limited phosphorous, but does not play an essential role in regulation of phosphorous aquisition [172]; the CDKs play a central role in cell cycle control, apoptosis, transcription, and neuronal functions [181]; the enzyme interacts with kinesinlike proteins KCA1 and KCA2 and is required for their activity and protein folding, and is influenced by the phosphorylation status of KCA1 and KCA2, the interaction plays a role in the cell cycle and cell division, overview [199]; the phosphatidylinositol-linked dopamine receptor is involved in regulation of cdk5 enzyme activity in the brain [191]; the plant-specific kinase CDKF,1 is involved in activating phosphorylation of CDK-activating kinases in Arabidopsis [197]; the polo-kinase 1, EC 2.7.11.21, also phosphorylates Wee1A at S53 and S123, casein kinase II, EC 2.7.11.1, also phosphorylates Wee1A at S121 [203]; there is cross-talk between the NF-kB/IkBa pathway and the p16/CDK4/Rb pathway in cells with IkBa being capable to substitute for the inhibitory function of p16 on CDK4, regulation [163]; viral infection causes dysregulation of multiple human host cell cycle-regulatory proteins, cdks are involved in viral replication, overview, cdk is required at early times for accurate processing and accumulation of the human cytomegalovirus UL122-123 and UL37 immediate-early transcripts and at later times for virus production [188]; viral K-cyclin has a much longer half-life compared to celllar cyclins because it lacks the PEST degradation sequence, the viral K-cyclin can substitute the cellular cyclins in binding to the cellular CDKs, which is important for the virus development, chimeric K-cyclin-cdks are also translocated to the nucleus, chimeric K-cyclin/cdk6 kinase is constitutively active in BC cells, chimeric K-cyclin-cyclin D2 can act as a CDK [182]) (Reversibility: ?) [3, 4, 15, 26, 28, 31, 38, 39, 42, 43, 47, 49, 51, 53, 58, 65, 66, 67, 84, 85, 87, 88, 89, 91, 92, 93, 98, 104, 107, 108, 114, 115, 124, 134, 135, 140, 143, 147, 157, 158, 160, 163, 164, 165, 166, 167, 168, 170, 171, 172, 173, 174, 176, 177, 181, 182, 184, 185, 186, 187, 188, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 203, 204] P ? Substrates and products S ATP + ADAQHATPPKKKRKVEDPKDF ( a histone peptide substrate [192]) (Reversibility: ?) [192] P ADP + ADAQHAT(P)PPKKKRKVEDPKDF S ATP + C-terminal domain of RNA polymerase II (Reversibility: ?) [178] P ADP + phosphorylated C-terminal domain of RNA polymerase II S ATP + CAK ( substrate of cyclin-dependent kinase cdk7 [4]) (Reversibility: ?) [4] P ADP + phosphorylated CAK

170

2.7.11.22

Cyclin-dependent kinase

S ATP + Cdc20 ( Cdk phosphorylation affects interaction of Cdc20 with Mad2 and the anaphase-promoting complex-cyclosome in HeLa cells [171]; substrate of Cdk1, rather than of Cdk2 [171]; in vitro substrate of Cdk1 and Cdk2 [171]) (Reversibility: ?) [171] P ADP + phosphorylated Cdc20 S ATP + Cprk ( i.e. Cdk5/p35-regulated kinase [166]) (Reversibility: ?) [166] P ADP + phosphorylated Cprk S ATP + ErbB2 ( phosphorylation of the neuregulin receptor by Cdk5 is involved in regulation of neuregulin [166]; phosphorylation at Thr871 [166]) (Reversibility: ?) [166] P ADP + phosphorylated ErbB2 S ATP + ErbB3 ( phosphorylation of the neuregulin receptor by Cdk5 is involved in regulation of neuregulin [166]; phosphorylation at Ser1120 [166]) (Reversibility: ?) [166] P ADP + phosphorylated ErbB3 S ATP + Fin1 (Reversibility: ?) [192] P ADP + phosphorylated Fin1 S ATP + Fkh2p ( phosphorylation of forkhead transcription factor Fkh2p is part of regulation of cell cycle-specific gene expression, e.g. of the CLB2 cluster, Fkh2p phosphorylation by Cdc28p is regulated by complex formation with Mcm1p and Ndd1p, and phosphorylation, overview [189]; forkhead transcription factor Fkh2p, C-terminally phosphorylation of Fkh2p promotes interaction with the activator Ndd1p, which becomes also phosphorylated, activity with Fkh2p mutants, overview [189]) (Reversibility: ?) [189] P ADP + phosphorylated Fkh2p S ATP + HHASPRK (Reversibility: ?) [205] P ADP + HHAS(P)PRK S ATP + MAP1B ( reaction in growth cones is important for stability of microtubules [193]; type 1 phosphorylation in the mab1E11 recognition site [193]) (Reversibility: ?) [193] P ADP + phosphorylated MAP1B S ATP + MEK1 ( Cdk5 regulates the ERK1/2 pathway through phosphorylation of MEK1, overview [166]; phosphorylation at Thr286 [166]) (Reversibility: ?) [166] P ADP + phosphorylated MEk1 S ATP + Munc-18 ( involved in regulation of exocytosis involving SNARE proteins, Munc-18 is required for mediating secretory responsesoverview [166]) (Reversibility: ?) [166] P ADP + phosphorylated Munc-18 S ATP + NF-H ( neurofilament protein that correlates neurit outgrowth, phosphorylation at the KSP repeats, regulated by the myelin-associate glycoprotein [166]; neurofilament protein, phosphorylation at the KSP repeats, regulated by the myelin-associate glycoprotein [166]; neurofilament protein, phosphorylation at

171

Cyclin-dependent kinase

P S P S

P S P S

P S P S P S

P S

P S P S

P S

172

2.7.11.22

the KSP repeats [166]; neurofilament protein, phosphorylation at the KSP repeats, hyperactivated Cdk5-p25 [166]) (Reversibility: ?) [166] ADP + phosphorylated NF-H ATP + NF-H peptide ( i.e. RREAKSPAKAKSPAKE [184]) (Reversibility: ?) [184] ADP + phosphorylated NF-H peptide ATP + NF-M ( neurofilament protein, phosphorylation at the KSP repeats, regulated by the myelin-associate glycoprotein [166]; neurofilament protein, phosphorylation at the KSP repeats [166]; neurofilament protein, phosphorylation at the KSP repeats, hyperactivated Cdk5-p25 [166]) (Reversibility: ?) [166] ADP + phosphorylated NF-M ATP + NR1 receptor ( involved in synaptic transmission, overview [166]) (Reversibility: ?) [166] ADP + phosphorylated NR1 receptor ATP + NR2 receptor ( involved in synaptic transmission, phosphorylation of Ser1232 on the A subunit upregulates NMCAR activity, overview [166]; with phosphorylation sites on both, A and B subunits, e.g. Ser1232 on the A subunit [166]) (Reversibility: ?) [166] ADP + phosphorylated NR2 receptor ATP + RNA polymerase II (Reversibility: ?) [38] ADP + phosphorylated RNA polymerase II ATP + RNA polymerase II largest subunit ( specifically hyperphosphorylates the carboxyl-terminal [131]) (Reversibility: ?) [131] ADP + phosphorylated RNA polymerase II largest subunit ATP + SCR-1 ( Cdk2-cyclin A, phosphorylation at Lys5 regulates SCR-1 interaction with the progesterone receptor [190]; Cdk2-cyclin A, phosphorylation at Lys5 [190]) (Reversibility: ?) [190] ADP + phosphorylated SCR-1 ATP + STAT3 ( specific phosphorylation at Ser727 by CDK5-p35, CDK5 is involved in regulation of the signal transducer and transcription activator STAT3 in brain and muscle [202]; specific phosphorylation at Ser727 by CDK5-p35 [202]) (Reversibility: ?) [202] ADP + phosphorylated STAT3 ATP + Swi6 ( substrate of cdc28p [161]) (Reversibility: ?) [161] ADP + phosphorylated Swi6 ATP + T-cell protein tyrosine phosphatase ( phosphorylation of the two splicing varaints TC45 and TC48 at Ser304 in a cell cycle-dependent manner, optimally in mitosis, overview [162]; phosphorylation of the two splicing varaints TC45 and TC48 at Ser304 in the sequence AFDHS(P), no activity with substrate mutant S304A [162]) (Reversibility: ?) [162] ADP + phosphorylated T-cell protein tyrosine phosphatase ATP + VGCC ( a voltage-dependent calcium channel, phosphorylation within the intracellular loop of the channel inhibiting interaction with SNARE proteins, SNAP-25, and synaptotagmin I required for neurotransmitter release, overview [166]; a voltage-dependent calcium

2.7.11.22

P S

P S

P S

P S

P S

P S

Cyclin-dependent kinase

channel, phosphorylation within the intracellular loop of the channel [166]) (Reversibility: ?) [166] ADP + phosphorylated NR1 receptor ATP + Varicella-Zoster virus IE63 protein ( phosphorylation at Ser224 by CDK1 in vivo is required for correct localization of the virus protein, e.g. in the host cytoplasm during latency, S224A mutation leads to inhibition of phosphorylation and exclusive localization of IE63 protein in the nucleus [175]; recombinant wild-type and mutant IE63 proteins expressed in Vero cells, phosphorylation at Ser224 of wild-type and mutants T222E and T222A by CDK1 and CDK5, but not by CDK2, CDK7, and CDK9 in vitro, mutant S224A is no substrate [175]) (Reversibility: ?) [175] ADP + phosphorylated Varicella-Zoster virus IE63 protein ATP + Wee1A ( phosphorylation at S123, S53, and S121 promotes binding of Wee1A by b-TrCP, the b-transducin repeat-containing protein, which is the substrate recognition component of the ubiquitin ligase, leading to proteasomal degradation of Wee1A, overview [203]; phosphorylation at S123, S53, and S121 [203]) (Reversibility: ?) [203] ADP + phosphorylated Wee1A ATP + [tau protein] ( Cdk5-p25 or Cdk5-p35, see also EC 2.7.11.26 [194]; Cdk5-p25 or Cdk5-p35, see also EC 2.7.11.26, phosphorylation at Ser202 and Thr205 [194]) (Reversibility: ?) [194] ADP + O-phospho-[tau-protein] ATP + [tau protein] ( substrate of CDK5 in the central nervous system, see also EC 2.7.11.26, tau hyperphosphorylation is involved in neurodegeneration and Alzheimers disease, tau protein phosphorylation by CDK5 is involved in apoptosis in cortical cells [159]; substrate of CDK5 in the central nervous system, see also EC 2.7.11.26, phosphorylation at the PHF-1 epitope, not the Tau-1 epitope, of tau protein by CDK5p25 [159]) (Reversibility: ?) [159] ADP + [O-phospho-tau protein] ATP + [tau-protein] ( activity in organisms with mutated APP and tau, not in wild-type, overview [160]; cdk5 associated with p25, cdk5 substrate in brain [157]; hyperphosphorylation of tau by CDK5 is involved in apoptosis and neurodegeneration in Alzheimers disease, overview [159]; tau is microtubule-associated, phopshorylation at T231 by CDK5 causes its release into the cytoplasm [158]; cdk5 associated with p25, recombinant bacterially expressed human tau protein as substrate, phosphorylation of the AT8 and AT180 epitopes, and at T231 of the Alzheimers mitotic epitope TG-3 [157]; phosphorylation at T231, no activity with tau mutant T231A [158]; phosphorylation of the PHF-1 epitope at Ser396 and Ser404 by CDK5 [159]) (Reversibility: ?) [157, 158, 159, 160] ADP + O-phospho-[tau-protein] ATP + [tau-protein] ( cdk5 substrate in brain, cdk5 associated with p39, tau is a microtubule-associated and developmentally regulated protein involved in axonal development in neurons, tau phosphorylation

173

Cyclin-dependent kinase

P S

P S P S

P S P S P S P S

P S P S

P S P S P S P

174

2.7.11.22

by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules, reaction of EC 2.7.11.26 [156]; preferred substrate of cdk5 associated with p39, recombinant bacterially expressed human tau protein as substrate, phosphorylation at Ser202 and Thr205, reaction of EC 2.7.11.26 [156]) (Reversibility: ?) [156] ADP + O-phospho -[tau-protein] ATP + a protein ( cdk2-cyclin A phosphorylates e.g. protein substrate p107 and peptide substrate PKTPKKAKKL, requiring a small hydrophobic patch RXL, known as a recruitment peptide [8]) (Reversibility: ?) [1, 4, 5, 6, 7, 8, 161] ADP + a phosphoprotein ATP + axonal cytoskeleton protein ( regulated by integrin a1 b1 [166]) (Reversibility: ?) [166] ADP + phosphorylated axonal cytoskeleton protein ATP + c-Jun N-terminal kinase 3 ( i.e. JNK3, phosphorylation inhibits JNK3 and leads to reduced phosphorylation of c-jun and to reduced apoptosis [166]; i.e. JNK3, phosphorylation at Thr131 [166]) (Reversibility: ?) [166] ADP + phosphorylated c-Jun N-terminal kinase 3 ATP + casein (Reversibility: ?) [137] ATP + phosphorylated casein ATP + cdc2 ( phosphorylation of Thr161 [61]) (Reversibility: ?) [61] ADP + phosphorylated cdc2 ATP + cdc2 PK ( substrate of cyclin-dependent kinase activating kinase CAK [4]) (Reversibility: ?) [4] ADP + phosphorylated cdc2 PK ATP + cdc2-like protein ( from Caenorhabditis in chimeric complexes including both mitotic and G1/S cyclins [61]) (Reversibility: ?) [61] ADP + phosphorylated cdc2-like protein from Caenorhabditis in chimeric complexes including both mitotic and G1/S cyclins ATP + cdk2 (Reversibility: ?) [61] ADP + phosphorylated cdk2 ATP + cyclin dependent kinase 2 ( cyclin activating kinase CAK phosphorylates Thr160 of cdk2, a prerequisite for cell cycle control [7]) (Reversibility: ?) [7] ADP + phosphorylated cyclin dependent kinase 2 ATP + cyclin-dependent kinase (Reversibility: ?) [151] ADP + phosphorylated cyclin-dependent kinase ATP + dephosphin ( Cdk5 regulates endocytosis involving dephosphin activity, overview [166]) (Reversibility: ?) [166] ADP + phosphorylated dephosphin ATP + dopamine ( phosphorylation by cdk5 [191]) (Reversibility: ?) [191] ADP + phosphorylated dopamine

2.7.11.22

Cyclin-dependent kinase

S ATP + dopamine and cAMP-regulated phosphoprotein ( i.e. DARPP-32, phosphorylation by cdk5 at Thr75 and Thr34 [191]) (Reversibility: ?) [191] P ADP + phosphorylated dopamine and cAMP-regulated phosphoprotein S ATP + high-molecular-weight neurofilament (Reversibility: ?) [105] P ADP + phosphorylated high-molecular-weight neurofilament S ATP + histone H1 (Reversibility: ?) [61] P ADP + dephosphorylated histone H1 S ATP + histone H1 ( commercial substrate [175]; preferred substrate of cdk5 associated with p35 [156]; substrate of Cdk-A/cyclin D2 [198]; commercial substrate, Cdk5 [173]; substrate of Cdk-A/cyclin D2 and of proliferating cell nuclear antigen/cyclin D2 [198]; substrate of CDK11p110 [165]; substrate of CDKB [200]; substrate of e.g. of cheimeric K-cyclin/cdk6 and K-cyclin-cyclin D2 [182]) (Reversibility: ?) [137, 156, 158, 159, 165, 173, 174, 175, 180, 181, 182, 183, 184, 192, 195, 198, 200] P ADP + phosphorylated histone H1 S ATP + microtubule-associated tau (Reversibility: ?) [105] P ADP + phosphorylated microtubule-associated tau S ATP + neuregulin receptor ErbB2 ( phosphorylation at Ser1176 by Cdk5 [173]; phosphorylation at Ser1176 in the sequence RPKTLSPGKN by Cdk5 [173]) (Reversibility: ?) [173] P ADP + phosphorylated neuregulin receptor ErbB2 S ATP + neuregulin receptor ErbB3 ( phosphorylation at Thr871 and Ser1120 by Cdk5 [173]; phosphorylation at Thr871 and Ser1120 in the consensus sequence RSRSPR by Cdk5, Cdk5 associates with Erb3 in vivo [173]; phosphorylation at Thr871 in the sequence AKTPIKWAL and Ser1120 in the consensus sequence RSRSPR by Cdk5, weak phosphorylation of Ser1204 in the proline-rich sequence RRGSPPRPPR [173]) (Reversibility: ?) [173] P ADP + phosphorylated neuregulin receptor ErbB3 S ATP + neuronal cytoskeletal protein NF-H (Reversibility: ?) [118] P ADP + phosphorylated neuronal cytoskeletal protein NF-H S ATP + neuronal cytoskeletal protein tau (Reversibility: ?) [118] P ADP + phosphorylated neuronal cytoskeletal protein tau S ATP + neuronal cytoskeletal proteins NF-M (Reversibility: ?) [118] P ADP + phosphorylated neuronal cytoskeletal protein NF-M S ATP + pocket protein p107 ( hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis [168]; hyperphosphorylation by CDK/cyclin [168]) (Reversibility: ?) [168] P ADP + phosphorylated pocket protein 107 S ATP + pocket protein p130 ( hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc,

175

Cyclin-dependent kinase

P S

P S

P S

P S

P S

P

176

2.7.11.22

Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis [168]; hyperphosphorylation by CDK/cyclin [168]) (Reversibility: ?) [168] ADP + phosphorylated pocket protein 130 ATP + progesterone receptor ( cyclin-dependent kinase activity is required for progesterone receptor PR function, the phosphorylation of the receptor protein has little effect, but cyclin A/Cdk2 acts as a progesterone receptor coactivator via stimulation of PR transcription, Cdk2-cyclin A is PR-dependently recruited to the PR promoter binding to cyclin A, mechanism involving SCR-1 and regulation, overview [190]; Cdk2cyclin A [190]) (Reversibility: ?) [190] ADP + phosphorylated progesterone receptor ATP + protein ( serine/threoninespecific protein kinase [132]; the enzyme is likely to be involved in regulating the cell cycle and therefore may have a role in oncogenesis [138]; proline-directed kinase [109,125]; receptor protein tyrosine kinase [3]; Ser/Thr kinase [20,27]; NIMA is a cell cycle regulated protein kinase required, in addition to p34cdc2/cyclin B, for initiation of mitosis. NIMA accumulates when cells are arrested in G2 and is degraded as cells traverse mitosis. NIMA degradation during mitosis is required for correct mitotic progression in Aspergillus nidulans [153]) (Reversibility: ?) [3, 20, 26, 27, 109, 125, 132, 138, 140, 153] ADP + phosphoprotein ATP + retinoblastoma protein ( i.e. Rb protein [162, 163, 182, 185]; i.e. Rb protein, hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis [168]; phosphorylation by CDK4/ cyclin D at one site, or by CDK2/cyclin E or A at multiple sites in the cell cycle G1 phase [176]; i.e. Rb protein, hyperphosphorylation by CDK/cyclin [168]; i.e. Rb protein, phosphorylation by CDK4/cyclin D [164]; i.e. Rb protein, phosphorylation by CDK4/cyclin D at one site, or by CDK2/cyclin E or A at multiple sites [176]; i.e. Rb protein, recombinant GST-tagged substrate, substrate of e.g. of chimeric K-cyclin/ cdk6 and K-cyclin-cyclin D2 [182]) (Reversibility: ?) [162, 163, 164, 168, 176, 182, 185] ADP + phosphorylated retinoblastoma protein ATP + retinoblastoma-related protein ( i.e. RBR, substrate of Cdk-A/cyclin D2 [198]; i.e. RBR, substrate of Cdk-A/cyclin D2 and of proliferating cell nuclear antigen/cyclin D2 [198]) (Reversibility: ?) [198] ADP + phosphorylated retinoblastoma-related protein ATP + tau protein ( cdk5 substrate in brain, Cdk5-p25 or Cdk5-p35 [194]; hyperactivated Cdk5-p25 [166]) (Reversibility: ?) [166, 19] ADP + phosphorylated tau protein

2.7.11.22

Cyclin-dependent kinase

S Additional information ( the gene coding for the enzyme is a candidate for the following disorders: Nance-Horan syndrome, oral-facial-digital syndrome type 1, and nonsyndromic sensorineural deafness [15]; enzyme is required for initiation of meiosis and sporulation [85]; enzyme may play a role in the regulation of plant growth and development [98]; enzyme is required for mitosis [93]; CDK4 amplification might contribute to oncogenesis [43]; the cdc2 protein kinase plays a role in transcriptional regulation [38]; mutation of CDK4 can create a tumor-specific antigen and can disrupt the cell-cycle regulation exerted by the tumor suppressor p16INK4a [42]; CDK9 is the catalytic subunit of a general RNA polymerase II elongation factor termed p-TEFb which is targeted by the human immunodeficiency virus Tat protein to activate elongation of the integrated proviral genome [114,115]; enzyme is required for M phase in meiotic and mitotic cell divisions, but not for S phase [88]; enzyme is involved in Dictyostelium differentiation rather than growth [87]; control point in cell cycle [135]; the enzyme is a component of maturation-promoting factor [147]; proper regulation of p58 protein kinase is essential for normal cell cycle progression in these cells [53]; PISSLRE could be involved in processes distinct from cell proliferation [140]; negative regulatory factors of the PHO system [47]; enzyme plays a central role in control of the mitotic cell cycle [65]; human K35-cyclin C might be functionally associated with the mammalian transcription apparatus, perhaps involved in relaying growth-regulatory signals [104]; enzyme is required both for entry into S phase and mitosis [58]; enzyme is required for both the G1-S and G2-M transitions during mitotic growth, and also for the second meiotic nuclear division [26]; potential function in sensory cells [134]; the enzyme is required during both G1 and G2 phases of the cell division cycle [28]; enzyme may have a critical function during normal embryonic development and continues to be expressed in differentiated adult tissues [67]; key component of the eukaryotic cell cycle, which is required for G1 to S-phase transition and for entry into mitosis [66]; enzyme is involved in signal transduction process of pattern formation in the hindbrain [3]; Kin28 may be a cyclin dependent kinase which is required for cell proliferation [31]; enzyme is required for induction of meiosis [84]; enzyme plays an important role in spermatogenesis [49]; TFIIH is a multisubunit complex, containing ATPase, helicases, and kinase subunit of TFIIH. In mitosis the CDK7 subunit of TFIIH and the largest subunit of RNAPII become hyperphosphorylated. MPF-induced phosphorylation of CDK7 results in inhibition of the TFIIH-associated kinase and transcription activities [108]; enzyme may be involved in controlling aspects of the cell cycle which are linked to the differentiation of the parasite during its complex life cycle [92]; csk1 may encode a protein

177

Cyclin-dependent kinase

2.7.11.22

kinase physically associated with mcs2 or alternatively may function as an upstream activator of the mcs2-associated kinase [91]; enzyme is involved in negative regulation of meiotic maturation of Xenopus oocytes [51]; Cdk2 protein might be required for entry into the S phase of the cell cycle in FRTL-Tc cells [143]; CDK4 gene is a melanomapredisposing gene [39]; enzyme is involved in controlling aspects of the cell cycle which are linked to the differentiation of the parasite during its complex life cycle [92]; cdk7 is a subunit of the transcription/ DNA repair factor TFIIH, cdk7 may phosphorylate the carboxy-terminal domain of RNA pol II in the absence of promoter opening [107]; can properly regulate the cell cycle [89]; abnormal phosphorylation of tau in dividing cells leads to its accumulation in the cytosol as microtubule-free form, Cdk5 is involved in neurodegenerative mechanisms [157]; CDK5-dependent clustering of endoplasmic reticulum ER and mitochondria during ceramide-mediated neuronal death: neurotoxic calcium transfer from ER to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau, inhibition of the process leads to cell death [158]; naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of mutants leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2 -terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of mutants leads to age-dependent memory deficits [160]; naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of organisms with Alzheimers disease leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2 -terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of patients suffering from Alzheimers disease leads to age-dependent memory deficits [160]; regulation mechanisms, overview [4]; cdk5 catalyzes tau phosphorylation in brain, but cyclin-dependent phosphorylation of other proteins, EC 2.7.11.22, in different tissues [160]; poor activity on free amino acids, consensus sequence of cdk2 is S/TP-XR/K [8]; the enzyme depends on basic residues for substrate recognition, autoregulation by a pseudosubstrate mechanism, overview [5]; CDK is involved in control of cell differentiation and organogenesis [201]; Cdk-A/cyclin D2 is involved in DNA replication progress and cell proliferation [198]; CDK-cyclins and CDK inhibitory proteins are involved in the cell cycle regulation and of vascular cell proliferation and migration, as well as in the control of neointimal thickening, modeling, overview [168]; Cdk1/cyclin B is induced in cells with dysregulated cell cycle, e.g. after infection with the human cytomegalovirus, regulation mechanisms, overview [187]; CDK11p110 is involved in transcription and RNA processing [165]; CDK11p58 interacts with the histone acetyltransferase HBO1 in vitro and in vivo, CDK11p58 acts as a regulator of HBO1 activity

178

2.7.11.22

Cyclin-dependent kinase

in eukaryotic transcription [170]; CDK4 governs cell cycle progression through the G1 phase, CDK2 is involved in all cell cycle phases, overview [176]; Cdk5 is crucial for stability of axons and growth cones in retina, overview [193]; Cdk5 is involved in neuronal migration and phosphorylation of neurofilaments and cytoskeletal proteins [166]; Cdk5 regulates Akt activation and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway, null mutants show lower phosphatidylinositol 3-kinase activity, Cdk5-p35 mediates neuroprotection [173]; Cdk5 regulation, overview, Cdk5 is involved in neuronal migration and phosphorylation of neurofilaments and cytoskeletal proteins, and is critical for neuronal survival, deregulation of Cdk5 occurs in neurodegeneration [166]; Cdk5 regulation, overview, Cdk5 is involved in neuronal migration and phosphorylation of neurofilaments and cytoskeletal proteins, deregulation of Cdk5 occurs in neurodegeneration [166]; Cdk5 regulation, overview, Cdk5 regulates endocytosis through association with amphiphysin and dynamin, Cdk5 is involved in neuronal migration and phosphorylation of neurofilaments and cytoskeletal proteins, deregulation of Cdk5 occurs in neurodegeneration [166]; Cdk5-p35 is negatively regulated by interaction with membranes in brain and liver, mechanism [184]; CDK6/cyclin D1 enhances the transition of cells through the G1 phase of the cell cycle, CDK6 without bound cyclin D1 associates with the androgen receptor AR and enhances, independently of its kinase activity, its transcriptional activity in presence of dihydrotestosterone in prostate cancer cells, this stimulation is highly exaggerated with AR mutant T877A found in prostate cancer, thus CDK6 is probably important for prostate cancer development, CDK6 is no essential for stimulation of AR, overview [204]; CDKA1 is involved in cell cycle regulation and dormancy [177]; CDKB and CDKA are regulated through phosphorylation and cyclins A and B during the cll cycle, regulation overview [200]; CDKB1 is involved in cell cycle regulation and dormancy [177]; Cdks are cell cycle regulating enzymes, Cdk1 phosphorylates the anaphase-promoting complex-cyclosome during mitosis, which is a prerequisite for its activity but reduces the anaphase-promoting complex-cyclosome interaction with Cdc20 involving Mad2, the spindle checkpoint requires cyclin-dependent kinase activity, inhibition of Cdk overrides checkpoint-dependent arrest in eggs increasing the interaction of the anaphase-promoting complex-cyclosome with Cdc20, regulation overview [171]; Cdks are cell cycle regulating enzymes, the spindle checkpoint requires cyclin-dependent kinase activity, regulation overview [171]; CDKs are cell cycle-related enzymes, CDK5 activity increases 1.6fold within 5 weeks during neuronal cell differentiation induced by retinoic acid, while the activity of CDK1 and CDK2 decreases by 14.4fold, overview [195]; constitutitve activation of CDK2-cyclin E leads to G1/S deregulation and tumor progression [174]; cyclin-dependent kinase activity is required for apoptotic death involving the retinoblastoma protein but not inclusion formation in cortical neurons after proteasomal inhibition, Cdk2, Cdk4, and Cdk6

179

Cyclin-dependent kinase

2.7.11.22

promote the apoptosis induced by lactacystin and other proteasome inhibitors, expression of a defective retinoblastoma protein is neuroprotective [185]; determination of cyclin specificity of Cdk1 during cell cycle using mutant Cdk1-as1 with an enlarged ATP binding site, overview [192]; herpes simplex virus type 1 ICP0 directs the degradation of cellular proteins associated with nuclear structures called ND10 by transactivation of promoters and gene expression involving cdks, overview, virus replication, of HSV-1, HSV-2, HMCV, and varicella-zoster virus, is inhibited by inhibition of cdks by inhibiting specific steps or activities of viral regulatory proteins, thus cdks have broad and pleiotropic effects on virus replication, overview [186]; multisite phosphorylation and network dynamics of cyclin-dependent kinase signaling in the eukaryotic cell cycle, determination of the importance of phosphorylations of regulatory proteins in the cell cycle and biological network, CDK regulation involving positive feedback by Cdc25, Wee1, and CAK, mathematical modeling, overview [167]; p34SEI-1 is involved in regulation of CDK4-cyclin D2 activity [164]; plant-specific cyclin-dependent kinase CDKB1,1 and transcription factor E2Fa-DPa control the balance of mitotically dividing and endoreduplicating cells in Arabidopsis thaliana, CDKB1,1 is required to inhibit the endocycle and promote the ectopic cell divisions triggered by E2Fa-DPa, regulation model [196]; the CDKs are involved in regulation of cell cycle and neuronal differentiation [194]; the CDKs are involved in regulation of cell cycle and neuronal differentiation, cleavage of p35 to p25 occurs in neurons undergoing induced cell death and in brains exposed to ischaemia [194]; the CDKs PHOA is involved in modulation of differentiation in response to environmental conditions, including limited phosphorous, but does not play an essential role in regulation of phosphorous aquisition [172]; the CDKs play a central role in cell cycle control, apoptosis, transcription, and neuronal functions [181]; the enzyme interacts with kinesinlike proteins KCA1 and KCA2 and is required for their activity and protein folding, and is influenced by the phosphorylation status of KCA1 and KCA2, the interaction plays a role in the cell cycle and cell division, overview [199]; the phosphatidylinositol-linked dopamine receptor is involved in regulation of cdk5 enzyme activity in the brain [191]; the plant-specific kinase CDKF,1 is involved in activating phosphorylation of CDK-activating kinases in Arabidopsis [197]; the polo-kinase 1, EC 2.7.11.21, also phosphorylates Wee1A at S53 and S123, casein kinase II, EC 2.7.11.1, also phosphorylates Wee1A at S121 [203]; there is cross-talk between the NF-kB/IkBa pathway and the p16/CDK4/Rb pathway in cells with IkBa being capable to substitute for the inhibitory function of p16 on CDK4, regulation [163]; viral infection causes dysregulation of multiple human host cell cycle-regulatory proteins, cdks are involved in viral replication, overview, cdk is required at early times for accurate processing and accumulation of the human cytomegalovirus UL122-123 and UL37 immediate-early transcripts and at later times for virus production [188]; viral K-cyclin has a much longer half-life compared to celllar

180

2.7.11.22

Cyclin-dependent kinase

cyclins because it lacks the PEST degradation sequence, the viral K-cyclin can substitute the cellular cyclins in binding to the cellular CDKs, which is important for the virus development, chimeric K-cyclin-cdks are also translocated to the nucleus, chimeric K-cyclin/cdk6 kinase is constitutively active in BC cells, chimeric K-cyclin-cyclin D2 can act as a CDK [182]; CDK11p110 interacts with Hsp90, and the serine/threonine kinase CK2, the C-terminal domain of the largest subunit of RNA polymerase II is no substrate of CDK11p110, but of CK2 [165]; CDK11p58 interacts with the histone acetyltransferase HBO1 in vitro and in vivo [170]; Cdk5 associates with amphiphysin and dynamin [166]; CDKB ia a B1-type CDK with A-type features [200]; determination and analysis of CDK2 consensus sequence X-S/T(P)-P-X-K/R, modeling of substrate binding, structure analysis [205]; determination of cyclin specificity of Cdk1 with different enzyme substrates using mutant Cdk1-as1 with an enlarged ATP binding site, overview [192]; enzyme cdk2, cdk4, and especially cdk6 interact with the KSHV viral Kcyclin, a homologue of cellular cyclin D, in BC3 cells, K-cyclin also interacts with p21Cip1 and p27Kip1 in the cells, chimeric K-cyclin/cdk6 kinase is constitutively active, chimeric K-cyclin-cyclin D2 can act as a CDK [182]; the enzyme interacts with kinesin-like proteins KCA1 and KCA2, which possess N-terminal ATP and microtubule binding sites, as well as potential C-terminal CDK phosphorylation sites at positions 698, 849, and 853 in KCA1, and at positions 827 and 831 in KCA2, overview [199]) (Reversibility: ?) [3, 4, 5, 8, 15, 26, 28, 31, 38, 39, 42, 43, 47, 49, 51, 53, 58, 65, 66, 67, 84, 85, 87, 88, 89, 91, 92, 93, 98, 104, 107, 108, 114, 115, 124, 134, 135, 140, 143, 147, 157, 158, 160, 163, 164, 165, 166, 167, 168, 170, 171, 172, 173, 174, 176, 177, 181, 182, 184, 185, 186, 187, 188, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 203, 204, 205] P ? Inhibitors (-)-cis-5,7-dihydroxyphenyl-8-[4-(3-hydroxy-1-methyl)piperidinyl]-4H-1benzopyran-4-one hydrochloride hemihydrate [73] (3Z)-3-(2-oxo-2-phenylethylidene)-1,3-dihydro-2H-indol-2-one ( IC50 for CDK1 is above 0.016 mM [178]; IC50 for mrk is 0.0040 mM, and for PK5 0.15 mM, only weak inhibition of parasite strains D6 and W2 growth [178]) [178] (3Z)-3-[2-(4-bromophenyl)-2-oxoethylidene]-1,3-dihydro-2H-indol-2-one ( IC50 for CDK1 is 0.012 mM [178]; IC50 for mrk is 0.0035 mM, and for PK5 0.13 mM, only weak inhibition of parasite strains D6 and W2 growth [178]) [178] (3Z)-5-bromo-3-(2-oxo-2-phenylethylidene)-1,3-dihydro-2H-indol-2-one ( IC50 for CDK1 is 0.030 mM [178]; IC50 for mrk is 0.0031 mM, and for PK5 0.12 mM, only weak inhibition of parasite strains D6 and W2 growth [178]) [178] (3Z)-5-bromo-3-[2-(4-fluorophenyl)-2-oxoethylidene]-1,3-dihydro-2H-indol2-one ( IC50 for CDK1 is 0.029 mM [178]; IC50 for mrk is

181

Cyclin-dependent kinase

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0.0014 mM, and for PK5 0.19 mM, only weak inhibition of parasite strains D6 and W2 growth [178]) [178] (3Z)-5-bromo-3-[2-(4-methylphenyl)-2-oxoethylidene]-1,3-dihydro-2H-indol-2-one ( IC50 for CDK1 is 0.029 mM [178]; IC50 for mrk is 0.0029 mM, and for PK5 0.12 mM, only weak inhibition of parasite strains D6 and W2 growth [178]) [178] (4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)hydrazine trihydrochloride [180] (R)-roscovitine [195] 1,2-di(2-pyridyl)-1H-pyrazolo[3,4-c]pyiridazine [180] 1,2-dimethyl-1H-pyrazolo[3,4-c]pyiridazine [180] 1-(4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-3-ethylurea [180] 1-(4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-3-phenylurea [180] 1-acetyl-3-amino-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine [180] 1-amino-3H-dibenzo[f,h]pyrazolo[3,4-c]cinnoline [180] 2-(3-chloro-4-piperazin-1-yl-phenylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one [179] 2-[(3-amino-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)methoxy]ethanol [180] 2-[2-(3-amino-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)ethoxy]ethanol [180] 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one [179] 3-[[(2,2-dioxido-1,3-dihydro-2-benzothien-5-yl)amino]methylene]-5-(1,3-oxazol-5-yl)-1,3-dihydro-2H-indol-2-one [169] 3-[[4-([[amino(imino)methyl]amino]sulfonyl)anilino]methylene]-2-oxo-2,3dihydro-1H-indole [169] 3-acetamide-1-acetyl-4,5-diphenyl-1H-pyrazolo[3,4-c]-pyridazine [180] 3-acetamide-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine [180] 3-amino-1-benzyl-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine [180] 3-amino-4,5-bis(p-aminophenyl)-1H-pyrazolo[3,4-c]-pyridazine [180] 3-amino-4,5-bis(p-methoxyphenyl)-1H-pyrazolo[3,4-c]-pyridazine [180] 3-amino-4,5-bis(p-nitrophenyl)-1H-pyrazolo[3,4-c]pyridazine [180] 3-amino-4,5-bis(p-tert-butylphenyl)-1H-pyrazolo[3,4-c]-pyridazine [180] 3-amino-4,5-bis(p-trifluoromethylphenyl)-1H-pyrazolo-[3,4-c]pyridazine [180] 3-amino-4,5-di(2-furyl)-1H-pyrazolo[3,4-c]pyridazine [180] 3-amino-4-phenyl-1H-pyrazolo[3,4-c]pyiridazine [180] 3-amino-5-(2-furyl)-1H-pyrazolo[3,4-c]pyiridazine [180] 3-amino-5-methyl-4-phenyl-1H-pyrazolo[3,4-c]pyridazine [180] 3-amino-5-phenyl-1H-pyrazolo[3,4-c]pyiridazine [180]

182

2.7.11.22

Cyclin-dependent kinase

4-(1,4-dioxo-1,4-dihydro-naphthalen-2-ylamino)-N-(2-hydroxy-ethyl)-benzenesulfonamide [169] 4-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]benzenesulfonamide [169] 4-[4-(8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido-[2,3-d]pyrimidin-2ylamino)-phenyl]-piperazine-1-carbaldehyde [179] 4-[4-(8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido-[2,3-d]pyrimidin-2ylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester [179] 4-[4-(8-cyclopentyl-7-oxo-5-trifluoromethyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-7-one [179] 4-[[(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino]-N-(1,3-thiazol-2yl)benzenesulfonamide [169] 4-[[(7-oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino]-N-(2-pyridinyl)benzenesulfonamide [169] 6,7-dimethoxy-N-(3hydroxyphenyl)quinazolin-4-amine [169] 6-acetyl-8-cyclopentyl-5-methyl-2-(4-piperazin-1-ylphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one [179] 6-bromo-8-cyclopentyl-5-methyl-2-(4-piperazin-1-ylphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one [179] 6-chloro-8-cyclopentyl-5-methyl-2-(4-piperazin-1-ylphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-(1-ethyl-propyl)-5-methyl-2-(4-piperazin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-2-(4-[1,4]diazepan-1-yl-phenylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-2-(4-morpholin-4-yl-phenylamino)-8Hpyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-2-(4-piperazin-1-yl-phenylamino)-5-trifluoromethyl-8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-2-(4-piperazin-1-yl-phenylamino)-8Hpyrido[2,3-d]pyrimidin7-one [179] 8-cyclopentyl-2-(4-piperidin-1-yl-phenylamino)-8Hpyrido[2,3-d]pyrimidin7-one [179] 8-cyclopentyl-2-[4-(3,3-dimethyl-piperazin-1-yl)-phenylamino]-5-methyl8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-2-[4-(3,5-dimethyl-piperazin-1-yl)-phenylamino]-5-methyl8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-2-[4-(3-hydroxy-pyrrolidin-1-yl)-phenylamino]-5-methyl-8Hpyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-2-{4-[4-(3-hydroxy-propyl)-piperidin-1-yl]-phenylamino}-5methyl-8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-5,6-dimethyl-2-(4-piperazin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-5-ethyl-2-(4-piperazin-1-yl-phenylamino)-8H-pyrido[2,3d]pyrimidin-7-one [179] 8-cyclopentyl-5-methyl-2-(4-morpholin-4-yl-phenylamino)-8H-pyrido[2,3d]pyrimidin-7-one [179]

183

Cyclin-dependent kinase

2.7.11.22

8-cyclopentyl-5-methyl-2-(4-piperazin-1-yl-phenylamino)-8H-pyrido[2,3d]pyrimidin-7-one [179] 8-cyclopentyl-5-methyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3d]pyrimidin-7-one [179] 8-cyclopentyl-5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8Hpyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-5-methyl-7-oxo-2-(4-piperazin-1-yl-phenylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid [179] 8-cyclopentyl-5-methyl-7-oxo-2-(4-piperazin-1-yl-phenylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester [179] 8-cyclopentyl-5-methyl-7-oxo-2-(4-piperazin-1-yl-phenylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl ester [179] 8-cyclopentyl-6-ethyl-5-methyl-2-(4-piperazin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-6-fluoro-5-methyl-2-(4-piperazin-1-ylphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-cyclopentyl-6-iodo-5-methyl-2-(4-piperazin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one [179] 8-ethyl-2-[4-(4-methylpiperazin-1-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one [169] 8-isopropyl-5-methyl-2-(4-piperazin-1-yl-phenylamino)-8H-pyrido[2,3d]pyrimidin-7-one [179] apigenin ( a flavonoid inhibitor of CDK6, CDK5, and CDK1 [181]) [181] CDK inhibitory proteins ( members of the family of CDK inhibitory proteins, e.g. INK4 proteins, overview, CKIs may play a role as regulators in neointimal hyperplasia [168]) [168] CDK1 inhibitor III ( i.e. ethyl(6-hydroxy-4-phenylbenzo[4,5]furo[2,3-b])pyridine-3-carboxylate, inhibition of IE63 protein phosphorylation at Ser224 leads to exclusive localization of IE63 protein in the host nucleus [175]) [175] CVT-313 ( inhibitor used in treatment of neointimal hyperplasia, IC50 for CDK1 is 0.004 mM, for CDK2 0.0005 mM, and for CDK4 0.215 mM [168]) [168] H717 [169] INK4 proteins ( inhibit CDK4 [168]) [168] IkBa ( human protein, competes with INK4 proteins for binding sites on CDK4, CDK4 is bound at the N-terminal ankyrin repeats, while the C-terminal ankyrin repeats bind NF-kB, structure analysis [163]) [163] isopentenyladenine [169] kaempferol ( a less potent flavonoid inhibitor of CDK6, CDK5, and CDK1 [181]) [181] LiCl ( slight inhibition of T231 phosphorylation by p25-Cdk5 kinase complex [157]) [157] luteolin ( a flavonoid inhibitor of CDK5 and CDK1 [181]) [181] Myt1 ( Cdk1 inhibitor [187]) [187] N-(6-amino-pyrimidin-4-yl)-sulfanilic acid amide [169]

184

2.7.11.22

Cyclin-dependent kinase

N-[(9bR)-5-oxo-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N’-pyridin-2-yl urea [169] N-[(9bR)-5-oxo-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N’-{5[(2S)-pyrrolidin-2-yl]-1H-pyrazol-3-yl urea [169] N-methyl-4-[[(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino]benzenesulfonamide [169] N-methyl-[4-[2-(7-oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)hydrazino]phenyl]methanesulfonamide [169] N6 -dimethylaminopurine ( unspecific inhibitor of protein kinases [1]) [1] NMDA ( inactivates Cdk5 by modulation of Ser67 on the protein phosphatase inhibitor-I, overview [183]) [183] NU2058 [169] NU6027 [169] OL567 [169] Olomoucine [1, 169, 179, 200] PKF049-365 [169] quercetin ( a less potent flavonoid inhibitor of CDK6, CDK5, and CDK1 [181]) [181] SU9516 ( inhibition in vitro and in vivo [162]) [162] staurosporine [69, 169] UCN- 01 [179] Wee1 ( Cdk1 inhibitor [187]) [187] alsterpaullone ( 95% inhibition of CDK2 at 0.01 mM [155]) [155, 195] aminopurvalanol [195] butyrolactone-1 [179] chrysin ( a flavonoid inhibitor of CDK6, CDK5, and CDK1 [181]) [181] cyclin D1 ( inhibits the association and activation of androgen receptor by CDK6 [204]) [204] fisetin ( a flavonol inhibitor of CDK6, CDK5, and CDK1, binding structure with CDK6 involving V101, E61, K43, D163, and E99 of CDK6, overview [181]) [181] flavopiridol ( an effective flavonoid inhibitor of CDK6, CDK5, and CDK1 [181]; inhibitor used in treatment of neointimal hyperplasia, IC50 for CDK1 is 0.0005 mM, for CDK2 0.0001 mM, for CDK4 0.000065 mM, for CDK6 0.00006 mM, and for CDK7 0.00011-0.0003 mM [168]; specific cyclin-dependent kinase inhibitor [188]) [168, 169, 179, 181, 185, 188] hymenialdisine [169] indirubin-3’-monoxime ( 82% inhibition of CDK2 at 0.01 mM [155]) [155, 169] indirubin-5-sulfonic acid [169] kenpaullone ( 78% inhibition of CDK2 at 0.01 mM [155]) [155] membranes ( of brain and liver, Cdk5-p35 is negatively regulated by interaction with membranes, mechanism [184]) [184]

185

Cyclin-dependent kinase

2.7.11.22

oxindole-based compounds ( highly selective for mrk, IC50 of mrk is 0.0015 mM, low cross-reactivity with PK5 and human CDK1 [178]) [178] p15Ink4b ( INK4 protein [168]) [168] p16 ( i.e. p16INK4, inhibits CDK4, not CDK2 [176]; wild-type and D84A mutant human INK4 protein, the mutant is only slightly inhibitory, p16 has regulatory function on the CDK4/cyclin D2 activity, p16 competes with IkBa for binding sites on CDK4, structure analysis [163]) [163, 176, 185] p16Ink4a ( inhibits the association and activation of androgen receptor by CDK6 [204]; INK4 protein [168]) [168, 204] p18 ( wild-type and D76A mutant human INK4 protein, the mutant is only slightly inhibitory, p18 competes with IkBa for binding sites on CDK4, structure analysis [163]) [163] p18Ink4c ( INK4 protein [168]) [168] p19Ink4d ( INK4 protein [168]) [168] p21 protein ( i.e. Cip1 or Waf1, a Cdk-inhibitor [171]) [171] p27 [185] p27Kip1 cyclin-dependent-kinase inhibitor [69] purvalanol ( 98% inhibition of CDK2 at 0.01 mM [155]) [155, 169] purvalonol A [179] pyrazolopyridazine [180] roscovitine ( 93% inhibition of CDK2 at 0.01 mM [155]; complete inhibition of T231 phosphorylation by 25-Cdk5 kinase complex [157]; inhibition of CDK5 [158]; Cdk5 inhibition induces neurotransmitter release in vivo [166]; inhibition in vitro and in vivo [162]; inhibition of IE63 protein phosphorylation at Ser224 leads to exclusive localization of IE63 protein in the host nucleus [175]; inhibits Cdk2 activity which inhibits also the progesterone receptor activity in vivo [190]; inhibits Cdk5 activity, including the p35 phosphorylation activity [183]; specific cyclin-dependent kinase inhibitor, inhibits cdk1, cdk2, cdk5, cdk7, and cdk9, no proteasome-dependent inhibition, time course of inhibition after treatment of infected cells in vivo, effects on viral replication, overview [188]) [155, 157, 158, 162, 166, 169, 171, 173, 175, 179, 183, 186, 188, 190, 191, 193, 194, 201, 202] roscovtine [184] simvastatin ( inhibition of CDK2 [168]) [168] tranilast ( inhibition of CDK2 and CDK4 [168]) [168] tumour suppressor p16INK4a [122] Additional information ( inhibition mechanism [163]; autoregulation by a pseudosubstrate mechanism, overview [5]; no inhibition of the p25-Cdk5 kinase complex by PD98059 and SB203580 [157]; regulation by reversible phosphorylation, overview [4]; some cyclin-dependent kinases are inactivated by a complex of rapamycin with rapamycin-associated protein and FK506-binding protein [1]; analysis of interactions between small molecule inhibitors with the ATP binding pocket of CDK2, determinations of binding structures and design of an inhibitor scaffold, overview [169]; CDK is inhibited by phosphorylation

186

2.7.11.22

Cyclin-dependent kinase

through somatic Wee1A in M phase [203]; CDK2 is inhibited by phosphorylation at Y14 and/or Y15 in the glycine-rich loop causing opening of the substrate binding box and affects binding of ATP [205]; cell toxicity of the pyrazolo[3,4-c]pyridazine inhibitors on HeLa cells, overview, molecular modeling and analysis of binding structure of inhibitors to CDK2 using the CDK2 crystal structure, PDB code 1hck, modeling of ligand docking to the CDK2 structure, overview [180]; enzyme cofactor p35 levels in primary embryonal cortical neurons are reduced by glutamate-induced stimulation of NMDA or kainate receptors through NMDA or kainate, p35 is reduced via proteasomal degradation, reduced p35 leads to inhibition of Cdk5, no inhibition by casein kinase inhibitor CKI-7 [183]; enzyme inhibition results in a decrease in virus titers in vivo, overview [188]; glutamate triggers the ubiquitination and subsequent degradation of p35 in neurons after autophosphorylation of Cdk5-p35 at p35 [194]; IC50 values for CDK1-cyclin B with pyrazolo[3,4-c]pyridazine inhibitors, overview [180]; IC50 values of pyrido[2,3-d]pyrimidin-7-one inhibitors on Cdk4/cyclin D1, Cdk1/cyclin B, Cdk2/cyclinA, and Cdk2/cyclin E, overview, antiproliferating activity of pyrido[2,3-d]pyrimidin-7-one inhibitors on MDA-MB-435 cells, overview [179]; integrin a1 b1 regulates phosphorylation of the axonal cytoskeleton protein, development of inhibitory peptides [166]; molecular modeling of inhibitor-enzyme interactions [178]; negative feedback regulation mechanism via reduced stability, CDK-cyclin oscillates during the cell cycle, overview [167]; no effect by doxycycline on enzyme expression and activity [159]; physiological effects of CDK inhibition, overview, CDKs are deactivated by dephosphorylation, protein p27Kip1 mediates CDK2 inhibition [168]; R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5tetrahydro-1H-3-benzazepine, i.e. SCH23390, or the PLCb antagonist 1-[6([17b-methoxyestra-1,3,5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5dione, i.e. U-73122, inhibit cdk5 transactivation by SKF83959 via the brain phosphatidylinositol-linked dopamin receptor, the transactivation is attenuated by calphostin C or by intracellular calcium chelator BAPTA [191]; structure-function relationship of flavonoid inhibitors, IC50 values, overview [181]; T-cell protein tyrosine phosphatase phosphorylation by CDK-cyclin is not affected by diverse stress-inducing agents, hyperosmotic shock, cold shock, heat, oxidative stress, nocodazole, and anisomycin, as well as mitogens such as EGF and FBS [162]) [1, 4, 5, 157, 159, 162, 163, 166, 167, 168, 169, 178, 179, 180, 181, 183, 188, 191, 194, 203, 205] Cofactors/prosthetic groups ATP ( dependent on [8]; the binding site is a deep pocket lined by hydrophobic residues, enzyme affinity of cdk2 for ATP is not influenced by phosphorylation of the activation loop [7]; ATP binding pocket structure, the pocket is a cleft located at the interface between two domains, involvd residues, overview [169]; binding at the active site between the Cand N-terminal enzyme domains [205]; mutant Cdk1-as1 has an enlarged ATP binding site [192]) [1, 4, 5, 6, 7, 8, 155, 156, 157, 158, 159, 160,

187

Cyclin-dependent kinase

2.7.11.22

161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 197, 198,199,200,202,203,204,205] cyclin ( active CDK-cyclin oscillates during the cell cycle [167]; dependent on as regulatory subunit [162]; regulatory subunit of CDK [168]; regulatory subunit of the CDK [203]) [162, 167, 168, 203] cyclin A ( competes with cyclin E isoforms [174]; complexes with CDKA [200]; is required as regulatory subunit of CDK2 in cell cycle S, M, and G1 phases [176]; regulatory subunit of Cdk2 [179, 180, 190]; required regulatory subunit of CDKs [182]) [174, 176, 179, 180, 182, 190, 200, 205] cyclin B ( complexes with CDKA and CDKB [200]; interacts with and activates Cdc2/Cdk1 [194]; is required as regulatory subunit of CDK2 in cell cycle G2 and M phases [176]; regulatory subunit cyclin B and catalytic subunit Cdk1, HCMV-infection leads to accumulation of active cyclin B in cells due to increased synthesis and reduced degradation [187]; regulatory subunit of CDK1 [180,181,195]; regulatory subunit of CDKA,1 [199]; stabilizing regulatory subunit of Cdk1 [171]) [171,176,180,181,187,194,195,199,200] cyclin B1 ( required regulatory subunit of CDKs [182]) [182] cyclin B2 ( i.e. Clb2 [192]) [192] cyclin B5 ( i.e. Clb5, specificity mechanism, overview [192]) [192] cyclin D ( is required as regulatory subunit of CDK4 [176]; required regulatory subunit of CDKs [182]) [176,182] cyclin D1 ( regulatory subunit of Cdk2 [179]; regulatory subunit of CDK6, activates [204]; regulatory subunit of CDKs, SwissProt-ID Q8GVE0 [177]) [177,179,204] cyclin D2 ( expression analysis in response to Cdk-Activity and phytohormone levels, e.g. of cytokinin and abscisic acid, cytokinin stimulates sucrose-dependently the expression of cyclin D2 at the late germination state of the embryo [198]; regulatory subunit of the holoenzyme formed with CDK4 [163]; regulatory subunit, dependent on [164]; required regulatory subunit of cdk6 [182]) [163,164,182,198] cyclin D3 ( regulatory subunit of CDKs, SwissProt-ID Q8GVD9 [177]) [177] cyclin E ( dependent on, high expression level in breast cancer cells, activating low molecular weight forms L, T1, and T2 of the cyclin E are expressed in breast cancer, modeling of CDK2 activation by cyclin E, overview [174]; interacts with and activates Cdk2 [194]; is required as regulatory subunit of CDK2 in cell cycle G1 phase [176]; regulatory subunit of Cdk2 [179]; required regulatory subunit of CDKs [182]; stabilizing regulatory subunit of Cdk2 [171]) [171,174,176,179,182,194] cyclin H ( dependent on, regulatory subunit [201]; interacts with CDKF,1, dependent on, CDK activity requires specific cyclin partners [197]) [197,201] cyclin V ( regulatory subunit of CDK6 [181]) [181]

188

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cyclin-1 ( regulatory subunit [178]) [178] Additional information ( determination of cyclin specificity of Cdk1 during cell cycle and with different enzyme substrates, overview [192]; viral K-cyclin has a much longer half-life compared to celllar cyclins because it lacks the PEST degradation sequence, the viral K-cyclin can substitute the cellular cyclins in binding to the cellular CDKs, which is important for the virus development [182]) [182,192] Activating compounds CHAPS ( the detergent increases Cdk5-p35 activity with histone H1 and the autophosphorylation at p35 [184]) [184] Calmodulin ( Ca2+ /calmodulin induce the phosphorylation of p35 by Cdk5 after stimulation of the Ca2+ -permeable cation channels NMDA receptor and kainate receptor, leading to cleavage of p35 to p25 [183]) [183] Clbp1-Clbp6 ( cyclins, possible regulatory subunits of Cdc28p, each influencing the enzyme activity in a distinct way, overview [189]) [189] Mcm1p ( regulatory coactivator, Fkh2p phosphorylation by Cdc28p is regulated by complex formation with Mcm1p and Ndd1p, and phosphorylation [189]) [189] NP-40 ( the detergent increases Cdk5-p35 activity with histone H1 and the autophosphorylation at p35 [184]) [184] Ndd1p ( regulatory coactivator, Fkh2p phosphorylation by Cdc28p is regulated by complex formation with Mcm1p and Ndd1p, and phosphorylation [189]) [189] Triton X-100 ( the detergent increases Cdk5-p35 activity with histone H1 and the autophosphorylation at p35 [184]) [184] Tween 20 ( the detergent increases Cdk5-p35 activity with histone H1 and the autophosphorylation at p35 [184]) [184] cyclin ( dependent on [1,5,161]; dependent on, forms complexes with cyclin A [6]; e.g. cyclin A and cyclin B, dependent on, forms a subunit of the enzyme after binding [4]) [1, 4, 5, 6, 161] cyclin A ( dependent on [155]; cdk2 is dependent on, required as activating subunit, complexes with cdk2 [8]) [8, 155] neuregulin ( activates phosphorylation of STAT3 in vivo [202]) [202] p25 ( activator required for CDK5 activity, activation of CDK5 by p25 which is activated by cleavage of p35 to p25 [158]; cyclin activator, dependent on, over 10fold increase in activity of CDK5 [159]; inducible cytotoxic expression factor required for Cdk5 activity, formation of a complex with Cdk5, p25 overexpression increases tau phosphorylation rate [157]; interacts with CDK5 [195]; regulatory and activating subunit, soluble localization of enzyme complex [159]; regulatory subunit and activator of Cdk5, soluble, p35 is cleaved to p25 by calpain leading to hyperactivation of Cdk5 [166]; regulatory subunit of Cdk5 [181]; soluble cofactor of Cdk5, cleavage of p35 to p25 [183]) [157, 158, 159, 166, 181, 183, 195, 202] p34SEI-1 ( i.e. TRIP-Br1, the protein binds directly to CDK4 and activates it at lower concentrations, but inhibits the enzyme at higher concen-

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Cyclin-dependent kinase

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trations, p34SEI-1 has regulatory function, the binding is not affected by INK4 proteins p16 and p18, complex formation of CDK4, cyclin D2, p16, and p34SEI-1, p34SEI-1 has a LexA-mediated transactivation activity, determination of functional sequence units/fragments in the protein, overview [164]) [164] p35 ( tightly bound neuronal activators of cdk5, required for activity with regulatory function, p39 activates to a greater extent compared to p35 in vitro [156]; activation subunit, required, interacts with and activates Cdk5, laminin induces upregulation of p35, regulation of p35 expression, overview [194]; membrane-bound cofactor of Cdk5, levels in primary embryonal cortical neurons are reduced by glutamate-induced stimulation of NMDA or kainate receptors through NMDA or kainate, cleavage of p35 to p25, reduced p35 leads to inhibition of Cdk5 [183]; regulatory activating cofactor of cdk5 [191]; regulatory and activating subunit, particulate localization of enzyme complex [159]; regulatory subunit and activator of Cdk5 [166]; regulatory subunit and activator of Cdk5, membrane-bound, in neuronal growth cones, p35 is cleaved to p25 by calpain leading to hyperactivation of Cdk5 [166]; regulatory subunit of Cdk5 [184,193]; the cyclin is the regulatory subunit, dependent on [173]) [156, 159, 166, 173, 183, 184, 191, 193, 194, 202] p39 ( tightly bound neuronal activators of cdk5, required for activity with regulatory function, p39 activates to a greater extent compared to p35 in vitro, p39 is the activator activator in vivo [156]; activation subunit, can substitute for p35, interacts with and activates Cdk5 [194]; regulatory activating cofactor of cdk5 [191]; regulatory subunit and activator of Cdk5 [166]) [156, 166, 191, 194] p58 ( regulatory subunit of CDK11 [170]) [170] Additional information ( activation of cyclin-dependent kinase 4 by mouse MO15-associated kinase [129]; autoregulation by a pseudosubstrate mechanism, overview [5]; phosphorylation regulates the enzyme activity, cyclin activating kinase CAK phosphorylates Thr160 of cdk2 leading to activation of cdk2 [7]; regulation by reversible phosphorylation, activation by e.g. CAK, i.e. cyclin-dependent kinase activating kinase, overview [4]; 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine, i.e. SKF83959, induces transctivation of cdk5 via the brain phosphatidylinositol-linked dopamine receptor, which is inhibited by SCH2 3390 or U-73122 [191]; activation mechanism and pathway of Cdk1/cyclin B, overview [187]; CDK is phosphorylated by a CDK-activating kinase, positive feedback by Cdc25, Wee1, and CAK is involved in CDK regulation [167]; CDK2 is activated by phosphorylation and cyclin binding [174]; Cdk5 is activated by phosphorylation, integrin a1 b1 regulates phosphorylation of the axonal cytoskeleton protein [166]; CDKF,1 is activated by phosphorylation at the activation T-loop by CDK-activating kinases, CAKs [197]; CDKs are activated by phosphorylation [168]; T-cell protein tyrosine phosphatase phosphorylation by CDK-cyclin is not affected by diverse stress-inducing agents, hyperosmotic shock, cold shock, heat, oxidative stress, nocodazole,

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and anisomycin, as well as mitogens such as EGF and FBS [162]; thapsigargin-induced apoptosis might enhance the phosphorylation of the PHF-1 epitope of tau protein by CDK5-p25, no effect by doxycycline on enzyme expression and activity [159]; the proteasomal inhibitor lactacystin induces the Cdk-dependent phosphorylation of the retinoblastoma protein [185]) [4, 5, 7, 129, 159, 162, 166, 167, 168, 174, 185, 187, 191, 197] Metals, ions Ca2+ ( induces cleavage of p35 to p25 by calpains, which changes the localization of Cdk5 from the particluate to the soluble fraction [194]; induces cleavage of p35 to p25 by calpains, which changes the localization of Cdk5 from the particulate to the soluble fraction [194]; stimulates Cdk5, Ca2+ /calmodulin induce the phosphorylation of p35 by Cdk5 after stimulation of the Ca2+ -permeable cation channels NMDA receptor and kainate receptor, leading to cleavage of p35 to p25 [183]) [183, 194] Cd2+ ( can partially substitue Mg2+ [8]) [8] Co2+ ( can partially substitue Mg2+ [8]) [8] Mg2+ ( dependent on, Mg2+ is the physiologic metal ion, other divalent cations are able to support nucleotide binding, but only Mn2+ , Co2+ , and Cd2+ can substitute Mg2+ in supporting the catalytic activity [8]; coordinated by D145 [205]) [1, 4, 5, 6, 7, 8, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 173, 174, 175, 179, 180, 181, 182, 184, 191, 192, 195, 198, 200, 203, 204, 205] Mn2+ ( can partially substitue Mg2+ [8]) [8, 178] Turnover number (min–1) 1.7 (Fin1, pH 7.4, Cdk1-as1/cyclin 5B [192]) [192] 1.9 (ADAQHATPPKKKRKVEDPKDF, pH 7.4, Cdk1-as1/cyclin 5B [192]) [192] 3.15 (ADAQHATPPKKKRKVEDPKDF, pH 7.4, Cdk1-as1/cyclin 2B [192]) [192] Specific activity (U/mg) Additional information ( large scale activity assay with recombinant enzyme in a protein chip consisting of a microwell array with protein covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker, overview [161]) [161, 191] Km-Value (mM) 0.003 (Fin1, pH 7.4, Cdk1-as1/cyclin 5B [192]) [192] 0.046 (ADAQHATPPKKKRKVEDPKDF, pH 7.4, Cdk1-as1/cyclin 2B [192]) [192] 0.521 (ADAQHATPPKKKRKVEDPKDF, pH 7.4, Cdk1-as1/cyclin 5B [192]) [192] Additional information ( kinetics of Cdk1-As1 mutant with cyclins 5B and 2B in reaction with different substrates, overview [192]; multisite phosphorylation and network dynamics of cyclin-dependent kinase signaling in the eukaryotic cell cycle, mathematical modeling of the enzyme

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complex behaviour, calculation of kinetics and dynamics, overview [167]) [167, 192] pH-Optimum 7 ( assay at [162,165,181]) [162, 165, 181] 7.2 ( assay at [157,158,195]) [157, 158, 195] 7.4 ( assay at [156,173,175,179,182,184,191,192]; in vitro cytotoxicity assay at [180]) [156, 173, 175, 179, 180, 182, 184, 191, 192] 7.5 ( assay at [155, 159, 163, 164, 174, 178, 180, 198]) [155, 159, 163, 164, 174, 178, 180, 198] Temperature optimum ( C) 21 ( assay at room temperature [155]) [155] 23 ( assay at [171]) [171] 25 ( assay at [179]) [179] 30 ( assay at [156, 158, 159, 163, 164, 165, 175, 178, 180, 181, 182, 184, 191, 195, 198, 200, 202]) [156, 158, 159, 163, 164, 165, 175, 178, 180, 181, 182, 184, 191, 195, 198, 200, 202] 37 ( assay at [157, 162, 174]; in vitro cytotoxicity assay at [180]) [157, 162, 174, 180] Temperature range ( C) 25-37 ( in vivo [189]) [189]

4 Enzyme Structure Molecular weight Additional information ( resolution of CAK-CDK complexes by gel filtration, overview [197]) [197] Subunits ? ( x * 34000 [37,43,99]; x * 32000, calculation from nucleotide sequence [101]; x * 43000 [117]; x * 33000 + x * 25000 [125]; x * 33931, SDS-PAGE [102]; x * 58320, calculation from nucleotide sequence [96]; x * 110000, recombinant CDK11p110, SDS-PAGE [165]; x * 34000, PHOB, SDS-PAGE [172]; x * 37000, CDKB, SDS-PAGE, 3400035000, putative two isoforms of CDKA, SDS-PAGE [200]; x * 58000, CDK11p58 [170]) [37, 43, 96, 99, 101, 102, 117, 125, 165, 170, 172, 200] dimer ( active for, with cyclin bound as second subunit [4]) [4] monomer ( inactive form [4]) [4, 151] Additional information ( the enzyme has an open, active conformation and a closed, inactive conformation [6]; the enzyme requires a cyclin as activating subunit [8]; CDK2 exhibit a classical bi-lobal kinase fold with the C-terminus being a-helical and the N-terminus being a flexible hinge [205]; complex formation of the active enzyme, coactiva-

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tors and substrate, overview [189]; regulatory subunit cyclin B and catalytic subunit Cdk1 [187]) [6, 8, 187, 189, 205] Posttranslational modification phosphoprotein ( Tyr and Thr residues are sites of phosphorylation and are important for regulating kinase activity [92]; catalytic subunit, p34cdc2, of cdc2 kinase is controlled by phosphorylation–dephosphorylation reactions. Three phosphorylation sites are identified as Thr14, Tyr15 and Ser277. Phosphorylation of all four sites is cell cycle regulated. Thr14 and Tyr15 are phosphorylated maximally during G2 phase but dephosphorylated abruptly at the G2/M transition, concomitant with activation of p34cdc2 kinase. Phosphorylation of Thr14 and/or Tyr15 inhibits p34cdc2 kinase activity, in line with the location of these residues within the putative ATP binding site of the kinase. During M phase, p34cdc2 is also phosphorylated, but phosphorylation occurs on a Thr residue distinct from Thr14. Finally, phosphorylation of Ser277 peaks during G1 phase and drops markedly as cells progress through S phase [44]; the enzyme is phosphorylated on tyrosine as well as Ser and Thr residues in exponentially growing Schizosaccharomyces pombe. At mitosis, the level of pp34 phosphorylation on both Thr and Tyr residues decreases, site of Tyr phosphorylation in pp34 is Tyr15, tyrosine phosphorylation/dephosphorylation directly regulates pp34 function [27]; two major phosphorylation sites are Tyr15 and Thr160. Additional phosphorylation probably occurs on Thr14. Phosphorylation at Thr160 is required for kinase activity. Phosphorylation at Thr14 and Tyr15 is inhibitory. CDK2 phosphorylation on Thr160 increases during S phase and G2, when CDK2 is most active. Phosphorylation on the inhibitory sites Thr14 and Tyr15 is also maximal during S phase and G2 [77]; p34cdc2/cyclin B-dependent phosphorylation of NIMA during mitotic initiation [154]; phosphorylation at Thr160 leads to inactivation and closed conformation [6]; phosphorylation regulates the enzyme activity, cyclin activating kinase CAK phosphorylates Thr160 of cdk2 leading to activation of cdk2, phosphorylation increases substrate binding of cdk2 by 2fold [7]; regulation by de-/phosphorylation at Thr residues, overview, phosphorylation has both negative and positive regulating function, overview, CAK phoshorylates and activates cdc2 PK, cdk7 phosphorylates and activates CAK [4]; regulation by phosphorylation of the activation loop, does not affect ATP binding, but enhances the phosphotransfer rate and the substrate binding [8]; the enzyme performs autophosporylation [161]; CDK is inhibited by phosphorylation through somatic Wee1A in M phase [203]; CDK is phosphorylated by a CDK-activating kinase [167]; CDK is regulated by de-/phosphorylation [168]; Cdk1 is inhibted by phosphorylation at Thr15, removal of the phosphates by the Cdc25 phosphatase reactivates the enzyme [187]; CDK11p110 is phosphorylated at Ser227 by the serine/threonine kinase CK2 [165]; CDK2 is activated by phosphorylation at Thr160 and cyclin binding [174]; CDK2 is inhibited by phosphorylation at Y14 and/or Y15 in the glycine-rich loop causing opening of the substrate binding box and affects binding of ATP

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[205]; Cdk5 autophosphorylates at its cofactor p35 which activates the complex [184]; Cdk5 is regulated by reversible phosphorylation [166]; CdkB is deactivated by phosphorylation at a Tyr residue through Wee1, reactivating dephosphorylation is performed by Cdc25 [200]; CDKF,1 is activated by phosphorylation at the activation T-loop by CDK-activating kinases, CAK2At-CAK4At, while CAK1At is a subunit of a protein complex of 130 kD, which phosphorylates the T-loop of CAK2At and CAK4At and activates the CTD-kinase activity of CAK4At in vitro and in root protoplasts, CAK2At activates CDKD,3 and CAK4At activates CDKD,2, both interact with cyclin H [197]; Fkh2p phosphorylation by Cdc28p is regulated by complex formation with Mcm1p and Ndd1p, and phosphorylation [189]; in S/G2 phase of the cell cycle, Cdk1/Cdc2, upon binding of cyclin B, is phosphorylated and inactivated at T14, Y15, and T161 by protein kinases Wee1 and CAK, to activate the enzyme T14 and Y15 are dephosphorylated by phosphatase Cde25, the active enzyme is only phosphorylated at T161, release of cyclin B results in complete dephosphorylation of Cdk1/Cdc2, overview, Cdk5 binds p35 and is then activated by phosphorylation at T14, Y15, and S519, the bound p35 is also autophosphorylated by Cdk5-p35 at a single site, which induces ubiquitination and subsequent degradation of p35 in neurons, release of p35 leads to dephosphorylation of Cdk5, overview [194]; in S/G2 phase of the cell cycle, Cdk1/Cdc2, upon binding of cyclin B, is phosphorylated and inactivated at T14, Y15, and T161 by protein kinases Wee1 and CAK, to activate the enzyme T14 and Y15 are dephosphorylated by phosphatase Cde25, the active enzyme is only phosphorylated at T161, release of cyclin B results in complete dephosphorylation of Cdk1/Cdc2, overview, Cdk5 binds p35 and is then activated by phosphorylation at T14, Y15, and S519, the bound p35 is also autophosphorylated by Cdk5-p35 at a single site, which induces ubiquitination and subsequent degradation of p35 in neurons, release of p35 leads to dephosphorylation of Cdk5, overview, cyclin E is bound to and autophosphorylated by Cdk2 leading to its degradation [194]; p35 is degraded by the proteasome after stimulation of NMDA or kainate receptors and subsequent Ca2+ /calmodulin-dependent phosphorylation of p35 by Cdk5, reduced p35 leads to inhibition of Cdk5 [183]) [4, 6, 7, 8, 27, 44, 77, 92, 154, 161, 165, 166, 167, 168, 174, 183, 184, 187, 189, 194, 197, 200, 203, 205] proteolytic modification ( p35 is degraded by the proteasome after stimulation of NMDA or kainate receptors and subsequent Ca2+ /calmodulindependent phosphorylation of p35 by Cdk5, p35 is cleaved to p25, reduced p35 leads to inhibition of Cdk5, overview [183]) [183] Additional information ( p35 and cyclin B are ubiquitinated prior to degradation, proteasomal degradation of p35 is induced by phosphatase inhibitor okadaic acid, proteolytic patterns of p35 amd p39, overview [194]; the PEST degradation sequence determines the short half-life of cyclin enzyme cofactors [182]) [182, 194]

194

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Cyclin-dependent kinase

5 Isolation/Preparation/Mutation/Application Source/tissue BC-1 cell ( primary effusion lymphoma cell line with Kaposi sarcoma-associated herpesvirus-infection, constitutively active K-cyclin/cdk6 kinase [182]) [182] BC-2 cell ( primary effusion lymphoma cell line with Kaposi sarcoma-associated herpesvirus-infection, constitutively active K-cyclin/cdk6 kinase [182]) [182] BC-3 cell ( primary effusion lymphoma cell line with Kaposi sarcoma-associated herpesvirus-infection, constitutively active K-cyclin/cdk6 kinase [182]) [182] BT-20 cell ( human breast cancer cell line [111]) [111] C2C12 cell ( myotube cells [202]) [202] CN1.4 cell ( immortilized embryonic brain cortex cell line [159]; immortalized embryonic brain cortical cells [159]) [159] HEK-293 cell [162] HTAU cell ( immortilized embryonic brain cortex cell line overexpressing the human tau protein [159]; immortalized embryonic brain cortical cells, CN1.4 cells stably overexpressing human tau protein with four microtubule-binding repeats and no N-terminal inserts [159]) [159] HeLa cell [171, 190] Leydig cell tumor cell [176] MDA-MB-435 cell ( breast carcinoma cell line [179]) [179] NTERA-2 cell ( teratocarcinoma cell line [195]) [195] SH-SY5Y cell [194] WI-38 cell ( embryonic lung cell line, infected with herpes simplex virus type 1, HSV-1, or an IPO- mutant 7134 [186]) [186] brain ( PCTAIRE 2 is concentrated in the neuronal layers of the hippocampus and olfactory bulb, which mostly consist of post-mitotic neurons. PCTAIRE 2 is detected in the cell bodies and extended neurites of neurons, but not in astrocytes [20]; enzyme is highly expressed in mature brain. Expression of CDK5 is already seen at embryonal 12.5 days, and it gradually increases through the embryonal stage. After birth, the expression is maintained at a high level to adulthood [106]; developing postnatal and embryonic [156]; distribution in brain regions, overview [160]; frontal cortex [191]) [20, 106, 132, 146, 156, 159, 160, 166, 173, 183, 184, 191, 194, 202] brain cortex [159] brain stem [156] breast cancer cell [33, 174] breast carcinoma cell [179] cell culture ( only expressed during vegetative cell growth [120]; primary midbrain mesencephalonic cells [158]) [120, 158] central nervous system ( primary localization of CDK5 [159]) [159] cerebellar Purkinje cell [106]

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cerebellum [156, 166] cerebral cortex [156, 159, 166, 194] egg ( fertilized [193]; in cytostatic-arrested M-phase [171]) [56, 171, 193] embryo ( p58 expression is elevated early in embryogenesis and then decreases dramatically [67]; blastocyst-stage embryos [102]; expressed between the midblastula transition and gastrulation [118]; contains two type A CDKs, expression of cyclin D2 cofactor during germination in absence or presence of benzyladenine, cytokinin and abscisic acid, overview [198]) [67, 102, 118, 159, 183, 198] endothelial cell [116] fibroblast ( foreskin fibroblasts [188]; cells infected with the human cytomegalovirus HCMV [187]) [140, 187, 188] germ cell ( highly expressed at and after meiosis [49]) [49] heart [111] hematopoietic stem cell [81, 130] hindbrain [3] hippocampal pyramidal layer [106] hippocampus [183, 194] insulinoma cell [176] intestine [132] keratinocyte [168] kidney [106, 132, 140] leaf ( young [177]; CDKB1,1 is expressed only during mitotic phase of the leaf development, mutant leaves overexpressing CDKB1,1 dominant negative mutant show half the number of epidermal cells at maturity and increased temperature compared to wild-type leaves [196]) [177, 196] liver ( fetal [170]) [140, 170, 184] lung [140] lymphoma cell ( pre-T, expressed during the prolactin (PRL)induced G1/S transition in rat Nb2 pre-T lymphoma cell [144]) [144] melanoma cell [176] mitotic cell ( NIMA accumulates when cells are arrested in G2 and is degraded as cells traverse mitosis [153]) [153] mitral cell [106] muscle [194, 202] mycelium ( more actively transcribed in the yeast than in the mycelial phase [119]) [119] nervous system [166] neuroblastoma cell [157, 166] neuron ( predominantly expressed in terminally differentiated neurons [20]; differentiated postmitotic neurons [118]; cortical [173,185]; cortical, co-localization of Cdk5 and Erb3 [173]; from embryonic brain cortices [183]) [20, 105, 106, 118, 157, 158, 166, 173, 183, 185, 194, 195, 202] olfactory bulb [106]

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oocyte [61, 180] ovary [99, 106] parotid acinar cell ( b-adrenergic receptor agonist isoproternol treated mouse parotid gland acinar cells [100]) [100] peripheral ganglion [106] pituitary adenoma cell [176] prepuce ( fibroblasts [188]) [188] prostate cancer cell [204] retina ( embryonic retinal cell culture, developmental expression analysis of Cdk5-p35, Cdk5-p35 localize in the stable region of turning growth cones in developing retina [193]) [193] root [177, 197] sarcoma cell [43] spinal cord [106, 156] submandibular gland ( p58 expression is elevated between day 14 and day 16 post coitus [67]) [67] testis [99, 106] thyroid gland [111] trigeminal ganglion [106] trigeminal nucleus ( motor trigeminal nucleus [106]) [106] tuber [177] vascular cell [168] vero cell [175] zygote ( fertilized eggs [193]) [193] Additional information ( NIMA accumulates when cells are arrested in G2 and is degraded as cells traverse mitosis [153]; expression pattern during brain development [156]; CDK5 activity increases 1.6fold within 5 weeks during neuronal cell differentiation induced by retinoic acid, while the activity of CDK1 and CDK2 decreases by 14.4fold, overview [195]; Cdk5 is crucial for stability of axons and growth cones in retina [193]; CDKA and CDKB expression and activity analysis during cell cycle [200]; different CDK-cyclins are orderly activated at specific phases of the cell cycle [168]; human foreskin fibroblasts are infected with human cytomegalovirus UL122-123 and UL37 [188]) [153, 156, 168, 188, 193, 195, 200] Localization Golgi apparatus [166] centrosome [93] chromatin [204] cytoplasm ( LSTRA and quiescent salivary cells [100]; translocation to the nucleus [182]) [100, 158, 166, 175, 182, 193, 202] cytoskeleton ( neuronal [166]; Cdk5-p35 [194]) [166, 194] cytosol ( low activity [160]; present in approximately constant amounts throughout the intra-erythrocytic asexual reproductive

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Cyclin-dependent kinase

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stage of the life cycle [137]; determination of subcellular localization of Cdk1/cyclin B in HCMV-infected cells [187]) [137, 157, 160, 187] membrane ( associated to membrane in YC-8 and proliferating salivary cells [100]; mainly [160]; Cdk5-p35 [194]) [100, 160, 193, 194] microtubule [157, 158, 160] mitochondrion [185] nucleus ( CAK [4]; CDK11p58 and histone acetyltransferase HBO1 colocalize in the nucleus [170]; the enzyme contains no nuclear targeting signal sequence and associates tightly with interphase chromatin [199]; translocation from the cytoplasm [182]) [4, 93, 117, 170, 182, 189, 199, 202, 204] protoplast [197] soluble ( Cdk5-p25 [194]) [194] synapse [166] synaptosome [166] Additional information ( CDK5-dependent clustering of endoplasmic reticulum ER and mitochondria and translocation to the centrosome during ceramide-mediated neuronal death [158]; Ca2+ induces cleavage of p35 to p25 by calpains, which changes the localization of Cdk5 from the particulate to the soluble fraction [194]; subcellular localization of Cdk5-p35 [193]; subcellular localization of CDKA and CDKB [200]) [158, 193, 194, 200] Purification (recombinant GST-tagged CDK5 and p25 from Escherichia coli strain BL21 by glutathione affinity chromatography) [202] (native and active CDK1 and CDK2 from NT2 cells by affinity chromatography) [195] (recombinant C-terminally His6-tagged CDK4 from insect cells by affinity chromatography) [163] (recombinant GST-tagged Cdk2 and GST-tagged cyclin A from Sf9 insect cellsby glutathione affinity chromatography) [190] (subcellular fractionation) [182] (Cdk5 from rat brain) [194] (partial purification of Cdk5-p35 from brain homogenates, solubilization by NP-40 0.5% in presence of 0.6 M NaCl) [184] (tandem purification of Cdk1 with cyclin B2 or cyclin B5 by affinity chromatography) [192] (recombinant His6-tagged mrk, His6-tagged PK5, and GST-tagged cyclin-1 from Escherichia coli) [178] (native CDK1-cyclin B from cell homogenates by p9CKShs1 affinity chromatography) [180] [61] [151] (CDKA and CDKB by affinity chromatography) [200]

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(recombinant His6-tagged wild-type and mutant CDK11p110 from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, co-purification of CK2, overview) [165] Crystallization (bilobal structure analysis) [5] (cdk2, X-ray diffraction structure analysis) [8] (CDK6/cyclin V in complex with flavonol inhibitor fisetin, X-ray diffraction structure determination and analysis at 2.9 A resolution, modeling) [181] (analysis of the crystal structure of the phosphorylated CDK2-cyclin A/ substrate peptide complex, PDB-AC 1QMZ) [205] (molecular modeling of CDK2-cyclin A crystal structure, PDB code 1hck, with bound pyrazolo[3,4-c]pyridazine inhibitors) [180] (crystal structure and mutational analysis of the human CDK2 kinase complex with cell cycle-regulatory protein CksHs1) [74] (crystal structure of a complex between CDK2 and (-)-cis-5,7-dihydroxyphenyl-8-[4-(3-hydroxy-1-methyl)piperidinyl] -4H-1-benzopyran-4-one hydrochloride hemihydrate, L868276) [73] (crystal structure of the human cyclinA-cyclin-dependent kinase2 (CDK2)-ATP complex determined at 2.3 A resolution) [75] (crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex) [72] (crystal structure of the phosphorylated CDK2-cyclinA-ATP g S complex determined at 2.6 A resolution) [71] (crystal structures of the human CDK2 apoenzyme and its Mg2+ ATP complex, determined to 2.4 A resolution. The structure is bi-lobate, but contains a unique helix-loop segment that interferes with ATP and protein substrate binding and probably plays a key part in the regulation of all cyclindependent kinases) [76] (high-resolution crystal structures of cyclin-dependent kinase 2 with and without ATP) [70] Cloning (Cdk5, DNA sequence determination and analysis) [166] (Cdk5, DNA sequence determination and analysis) [166] (expression of GST-tagged CDK5 and p25 in Escherichia coli strain BL21) [202] (regulation of p35 expression, overview) [194] (transient expression of CDK5 and p25 in HTAU cells) [159] (CDK4, DNA and amino acid sequence determinations in pituitary adenomas, insulinomas, or Leydig cell tumours) [176] (Cdk5, DNA sequence determination and analysis, co-expression of Cdk5 and p35 in HEK293 cells) [166] (expression of C-terminally His6-tagged wild-type and mutant CDK4 in insect cells using the baculovirus infection system with co-expression of cyclin D2, expression of CDK4 and inhibitor IkBa in the two-hybrid system in Saccharomyces cerevisiae) [163]

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(expression of CDK11p58 and HBO1 in the two-hydrid system using Saccharomyces cerevisiae strain EGY48, overexpression of GST- or HAtagged CDK11p58 in HeLa and COS-1 cells leads to increased histone acetyltransferase HBO1 activity towards free histones) [170] (expression of GST-tagged Cdk2 and GST-tagged cyclin A in Spodoptera frugiperda Sf9 cells using the baculovirus infection system) [190] (expression of HA-tagged CDK6 in 293T cells, stable overexpression of CDK6 in LNCaP cells leads to altered cell colony formation and stimulation of cell growth) [204] (in vitro transcription and translation of CDK2 in rabbit reticulocyte lysate, expression of HA-tagged wild-type and mutant CDK2 in Sf9 insect cells) [174] (regulation of p35 expression, overview) [194] (Cdk5, DNA sequence determination and analysis) [166] (co-expression of Cdk5-p35 and HA-tagged Erb3, wild-type and mutants T871A and S1120A, or HA-tagged Erb2, wild-type and mutant S1176A, in COS-7 cells, in contrast to the wild-type substrates, the mutant substrates are not phosphorylated by Cdk5) [173] (co-expression of dominant negative EGFP-tagged CDK5 and p25 in PC12 cells) [158] (regulation of p35 expression, overview) [194] (Cdk5, DNA sequence determination and analysis) [166] (Cdk5, DNA sequence determination and analysis) [166] (phylogenetic tree of kinases derived from the kinase core sequence, overview, overexpression as GST-fusion protein under control of the galactose-inducible GAL1 promotor in Escherichia coli, determination of 5’-end sequences) [161] (genes phoA and phoB, DNA and amino acid sequence determination and analysis) [172] (expression of CDKA,1 and KCA1/KCA2 in a two-hybrid system in Saccharomyces cerevisiae revealing interactions between the enzyme and the kinesin-like proteins, CDKA,1 binding site mapping by expression of fragments of KCA1/2, overview, co-expression of GFP-tagged CDKA,1 and GFP-tagged KCA1/2 in BY-2 cells and determination of subcellular localization, overview) [199] (expression of GST-tagged CDK2 in Escherichia coli BL21(DE3)) [197] (gene CDKB1,1 transcription is controlled by the E2F pathway with transcription factor E2Fa-DPa binding to the CDKB1,1 promoter, thus there is crosstalk between the G1-S and G2-M transition points, promoter analysis) [196] (Cdk5, DNA sequence determination and analysis) [166] (Cdk5, DNA sequence determination and analysis) [166] (expression of His6-tagged mrk and His6-tagged PK5 in Escherichia coli, co-expression with GST-tagged cyclin-1) [178] (gene R2, transient overexpression of R2 CDK in Nicotiana tabacum leaf explants using the glucocorticoid-mediated transcriptional induction sys-

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tem in the Agrobacterium tumefaciens infection system, co-expression of cyclin H, gene cycH) [201] (Cdk5, DNA sequence determination and analysis) [166] (Cdk5, DNA sequence determination and analysis) [166] [37] (isolation of cDNA) [51] (overexpressed in CHO cells) [53] (isolation of cDNA) [54] [56, 60] [60] (CDC2a cDNA expressed in Schizosaccharomyces pombe corrects the elongated morphology, caused by the temperature-sensitive cdc2-33 mutation) [65] [78, 79] (site-directed mutant proteins, expressed by transient transfection of COS cells) [77] (isolation of cDNA) [65] (baculoviral vector, expression in Sf9 insect cells) [82] [85] [90] [92] [94, 95] [98] [100] [101] [103] [105] [109, 111, 113] (expression in Escherichia coli) [110] [116] (isolation of cDNA) [117] [92] [92] [123] [125] (isolation of cDNA) [128] (gene encoding the 58 kDa a subunit) [131] (isolation of cDNA) [132] [133] (expression in Escherichia coli) [137] [140] [147] (expression in Escherichia coli) [151] [154] (complementation of the deficient Saccharomyces cerevisiae cdc28-4 mutant strain by expression of CDKB) [200]

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(DNA and amino acid sequence determination of CDKA1, expression analysis during cell cycle phases, phylogenetric tree, co-expression of CDKA1 and CDKB1 with cyclin D1 and cyc D3) [177] (DNA and amino acid sequence determination of CDKB1, expression analysis during cell cycle phases, phylogenetric tree, co-expression of CDKA1 and CDKB1 with cyclin D1 and cyc D3) [177] (DNA and amino acid sequence determination of isozyme a2-2, expression of FLAG-tagged or HA-tagged CDK11p110 in COS-7 or HEK293 cells, expression of CDK11p110 in Spodoptera frugiperda Sf9 cells via baculovirus infection system, expression of His6-tagged wild-type and mutant CDK11p110 in Escherichia coli strain BL21(DE3), optimization of an expression system producing enzyme free of CK2, overview) [165] Engineering C67W ( mutation renders the resulting mutant protein p80cdc25independent, while neither Leu, Ile nor Val has this effect [26]) [26] K22Q ( site-directed mutagenesis, analysis of alterations in binding of INK4 proteins and IkBa compared to the wild-type enzyme [163]) [163] K33R ( site-directed mutagenesis of CDK2, mutant is a substrate of the CAK1At complex and of the smaller CAK2At complex, overview [197]) [197] K39R ( site-directed mutagenesis, negative dominant kinase inactive mutant of PHOA, mutant strain shows defects in cell cycle and nuclear division [172]) [172] N41S ( site-directed mutagenesis, analysis of alterations in binding of INK4 proteins and IkBa compared to the wild-type enzyme [163]) [163] R24C ( naturally occurring activating point mutations R24C and R24H in CDK4 are not seen in sporadic pituitary adenomas, insulinomas, or Leydig cell tumours, but in melanomas, overview [176]; site-directed mutagenesis, analysis of alterations in binding of INK4 proteins and IkBa compared to the wild-type enzyme [163]) [163, 176] R24H ( naturally occurring activating point mutations R24C and R24H in CDK4 are not seen in sporadic pituitary adenomas, insulinomas, or Leydig cell tumours, but in melanomas, overview [176]) [176] S227A ( site-directed mutagenesis, phosphorylation site mutant [165]) [165] T14A ( mutant enzyme does not induce germinal vesicle breakdown upon microinjection into oocytes [62]) [62] T14A/Y15F ( mutant enzyme does induce germinal vesicle breakdown upon microinjection into oocytes [62]) [62] T14A/Y15F/T161A ( mutant enzyme fails to induce germinal vesicle breakdown in oocytes and shows a decreased binding to cyclin B1 in coimmunoprecipitations [62]) [62]

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T14A/Y15F/T161E ( mutant enzyme fails to induce germinal vesicle breakdown in oocytes and shows a decreased binding to cyclin B1 in coimmunoprecipitations [62]) [62] T160A ( site-directed mutagenesis of CDK2, phosphorylation site mutant, the mutant is activated upon binding of cyclin E [174]) [174] T161A ( mutant enzyme fails to induce germinal vesicle breakdown in oocytes and shows a decreased binding to cyclin B1 in coimmunoprecipitations [62]) [62] T161E ( mutant enzyme fails to induce germinal vesicle breakdown in oocytes and shows a decreased binding to cyclin B1 in coimmunoprecipitations [62]) [62] Y15F ( mutant enzyme does not induce germinal vesicle breakdown upon microinjection into oocytes [62]) [62] Additional information ( a variant of human CDC2, that lacks 171 nucleotides corresponding to 57 amino acids, which compose most of the T-loop,is unable to complex with cyclin B1 and lacks histone H1 kinase activity. CDC2dT also fails to bind to the CDK inhibitor p21 [33]; mutation of CDK4 can create a tumor-specific antigen and can disrupt the cell-cycle regulation exerted by the tumor suppressor p16INK4a [42]; enzyme contains a conserved threonine required for full activity [112]; mutation of this residue severely reduces activity [112]; an isoleucine to valine change in the PSTAIR region, and a proline to serine change at the C-terminal region of the protein p34 cause the p34 protein kinase to become inactivated and degraded in FT210 cells at the restrictive temperature, 39 C [36]; partial C-terminal deletion of NIMA generates a highly toxic kinase although the kinase domain alone is not toxic [153]; mutation of Thr199 inhibits NIMA b-casein kinase activity and abolishes its in vivo function [154]; a cdk-deficient mouse mutant lacks tau phosphorylation activity [156]; naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of organisms with Alzheimers disease leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2 -terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of patients suffering from Alzheimers disease leads to age-dependent memory deficits [160]; construction and expression of a dominant negative CDK5 mutant inhibiting CDK5 activity in C2C12 cells [202]; construction of CDK-null mutant mice [168]; construction of Cdk5-knockout mutant mice that are embryonically lethal with very few viable at birth dying a few hours postpartum, p35 and p39 double-knockout mutant mice show a similar phenotype, the KO mice show higher ERK1/2 activity and increased neurofilament phosphorylation [166]; construction of mutant Cdk1-as1 with an enlarged ATP binding site [192]; construction of PHOA and PHOB null mutant strains, deletion of PHOB causes no phenotype, while deletion of PHOA inhibits growth, a double null mutant shows defects in cell cycle and nuclear division and is lethal, overview, complementation of the double null mutant with expression of human CDK5 [172];

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construction of transgenic plants expressing a negative dominant mutant of CDKB1,1 leading to stimulation to exit the mitosis, and of plants overexpressing the transcription factor E2Fa-DPa, these plants show two different cellspecific phenotypes: some divide ectopically and others are stimulated to endocycle, overexpression of the negative dominant CDKB1,1 mutant increases the endoreduplication phenotype, overview [196]; expression of dominant negative mutants of Cdks or of Cdk inhibitors p16 and p27 can protect cells against lactcystin-induced cell death [185]; genetic analysis of diverse human cancers, overview [176]; null mutant mice show lower phosphatidylinositol 3-kinase activity and phosphorylation of Akt in brain compared to wild-type mice [173]; p35 null mutant mice have a longer threshold for long term potentiation, overview [183]; transient overexpression of R2 CDK in Nicotiana tabacum leaf explants results in the first 7 days in increased callus formation in absence of cytokinin, later the cell differentiation is no longer influenced, the phenotype is enhanced by co-expression of cyclin H [201]) [33, 36, 42, 112, 153, 154, 156, 160, 166, 168, 172, 173, 176, 183, 185, 192, 196, 201, 202] Application analysis ( development of a protein chip consisting of a silicone elastomer microwell array with recombinant enzyme covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker for large scale activity assay, overview [161]) [161] drug development ( CDK2 is a target for development of small molecule inhibitors binding to the ATP binding pocket, determinations of binding structures and design of an inhibitor scaffold, overview [169]; CDKs are important targets for the design of drug with antimitotic and antineurodegenerative effects [181]) [169, 181] medicine ( the CDK-cyclins are targets for pharmacological and gene therapy strategies for the treatment of cardiovascular disease [168]) [168] pharmacology ( the enzyme is a target for drug development in human malaria treatment [178]) [178]

6 Stability General stability information , the PEST degradation sequence determines the short half-life of cyclin enzyme cofactors [182] , partially truncated NIMA is far more stable than the full length NIMA protein which likely accounts for its toxicity [153]

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[43] Khatib, Z.A.; Matsushime, H.; Valentine, M.; Shapiro, D.N.; Sherr, C.J.; Look, A.T.: Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res., 53, 5535-5541 (1993) [44] Krek, W.; Nigg, E.A.: Differential phosphorylation of vertebrate p34cdc2 kinase at the G1/S and G2/M transitions of the cell cycle: identification of major phosphorylation sites. EMBO J., 10, 305-316 (1991) [45] Krek, W.; Nigg, E.A.: Structure and developmental expression of the chicken CDC2 kinase. EMBO J., 8, 3071-3078 (1989) [46] Kaffman, A.; Herskowitz, I.; Tjian, R.; O’Shea, E.K.: Phosphorylation of the transcription factor PHO4 by a cyclin-CDK complex, PHO80-PHO85. Science, 263, 1153-1156 (1994) [47] Toh-e, A.; Tanaka, K.; Uesono, Y.; Wickner, R.B.: PHO85, a negative regulator of the PHO system, is a homolog of the protein kinase gene, CDC28, of Saccharomyces cerevisiae. Mol. Gen. Genet., 214, 162-164 (1988) [48] Uesono, Y.; Tanaka, K.; Toh-e, A.: Negative regulators of the PHO system in Saccharomyces cerevisiae: isolation and structural characterization of PHO85. Nucleic Acids Res., 15, 10299-10309 (1987) [49] Matsushime, H.; Jinno, A.; Takagi, N.; Shibuya, M.: A novel mammalian protein kinase gene (mak) is highly expressed in testicular germ cells at and after meiosis. Mol. Cell. Biol., 10, 2261-2268 (1990) [50] Labbe, J.C.; Martinez, A.M.; Fesquet, D.; Capony, J.P.; Darbon, J.M.; Derancourt, J.; Devault, A.; Morin, N.; Cavadore, J.C.; Doree, M.: p40MO15 associates with a p36 subunit and requires both nuclear translocation and Thr176 phosphorylation to generate cdk-activating kinase activity in Xenopus oocytes. EMBO J., 13, 5155-5164 (1994) [51] Shuttleworth, J.; Godfrey, R.; Colman, A.: p40MO15, a cdc2-related protein kinase involved in negative regulation of meiotic maturation of Xenopus oocytes. EMBO J., 9, 3233-3240 (1990) [52] Eipers, P.G.; Lahti, J.M.; Kidd, V.J.: Structure and expression of the human p58clk-1 protein kinase chromosomal gene. Genomics, 13, 613-621 (1992) [53] Bunnell, B.A.; Heath, L.S.; Adams, D.E.; Lahti, J.M.; Kidd, V.J.: Increased expression of a 58-kDa protein kinase leads to changes in the CHO cell cycle. Proc. Natl. Acad. Sci. USA, 87, 7467-7471 (1990) [54] Colasanti, J.; Tyers, M.; Sundaresan, V.: Isolation and characterization of cDNA clones encoding a functional p34cdc2 homologue from Zea mays. Proc. Natl. Acad. Sci. USA, 88, 3377-3381 (1991) [55] Poon, R.Y.; Yamashita, K.; Adamczewski, J.P.; Hunt, T.; Shuttleworth, J.: The cdc2-related protein p40MO15 is the catalytic subunit of a protein kinase that can activate p33cdk2 and p34cdc2. EMBO J., 12, 3123-3132 (1993) [56] Paris, J.; Le Guellec, R.; Couturier, A.; Le Guellec, K.; Omilli, F.; Camonis, J.; MacNeill, S.; Philippe, M.: Cloning by differential screening of a Xenopus cDNA coding for a protein highly homologous to cdc2. Proc. Natl. Acad. Sci. USA, 88, 1039-1043 (1991) [57] Stern, B.; Ried, G.; Clegg, N.J.; Grigliatti, T.A.; Lehner, C.F.: Genetic analysis of the Drosophila cdc2 homolog. Development, 117, 219-232 (1993)

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[170] Zong, H.; Li, Z.; Liu, L.; Hong, Y.; Yun, X.; Jiang, J.; Chi, Y.; Wang, H.; Shen, X.; Hu, Y.; Niu, Z.; Gu, J.: Cyclin-dependent kinase 11(p58) interacts with HBO1 and enhances its histone acetyltransferase activity. FEBS Lett., 579, 3579-3588 (2005) [171] Dngiolella, V.; Mari, C.; Nocera, D.; Rametti, L.; Grieco, D.: The spindle checkpoint requires cyclin-dependent kinase activity. Genes Dev., 17, 2520-2525 (2003) [172] Dou, X.; Wu, D.; An, W.; Davies, J.; Hashmi, S.B.; Ukil, L.; Osmani, S.A.: The PHOA and PHOB cyclin-dependent kinases perform an essential function in Aspergillus nidulans. Genetics, 165, 1105-1115 (2003) [173] Li, B.S.; Ma, W.; Jaffe, H.; Zheng, Y.; Takahashi, S.; Zhang, L.; Kulkarni, A.B.; Pant, H.C.: Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J. Biol. Chem., 278, 35702-35709 (2003) [174] Harwell, R.M.; Mull, B.B.; Porter, D.C.; Keyomarsi, K.: Activation of cyclindependent kinase 2 by full length and low molecular weight forms of cyclin E in breast cancer cells. J. Biol. Chem., 279, 12695-12705 (2004) [175] Habran, L.; Bontems, S.; Di Valentin, E.; Sadzot-Delvaux, C.; Piette, J.: Varicella-Zoster virus IE63 protein phosphorylation by roscovitine-sensitive cyclin-dependent kinases modulates its cellular localization and activity. J. Biol. Chem., 280, 29135-29143 (2005) [176] Vax, V.V.; Bibi, R.; Diaz-Cano, S.; Gueorguiev, M.; Kola, B.; Borboli, N.; Bressac-de Paillerets, B.; Walker, G.J.; Dedov, II; Grossman, A.B.; Korbonits, M.: Activating point mutations in cyclin-dependent kinase 4 are not seen in sporadic pituitary adenomas, insulinomas or Leydig cell tumours. J. Endocrinol., 178, 301-310 (2003) [177] Freeman, D.; Riou-Khamlichi, C.; Oakenfull, E.A.; Murray, J.A.: Isolation, characterization and expression of cyclin and cyclin-dependent kinase genes in Jerusalem artichoke (Helianthus tuberosus L.). J. Exp. Bot., 54, 303-308 (2003) [178] Woodard, C.L.; Li, Z.; Kathcart, A.K.; Terrell, J.; Gerena, L.; Lopez-Sanchez, M.; Kyle, D.E.; Bhattacharjee, A.K.; Nichols, D.A.; Ellis, W.; Prigge, S.T.; Geyer, J.A.; Waters, N.C.: Oxindole-based compounds are selective inhibitors of Plasmodium falciparum cyclin dependent protein kinases. J. Med. Chem., 46, 3877-3882 (2003) [179] VanderWel, S.N.; Harvey, P.J.; McNamara, D.J.; Repine, J.T.; Keller, P.R.; Quin, J., 3rd; Booth, R.J.; Elliott, W.L.; Dobrusin, E.M.; Fry, D.W.; Toogood, P.L.: Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4. J. Med. Chem., 48, 2371-2387 (2005) [180] Brana, M.F.; Cacho, M.; Garcia, M.L.; Mayoral, E.P.; Lopez, B.; de PascualTeresa, B.; Ramos, A.; Acero, N.; Llinares, F.; Munoz-Mingarro, D.; Lozach, O.; Meijer, L.: Pyrazolo[3,4-c]pyridazines as novel and selective inhibitors of cyclin-dependent kinases. J. Med. Chem., 48, 6843-6854 (2005) [181] Lu, H.; Chang, D.J.; Baratte, B.; Meijer, L.; Schulze-Gahmen, U.: Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin. J. Med. Chem., 48, 737-743 (2005)

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[182] Van Dross, R.; Yao, S.; Asad, S.; Westlake, G.; Mays, D.J.; Barquero, L.; Duell, S.; Pietenpol, J.A.; Browning, P.J.: Constitutively active K-cyclin/ cdk6 kinase in Kaposi sarcoma-associated herpesvirus-infected cells. J. Natl. Cancer Inst., 97, 656-666 (2005) [183] Wei, F.Y.; Tomizawa, K.; Ohshima, T.; Asada, A.; Saito, T.; Nguyen, C.; Bibb, J.A.; Ishiguro, K.; Kulkarni, A.B.; Pant, H.C.; Mikoshiba, K.; Matsui, H.; Hisanaga, S.: Control of cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability. J. Neurochem., 93, 502-512 (2005) [184] Zhu, Y.S.; Saito, T.; Asada, A.; Maekawa, S.; Hisanaga, S.: Activation of latent cyclin-dependent kinase 5 (Cdk5)-p35 complexes by membrane dissociation. J. Neurochem., 94, 1535-1545 (2005) [185] Rideout, H.J.; Wang, Q.; Park, D.S.; Stefanis, L.: Cyclin-dependent kinase activity is required for apoptotic death but not inclusion formation in cortical neurons after proteasomal inhibition. J. Neurosci., 23, 1237-1245 (2003) [186] Davido, D.J.; Von Zagorski, W.F.; Maul, G.G.; Schaffer, P.A.: The differential requirement for cyclin-dependent kinase activities distinguishes two functions of herpes simplex virus type 1 ICP0. J. Virol., 77, 12603-12616 (2003) [187] Sanchez, V.; McElroy, A.K.; Spector, D.H.: Mechanisms governing maintenance of Cdk1/cyclin B1 kinase activity in cells infected with human cytomegalovirus. J. Virol., 77, 13214-13224 (2003) [188] Sanchez, V.; McElroy, A.K.; Yen, J.; Tamrakar, S.; Clark, C.L.; Schwartz, R.A.; Spector, D.H.: Cyclin-dependent kinase activity is required at early times for accurate processing and accumulation of the human cytomegalovirus UL122-123 and UL37 immediate-early transcripts and at later times for virus production. J. Virol., 78, 11219-11232 (2004) [189] Pic-Taylor, A.; Darieva, Z.; Morgan, B.A.; Sharrocks, A.D.: Regulation of cell cycle-specific gene expression through cyclin-dependent kinasemediated phosphorylation of the forkhead transcription factor Fkh2p. Mol. Cell. Biol., 24, 10036-10046 (2004) [190] Narayanan, R.; Adigun, A.A.; Edwards, D.P.; Weigel, N.L.: Cyclin-dependent kinase activity is required for progesterone receptor function: novel role for cyclin A/Cdk2 as a progesterone receptor coactivator. Mol. Cell. Biol., 25, 264-277 (2005) [191] Zhen, X.; Goswami, S.; Abdali, S.A.; Gil, M.; Bakshi, K.; Friedman, E.: Regulation of cyclin-dependent kinase 5 and calcium/calmodulin-dependent protein kinase II by phosphatidylinositol-linked dopamine receptor in rat brain. Mol. Pharmacol., 66, 1500-1507 (2004) [192] Loog, M.; Morgan, D.O.: Cyclin specificity in the phosphorylation of cyclin-dependent kinase substrates. Nature, 434, 104-108 (2005) [193] Hahn, C.M.; Kleinholz, H.; Koester, M.P.; Grieser, S.; Thelen, K.; Pollerberg, G.E.: Role of cyclin-dependent kinase 5 and its activator P35 in local axon and growth cone stabilization. Neuroscience, 134, 449-465 (2005)

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[194] Hisanaga, S.; Saito, T.: The regulation of cyclin-dependent kinase 5 activity through the metabolism of p35 or p39 Cdk5 activator. Neurosignals, 12, 221-229 (2003) [195] Gompel, M.; Soulie, C.; Ceballos-Picot, I.; Meijer, L.: Expression and activity of cyclin-dependent kinases and glycogen synthase kinase-3 during NT2 neuronal differentiation. Neurosignals, 13, 134-143 (2004) [196] Boudolf, V.; Vlieghe, K.; Beemster, G.T.; Magyar, Z.; Torres Acosta, J.A.; Maes, S.; Van Der Schueren, E.; Inze, D.; De Veylder, L.: The plant-specific cyclin-dependent kinase CDKB1;1 and transcription factor E2Fa-DPa control the balance of mitotically dividing and endoreduplicating cells in Arabidopsis. Plant Cell, 16, 2683-2692 (2004) [197] Shimotohno, A.; Umeda-Hara, C.; Bisova, K.; Uchimiya, H.; Umeda, M.: The plant-specific kinase CDKF;1 is involved in activating phosphorylation of cyclin-dependent kinase-activating kinases in Arabidopsis. Plant Cell, 16, 2954-2966 (2004) [198] Gutierrez, R.; Quiroz-Figueroa, F.; Vazquez-Ramos, J.M.: Maize cyclin D2 expression, associated kinase activity, and effect of phytohormones during germination. Plant Cell Physiol., 46, 166-173 (2005) [199] Vanstraelen, M.; Torres Acosta, J.A.; De Veylder, L.; Inze, D.; Geelen, D.: A plant-specific subclass of C-terminal kinesins contains a conserved a-type cyclin-dependent kinase site implicated in folding and dimerization. Plant Physiol., 135, 1417-1429 (2004) [200] Corellou, F.; Camasses, A.; Ligat, L.; Peaucellier, G.; Bouget, F.Y.: Atypical regulation of a green lineage-specific B-type cyclin-dependent kinase. Plant Physiol., 138, 1627-1636 (2005) [201] Yamaguchi, M.; Kato, H.; Yoshida, S.; Yamamura, S.; Uchimiya, H.; Umeda, M.: Control of in vitro organogenesis by cyclin-dependent kinase activities in plants. Proc. Natl. Acad. Sci. USA, 100, 8019-8023 (2003) [202] Fu, A.K.; Fu, W.Y.; Ng, A.K.; Chien, W.W.; Ng, Y.P.; Wang, J.H.; Ip, N.Y.: Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity. Proc. Natl. Acad. Sci. USA, 101, 6728-6733 (2004) [203] Watanabe, N.; Arai, H.; Iwasaki, J.-i.; Shiina, M.; Ogata, K.; Hunter, T.; Osada, H.: Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic wee1 via multiple pathways. Proc. Natl. Acad. Sci. USA, 102, 11663-11668 (2005) [204] Lim, J.T.; Mansukhani, M.; Weinstein, I.B.: Cyclin-dependent kinase 6 associates with the androgen receptor and enhances its transcriptional activity in prostate cancer cells. Proc. Natl. Acad. Sci. USA, 102, 5156-5161 (2005) [205] Bartova, I.; Otyepka, M.; Kriz, Z.; Koca, J.: The mechanism of inhibition of the cyclin-dependent kinase-2 as revealed by the molecular dynamics study on the complex CDK2 with the peptide substrate HHASPRK. Protein Sci., 14, 445-451 (2005)

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[RNA-Polymerase]-subunit kinase

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1 Nomenclature EC number 2.7.11.23 Systematic name ATP:[DNA-directed RNA polymerase] phosphotransferase Recommended name [RNA-polymerase]-subunit kinase Synonyms Bur1 [21] C-terminal domain kinase [21] C-terminal repeat domain kinase C-terminal repeat domain kinase I [22] CDK9 [19, 24] CDKC1 [28] CTD kinase [17, 19, 20, 21, 25] CTD kinase I [16, 27] CTDK-I [22] Cdk1 [19] Ctdk-1 [16, 27] Ctk1 [20, 21] Ctk1 kinase [18, 26, 27] Kin28 [21] MAPK [19] RNA pol II C-terminal domain kinase [20] RNA polymerase II CTD kinase Srb10 [21] TFIIH CTD kinase [23] cdk7 [19, 24] kinase, ribonucleate nucleotidyltransferase II C-terminal domain (phosphorylating) kinase, ribonucleate nucleotidyltransferase isozyme II IIa subunit (phosphorylating) Additional information ( see also EC 2.7.11.22 [24]; see also EC 2.7.11.22 and EC 2.7.11.24 [19]; the enzyme is organized in the CDKC-1/CYCLINT-1 kinase complex, see also EC 2.7.11.22 [28]) [19, 24, 28] CAS registry number 122097-00-1

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[RNA-Polymerase]-subunit kinase

2 Source Organism







Drosophila melanogaster (no sequence specified) [19] Drosophila sp. (no sequence specified) [2, 13] Mus musculus (no sequence specified) [1, 4, 10, 13] Homo sapiens (no sequence specified) [1, 2, 3, 5, 6, 17, 19, 24, 25] Saccharomyces cerevisiae (no sequence specified) [1, 2, 9, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 26] Triticum aestivum (no sequence specified) [1,7] Schizosaccharomyces pombe (no sequence specified) [19,27] Medicago sativa (no sequence specified) [28] Aspergillus sp. (no sequence specified) [8]

3 Reaction and Specificity Catalyzed reaction ATP + [DNA-directed RNA polymerase] = ADP + phospho-[DNA-directed RNA polymerase] Reaction type phospho group transfer Natural substrates and products S ATP + [DNA-directed RNA polymerase] ( CTD phosphorylation and transcription cycle overview [19]; CTD phosphorylation facilitates pre-mRNA processing, CTD phosphorylation and transcription cycle overview [19]; hyperphosphorylation of the C-terminal domain CTD of the RNA polymerase II large subunit by Ctk1 is essentially required for methylation of histone H3 Lys36 in transcription elongation in volving association of Set2 to the hyperphosphorylated RNA polymerase II, overview [20]; hyperphosphorylation of the Cterminal domain CTD of the RNA polymerase II large subunit is required for transcription and 3 processing of snRNA, e.g. U1 and U2, recognition of the 3 box by the phosphorylated CTD, CTD kinase activity is not required for b-actin expression, overview [17]; hyperphosphorylation of the C-terminal repeat domain CTD of the RNA polymerase II large subunit is required for elongation of mRNA, the enzyme is involved in functional organization of transcription and nuclear metabolism [16]; phosphorylation of Ser2 within the RNA polymerase II C-terminal domain couples transcription and 3 end processing by recruiting factors for polyadenylation and 3 end processing, phosphorylation of Ser5 during initiation recruits the capping enzyme [26]; the CTD kinases Ctk1, Bur1, Kin28, and Srb10 are involved in preinitiation of transcription and elongation [21]; the CTD of the RNA polymerase II is the target for numerous enzymes, including cell cycle-dependent kinases and phosphatases, thus phosphorylation of the CTD becomes a key event during

221

[RNA-Polymerase]-subunit kinase

P S

P S

222

2.7.11.23

mRNA metabolism and physiological regulation of transcription, and is affected by cell stress or embryonic development, CTD phosphorylation and transcription cycle overview [19]; the enzyme is involved, together with several factors, in regulation of RNA elongation, transition at the 3 end, and polyadenylation, the enzyme is responsible for crosslinking of polyadenylation factors, overview [18]; the enzyme phosphorylates the C-terminal CTD domain of the RNA polymerase II large subunit, which has specific phosphorylation patterns for regulation of mRNA and snRNA processing [25]; the enzyme preferentially phosphorylates RNA poylmerase II bound in a native ternary complex in opposite to the Fcp1 phosphatase preferably dephosphorylating free RNA poylmerase II, after complex disruption, at Ser5, not Ser2, of the CTD, the TFIIH TD kinase is involved in RNA poylmerase II activity regulation, mechanism, overview [23]) (Reversibility: ?) [16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26] ADP + phospho-[DNA-directed RNA polymerase] ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa] ( presumably obligate part of transcription process [1]; CTD kinase 1 plays an important role in transcription elongation in vivo, the deletion of one ore more CTK genes is lethal but in combination with the deletion of PPR2 or ELP [12]; deletion of the kinase subunit Ctk1 results in phosphorylation of serine in position 5 of the CTD repeat during logarithmic growth and eliminates the transient increase in CTD serine 2 phosphorylation during the diauxic shift [15]; the CTD is essential for viability, although mutants with deletions that remove approximately half of the repeats are still viable [13]; CTD kinase I affects pre-mRNA 3 cleavage/polyadenylation through the processing component Pti1p [11]) (Reversibility: ?) [1, 2, 3, 4, 5, 6, 7, 11, 12, 13, 15] ADP + phospho-[DNA-directed RNA polymerase II subunit IIa] Additional information ( CTD kinase function is opposed by Ess1, an essential prolyl isomerase binding to the C-terminal domain of the RNA polymerase, Ess1 interacts with CTD kinases, especially with Ctk1 and Srb10, the kinase and Ess1 compete for Ser5 of RNA polymerase II [21]; phosphorylation of CTD is required to disrupt the interactions between unphosphorylated CTD and the mediator complex to form a holoenzyme of RNA polymerase II or with transcription factors to form a preinitiation complex of transcription, disruption of the interactions at elongation of transcription are required to assist the recruitment of premRNA modification enzymes [19]; the CDKC-1/CYCLINT-1 kinase complex is a positive regulator of transcription in Medicago sativa, the level and activity of the enzyme is not cell cycle dependent [28]; the cyclin-dependent kinase 7 and 9 are involved in processing of cytomegalovirus RNA in infected cells, enzyme inhibition results in changes in differential splicing and polyadenylation of viral immediate early and UL37 transcripts, overview, viral infection alters localization of RNA polymerase II [24]; the RNA polymerase II recruits factors including the enzyme that hyperphosphorylate its C-terminal domain, i.e. CTD, and the CTD in turn recruits proteins needed for mRNA splicing and polyadenylation,

2.7.11.23

[RNA-Polymerase]-subunit kinase

snRNA promoters probably recruit a CTD kinase, whose snRNA-specific phosphorylation patterns recruits factors required for promoter-coupled 3-end formation, overview [25]) (Reversibility: ?) [19, 21, 24, 25, 28] P ? Substrates and products S ATP + CTD-containing fusion proteins ( e.g. GAL4-CTD (formerly GC14 7) or HSP 90 [6]) (Reversibility: ?) [2, 6] P ADP + ? S ATP + [DNA-directed RNA polymerase] ( CTD phosphorylation and transcription cycle overview [19]; CTD phosphorylation facilitates pre-mRNA processing, CTD phosphorylation and transcription cycle overview [19]; hyperphosphorylation of the C-terminal domain CTD of the RNA polymerase II large subunit by Ctk1 is essentially required for methylation of histone H3 Lys36 in transcription elongation in volving association of Set2 to the hyperphosphorylated RNA polymerase II, overview [20]; hyperphosphorylation of the Cterminal domain CTD of the RNA polymerase II large subunit is required for transcription and 3 processing of snRNA, e.g. U1 and U2, recognition of the 3 box by the phosphorylated CTD, CTD kinase activity is not required for b-actin expression, overview [17]; hyperphosphorylation of the C-terminal repeat domain CTD of the RNA polymerase II large subunit is required for elongation of mRNA, the enzyme is involved in functional organization of transcription and nuclear metabolism [16]; phosphorylation of Ser2 within the RNA polymerase II C-terminal domain couples transcription and 3 end processing by recruiting factors for polyadenylation and 3 end processing, phosphorylation of Ser5 during initiation recruits the capping enzyme [26]; the CTD kinases Ctk1, Bur1, Kin28, and Srb10 are involved in preinitiation of transcription and elongation [21]; the CTD of the RNA polymerase II is the target for numerous enzymes, including cell cycle-dependent kinases and phosphatases, thus phosphorylation of the CTD becomes a key event during mRNA metabolism and physiological regulation of transcription, and is affected by cell stress or embryonic development, CTD phosphorylation and transcription cycle overview [19]; the enzyme is involved, together with several factors, in regulation of RNA elongation, transition at the 3 end, and polyadenylation, the enzyme is responsible for crosslinking of polyadenylation factors, overview [18]; the enzyme phosphorylates the C-terminal CTD domain of the RNA polymerase II large subunit, which has specific phosphorylation patterns for regulation of mRNA and snRNA processing [25]; the enzyme preferentially phosphorylates RNA poylmerase II bound in a native ternary complex in opposite to the Fcp1 phosphatase preferably dephosphorylating free RNA poylmerase II, after complex disruption, at Ser5, not Ser2, of the CTD, the TFIIH TD kinase is involved in RNA poylmerase II activity regulation, mechanism, overview [23]; CDKC1 phosphorylates the C-terminal YSPTSPS hexapeptide repeat domain CTD of the largest subunit of RNA polymerase II

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at Ser5, no activity with RNA polymerase II mutant S5A [28]; CTD kinase 1 hyperphosphorylates the C-terminal repeat domain CTD of the RNA polymerase II large subunit, phosphorylation of CTD leads to interaction/binding of several proteins with nuclear functions in vitro, i.e. phosphoCTD-associating proteins, purification and analysis of PCAPs, e.g. Ess1, Hrr25, Prp40, Ssd1, SSd1, and Set2, overview [16]; Ctk1 kinase phosphorylates Ser2 and Ser5 of the C-terminal CTD domain of the RNA polymerase II large subunit [26]; Ctk1 kinase phosphorylates the C-terminal CTD domain of the RNA polymerase II large subunit, primarily at Ser2 and Ser5 [18]; hyperphosphorylation of the Cterminal domain CTD of the RNA polymerase II large subunit [17,20]; hyperphosphorylation of the C-terminal domain CTD of the RNA polymerase II large subunit, e.g. at Ser2 and Ser5, by cyclin-dependent kinase 7 and 9, i.e. Cdk7 and Cdk9 [24]; phosphorylation of the Cterminal domain CTD of the RNA polymerase II large subunit at Ser2 and Ser5 [23]; recombinant GST-tagged protein substrate or synthetic GST-tagged peptide substrate derived from RNA polymerase II, CTD kinase 1 hyperphosphorylates the C-terminal repeat domain CTD of the RNA polymerase II large subunit at Ser2 and/or Ser5, determination of phosphorylation sites, already phosphorylated substrates are more efficient substrates for CTD kinase I [22]; the enzyme phosphorylates the C-terminal CTD domain of the RNA polymerase II large subunit [21,25]; the enzyme phosphorylates the C-terminal CTD domain of the RNA polymerase II large subunit, the CTD phosphorylation pattern is precisely modified as RNA polymerase II progresses along the genes and is involved in sequential recruitment of RNA processing factors, multiple phosphorylation sites and epitopes, e.g. at Ser2 and Ser5, overview [19]; the enzyme phosphorylates the C-terminal CTD domain of the RNA polymerase II large subunit, the CTD phosphorylation pattern is precisely modified as RNA polymerase II progresses along the genes and is involved in sequential recruitment of RNA processing factors, multiple phosphorylation sites and epitopes, e.g. at Ser5, overview [19]; the enzyme phosphorylates the C-terminal CTD domain of the RNA polymerase II large subunit, the CTD phosphorylation pattern is precisely modified as RNA polymerase II progresses along the genes and is involved in sequential recruitment of RNA processing factors, multiple phosphorylation sites and epitopes, overview [19]) (Reversibility: ?) [16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 28] P ADP + phospho-[DNA-directed RNA polymerase] S ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa] ( no substrate is phosvitin [2]; phosphorylates not Tyr-residues [2,6]; kinase CTDK1: 33 mol phosphate per mol IIAsubunit [5]; no substrates are dTTP and AMP-PNP [1]; phosphorylates to a lesser extent Thr-residues [2,7]; no substrates are bovine serum albumin and calf thymus histone [7]; no substrates are the RNA polymerases II of Drosophila melanogaster and yeast [10]; kinase CTDK1 almost exclusively phosphorylates Ser-residues [5];

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P S P S P S P S P S

P S

P S P S

[RNA-Polymerase]-subunit kinase

no substrate is GTP [7]; phosphorylates Ser- and Thr-residues equally [6]; kinase CTDK2 phosphorylates to a lesser extent Thr-residues [2]; kinase CTDK2: 40-50 mol phosphate per mol IIA-subunit, i.e. 1 phosphate per heptapeptide repeat [5]; phosphorylates predominantly Ser-residues [1,2,3,5,7]; substrates are RNA-polymerase II subunits of wheat germ, soy bean, pea and human [7]; distinct from other protein phosphokinases, transfers about 20 phosphates to the heptapeptide repeats Pro-Thr-Ser-Pro-Ser-Tyr-Ser in C-terminal domain of MW 220000 subunit of RNA-polymerase II [7]; no substrates are CTP and UTP [1,7]; presumably obligate part of transcription process [1]; CTD kinase 1 plays an important role in transcription elongation in vivo, the deletion of one ore more CTK genes is lethal but in combination with the deletion of PPR2 or ELP [12]; deletion of the kinase subunit Ctk1 results in phosphorylation of serine in position 5 of the CTD repeat during logarithmic growth and eliminates the transient increase in CTD serine 2 phosphorylation during the diauxic shift [15]; the CTD is essential for viability, although mutants with deletions that remove approximately half of the repeats are still viable [13]; CTD kinase I affects pre-mRNA 3 cleavage/polyadenylation through the processing component Pti1p [11]) (Reversibility: ?) [1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 15] ADP + phospho-[DNA-directed RNA polymerase II subunit IIa] ATP + casein ( not [2]; phosphorylates at about 30% the rate of RNA-polymerase II subunit [5,7]) (Reversibility: ?) [2, 5, 7] ADP + phosphocasein ATP + chicken myosin regulatory light-chain (Reversibility: ?) [4] ADP + chicken myosin regulatory light-chain phosphate ATP + histone H1 ( not [2,5]) (Reversibility: ?) [1, 2, 4, 5] ADP + phosphohistone H1 ATP + numatrin ( and other nuclear proteins [4]) (Reversibility: ?) [4] ADP + phosphonumatrin ATP + synthetic peptides ( hepta-six or Arg-hepta [1]; e.g. Lys-(Tyr-Ser-Pro-Thr-Ser-Pro-Ser)4 [3]; bovine serum albumin conjugated to heptapeptide [7]) (Reversibility: ?) [1, 3, 7] ADP + ? GTP + [DNA-directed eukaryotic RNA polymerase II subunit IIa] ( poor substrate [6]; kinase CTDK1, not kinase CTDK2 [5]) (Reversibility: ?) [5, 6] GDP + ? dATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa] (Reversibility: ?) [5] dADP + ? Additional information ( human enzyme consists of 2 components: component A bears the active site and is capable of DNAindependent autophosphorylation, component B stimulates component A and is phosphorylated only in the presence of DNA [6]; CTD kinase

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[RNA-Polymerase]-subunit kinase

2.7.11.23

function is opposed by Ess1, an essential prolyl isomerase binding to the C-terminal domain of the RNA polymerase, Ess1 interacts with CTD kinases, especially with Ctk1 and Srb10, the kinase and Ess1 compete for Ser5 of RNA polymerase II [21]; phosphorylation of CTD is required to disrupt the interactions between unphosphorylated CTD and the mediator complex to form a holoenzyme of RNA polymerase II or with transcription factors to form a preinitiation complex of transcription, disruption of the interactions at elongation of transcription are required to assist the recruitment of pre-mRNA modification enzymes [19]; the CDKC1/CYCLINT-1 kinase complex is a positive regulator of transcription in Medicago sativa, the level and activity of the enzyme is not cell cycle dependent [28]; the cyclin-dependent kinase 7 and 9 are involved in processing of cytomegalovirus RNA in infected cells, enzyme inhibition results in changes in differential splicing and polyadenylation of viral immediate early and UL37 transcripts, overview, viral infection alters localization of RNA polymerase II [24]; the RNA polymerase II recruits factors including the enzyme that hyperphosphorylate its C-terminal domain, i.e. CTD, and the CTD in turn recruits proteins needed for mRNA splicing and polyadenylation, snRNA promoters probably recruit a CTD kinase, whose snRNA-specific phosphorylation patterns recruits factors required for promoter-coupled 3-end formation, overview [25]; Ctdk-1 interacts with RNA polymerase I forming a complex [27]; cyclin-dependent kinase 7 and 9, i.e. Cdk7 and Cdk9, perform also the cyclin-dependent phosphorylation of other proteins, EC 2.7.11.22 [24]; cyclin-dependent kinase Cdk1, Cdk7, and Cdk9, EC 2.7.11.22, and by MAPK, EC 2.7.11.24, phosphorylating specific serine residues [19]; the enzyme also performs the reaction of EC 2.7.11.22 [28]; the reaction is also in vitro performed by cyclin-dependent kinase Ctk1, and Bur1, EC 2.7.11.22, phosphorylating specific serine residues [19]) (Reversibility: ?) [6, 19, 21, 24, 25, 27, 28] P ? Inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine ( i.e. H7, CTD kinase inhibitor [17]; i.e. H7, CTD kinase inhibitor, blocks mRNA elongation in vivo, but does not affect U2 snRNA transcription [25]) [17, 25] 5,6-dichloro-1-b-d-ribofuranosylbenzimidazole ( nucleotide analog [1,3]; CTD kinase inhibitor, blocks mRNA elongation in vivo, but does not affect U2 snRNA transcription [25]; inhibits the CTD kinase [17]) [1, 3, 17, 25] 8-(methylthio)-4,5-dihydrothieno[3’,4’:5,6]benzoisoxazole-6-carboamide ( KM05283, CTD kinase inhibitor [17]) [17] Bovine serum albumin conjugated to heptapeptide ( with RNA-polymerase II subunit as substrate [7]) [7] GST-CTD ( overexpression of this fragment inhibits tyrosine phosphorylation of RNAP II in vivo [10]) [10] heparin [7]

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2.7.11.23

[RNA-Polymerase]-subunit kinase

High salt concentrations ( above 250 mM [1]) [1] Spermidine ( 3 mM [7]) [7] Synthetic peptide ( multimers of consensus heptapeptide repeat ProThr-Ser-Pro-Ser-Tyr-Ser, with RNA-polymerase II subunit as substrate [7]) [7] roscovitine [24] Additional information ( no inhibition by EGTA [3,7]; no inhibition by CTP, GTP, UTP, bovine serum albumin alone [7]; no inhibition by cycloheximide, inhibition of the CTD kinase in vivo affects the 3 processing of snRNA, but only slightly the initiation and elongation of transcription of U2 genes, overview [17]; the level and activity of the enzyme is not cell cycle dependent [28]; transcription through the polyadenylation site leads to a reduction in the levels of Ctk1 kinase protein and activity [18]) [3, 7, 17, 18, 28] Cofactors/prosthetic groups ATP [16,17,18,19,20,21,22,23,24,25,26,28] Additional information ( no activation by cyclic nucleotides, phospholipids [1]; no activation by cAMP [2]; no activation by spermidine and EGTA [7]; no activation by calmodulin and cGMP [2]) [1,2,7] Activating compounds CYCLINT protein ( endogenous from Medicago sativa and from Medicago trunculata, the enzyme is organized in the CDKC-1/CYCLINT-1 kinase complex, CYCLINT protein is a specific interactor of the enzyme forming the active kinase complex which localizes to the nucleus [28]) [28] DNA ( activation [6]) [6] cyclin H ( required by Cdk7 [24]) [24] cyclin T1 ( required by Cdk9 [24]) [24] Additional information ( infection with human cytomegalovirus increases Cdk7 and Cdk9 activities and phosphorylation levels of the large subunit of RNA polymerase II CTD [24]; the level and activity of the enzyme is not cell cycle dependent [28]; UV irradiation and actinomycin D induce enzyme activity leading to inhibition of U2 snRNA transcription, inhibition by UV irrardiation can be rescued by 5,6-dichloro-1-b-d-ribofuranosylbenzimidazole and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine [25]) [24, 25, 28] Metals, ions Mg2+ ( requirement [1,2,3,7]; 10 mM [1,3]; above 1 mM [2]; 2-5 mM [7]) [1, 2, 3, 7, 22, 23, 24, 28] Mn2+ ( activation [1,7]; 2-10 mM, can replace Mg2+ to some degree [7]) [1, 7] Additional information ( no activation by Ca2+ [1,2,7]; no activation by Cu2+ and Zn2+ [1]) [1, 2, 7]

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Specific activity (U/mg) 1.238 ( after second phenyl-superose chromatography [1]) [1] 65040 ( after purification with Mono S column [2]) [2] Km-Value (mM) 0.00022 (CTD-containing fusion protein, room temperature, pH 7.8 [2]) [2] 0.027 (ATP, room temperature, pH 7.8 [2]) [2] 0.03 (ATP, 30 C, pH 7.9 [1]; 27 C, pH 7.5 [3]; 30 C, pH 7.9, kinase CTDK1 [5]) [1, 3, 5] 0.06 (ATP, 30 C, pH 7.9, kinase CTDK2 [5]) [5] 0.15 (synthetic peptide, 27 C, pH 7.5 [3]) [3] 0.18 (GTP, 30 C, pH 7.9 [1]) [1] 0.189 (hepta-six peptide, 30 C, pH 7.9 [1]) [1] 0.2 (hepta-six peptide, 30 C, pH 7.9 [1]) [1] 0.212 (Arg-hepta peptide, 30 C, pH 7.9 [1]) [1] 0.243 (Arg-hepta peptide, 30 C, pH 7.9 [1]) [1] Additional information ( kinetics [22]) [22] pH-Optimum 6-9 [7] 7-8.2 [1] 7.4 ( 7.5 ( 7.5-8 [3] 7.6 ( 7.8 (

assay at [24]) [24] assay at [23]) [23] assay at [22]) [22] assay at [28]) [28]

Temperature optimum ( C) 22 ( assay at room temperature [28]) [28] 27-28 [3] 30 ( assay at [22,23]) [22, 23] 37 ( assay at [24]) [24]

4 Enzyme Structure Molecular weight 120000 ( 180000 ( 200000 ( 340000 (

glycerol density gradient centrifugation [2]) [2] gel filtration, enzyme component B [6]) [6] gel filtration [7]) [7] gel filtration, enzyme component A [6]) [6]

Subunits dimer ( 1 * 67000 + 1 * 83000, component B, SDS-PAGE [6]) [6] trimer ( tentatively abg, 1 * 58000 + 1 * 38000 + 1 * 32000, SDSPAGE [2]) [2] Additional information ( enzymes from mouse consist of 2 components each: cdc2/p58: a cdc2 kinase (p34) and a p58 subunit, cdc2/p62: a

228

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cdc2 kinase and a p62 subunit (cyclin B), the latter is also called M phasespecific histone H1 kinase [1,4]; three specific subunits: Ctk1 is the catalytic subunit, Ctk2 is a catalytic subunit, Ctk3 is unknown in its function but the physical interaction betwenn Ctk2 and Ctk3 is neccesary for kinase activity and protects both subunits against degradation [14]) [1, 4, 14]

5 Isolation/Preparation/Mutation/Application Source/tissue Ehrlich ascites carcinoma cell [1, 4] HT-1080 cell ( fibrosarcoma cell line [25]) [25] HeLa cell [1, 2, 3, 5, 6] cell culture [1, 2, 3, 4, 5, 6] cell suspension culture [28] fibroblast ( foreskin fibroblasts [24]) [24] fibrosarcoma cell [25] foreskin ( foreskin fibroblasts [24]) [24] germ [1, 7] nucleus [26] Localization nucleolus [27] nucleoplasm [27] nucleus ( Cdk7 and Cdk9 are distributed throughout the nuclei of infected cells [24]; CDKC-1/CYCLINT-1 kinase complex [28]) [2, 6, 10, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 28] Additional information ( Cdk9 localizes with the input viral DNA at early infection time, later aggregation of Cdk7, Cdk9, and S2- phosphorylated RNAP II CTD occurs, colocalized with IE1/IE2 proteins adjacent to promyelocytic leukemia protein oncogenic domains, overview [24]; the level and activity of the enzyme is not cell cycle dependent [28]) [24, 28] Purification (two kinases: cdc2/p58 and cdc2/p62) [1] (partial) [3, 5] (two components: A and B) [6] (two kinases: CDTK1 and CDTK2) [5] (native CTDK-I) [22] (partial) [2] (purification of either recombinant Myc-tagged Ctk1 and recombinant HA-tagged Ctk1 in complex with RNA polymerase I by several chromatographic steps) [27] (recombinant His-tagged CDKC-1 from Escherichia coli by nickel affinity chromatography, native CDKC-1 partially from cell suspension cultured cells by immunoprecipitation, immobilization of the enzyme on protein A agarose) [28]

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Cloning (expression in saos-2 cells) [10] (analysis of genetic interaction between ESS1 and CTD kinase genes, overexpression of wild-type and mutant CTD kinases Ctk1, Bur1, Kin28, and Srb10 in wild-type or mutant yeast strains, the latter being deficient in enzyme activity or in Ess1, overview) [21] (expression of plasmid-encoded Ctk1 in enzyme-deficient ctk1D mutant strain) [20] (expression of the substrate as GST-CTD fusion protein in Escherichia coli) [9] (expression of HA-tagged Ctk1 and of Myc-tagged Ctk1 in strain HIS5) [27] (in vitro transcription of CDKC-1, transient co-expression of Myc-tagged CDKC-1 and HA-tagged CYCLINT in Arabidopsis thaliana protoplasts for transcription analysis, expression of CDKC-1 as His-tagged and as GST-tagge protein in Escherichia coli strain BL21(DE3)) [28] Engineering D324N ( inactive Ctk1 mutant [21]) [21] Additional information ( construction of an enzyme-deficient ctk1D mutant strain which shows selective abolishment of histone H3 Lys36 methylation [20]; construction of ctk-disruption mutant strains displaying defects in nucleolar structure, the RNA polymerase I functions less effective in the mutant cells, the in vitro transcription is impaired [27]; construction of several enzyme-deficient disruption mutant strains, overview, CTK1 can rescue the growth defects of an Ess1-deficient mutant at low concentration, but enhances the defects if overexpressed [21]; ctk1 deletion affects pre-mRNA processing in vivo due to a defective recruitment of polyadenylation factors to the 3 end, but the mutation does not affect transcription termination, overview [26]; the CDKC-1/CYCLINT-1 kinase complex can recombinantly restore the transcription activity of HeLA nuclear cell extracts depleted of endogenous CDK9 kinase complexes [28]; the ctk1D cells are defective in splicing [16]) [16, 20, 21, 26, 27, 28]

6 Stability General stability information , purified mouse enzymes are rather unstable with a half-life of several days, bovine serum albumin does not stabilize [1] Storage stability , -70 C, glycerol, 20% v/v [6]

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References [1] Cisek, L.J.; Corden, J.L.: Purification of protein kinases that phosphorylate the repetitive carboxyl-terminal domain of eukaryotic RNA polymerase II. Methods Enzymol., 200, 301-325 (1991) [2] Lee, J.M.; Greenleaf, A.L.: A protein kinase that phosphorylates the C-terminal repeat domain of the largest subunit of RNA polymerase II. Proc. Natl. Acad. Sci. USA, 86, 3624-3628 (1989) [3] Stevens, A.; Maupin, M.K.: 5,6-Dichloro-1-b-d-ribofuranosylbenzimidazole inhibits a HeLa protein kinase that phosphorylates an RNA polymerase II-derived peptide. Biochem. Biophys. Res. Commun., 159, 508-515 (1989) [4] Feuerstein, N.: Phosphorylation of numatrin and other nuclear proteins by cdc2 containing CTD kinase cdc2/p58. J. Biol. Chem., 266, 16200-16206 (1991) [5] Payne, J.M.; Dahmus, M.E.: Partial purification and characterization of two distinct protein kinases that differentially phosphorylate the carboxylterminal domain of RNA polymerase subunit IIa. J. Biol. Chem., 268, 8087 (1993) [6] Dvir, A.; Stein, L.Y.; Calore, B.L.; Dynan, W.S.: Purification and characterization of a template-associated protein kinase that phosphorylates RNA polymerase II. J. Biol. Chem., 268, 10440-10447 (1993) [7] Guilfoyle, T.J.: A protein kinase from wheat germ that phosphorylates the largest subunit of RNA polymerase II. Plant Cell, 1, 827-836 (1989) [8] Stone, N.; Reinberg, D.: Protein kinases from Aspergillus nidulans that phosphorylate the carboxyl-terminal domain of the largest subunit of RNA polymerase II. J. Biol. Chem., 267, 6353-6360 (1992) [9] Morris, D.P.; Lee, J.M.; Sterner, D.E.; Brickey, W.J.; Greenleaf, A.L.: Assaying CTD kinases in vitro and phosphorylation-modulated properties of RNA polymerase II in vivo. Methods, 12, 264-275 (1997) [10] Baskaran, R.; Escobar, S.R.; Wang, J.Y.: Nuclear c-Abl is a COOH-terminal repeated domain (CTD)-tyrosine (CTD)-tyrosine kinase-specific for the mammalian RNA polymerase II: possible role in transcription elongation. Cell Growth Differ., 10, 387-396 (1999) [11] Skaar, D.A.; Greenleaf, A.L.: The RNA polymerase II CTD kinase CTDK-I affects pre-mRNA 3’ cleavage/polyadenylation through the processing component Pti1p. Mol. Cell, 10, 1429-1439 (2002) [12] Jona, G.; Wittschieben, B.O.; Svejstrup, J.Q.; Gileadi, O.: Involvement of yeast carboxy-terminal domain kinase I (CTDK-I) in transcription elongation in vivo. Gene, 267, 31-36 (2001) [13] Prelich, G.: RNA polymerase II carboxy-terminal domain kinases: emerging clues to their function. Eukaryot. Cell, 1, 153-162 (2002) [14] Hautbergue, G.; Goguel, V.: Activation of the cyclin-dependent kinase CTDK-I requires the heterodimerization of two unstable subunits. J. Biol. Chem., 276, 8005-8013 (2001) [15] Patturajan, M.; Conrad, N.K.; Bregman, D.B.; Corden, J.L.: Yeast carboxylterminal domain kinase I positively and negatively regulates RNA polymer-

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ase II carboxyl-terminal domain phosphorylation. J. Biol. Chem., 274, 27823-27828 (1999) [16] Phatnani, H.P.; Jones, J.C.; Greenleaf, A.L.: Expanding the functional repertoire of CTD kinase I and RNA polymerase II: novel phosphoCTD-associating proteins in the yeast proteome. Biochemistry, 43, 15702-15719 (2004) [17] Medlin, J.E.; Uguen, P.; Taylor, A.; Bentley, D.L.; Murphy, S.: The C-terminal domain of pol II and a DRB-sensitive kinase are required for 3’ processing of U2 snRNA. EMBO J., 22, 925-934 (2003) [18] Kim, M.; Ahn, S.-H.; Krogan, N.J.; Greenblatt, J.F.; Buratowski, S.: Transitions in RNA polymerase II elongation complexes at the 3’ ends of genes. EMBO J., 23, 354-364 (2004) [19] Palancade, B.; Bensaude, O.: Investigating RNA polymerase II carboxylterminal domain (CTD) phosphorylation. Eur. J. Biochem., 270, 3859-3870 (2003) [20] Xiao, T.; Hall, H.; Kizer, K.O.; Shibata, Y.; Hall, M.C.; Borchers, C.H.; Strahl, B.D.: Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast. Genes Dev., 17, 654-663 (2003) [21] Wilcox, C.B.; Rossettini, A.; Hanes, S.D.: Genetic interactions with C-terminal domain (CTD) kinases and the CTD of RNA Pol II suggest a role for ESS1 in transcription initiation and elongation in Saccharomyces cerevisiae. Genetics, 167, 93-105 (2004) [22] Jones, J.C.; Phatnani, H.P.; Haystead, T.A.; MacDonald, J.A.; Alam, S.M.; Greenleaf, A.L.: C-terminal repeat domain kinase I phosphorylates Ser2 and Ser5 of RNA polymerase II C-terminal domain repeats. J. Biol. Chem., 279, 24957-24964 (2004) [23] Kong, S.E.; Kobor, M.S.; Krogan, N.J.; Somesh, B.P.; Sogaard, T.M.; Greenblatt, J.F.; Svejstrup, J.Q.: Interaction of Fcp1 phosphatase with elongating RNA polymerase II holoenzyme, enzymatic mechanism of action, and genetic interaction with elongator. J. Biol. Chem., 280, 4299-4306 (2005) [24] Tamrakar, S.; Kapasi, A.J.; Spector, D.H.: Human cytomegalovirus infection induces specific hyperphosphorylation of the carboxyl-terminal domain of the large subunit of RNA polymerase II that is associated with changes in the abundance, activity, and localization of cdk9 and cdk7. J. Virol., 79, 15477-15493 (2005) [25] Jacobs, E.Y.; Ogiwara, I.; Weiner, A.M.: Role of the C-terminal domain of RNA polymerase II in U2 snRNA transcription and 3’ processing. Mol. Cell. Biol., 24, 846-855 (2004) [26] Ahn, S.H.; Kim, M.; Buratowski, S.: Phosphorylation of serine 2 within the RNA polymerase II C-terminal domain couples transcription and 3’ end processing. Mol. Cells, 13, 67-76 (2004) [27] Bouchoux, C.; Hautbergue, G.; Grenetier, S.; Carles, C.; Riva, M.; Goguel, V.: CTD kinase I is involved in RNA polymerase I transcription. Nucleic Acids Res., 32, 5851-5860 (2004) [28] Fulop, K.; Pettko-Szandtner, A.; Magyar, Z.; Miskolczi, P.; Kondorosi, E.; Dudits, D.; Bako, L.: The Medicago CDKC;1-CYCLINT;1 kinase complex phosphorylates the carboxy-terminal domain of RNA polymerase II and promotes transcription. Plant J., 42, 810-820 (2005)

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1 Nomenclature EC number 2.7.11.24 Systematic name ATP:protein phosphotransferase (MAPKK-activated) Recommended name mitogen-activated protein kinase Synonyms ATMPK1 [93] ATMPK2 [93] BMK1 [87, 141] CSAID binding protein CSBP Cytokine suppressive anti-inflammatory drug binding protein D-p38b [26] DJNK [76] Dp38 [28] ERK [117, 125, 126, 137, 147] ERK1 [3, 4, 9, 39, 118, 119, 123, 135, 140, 141, 144] ERK1-MAP kinase [36] ERK1b [35] ERK2 [4, 8, 9, 116, 118, 119, 123, 125, 135, 138, 140, 141, 144] ERK3 [91, 99, 143] ERK5 Fus3 [4, 120, 122] Fus3p [141] Gpmk1 MAP kinase [129] Hog1 [120, 122] Hog1p [141] JNK [117, 135, 144] JNK/SAPK1c [116] JNK1 [64, 141] JNK2 [65, 141, 147] JNK3 [138, 141, 147] JNKb [24] Jun-amino-terminal kinase [75, 77]

233

Mitogen-activated protein kinase

2.7.11.24

Kss1 [4, 122] Kss1p [141] MAP kinase [4, 9, 40, 41, 42, 122, 123, 125, 126, 131, 135, 137, 139, 140, 141, 149] MAP kinase 4 [132] MAP kinase MXI2 MAP kinase p38 b MAP kinase p38 d MAP kinase p38 g MAP kinase p38a MAP kinase p38a MAP kinase p38b MAPK [4, 5, 9, 117, 118, 128, 137, 141, 144, 148, 149] MAPK-activated protein kinase-2 [69] MAPK2 [116] MAPKAP kinase-2 [69] MMK2 [95, 148] MMK3 [148] MPK4 [132] Mek1p [120] mitogen-activated protein kinase p38 b mitogen-activated protein kinase p38 d mitogen-activated protein kinase p38 g mitogen-activated protein kinase p38a mitogen-activated protein kinase p38a mitogen-activated protein kinase p38b Mpk1p [141] MsERK1 [83] PMEK1 [98] PMK1 [111] SAMK [148] SAPK [135, 144] SAPK2A SAPK2a/p38 [116] SAPK2b/p38b [116] SAPK3/p38g [116] SAPK4 [21] SAPK4/p38d [116] SIMK [148] SLT2 (MPK1) MAP kinase homolog [78, 79] Smk1p [141] Spc1 kinase [84] Spm1 [112] Stress-activated protein kinase 2a Sur-1 MAP kinase [56] TmkA [133]

234

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Mitogen-activated protein kinase

UNC-16 [104] c-Jun N-terminal kinase 3 [138] cell division control protein 7 [12] cp38a cp38b extracellular regulated kinase-2 [8] extracellular signal-regulated kinase 1 [39, 53, 60] extracellular signal-regulated kinase 2 [138] extracellular-regulated kinase [135] extracellular-regulated kinase-1 [9] extracellular-regulated kinase-2 [9] extracellular-signal-regulated protein kinase 3 [14, 99] mitogen-activated protein kinase [40, 80, 149] mitogen-activated protein kinase 1 [14, 44, 45, 48, 49, 50, 51, 52] mitogen-activated protein kinase 10 [62, 72, 100, 101, 102] mitogen-activated protein kinase 11 [11, 21, 23, 88, 89, 90] mitogen-activated protein kinase 13 [16, 17, 18, 19, 20, 21, 22, 23] mitogen-activated protein kinase 14 [14, 18, 63, 67, 68] mitogen-activated protein kinase 14A [2, 13, 27, 28] mitogen-activated protein kinase 14B [2, 25, 26, 27, 114, 115] mitogen-activated protein kinase 2 [69] mitogen-activated protein kinase 3 [3, 35, 36, 37, 38, 39, 43] mitogen-activated protein kinase 4 [45] mitogen-activated protein kinase 6 [52, 91, 99] mitogen-activated protein kinase 7 [86, 87] mitogen-activated protein kinase 8 [61, 62, 63, 64, 70, 71, 100, 103, 106, 107, 108, 109, 114] mitogen-activated protein kinase 8A [24] mitogen-activated protein kinase 8B [24] mitogen-activated protein kinase 9 [61, 62, 65, 66, 71, 100] mitogen-activated protein kinase ERK-A [2, 13, 58] mitogen-activated protein kinase FUS3 [30, 32, 33, 34] mitogen-activated protein kinase HOG1 [54, 55, 110] mitogen-activated protein kinase KSS1 [29, 30, 31] mitogen-activated protein kinase SLT2/MPK1 [10, 78] mitogen-activated protein kinase homolog 1 [1, 93, 98] mitogen-activated protein kinase homolog 2 [1, 93] mitogen-activated protein kinase homolog 3 [94] mitogen-activated protein kinase homolog 4 [94] mitogen-activated protein kinase homolog 5 [94] mitogen-activated protein kinase homolog 6 [15, 94] mitogen-activated protein kinase homolog D5 [81] mitogen-activated protein kinase homolog MMK1 [82, 83] mitogen-activated protein kinase homolog MMK2 [95] mitogen-activated protein kinase homolog NTF3 [96, 97] mitogen-activated protein kinase homolog NTF4 [96]

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Mitogen-activated protein kinase

2.7.11.24

mitogen-activated protein kinase homolog NTF6 [96] mitogen-activated protein kinase p44erk1 [43, 44] mitogen-activated protein kinase spk1 [46, 47] mitogen-activated protein kinase spm1 [112, 113] mitogen-activated protein kinase sty1 [84, 85] mitogen-activated protein kinase sur-1 [56, 57] p38 [9, 68, 117, 118, 124, 130, 149] p38 MAP kinase [114, 127, 135, 136] p38 MAP kinase a [134] p38 MAPK [136, 142, 145, 146] p38 MAPKa [121, 134] p38 mitogen-activated protein kinase [17, 124, 142] p38 mitogen-activated protein kinase a [121, 134] p38-2 [89] p38-MAPK [144] p38-d mitogen-activated protein kinase [17] p38a [141] p38a MAP kinase [147, 150] p38b p38b [90, 141] p38d [17] p38g [141] p42 [118] p44 [118] p493F12 kinase [72, 102] p97MAPK [92] pathogenicity MAP kinase 1 [111] pp42/mitogen-activated protein kinase [50] receptor-linked ribosomal protein S6 [7] signal-regulated kinase 3 [91, 92] sporulation-specific mitogen-activated protein kinase SMK1 [59] stress-activated protein kinase [135] stress-activated protein kinase JNK [2, 73, 74, 75, 76] stress-activated protein kinase JNK1 [104, 105] stress-activated protein kinase-4 [23] Additional information ( the enzyme belongs to the MAPK superfamily of enzymes [144]) [144] CAS registry number 142243-02-5

2 Source Organism Gallus gallus (no sequence specified) [140, 145] Mammalia (no sequence specified) [5, 6, 141] eukaryota (no sequence specified) [4, 7, 8, 9]

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Mitogen-activated protein kinase

Mus musculus (no sequence specified) [116, 134, 136, 144, 147, 150] Homo sapiens (no sequence specified) [116, 117, 118, 119, 121, 124, 127, 128, 130, 139, 144, 146, 149] Rattus norvegicus (no sequence specified) [123,135,138,142,143,144] Sus scrofa (no sequence specified) [144] Saccharomyces cerevisiae (no sequence specified) [120,122,141] Oryctolagus cuniculus (no sequence specified) [144] Arabidopsis thaliana (no sequence specified) [132] Canis familiaris (no sequence specified) [144] Xenopus laevis (no sequence specified) [131] Medicago sativa (no sequence specified) [148] Mesocricetus auratus (no sequence specified) [139] vertebrata (no sequence specified) [137] Danio rerio (no sequence specified) [137] Homo sapiens (UNIPROT accession number: O15264) [16, 17, 18, 19, 20, 21, 22, 23] Cyprinus carpio (UNIPROT accession number: O42099) [24] Drosophila melanogaster (UNIPROT accession number: O61443) [2, 25, 26, 27] Drosophila melanogaster (UNIPROT accession number: O62618) [2, 13, 27, 28] Saccharomyces cerevisiae (UNIPROT accession number: P14681) [29, 30, 31] Saccharomyces cerevisiae (UNIPROT accession number: P16892) [30, 32, 33, 34] Rattus norvegicus (UNIPROT accession number: P21708) [3, 35, 36, 37, 38, 39] Xenopus laevis (UNIPROT accession number: P26696) [40, 41, 42] Homo sapiens (UNIPROT accession number: P27361) [43, 44] Schizosaccharomyces pombe (UNIPROT accession number: P27638) [45, 46, 47] Mus musculus (UNIPROT accession number: P27703) [14, 48, 49, 50, 51, 52] Rattus norvegicus (UNIPROT accession number: P27704) [52] Homo sapiens (UNIPROT accession number: P28482) [44, 45] Candida albicans (UNIPROT accession number: P28869) [53] Homo sapiens (UNIPROT accession number: P31152) [45] Saccharomyces cerevisiae (UNIPROT accession number: P32485) [54, 55] Caenorhabditis elegans (UNIPROT accession number: P39745) [56, 57] Drosophila melanogaster (UNIPROT accession number: P40417) [2, 13, 58] Saccharomyces cerevisiae (UNIPROT accession number: P41808) [59] Dictyostelium discoideum (UNIPROT accession number: P42525) [60] Homo sapiens (UNIPROT accession number: P45983) [61, 62, 63, 64] Homo sapiens (UNIPROT accession number: P45984) [61, 62, 65, 66] Mus musculus (UNIPROT accession number: P47811) [14, 63, 67, 68] Xenopus laevis (UNIPROT accession number: P47812) [69]

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Mitogen-activated protein kinase





























238

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Rattus norvegicus (UNIPROT accession number: P49185) [70, 71] Rattus norvegicus (UNIPROT accession number: P49186) [71] Rattus norvegicus (UNIPROT accession number: P49187) [71] Homo sapiens (UNIPROT accession number: P53779) [62, 72] Drosophila melanogaster (UNIPROT accession number: P92208) [2, 73, 74, 75, 76, 77] Saccharomyces cerevisiae (UNIPROT accession number: Q00772) [10, 78, 79] Fusarium solani (UNIPROT accession number: Q00859) [80] Pisum sativum (UNIPROT accession number: Q06060) [81] Medicago sativa (UNIPROT accession number: Q07176) [82, 83] Schizosaccharomyces pombe (UNIPROT accession number: Q09892) [84, 85] Homo sapiens (UNIPROT accession number: Q13164) [86,87] Homo sapiens (UNIPROT accession number: Q15759) [11,21,23,88,89,90] Homo sapiens (UNIPROT accession number: Q16659) [91,92] Arabidopsis thaliana (UNIPROT accession number: Q39021) [1,93] Arabidopsis thaliana (UNIPROT accession number: Q39022) [1,93] Arabidopsis thaliana (UNIPROT accession number: Q39023) [94] Arabidopsis thaliana (UNIPROT accession number: Q39024) [94] Arabidopsis thaliana (UNIPROT accession number: Q39025) [94] Arabidopsis thaliana (UNIPROT accession number: Q39026) [15,94] Arabidopsis thaliana (UNIPROT accession number: Q39027) [15,94] Medicago sativa (UNIPROT accession number: Q40353) [95] Nicotiana tabacum (UNIPROT accession number: Q40517) [96,97] Nicotiana tabacum (UNIPROT accession number: Q40531) [96] Nicotiana tabacum (UNIPROT accession number: Q40532) [96] Petunia hybrida (UNIPROT accession number: Q40884) [98] Mus musculus (UNIPROT accession number: Q61532) [14,99] Mus musculus (UNIPROT accession number: Q61831) [100,101,102] Xenopus laevis (UNIPROT accession number: Q8QHK8) [103] Caenorhabditis elegans (UNIPROT accession number: Q8WQG9) [104, 105] Cyprinus carpio (UNIPROT accession number: Q90327) [24] Mus musculus (UNIPROT accession number: Q91Y86) [100, 106, 107, 108, 109] Candida albicans (UNIPROT accession number: Q92207) [110] Magnaporthe grisea (UNIPROT accession number: Q92246) [111] Schizosaccharomyces pombe (UNIPROT accession number: Q92398) [112, 113] Pan troglodytes (UNIPROT accession number: Q95NE7) [18] Brachydanio rerio (UNIPROT accession number: Q9DGD9) [114] Brachydanio rerio (UNIPROT accession number: Q9DGE1) [114] Brachydanio rerio (UNIPROT accession number: Q9DGE2) [114] Cyprinus carpio (UNIPROT accession number: Q9I958) [115] Pan troglodytes (UNIPROT accession number: Q9N272) [18] Mus musculus (UNIPROT accession number: Q9WTU6) [100]

2.7.11.24





Mitogen-activated protein kinase

Rattus norvegicus (UNIPROT accession number: Q9WTY9) [17] Schizosaccharomyces pombe (UNIPROT accession number: P41892) [12] Mus msuculus (no sequence specified) [125,126] Fusarium graminearum (no sequence specified) [129] Rattus norvegicus (UNIPROT accession number: P63086) [138] Trichoderma virens (UNIPROT accession number: Q8J1Y8) [133]

3 Reaction and Specificity Catalyzed reaction ATP + a protein = ADP + a phosphoprotein ( reaction mechanism [9]; activation involves the activation loop, a polypeptide region outside the active site cleft, which is reversibly phosphorylated [8]; catalytic aspartate residue [6]; the kinetics of p38 MAPK follow a rapid-equilibrium random-order ternary-complex mechanism, the enzyme is highly specific for Ser-Pro or Thr-Pro motifs [134]) Reaction type phospho group transfer Natural substrates and products S ATP + AP1 ( substrate of ERK1/2, ERK access to the substrate is regulated by the all-trans retinoic acid receptor, RAR [141]) (Reversibility: ?) [141] P ADP + phosphorylated AP1 S ATP + DNA polymerase II ( substrate of Hog1p [141]) (Reversibility: ?) [141] P ADP + phosphorylated DNA polymerase II S ATP + Elk1 ( the reaction is performed by activated phosphorylated ERK2 [138]; the reaction is performed by activated phosphorylated JNK3 [138]) (Reversibility: ?) [138] P ADP + phosphorylated Elk1 S ATP + Hot1p ( substrate of Hog1p, phosphorylation of Hot1p is not required for Hot1p-mediated gene expression [141]) (Reversibility: ?) [141] P ADP + phosphorylated Hot1p S ATP + Lin-1 ( substrate of ERK2, negative regulation of Lin-1 [117]) (Reversibility: ?) [117] P ADP + phosphorylated Lin-1 S ATP + MAPKAP-K2 (Reversibility: ?) [134] P ADP + phosphorylated MAPKAP-K2 S ATP + MAPKAP-K3 (Reversibility: ?) [134] P ADP + phosphorylated MAPKAP-K3 S ATP + MEF2 (Reversibility: ?) [134] P ADP + phosphorylated MEF2 S ATP + MKS1 ( MPK4 acts as a regulator of pathogen defense responses and is required for repression of salicylic acid-dependent resis-

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Mitogen-activated protein kinase

P S

P S P S P S

P S P S

P S

P S

P S

P S

P S

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tance and for activation of jasmonate-dependent defense gene expression via MSK1, which interacts with the transcription factors WRKY25 and WRKY33 [132]) (Reversibility: ?) [132] ADP + phosphorylated MKS1 ATP + Smad1 ( the MAP kinase antagonizes Smad1 in signaling during development of axis and neural specification, Smad1 is involved in dorsal-ventral patterning in embryos [131]) (Reversibility: ?) [131] ADP + phosphorylated Smad1 ATP + Smad3 ( substrate of MAPKs, e.g. ERK2 [125]) (Reversibility: ?) [125] ADP + phosphorylated Smad3 ATP + TBP ( substrate of p38 MAPK [141]) (Reversibility: ?) [141] ADP + phosphorylated TBP ATP + a protein ( MAPK activate mitogen-activated proteins in several signal transduction pathways, overview [117]) (Reversibility: ?) [4, 5, 6, 7, 8, 9, 117, 119, 120] ADP + a phosphoprotein ATP + activating transcription factor 2 ( ATF2 [134]) (Reversibility: ?) [134] ADP + phosphorylated activating transcription factor 2 ATP + c-Jun ( substrate of JNK [117]; the reaction is performed by activated phosphorylated ERK2 [138]; the reaction is performed by activated phosphorylated JNK3 [138]) (Reversibility: ?) [117, 14] ADP + phosphorylated c-Jun ATP + human glucocorticoid receptor ( specific phosphorylation at Ser211 by p38 MAPK, p38 MAPK is a mediator in glucocorticoid-induced apoptosis of lymphoid cells, interaction of MAPK and glucocorticoid pathways, overview [146]) (Reversibility: ?) [146] ADP + phosphorylated human glucocorticoid receptor ATP + multifunctional protein CAD ( CAD initiates and regulates de novo pyrimidine biosynthesis and is activated by phosphorylation at Thr456 by nuclear MAPKs, nuclear import of CAD is required for optimal cell growth [139]) (Reversibility: ?) [139] ADP + phosphorylated multifunctional protein CAD ATP + phospholipase C-g1 ( the reaction is performed by activated phosphorylated ERK2, phosphorylation inhibits phospholipase C-g1 [138]) (Reversibility: ?) [138] ADP + phosphorylated phospholipase C-g1 ATP + tyrosine hydroxylase ( phosphorylation of tyrosine hydroxylase at Ser8 and Ser31 by ERK1 and ERK2 is involved in regulation of catecholamine biosynthesis [123]) (Reversibility: ?) [123] ADP + phosphorylated tyrosine hydroxylase Additional information ( the mitogen-activated protein kinase homolog HOG1 gene controls glycerol accumulation in the pathogenic fungus Candida albicans [110]; p38-d is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7, suggesting that p38-d is a unique stress-responsive protein kinase [17]; Jnk3-mediated signalling pathway is an important component in the pathogenesis of glutamate neurotoxicity [101]; JUN N-terminal kinase signaling is required to initiate the cell shape change at the onset of the epithelial wound healing. The embryonic JUN N-terminal kinase gene cassette is induced at the edge of the wound [73]; functions of Dp38 is to attenuate antimicrobial peptide gene expression following exposure to lipopolysaccharide [27]; enzyme plays a pivotal role in a variety of signal transduction pathways [46]; enzyme is required for the transition from mitosis into conjugation [34]; DJNK signal transduction pathway mediates an immune response and morphogenesis [76]; enzyme functions as a part of the fission yeast growth control pathway [47]; dorsal closure, a morphogenetic movement during Drosophila embryogenesis, is controlled by the Drosophila JNK pathway, D-Fos and the phosphatase Puckered [74]; possible role of asymmetric p38 activation in zebrafish in symmetric and synchronous cleavage [114]; the enzyme regulates cell integrity and functions coordinately with the protein kinase C pathway [113]; the enzyme is involved in regulating the response of eukaryotic cells to extracellular signals [39]; enzyme is required for restoring the osmotic gradient across the cell membrane [55]; enzyme is implicated in signal transduction pathways [45]; PMK1 is part of a highly conserved MAP kinase signal transduction pathway that acts cooperatively with a cAMP signaling pathway for fungal pathogenesis [111]; BMK1 may regulate signaling events distinct from those controlled by the ERK group of enzymes [87]; stress-activated MAP kinase regulates morphogenesis in Schizosaccharomyces pombe [112]; MAP kinase functions as an intermediate between MPF and the interphase-M phase transition of microtubule organization [42]; MKK4 is a JNK activator in vivo and an essential component of the JNK signal transduction pathway [108]; enzyme is activated in response to a variety of cellular stresses and is involved in apoptosis in neurons [105]; ERK1 plays an essential role during the growth and differentiation [60]; MAP kinase, ERK-A is required downstream of raf in the Sev signal transduction pathway [58]; the enzyme plays a crucial role in stress and inflammatory responses and is also involved in activation of the human immunodeficiency virus gene expression [17]; JNK1 is a component of a novel signal transduction pathway that is activated by oncoproteins and UV irradiation, JNK1 activation may play an important role in tumor promotion [64]; enzyme is involved in polarized cell growth [78]; kinase activation may play a role in the mitogenic induction of symbiotic root nodules on alfalfa by Rhizobium signal molecules [83]; conjugation, meiosis, and the osmotic stress response are regulated by Spc1

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kinase through Atf1 transcription factor in fission yeast [84]; enzyme may function to modulate Dpp signaling [26]; enzyme plays an important role in egg maturation or ectogenetic early development [24]; enzyme is involved in the signal transduction pathway initiated by proinflammatory cytokines and UV radiation [65]; the JNK pathway is conserved and it is involved in controlling cell morphogenesis in Drosophila [77]; UNC-16 may regulate the localization of vesicular cargo by integrating JNK signaling and kinesin-1 transport [104]; enzyme is required for spore wall assembly [59]; during Drosophila embryogenesis, ectodermal cells of the lateral epithelium stretch in a coordinated fashion to internalize the amnioserosa cells and close the embryo dorsally. This process, dorsal closure, requires two signaling pathways: the Drosophila Jun-amino-terminal kinase pathway and the Dpp pathway [75]; RKK, RK, and MAPKAP kinase-2 constitute a new stress-activated signal transduction pathway in vertebrates that is distinct from the classical MAPK cascade [69]; signal transduction in Saccharomyces cerevisiae requires Tyr and Thr phosphorylation of FUS3 and KSS1 [30]; JNK is necessary for T-cell differentiation but not for naive T-cell activation [107]; DAC2/FUS3 protein kinase is not essential for transcriptional activation of the mating pheromone response pathway [33]; acts downstream of the Wis1 MAP kinase kinase to control cell size at division in fission yeast [85]; the enzyme functions as a Scaffold factor in the JNK signaling pathway [100]; enzyme is involved in growth control pathway [31]; p493F12 gene maps to the human chromosome 21q21 region, a region that may be important in the pathogenesis of AD and Downs syndrome [72]; enzyme is activated by cellular stresses and plays an important role in regulating gene expression [20]; enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regulation mechanism, overview [4]; Hog1 is related to osmotic stress [120]; signaling pathway, including ERK, regulation, overview [119]; the enzyme is part of a signalling cascade resulting in an increase in Ca2+ -fluxes, activation of NF-kB, and expression of interleukin-8, the cascade is stimulated by pathogens, e.g. Pseudomonas aeruginosa PAO1 and Staphylococcus aureus RN6390, binding to asialo-glycolipid receptors, e.g. the asialoGM1 receptor, in epithelial membranes, no activation occurs with the pil mutant of Pseudomonas aeruginosa and the agr mutant of Staphylococcus aureus RN6911, Ca2+ -dependent signaling, overview [118]; ceramide activation of mitochondrial p38 mitogen-activated protein kinase is a potential mechanism for loss of mitochondrial transmembrane potential and apoptosis [145]; ERK, but not p38 and JNK, is involved in TGF-b production in macrophages, the phosphatidylserine-receptor is involved in the ERK signaling pathway, overview [126]; Fus3, Kss1, and Hog1 function during the mating pheromone response, the switch of filamentous growth, and the response to high osmolarity, respectively, detailed pathway overview, MAPK signaling pathways and specificity, pathway sequestering mechanism modeling, separation via subcellular compartmen-

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Mitogen-activated protein kinase

talization, temporal separation, scaffolding, combinatorial signaling, detailed overview [122]; Gpmk1 MAP kinase regulates the induction of secreted lipolytic enzymes [129]; MAPK pathways overview, interaction of MAPKs and transcription factors, overview, the MAPKs act as structural adaptors and enzymatic activators in transcription complexes, e.g. ERK1 and ERK2 interact with AP1-complex, which is regulated via the all-trans retinoic acid receptor and TPA, overview [141]; MAPK pathways overview, the MAPKs act as structural adaptors and enzymatic activators in transcription complexes, e.g. Hog1p, Hot1p, and Sko1p, overview [141]; MAPKs play a pivotal role in signal transduction [128]; MAPKs, e.g. p38, play a key role in the transductin of biological signals from cell surface receptors, through the cytoplasm, to the transcriptional machinery in the nucleus [130]; p38 isozymes are involved in multiple cellular functions such as cell proliferation, cell differentiation, apoptosis, and inflammation response, p38 expression and activity in signaling in erythroid cells is independent of erythropoietin [149]; p38 MAP kinase mediates the activation of neutrophils and repression of TNF-a-induced apoptosis in response to inhibition by plasma opsonized crystals of calcium diphosphate dihydrate, p38 MAP kinase is involved in apoptosis of neutrophils, regulation overview [127]; p38 MAPK, but not ERKs or JNKs, regulates the serotonin transporter, SERT, and subsequent signaling induced by 5-hydroxytryptamine, overview [142]; p38 MAPK, ERK1, and ERK2 are involved in regulation of connective tissue growth factor, CTGF, in chondrocyte maturation and function, particularly in the hypertrophic zone, as part of the retinoid and BMP signaling pathways, overview, p38 MAPK stimulates CTGF expression, while ERK1 and ERK2 supress it [140]; regulation mechanism of p38 MAPK activity involving the protein kinases MKK3, MKK4, and MKK6, overview [136]; signaling pathways overview, the enzyme is important in transduction of external stimuli and signals from the cell membrane to nuclear and other intracellular targets, the enzyme is involved in regulation of several celllular processes in cell growth, differentiation, development cell cycle, death and survival, the enzyme is also involved in pathogenesis of several processes in the heart, e.g. hypertrophy, ischemic and reperfusion injury, aas well as in cardioprotection, the MAPK family enzymes have regulatory function in the myocardium, overview [144]; signaling pathways overview, the enzyme is important in transduction of external stimuli and signals from the cell membrane to nuclear and other intracellular targets, the enzyme is involved in regulation of several celllular processes in cell growth, differentiation, development cell cycle, death and survival, the enzyme is also involved in pathogenesis of several processes in the heart, e.g. hypertrophy, ischemic and reperfusion injury, as well as in cardioprotection, the MAPK family enzymes have regulatory function in the myocardium, overview [144]; spatiotemporal control of the Ras/ERK MAP kinase signaling pathway, involving multiple factors, is a key factor for determining the specificity of cellular responses including cell proliferation, cell differen-

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tiation, and cell survival, the fidelity of the signaling is regulated by docking interactions and by scaffolding, molecular mechanism of negative regulation of Ras/ERK signaling [137]; tert-butyl hydroperoxide activation of MAPK might be involved in vascular dysfunction in oxidative stress responses and the vascular inflammatory process [135]; the enzyme is involved in biocontrol properties and repression of conidiation of the fungal hosts in the dark, effects of wild-type and mutant enzymes on host growth, morphology, and conidiation, overview [133]; the p38 MAPKa is involved in cell signal transduction and mediates responses to cell stresses and to growth factors [121]) (Reversibility: ?) [4, 17, 20, 24, 26, 27, 30, 31, 33, 34, 39, 42, 45, 46, 47, 55, 58, 59, 60, 64, 65, 69, 72, 73, 74, 75, 76, 77, 78, 83, 84, 85, 87, 100, 101, 104, 105, 107, 108, 110, 111, 112, 113, 114, 118, 119, 120, 121, 122, 126, 127, 128, 129, 130, 133, 135, 136, 137, 140, 141, 142, 144, 145, 149] P ? Substrates and products S ATP + AP1 ( substrate of ERK1/2, ERK access to the substrate is regulated by the all-trans retinoic acid receptor, RAR [141]; substrate of ERK1/2 [141]) (Reversibility: ?) [141] P ADP + phosphorylated AP1 S ATP + Axl2 ( substrate of Hog1 [120]) (Reversibility: ?) [120] P ADP + phospho-Axl2 S ATP + DNA polymerase II ( substrate of Hog1p [141]) (Reversibility: ?) [141] P ADP + phosphorylated DNA polymerase II S ATP + Elk1 ( the reaction is performed by activated phosphorylated ERK2 [138]; the reaction is performed by activated phosphorylated JNK3 [138]; recombinant GST-tagged Elk1, substrate of ERK2 [125]; recombinant GST-tagged substrate, the reaction is performed by activated phosphorylated ERK2 [138]; recombinant GST-tagged substrate, the reaction is performed by activated phosphorylated JNK3 [138]) (Reversibility: ?) [125, 14] P ADP + phosphorylated Elk1 S ATP + Gic2 ( substrate of Fus3, and of Hog1 [120]) (Reversibility: ?) [120] P ADP + phosphorylated Gic2 S ATP + Hog1D ( substrate of Hog1 [120]) (Reversibility: ?) [120] P ADP + phospho-Hog1D S ATP + Hot1p ( substrate of Hog1p [141]; substrate of Hog1p, phosphorylation of Hot1p is not required for Hot1p-mediated gene expression [141]) (Reversibility: ?) [141] P ADP + phosphorylated Hot1p S ATP + Hsl1 ( substrate of Hog1 [120]) (Reversibility: ?) [120] P ADP + phospho-Hsl1 S ATP + Lin-1 ( substrate of ERK2, negative regulation of Lin-1 [117]; Lin-1 is an ETS transcription factor, substrate of ERK2, bind-

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P S P S P S P S P S

P S P S P S

P S P S P S P S P S

P S

Mitogen-activated protein kinase

ing via the docking sequence of the substrate [117]) (Reversibility: ?) [117] ADP + phosphorylated Lin-1 ATP + MAPKAP kinase-2 (Reversibility: ?) [23] ADP + phosphorylated MAPKAP kinase-2 ATP + MAPKAP kinase-3 (Reversibility: ?) [23] ATP + phosphorylated MAPKAP kinase-3 ATP + MAPKAP-K2 (Reversibility: ?) [134] ADP + phosphorylated MAPKAP-K2 ATP + MAPKAP-K3 (Reversibility: ?) [134] ADP + phosphorylated MAPKAP-K3 ATP + MAPKAPK2-peptide ( the peptide substrate is derived from a sequence of a mitogen-activated protein kinase activated protein kinase-2, MAPKAPK2, phopshorylation site [127]) (Reversibility: ?) [127] ADP + phosphorylated MAPKAPK2-peptide ATP + MBP ( substrate of Hog1 [120]) (Reversibility: ?) [120] ADP + phospho-MBP ATP + MEF2 (Reversibility: ?) [134] ADP + phosphorylated MEF2 ATP + MKS1 ( MPK4 acts as a regulator of pathogen defense responses and is required for repression of salicylic acid-dependent resistance and for activation of jasmonate-dependent defense gene expression via MSK1, which interacts with the transcription factors WRKY25 and WRKY33 [132]; substrate of MPK4 [132]) (Reversibility: ?) [132] ADP + phosphorylated MKS1 ATP + Mek1 ( substrate of Hog1 [120]) (Reversibility: ?) [120] ADP + phospho-Mek1 ATP + RAD9 ( high activity with Fus3, low activity with Hog1 [120]) (Reversibility: ?) [120] ADP + phospho-RAD9 ATP + RAD9p ( substrate of Hog1 [120]) (Reversibility: ?) [120] ADP + phospho-RAD9p ATP + Red1 ( preferred substrate of Hog1 [120]) (Reversibility: ?) [120] ADP + phospho-Red1 ATP + Smad1 ( the MAP kinase antagonizes Smad1 in signaling during development of axis and neural specification, Smad1 is involved in dorsal-ventral patterning in embryos [131]; phosphorylation by MAP kinase inhibits Smad1 and the BMP-4/Smad1 signaling pathway, phosphorylation sites are S187, S195, S205, and S213, activity with Smad1 mutant S187/S195/S205/S213, overview [131]) (Reversibility: ?) [131] ADP + phosphorylated Smad1 ATP + Smad3 ( substrate of MAPKs, e.g. ERK2 [125]; substrate of MAPKs, e.g. ERK2, identification of phosphorylation sites Ser203, Ser207, and Thr187, Ser207 is the best phosphorylation site for

245

Mitogen-activated protein kinase

P S P S P S P S P S P S P S

P S P S

P S

P S P S P

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ERK2, other MAPKs than ERK2 also phosphorylate Ser212 [125]) (Reversibility: ?) [125] ADP + phosphorylated Smad3 ATP + Swe1 ( substrate of Hog1 [120]) (Reversibility: ?) [120] ADP + phospho-Swe1 ATP + Swi6 ( substrate of Hog1 [120]) (Reversibility: ?) [120] ADP + phospho-Swi6 ATP + TBP ( substrate of p38 MAPK [141]) (Reversibility: ?) [141] ADP + phosphorylated TBP ATP + Tub4p ( substrate of Hog1 [120]) (Reversibility: ?) [120] ADP + phospho-Tub4 ATP + WRKY25 ( the transcription factor is an in vitro substrate of MPK4 [132]) (Reversibility: ?) [132] ADP + phosphorylated WRKY25 ATP + WRKY33 ( the transcription factor is an in vitro substrate of MPK4 [132]) (Reversibility: ?) [132] ADP + phosphorylated WRKY33 ATP + a protein ( MAPK activate mitogen-activated proteins in several signal transduction pathways, overview [117]; ERK2 phosphorylates MBP, p38 phosphorylates the protein substrate MAPKAP2 and the peptide substrate KRELVEPLTPSGEAPNQALLR, other substrates of MAPK are transcription factors, such as c-Jun, ATF-2, and MEF2A [9]) (Reversibility: ?) [4, 5, 6, 7, 8, 9, 117, 119, 120] ADP + a phosphoprotein ATP + activating transcription factor 2 ( ATF2 [134]; ATF2, recombinant GST-tagged ATF2D115 [134]) (Reversibility: ?) [134] ADP + phosphorylated activating transcription factor 2 ATP + c-Jun ( substrate of JNK [117]; substrate of JNK, binding via d domain of c-Jun substrate [117]; the reaction is performed by activated phosphorylated ERK2 [138]; the reaction is performed by activated phosphorylated JNK3 [138]; recombinant GST-tagged substrate, the reaction is performed by activated phosphorylated ERK2 [138]; recombinant GST-tagged substrate, the reaction is performed by activated phosphorylated JNK3 [138]) (Reversibility: ?) [117, 14] ADP + phosphorylated c-Jun ATP + c-Jun activation domain ( enzyme binds to the c-Jun transactivation domain and phosphorylates it on Ser63 and Ser73 [64]; JNK2 binds c-Jun approximately 25 times more efficiently than JNK1 [66]) (Reversibility: ?) [64, 66] ADP + phosphorylated c-Jun activation domain ATP + casein ( substrate of Hog1 [120]) (Reversibility: ?) [120] ADP + phosphocasein ATP + cdc42 ( substrate of Gic2 [120]) (Reversibility: ?) [120] ADP + phosphorylated cdc42

2.7.11.24

Mitogen-activated protein kinase

S ATP + histone H1 ( substrate of Hog1 [120]) (Reversibility: ?) [120] P ADP + phospho-histone H1 S ATP + human glucocorticoid receptor ( specific phosphorylation at Ser211 by p38 MAPK, p38 MAPK is a mediator in glucocorticoid-induced apoptosis of lymphoid cells, interaction of MAPK and glucocorticoid pathways, overview [146]; specific phosphorylation at Ser211 by p38 MAPK [146]) (Reversibility: ?) [146] P ADP + phosphorylated human glucocorticoid receptor S ATP + multifunctional protein CAD ( CAD initiates and regulates de novo pyrimidine biosynthesis and is activated by phosphorylation at Thr456 by nuclear MAPKs, nuclear import of CAD is required for optimal cell growth [139]; phosphorylation at Thr456, native and recombinant CAD [139]; phosphorylation at Thr456, native and recombinant multifunctional protein CAD [139]) (Reversibility: ?) [139] P ADP + phosphorylated multifunctional protein CAD S ATP + myelin basic protein ( substrate of ERK2 [125]) (Reversibility: ?) [60, 95, 96, 125] P ADP + phosphorylated myelin basic protein S ATP + phospholipase C-g1 ( the reaction is performed by activated phosphorylated ERK2, phosphorylation inhibits phospholipase C-g1 [138]; recombinant substrate, the reaction is performed by activated phosphorylated ERK2 [138]) (Reversibility: ?) [138] P ADP + phosphorylated phospholipase C-g1 S ATP + protein ( autophosphorylation [43,96]; proline-directed kinase [71]; Ser/Thr kinase [99]; autophosphorylation on both tyrosine and threonine residues, autophosphorylation is probably involved in the MAP kinase activation process in vitro, but it may not be sufficient for full activation [37]; autophosphorylates both Thr and Tyr residues [72]) (Reversibility: ?) [37, 43, 71, 72, 96, 99] P ADP + phosphoprotein S ATP + protein ATF2 ( recombinant GST-tagged ATF2 substrate [149]; recombinant GST-tagged ATF2D11 5 [121]) (Reversibility: ?) [121, 147, 149] P ADP + phosphorylated protein ATF2 S ATP + protein tyrosine kinase 2 ( substrate of Hog1 [120]) (Reversibility: ?) [120] P ADP + phosphorylated protein tyrosine kinase 2 S ATP + transcription factor ATF2 (Reversibility: ?) [23] P ADP + phosphorylated transcription factor ATF2 S ATP + transcription factor Djun (Reversibility: ?) [76] P ADP + phosphorylated transcription factor Djun S ATP + transcription factor Elk-1 (Reversibility: ?) [23] P ADP + phosphorylated transcription factor Elk-1 S ATP + transcription factor SAP-1 (Reversibility: ?) [23] P ADP + phosphorylated transcription factor SAP-1

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Mitogen-activated protein kinase

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S ATP + tyrosine hydroxylase ( phosphorylation of tyrosine hydroxylase at Ser8 and Ser31 by ERK1 and ERK2 is involved in regulation of catecholamine biosynthesis [123]; recombinant rat wild-type and S8A, S31A, S19A, and S40A mutant tyrosine hydroxylase substrates, phosphorylation at Ser8 and Ser31 by ERK1 and ERK2, ERK2 prefers the Ser31 phosphorylation site, no activity with substrate mutant S8A/S31A [123]) (Reversibility: ?) [123] P ADP + phosphorylated tyrosine hydroxylase S phosphoprotein ( the MAPK is regulated in the MAPK signaling cascade by 2 mechanisms: 1. by MEK, EC 2.7.11.25, docking at the allosteric ED domain or the CD domain of MAPKs, or 2. by MKK7, MLK, JNK or MKP-7 docking at the scaffolding protein JIP in the JNK signaling pathway [137]) (Reversibility: ?) [137] P ? S Additional information ( substrate specificity [7]; no phosphorylation of the activation domain of c-Jun [23]; no phosphorylation of MAPK-activated protein kinase-2 and -3 [20]; the mitogen-activated protein kinase homolog HOG1 gene controls glycerol accumulation in the pathogenic fungus Candida albicans [110]; p38-d is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7, suggesting that p38-d is a unique stress-responsive protein kinase [17]; Jnk3-mediated signalling pathway is an important component in the pathogenesis of glutamate neurotoxicity [101]; JUN N-terminal kinase signaling is required to initiate the cell shape change at the onset of the epithelial wound healing. The embryonic JUN N-terminal kinase gene cassette is induced at the edge of the wound [73]; functions of D-p38 is to attenuate antimicrobial peptide gene expression following exposure to lipopolysaccharide [27]; enzyme plays a pivotal role in a variety of signal transduction pathways [46]; enzyme is required for the transition from mitosis into conjugation [34]; DJNK signal transduction pathway mediates an immune response and morphogenesis [76]; enzyme functions as a part of the fission yeast growth control pathway [47]; dorsal closure, a morphogenetic movement during Drosophila embryogenesis, is controlled by the Drosophila JNK pathway, D-Fos and the phosphatase Puckered [74]; possible role of asymmetric p38 activation in zebrafish in symmetric and synchronous cleavage [114]; the enzyme regulates cell integrity and functions coordinately with the protein kinase C pathway [113]; the enzyme is involved in regulating the response of eukaryotic cells to extracellular signals [39]; enzyme is required for restoring the osmotic gradient across the cell membrane [55]; enzyme is implicated in signal transduction pathways [45]; PMK1 is part of a highly conserved MAP kinase signal transduction pathway that acts cooperatively with a cAMP signaling pathway for fungal pathogenesis [111]; BMK1 may regulate signaling

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Mitogen-activated protein kinase

events distinct from those controlled by the ERK group of enzymes [87]; stress-activated MAP kinase regulates morphogenesis in Schizosaccharomyces pombe [112]; MAP kinase functions as an intermediate between MPF and the interphase-M phase transition of microtubule organization [42]; MKK4 is a JNK activator in vivo and an essential component of the JNK signal transduction pathway [108]; enzyme is activated in response to a variety of cellular stresses and is involved in apoptosis in neurons [105]; ERK1 plays an essential role during the growth and differentiation [60]; MAP kinase, ERK-A is required downstream of raf in the Sev signal transduction pathway [58]; the enzyme plays a crucial role in stress and inflammatory responses and is also involved in activation of the human immunodeficiency virus gene expression [17]; JNK1 is a component of a novel signal transduction pathway that is activated by oncoproteins and UV irradiation, JNK1 activation may play an important role in tumor promotion [64]; enzyme is involved in polarized cell growth [78]; kinase activation may play a role in the mitogenic induction of symbiotic root nodules on alfalfa by Rhizobium signal molecules [83]; conjugation, meiosis, and the osmotic stress response are regulated by Spc1 kinase through Atf1 transcription factor in fission yeast [84]; enzyme may function to modulate Dpp signaling [26]; enzyme plays an important role in egg maturation or ectogenetic early development [24]; enzyme is involved in the signal transduction pathway initiated by proinflammatory cytokines and UV radiation [65]; the JNK pathway is conserved and it is involved in controlling cell morphogenesis in Drosophila [77]; UNC-16 may regulate the localization of vesicular cargo by integrating JNK signaling and kinesin-1 transport [104]; enzyme is required for spore wall assembly [59]; during Drosophila embryogenesis, ectodermal cells of the lateral epithelium stretch in a coordinated fashion to internalize the amnioserosa cells and close the embryo dorsally. This process, dorsal closure, requires two signaling pathways: the Drosophila Junamino-terminal kinase pathway and the Dpp pathway [75]; RKK, RK, and MAPKAP kinase-2 constitute a new stress-activated signal transduction pathway in vertebrates that is distinct from the classical MAPK cascade [69]; signal transduction in Saccharomyces cerevisiae requires Tyr and Thr phosphorylation of FUS3 and KSS1 [30]; JNK is necessary for T-cell differentiation but not for naive T-cell activation [107]; DAC2/FUS3 protein kinase is not essential for transcriptional activation of the mating pheromone response pathway [33]; acts downstream of the Wis1 MAP kinase kinase to control cell size at division in fission yeast [85]; the enzyme functions as a Scaffold factor in the JNK signaling pathway [100]; enzyme is involved in growth control pathway [31]; p493F12 gene maps to the human chromosome 21q21 region, a region that may be important in the pathogenesis of AD and Downs syndrome [72]; enzyme is activated by cellular stresses and plays an important role in regulating gene expression [20]; enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regula-

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tion mechanism, overview [4]; Hog1 is related to osmotic stress [120]; signaling pathway, including ERK, regulation, overview [119]; the enzyme is part of a signalling cascade resulting in an increase in Ca2+ -fluxes, activation of NF-kB, and expression of interleukin-8, the cascade is stimulated by pathogens, e.g. Pseudomonas aeruginosa PAO1 and Staphylococcus aureus RN6390, binding to asialo-glycolipid receptors, e.g. the asialoGM1 receptor, in epithelial membranes, no activation occurs with the pil mutant of Pseudomonas aeruginosa and the agr mutant of Staphylococcus aureus RN6911, Ca2+ -dependent signaling, overview [118]; interaction motifs of substrates are crucial for MAPK activity, motif Leu-Xaa-Leu preceded by 3-5 basic residues is abundant, docking mechanism in MAPK signalling, the recognition modules can function synergistically or competitively, MAPK determinants recognizing docking motifs, overview [117]; poor activity on free amino acids, consensus sequence of ERK2 is P-XS/TP, substrate specificity and recognition elements, e.g. PXTP, the activity on the protein substrate is much higher compared to a 14-residue peptide containing the phosphorylation site [9]; the enzyme depends on basic residues for substrate recognition, autoregulation by a pseudosubstrate mechanism, overview [5]; the enzyme performs autophosporylation [120]; ceramide activation of mitochondrial p38 mitogen-activated protein kinase is a potential mechanism for loss of mitochondrial transmembrane potential and apoptosis [145]; ERK, but not p38 and JNK, is involved in TGF-b production in macrophages, the phosphatidylserine-receptor is involved in the ERK signaling pathway, overview [126]; Fus3, Kss1, and Hog1 function during the mating pheromone response, the switch of filamentous growth, and the response to high osmolarity, respectively, detailed pathway overview, MAPK signaling pathways and specificity, pathway sequestering mechanism modeling, separation via subcellular compartmentalization, temporal separation, scaffolding, combinatorial signaling, detailed overview [122]; Gpmk1 MAP kinase regulates the induction of secreted lipolytic enzymes [129]; MAPK pathways overview, interaction of MAPKs and transcription factors, overview, the MAPKs act as structural adaptors and enzymatic activators in transcription complexes, e.g. ERK1 and ERK2 interact with AP1-complex, which is regulated via the all-trans retinoic acid receptor and TPA, overview [141]; MAPK pathways overview, the MAPKs act as structural adaptors and enzymatic activators in transcription complexes, e.g. Hog1p, Hot1p, and Sko1p, overview [141]; MAPKs play a pivotal role in signal transduction [128]; MAPKs, e.g. p38, play a key role in the transductin of biological signals from cell surface receptors, through the cytoplasm, to the transcriptional machinery in the nucleus [130]; p38 isozymes are involved in multiple cellular functions such as cell proliferation, cell differentiation, apoptosis, and inflammation response, p38 expression and activity in signaling in erythroid cells is independent of erythropoietin [149]; p38 MAP kinase mediates the activation of neutrophils and repression of TNF-a-induced apoptosis in response to inhibition by plasma opsonized crystals of

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Mitogen-activated protein kinase

calcium diphosphate dihydrate, p38 MAP kinase is involved in apoptosis of neutrophils, regulation overview [127]; p38 MAPK, but not ERKs or JNKs, regulates the serotonin transporter, SERT, and subsequent signaling induced by 5-hydroxytryptamine, overview [142]; p38 MAPK, ERK1, and ERK2 are involved in regulation of connective tissue growth factor, CTGF, in chondrocyte maturation and function, particularly in the hypertrophic zone, as part of the retinoid and BMP signaling pathways, overview, p38 MAPK stimulates CTGF expression, while ERK1 and ERK2 supress it [140]; regulation mechanism of p38 MAPK activity involving the protein kinases MKK3, MKK4, and MKK6, overview [136]; signaling pathways overview, the enzyme is important in transduction of external stimuli and signals from the cell membrane to nuclear and other intracellular targets, the enzyme is involved in regulation of several celllular processes in cell growth, differentiation, development cell cycle, death and survival, the enzyme is also involved in pathogenesis of several processes in the heart, e.g. hypertrophy, ischemic and reperfusion injury, aas well as in cardioprotection, the MAPK family enzymes have regulatory function in the myocardium, overview [144]; signaling pathways overview, the enzyme is important in transduction of external stimuli and signals from the cell membrane to nuclear and other intracellular targets, the enzyme is involved in regulation of several celllular processes in cell growth, differentiation, development cell cycle, death and survival, the enzyme is also involved in pathogenesis of several processes in the heart, e.g. hypertrophy, ischemic and reperfusion injury, as well as in cardioprotection, the MAPK family enzymes have regulatory function in the myocardium, overview [144]; spatiotemporal control of the Ras/ERK MAP kinase signaling pathway, involving multiple factors, is a key factor for determining the specificity of cellular responses including cell proliferation, cell differentiation, and cell survival, the fidelity of the signaling is regulated by docking interactions and by scaffolding, molecular mechanism of negative regulation of Ras/ERK signaling [137]; tert-butyl hydroperoxide activation of MAPK might be involved in vascular dysfunction in oxidative stress responses and the vascular inflammatory process [135]; the enzyme is involved in biocontrol properties and repression of conidiation of the fungal hosts in the dark, effects of wild-type and mutant enzymes on host growth, morphology, and conidiation, overview [133]; the p38 MAPKa is involved in cell signal transduction and mediates responses to cell stresses and to growth factors [121]; MAPK phosphorylation consensus sequences [138]; measurement of ATPase activity of p38 MAPK in an NADH-coupled assay [134]; stoichiometry of phosphorylation of wild-type and mutant tyrosine hydroxylase substrates by ERK2 [123]; transcription factor protein domains consisting of the LXL motif, the FXFP motif, the LXLXXXF motif, or the ETS motif, are involved in stable interaction of MAPKs with transcription complexes [141]) (Reversibility: ?) [4, 5, 7, 9, 17, 20, 23, 24, 26, 27, 30, 31, 33, 34, 39, 42, 45, 46, 47, 55, 58, 59, 60, 64, 65, 69, 72, 73, 74, 75, 76, 77, 78, 83, 84, 85, 87, 100, 101, 104, 105, 107, 108, 110,

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111, 112, 113, 114, 117, 118, 119, 120, 121, 122, 123, 126, 127, 128, 129, 130, 133, 134, 135, 136, 137, 138, 140, 141, 142, 144, 145, 149] P ? Inhibitors (hydroxy-2-naphthalenylmethyl)phosphonic acid ( inhibits the insulin receptor tyrosine kinase, IC50 is 0.01 mM [7]) [7] 1-(2,6-dichloro-phenyl)-5-(2,4-difluoro-phenyl)-7-piperazin-1-yl-3,4-dihydro-1H-quinazolin-2-one ( highly selective for p38 isozyme a wildtype with IC50 of 3.2 nM, the IC50 for mutants G110A and G110D are 37 nM and 56 nM, respectively, no inhibition of JNK3, JNK2, and ERK [147]) [147] 1-(2,6-dichloro-phenyl)-5-(2,4-difluoro-phenyl)-7-piperidin-4-yl-3,4-dihydro-1H-quinolin-2-one ( highly selective for p38 isozyme a wildtype with IC50 of 0.74 nM, the IC50 for mutants G110A and G110D are 26 nM and 67 nM, respectively, no inhibition of JNK3, JNK2, and ERK [147]) [147] 1-(2,6-dichloro-phenyl)-6-(2,4-difluoro-phenylsulfanyl)-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one ( highly selective for p38 isozyme a wild-type with IC50 of 4.3 nM, the IC50 for mutants G110A and G110D are 61 nM and 160 nM, respectively, no inhibition of JNK3, JNK2, and ERK [147]) [147] ADP ( MgADP- shows an uncompetitive inhibition pattern [134]) [134] BIRB796 ( binding structure with isozyme p38a [147]) [147] PD169316 ( i.e. 4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)1H-imidazole, a specific p38 MAPK inhibitor, reduces 5-hydroxytryptamine uptake in cells, inhibits SERT phosphorylation [142]) [142] PD98059 ( specific p42/44 mitogen-activated protein (MAP) kinase cascade inhibitor [118]; ERK1/2 inhibitor [140]; inhibits ERK1 and ERK2 [135]) [118, 135, 140] SB202 ( p38 inhibitor SB202 [118]) [118] SB202190 ( i.e. 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole, a specific p38b isozyme inhibitor [124]; specific p38 MAPK inhibitor [145]) [124, 145] SB203580 ( i.e. 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole, a specific p38 MAPK inhibitor, reduces 5hydroxytryptamine uptake in cells, inhibits SERT phosphorylation [142]; i.e. 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole, a specific p38a isozyme inhibitor [124]; inhibits p38 MAP kinase [135]; inhibits the p38 isozymes isozymes a, b, and g [147]; noncompetitive in the kinase reaction, competitive versus ATP in the ATPase reaction, no classical linear inhibition kinetics at concentrations below 100 nM [134]; p38 isozyme a-specific inhibitor [149]; p38 MAP kinase specific inhibitor [127]; p38 MAPK inhibitor [140]; specific inhibitor of p38a MAP kinase, interaction analysis with immobilized enzyme in a surface plasmon resonance study, binding structure from the cyrstal structure of the enzyme-inhibitor complex [150]) [124, 127, 134, 135, 140, 142, 147, 149, 150]

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Staurosporine [47] U0126 ( specific inhibitor of ERK [126]) [126] VK19911 [147] VX745 [147] [4-[3-methyl-2-piperidin-4-yl-5-(3-trifluoromethyl-phenyl)-3H-imidazol-4yl]-pyrimidin-2-yl]-((S)-1-phenyl-ethyl)-amine ( highly selective for p38 isozyme a wild-type and mutants with IC50 of 0.10-0.14 nM, IC50 for JNK2 is 680 nM, for JNK3 970 nM and for ERK 660 nM [147]) [147] adenylyl-b,g-methylene diphosphonic acid ( i.e. AMP-PCP, MgAMPPCP shows a mixed inhibition pattern in the kinase reaction, and a competitive pattern in the ATPase reaction [134]) [134] all-trans retinoic acid receptor ( ERK access to the substrate is regulated by the all-trans retinoic acid receptor, RAR [141]) [141] alsterpaullone ( 36% inhibition of MAPK2/ERK2 at 0.01 mM [116]; inhibition of JNK/SAPK1c, SAPK2a/p38, SAPK2b/p38b, SAPK3/ p38g, and SAPK4/p38d [116]) [116] calcium diphosphate ( crystals in plasma inhibit the p38 MAP kinase mediating the activation of neutrophils and repression of TNF-a-induced apoptosis [127]) [127] indirubin-3’-monoxime ( 79% inhibition at 0.01 mM of JNK/ SAPK1c, 17% inhibition at 0.01 mM of SAPK2a/p38, 55% inhibition at 0.01 mM of SAPK2b/p38b, 26% inhibition at 0.01 mM of SAPK3/p38g, and 35% inhibition at 0.01 mM of SAPK4/p38d [116]) [116] kenpaullone ( 30% inhibition of MAPK2/ERK2 at 0.01 mM [116]; slight inhibition of SAPK2a/p38 and SAPK3/p38g, no inhibition of SAPK4/p38d, JNK/SAPK1c, SAPK2b/p38b, and SAPK4/p38d [116]) [116] phospholipase C-g1 d-domain ( a peptide containing the phospholipase C-g1 d-domain competitively inhibits the phosphorylation of Elk1 and c-Jun by ERK2, overview [138]; a peptide containing the phospholipase C-g1 d-domain competitively inhibits the phosphorylation of Elk1 and c-Jun by JNK3, overview [138]) [138] purvalanol ( 16% inhibition at 0.01 mM of JNK/SAPK1c, no inhibition of SAPK2a/p38, SAPK3/p38g, and SAPK4/p38d [116]; 74% inhibition of MAPK2/ERK2 at 0.01 mM [116]) [116] pyridinyl imidazole-type inhibitors ( IC50 of 15-48 nM [147]) [147] roscovitine ( 19% inhibition of MAPK2/ERK2 at 0.01 mM [116]) [116] Additional information ( p38a kinase inhibitor AMG 2372 minimally inhibits the kinase activity of p38d [20]; activity is not blocked by the pyridinyl imidazole, 4-(4-fluorophenyl)-2-2(4-hydroxyphenyl)-5-(4-pyridyl)-imidazole (identical to SB202190) [22]; not inhibited by the drugs SB 203580 and SB 202190 [23]; autoregulation by a pseudosubstrate mechanism, overview [5]; indirubin-3-monoxime is no inhibitor of MAPK2/ERK2 [116]; inhibition of the Ca2+ -dependent signaling and expression of interleukin-8 in 1HAEo cells by BAPTA/AM, verapamil, cyclosporin A, FK-506, and TEMPO, and by an anti-asialoGM1 receptor antibody [118]; roscovitine is a poor inhibitor

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of MAPKs [116]; synthesis of peptides behaving as pseudosubstrates, determination of inhibitory potential [7]; in vitro the recombinant phospholipase C-g1 activity is not inhibited by phosphorylation through activated ERK2 [138]; molecular mechanism of negative regulation of Ras/ERK signaling, Sef negatively regulates ERK phosphorylation by blocking dissocation of MEK and ERK [137]; no inhibition by AMP and adenine [134]; no inhibition by PD98059 [145]; PD 98059 inhibits EGF-induced nuclear translocation of CAD [139]; PD98059 and U0126 inhibit EGF-induced phosphorylation of Smad3 [125]; PD98059 inhibits EGF-induced nuclear translocation of multifunctional protein CAD [139]; pheromones can influence the phosphorylation of MAPKs [122]; phosphorylation of p38a occurs in vivo only in absence of growth factor in primary erythroid progenitors [149]; PKC isozymes, EC 2.7.11.13, suppress p38 activating phosphorylation under mechanical pressure of cells [124]; structural basis for inhibitor selectivity for p38 over other MAPKs such as ERK or JNK, overview [147]) [5, 7, 20, 22, 23, 116, 118, 122, 124, 125, 134, 137, 138, 139, 145, 147, 149] Cofactors/prosthetic groups ATP ( dependent on [9]; as MgATP2- [121]; the binding site is a deep pocket lined by hydrophobic residues, enzyme affinity for ATP is slightly increased by phosphorylation of the activation loop [8]) [4, 5, 6, 7, 8, 9, 116, 117, 118, 119, 120, 121, 122, 123, 125, 127, 131, 132, 134, 138, 139, 141, 144, 146, 147, 149, 150] Activating compounds 12-O-tetradecanoylphorbol-13-acetate ( activates ERK1 and ERK2 [141]) [141] d-amphetamine ( stimulates SERT phosphorylation [142]) [142] EGF ( induces phosphorylation of Smad3 [125]) [125] interleukin-1b ( activates the MAPKs, dexamethasone inhibits this activation [130]) [130] MEF2D ( is crucial for activating phosphorylation of substrates within a transcription complex by BMK1, possibly by anchoring BMK1 to specific genes [141]) [141] MKK3 ( activates [22]; strongly activates [20]) [20, 22] MKK6 ( activates [22,23]; strongly activates [20]) [20, 22, 23] N-acetylsphingosine ( i.e. C2-ceramide, an intracellular mediator of apoptosis, cell-permeable N-acetylsphingosine activates mitochondrial p38 MAPK [145]) [145] TNF-a ( activates p38 MAP kinase 6fold in neutrophils [127]; activates p38 MAPK mediated by protein kinases MKK3, MKK4, and MKK6, overview [136]; activates the MAPKs, dexamethasone inhibits this activation [130]) [127, 130, 136] UV radiation ( activates p38 MAPK mediated by protein kinases, overview [136]) [136]

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b-phorbol-13-acetate ( stimulates SERT phosphorylation [142]) [142] cytokines ( activate [22]) [22, 23] glucocorticoids ( activate p38 MAPK, e.g. by induction of activating MKK3 [146]) [146] purvalanol ( 17% activation of SAPK2b/p38b [116]) [116] thapsigargin ( stimulates 4-5fold the expression of p44/p42 [118]) [118] transforming growth factor-b ( i.e. TGF-b, activates p38, butenoside inhibits this activation [130]) [130] Additional information ( activated by cellular stress and proinflammatory cytokines [20]; activated by dual phosphorylation at Thr and Tyr during the UV response. Ha-Ras partially activates JNK1 and potentiates the activation caused by UV [64]; enzyme is activated in vitro by the p42 and p44 isoforms of MAPK, p42/p44MAPK [69]; addition of lipopolysaccharide does not significantly affect the phosphorylation of Dp38 in the LPS-responsive l(2)mbn cell line [28]; when expressed in KB cells, SAPK4 is activated in response to cellular stresses and pro-inflammatory cytokines [23]; activated by a group of extracellular stimuli including cytokines and environmental stresses [22]; p38b is activated by proinflammatory cytokines and environmental stress [90]; activation mechanism, phosphorylation/ activation of ERK1 and ERK2 by the MAPK kinase-1 [9]; activation of the Ca2+ -dependent signaling and expression of interleukin-8 in 1HAEo cells by EGTA at 1 mM and NiCl2 at 5-500 nM [118]; autoregulation by a pseudosubstrate mechanism, overview [5]; ERK phosphorylation activates the enzyme activity, stimulation by 7TMD receptors, e.g. the serotonin 5-HT2c receptor [119]; interaction motifs, i.e. docking sites or recognition sequences, of substrates are crucial for MAPK activity, i.e. motif LeuXaa-Leu preceded by 3-5 basic residues, overview [117]; phosphorylation activates the enzyme [8]; phosphorylation at Thr183 and Tyr185 activates the enzyme [6]; the enzyme is activated by mitogens, activation is induced by epidermal growth factor tyrosine protein kinase and nucelar growth factor tyrosine protein kinase [4]; AP1 and NF-kB recruit p38 MAPK to activate TBP [141]; ERK2 is activated by phosphorylation [125]; inhibition of the phosphatidylserine-receptor activates ERK and TGF-b production in vivo [126]; MAPKs are activated by phosphorxylation through MEK/MAPK kinases [144]; MAPKs are upregulated by upstream kinases such as BRAF and KRAS [128]; mechanism of p38 MAP kinase activation in vivo, coordinated and selective actions of protein kinases MKK3, MKK4, and MKK6 in response to cytokines and exposure to environmental stress are part of the regulation, overview [136]; oxidative stress activates the MAPKs, dexamethasone inhibits this activation [130]; p38 expression and activity in signaling in erythroid cells is independent of erythropoietin [149]; p38 is activated by phosphorylation through kinase Src, EC 2.7.10.2, mechanical pressure on the cell induces p38a and b isozyme phosphorylation, which is suppressed by PKC isozymes,

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EC 2.7.11.13 [124]; p38 MAPK is activated by phosphorylation [145]; p38 MAPk is activated through phosphorylation by MKK3, a MAPK kinase EC 2.7.11.25 [146]; p38 MAPK needs to be activated by phosphorylation [142]; pheromones can influence the phosphorylation of MAPKs, the scaffolding proteins Ste mediate MAPK function in signaling by recruitment of the kinases to reaction sites, e.g. the plasma membrane, or by concentrating and maybe also by orientating relevant reaction components, e.g. Ste5, overview [122]; phosphorylation activates ERK [137]; some heavy metals induce MAPK pathways in the plant [148]; tert-butyl hydroperoxide, causing oxidative stress incells, induces activation of ERK and p38 MAP kinase by increased phosphorylation, MAPKs are activated in response to intracellular reactive species, MAPK signaling cascade activation mechanism, overview [135]; the factors Sprouty1 and Sprouty2 are involved in ERK regulation, mechanism, phosphorylation activates ERK [137]; the recombinant detagged enzyme is activated by specific phosphorylation at Thr180 and Tyr182 through recombinant GST-tagged MKK6 mutant S207E/T211E [121,134]) [4, 5, 6, 8, 9, 20, 22, 23, 28, 64, 69, 90, 117, 118, 119, 121, 122, 124, 125, 126, 128, 130, 134, 135, 136, 137, 141, 142, 144, 145, 146, 148, 149] Metals, ions Cd2+ ( can partially substitue Mg2+ [9]; causes delayed but strong activation of SIMK, MMK2, MMK3, and SAMK, activation profiles, overview [148]) [9, 148] Co2+ ( can partially substitue Mg2+ [9]) [9] Cu2+ ( strongly activates the MAPK signaling pathways of SIMK, MMK2, MMK3, and SAMK, mediated by the MAPKK SIMKK, activation profiles, overview [148]) [148] Fe2+ ( activates MMK2, slight induction of SIMK [148]) [148] Mg2+ ( supports reaction with myelin basic protein [96]; as MgATP2- [121]; dependent on, Mg2+ is the physiologic metal ion, other divalent cations are able to support nucleotide binding, but only Mn2+ , Co2+, and Cd2+ can substitute Mg2+ in supporting the catalytic activity [9]; optimal at 10 mM [134]) [4, 5, 6, 7, 8, 9, 96, 118, 120, 121, 123, 125, 127, 132, 134, 138, 139, 146, 147, 149, 150] Mn2+ ( supports phosphorylation of myelin basic protein more strongly than Mg2+ [96]; can partially substitue Mg2+ [9]) [9, 96] Pb2+ ( slight induction of SIMK [148]) [148] Additional information ( SIMK activity is not or poorly influenced by Al3+ , Zn2+ , or Co2+ [148]) [148] Turnover number (min–1) 0.98 (protein ATF2, pH 7.6, 27 C, purified, recombinant detagged, activated p38 MAPKa [121]) [121]

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Specific activity (U/mg) Additional information ( large scale activity assay with recombinant enzyme in a protein chip consisting of a microwell array with protein covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker, overview [120]) [120] Km-Value (mM) 0.0019 (protein ATF2, pH 7.6, 27 C, purified, recombinant detagged, activated p38 MAPKa [121]) [121] 0.048 (ATP, pH 7.0, 30 C, mutant G110D of p38 isozyme a [147]) [147] 0.085 (ATP, pH 7.0, 30 C, mutant G110A of p38 isozyme a [147]) [147] 0.096 (ATP, pH 7.0, 30 C, wild-type p38 isozyme a [147]) [147] Additional information ( p38a: kinetic mechanism, reaction kinetics can be influenced by the sort of substrate [9]; signaling kinetics, overview [122]; steady-state kinetics, kinetic mechanism for p38 MAP kinase a kinase and ATPase activities, overview [134]) [9, 122, 123, 134] Ki-Value (mM) 0.000021 (SB203580, ATPase reaction versus ATP, pH 7.6, 27 C, recombinant p38 MAPK [134]) [134] 0.187 (AMP-PCP, kinase reaction, pH 7.6, 27 C, recombinant p38 MAPK [134]) [134] 0.242 (AMP-PCP, ATPase reaction versus ATP, pH 7.6, 27 C, recombinant p38 MAPK [134]) [134] 2 (ADP, above, pH 7.6, 27 C, recombinant p38 MAPK [134]) [134] Additional information ( inhibition kinetics [150]; Ki values of the pseudosubstrates in nano- to micromolar range [7]) [7, 150] pH-Optimum 7 ( assay at [147]) [147] 7-7.3 ( assay at [123]) [123] 7.2 ( assay at [127,138,146]) [127, 138, 146] 7.4 ( assay at [125,150]) [125, 150] 7.5 ( assay at [116,142]) [116, 142] 7.6 ( assay at [121,134]) [121, 134] Temperature optimum ( C) 21 ( assay at room temperature [116]) [116] 22 ( assay at room temperature [149]) [149] 25 ( assay at [150]) [150] 27 ( assay at [121,134]) [121, 134] 30 ( assay at [123,125,127,138,146,147]) [123, 125, 127, 138, 146, 147] 37 ( assay at [142]) [142]

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4 Enzyme Structure Subunits ? ( x * 45000 [47]; x * 43000, SDSPAGE [3]; x * 41194, calculation from nucleotide sequence [80]; x * 44000 [83]; x * 44400 [98]; x * 100000, about, recombinant ERK3, SDS-PAGE [143]; x * 43472-43556, unphosphorylated to trifold phosphorylated p38 MAPKa, mass spectrometry [121]; x * 44000, ERK1, SDS-PAGE, x * 42000, ERK2, SDS-PAGE [135]; x * 44000, MAPKS MMK2, MMK3, and SAMK, SDS-PAGE, x * 46000, SIMK, SDS-PAGE [148]; x * 64000, recombinant p38a MAP kinase, SDS-PAGE [150]) [3, 47, 80, 83, 98, 121, 135, 143, 148, 150] Additional information ( the enzyme has an open, active conformation and a closed, inactive conformation [6]; transcription factor protein domains consisting of the LXL motif, the FXFP motif, the LXLXXXF motif, or the ETS motif, are involved in stable interaction of MAPKs with transcription complexes [141]) [6, 141] Posttranslational modification phosphoprotein ( activation by phosphorylation [4]; DJNK is phosphorylated and activated by the Drosophila MAP kinase kinase HEP [76]; kinase p38 is tyrosine phosphorylated in response to LPS [68]; the two phosphorylation sites found in the loop between subdomain VII and VIII [98]; phosphorylated on tyrosine in vivo [60]; tyrosine phosphorylated during oocyte maturation [41]; contains the TGY dual phosphorylation site [22]; enzyme is regulated by Tyr phosphorylation [51]; enzyme contains a TGY dual phosphorylation site, which is required for its kinase activity [90]; enzyme is activated by dual phosphorylation [48]; activity requires phosphorylation of both Tyr and Thr residues, the two phosphorylation sites are separated by only a single residue [50]; dual phosphorylation site [87]; the enzyme is Tyr phosphorylated and activated in response to osmotic and heat stress. Spk1 is required for sexual differentiation and sporulation [112]; rapidly Tyr186-phosphorylated in response to osmotic stress, heat shock, serum starvation, and H2 O2 [28]; enzyme is activated through phosphorylation of Tyr and Thr residues [71]; autophosphorylation near the pseudosubstrate site [7]; ERKs are phosphorylated, involving protein kinase C and phospholipase D, in signaling pathways by kinases, which are stimulated by the serotonin 5-HT2c receptor, ERK phosphorylation activates its enzyme activity, overview [119]; Hog1 performs autophosporylation, while Fus3 does not [120]; phosphorylation at Thr183 and Tyr185 for activation [6]; regulation by phosphorylation of the activation loop, increases substrate and ATP binding as well as the phosphotransfer rate, phosphorylation/activation of ERK1 and ERK2 by the MAPK kinase-1 [9]; the enzyme is regulated by reversible phosphorylation of the activation loop, phosphorylation enhances the substrate binding of ERK2 by 2fold

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[8]; the mitogen-activated protein kinases are regulated by reversible phosphorylation [118]; ERK1 and ERK2 are activated by phosphorylation at Thr and Tyr residues, p38 MAPK is activated by phosphorylation at Thr180 and Tyr182 [135]; ERK2 is activated by phosphorylation [125,138]; JNK3 is activated by phosphorylation [138]; MAPKs are activated by phosphorylation through MAPK kinases, e.g. SIMKK mediates activation of SIMK and SAMK, not of MMK2 and MMK3, by Cu2+ , not by Cd2+ , no activation of MAPKs SIMK, SAMK, MMK2 and MMK3 by MAPKKs MEK1 and PRKK [148]; MAPKs are phosphorylated by their activating MAPK kinases, EC 2.7.11.25 [143]; MAPKs are specifically activated by phosphorylation through specific MAPK kinases, EC 2.7.11.25, Fus3 is phosphorylated at 2 sites and activated by scaffolding protein Ste11, pheromones can influence the phosphorylation of MAPKs [122]; native and recombinant p38 MAPKa is activated by phosphorylation at Thr180 and Tyr182 through recombinant GST-tagged MKK6b mutant S207E/T211E, for activation and specific dual phosphorylation of the recombinant enzyme [134]; p38 isozymes are activated by phosphorylation through MAPK kinases MKK3, MKK6, and MAPKAP-2, EC 2.7.11.25, except for isozyme b which is not activated by MKK3 [149]; p38 MAPK is activated by phosphorylation [145]; p38 MAPK is activated through phosphorylation by MKK3, a MAPK kinase EC 2.7.11.25 [146]; p38 MAPK needs to be activated by phosphorylation [142]; p38 MAPKa is activated by phosphorylation at Thr180 and Tyr182 through recombinant GST-tagged MKK6 mutant S207E/T211E, for activation and specific dual phosphorylation of the recombinant enzyme, the His-tag needs to be removed by thrombin, because it can cause unspecific phosphorylation at other sites [121]; p38a is activated by phosphorylation at Thr180/Tyr182 by kinase Src, EC 2.7.10.2, mechanical pressure on the cell induces p38 phosphorylation, which is suppressed by PKC isozymes, EC 2.7.11.13 [124]; p38a MAP kinase is phosphorylated by the MAPKK MKK6, EC 2.7.11.25, at Thr180 and Tyr182, phosphorylation activates p38a MAPK [150]; phosphorylation activates ERK [137]; the MAPK is phosphorylated and activated in the MAPK signaling cascade by 2 mechanisms: 1. by MEKs, EC 2.7.11.25, docking at the ED domain or the CD domain of MAPKs, or 2. by MKK7, MLK, JNK or MKP-7 docking at the scaffolding protein JIP in the JNK signaling pathway [137]; the MAPKs are activated by phosphorylation through MAPK kinases, overview [144]; the MAPKs are phosphorylated and activated by MAPKKs, EC 2.7.11.25, e.g. MKKs or MEKs, overview [141]; the MAPKs are phosphorylated and activated by MAPKKs, EC 2.7.11.25, e.g. Ste7p, Pbs2p, or MKK1/2p, overview [141]) [4, 6, 7, 8, 9, 22, 28, 41, 43, 48, 50, 51, 60, 68, 71, 76, 87, 90, 94, 98, 112, 118, 119, 120, 121, 122, 124, 125, 134, 135, 137, 138, 141, 142, 143, 144, 145, 146, 148, 149, 150]

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5 Isolation/Preparation/Mutation/Application Source/tissue 1HAEo cell ( SV40 immortalized airway epithelial cell [118]) [118] 293 cell [139] BHK-21 cell [139] C2C12 cell [125] CCRF-CEM cell ( cell line of a human with lymphoblastic leukemia [146]) [146] HaCaT cell ( spontaneously immortalized keratinocyte cell line [124]) [124] MCF-10A cell [139] MCF-7 cell [139] MSTO-211H cell ( mesothelioma cell line [139]) [139] T-lymphocyte [44] adrenal gland ( highly expressed in [20]) [20] brain [24, 102, 119, 138, 142] breast [139] breast cancer cell [139] bronchus ( primary epithelial cells [130]) [130] cardiac myocyte [145] cell culture ( hepatoma cell line [43]; inflammatory cell lineages [19]; insulin-treated rat 1 HIRc B cells [3]; neoplasmic l(2)mbn cell line [28]; expressed at low levels in G1 phase but at higher levels in S and G2 phases of the cell cycle [95]) [3, 19, 28, 43, 95, 102, 118] chondrocyte [140] embryo ( p38-d is expressed predominantly in the developing gut and the septum transversum in the mouse embryo at 9.5 days, its expression begins to be expanded to many specific tissues in the 12.5-day embryo. At 15.5 days, p38-d is expressed virtually in most developing epithelia in embryos [17]; ventricular cells [145]) [17, 131, 140, 145] embryonic kidney cell line [139] endothelial cell [17, 130] endothelium ( prostate endothelial cells [135]) [135] epithelial cell ( primary [130]) [124, 130] erythroid cell ( p38 isozymes a-d expression patterns during erythroid differentiation of primary erythroid progenitors, isozymes a and g are expressed in early hematopoietic progenitors as well as in late differentiating erythroblasts, isozyme d is only expressed and active during the terminal phase of erythroid differentiation, while isozyme b is minimally expresses in early CD34+ hematopoietic progenitors [149]) [149] fibroblast [136] gut epithelium [17] heart [35, 70, 87, 89, 144] hematopoietic stem cell [14]

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hepatoma cell [43] hippocampus [72, 138] hypha [133] keratinocyte [124] kidney [17, 87, 139] lymphoid cell [146] macrophage ( p38 MAPK [141]) [19, 126, 141] mesothelioma cell [139] monocyte ( low activity [19]) [19] mycelium [129, 133] myoblast [125] myocardium ( the MAPK family enzymes have regulatory function in the myocardium [144]) [144] neocortex [72] nervous system [72] neuron ( post-mitotic [102]) [72, 102, 131] neutrophil [127] oocyte [40, 41, 42] ovarian serous carcinoma cell ( 207 different sources, MAPK expression and immunohistochemical analysis, mutational analysis of up-regulating kinases BRAF and KRAS [128]) [128] ovary [24, 98] pancreas [21] placenta [87] prostate gland [135] root [95, 148] salivary gland ( highly expressed in [20]) [20] seedling [148] skeletal muscle [89, 92] small intestine [21] stem [95] sternum ( embryonic [140]) [140] testis [17, 21] vascular endothelial cell ( of airway and alveolar endothelium [130]) [130] whole plant ( flowering [83]) [83] Additional information ( no activity in liver [87]; significantly present in all organs except seeds [93]; PMEK1 is expressed in vegetative organs and preferentially accumulated in female reproductive organs [98]) [87, 93, 98] Localization Golgi apparatus ( ERK colocalizes with MEK and Sef [137]; ERK3 is targeted to the Golgi or endoplasmic reticulum as an intermediate compartment during translocation from cytoplasm to nucleus, ERK3 possesses a C-terminally targeting motif for the Golgi apparatus [143]) [137, 143]

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cytoplasm ( cytoplasmic MAPKs, e.g. ERK3, translocate to the nucleus subsequent to their phosphorylation by their activating MAPK kinases, EC 2.7.11.25 [143]; ERK localization is controlled by the cytoplasmic ERK anchoring proteins that have a nuclear export signal, ERK forms complexes with MEK, EC 2.7.11.25, in the cytoplasm, in response to activation ERK dissociates from MEK and is translocated to the nucleus [137]) [127, 137, 143] cytosol ( p38 MAPK [145]) [117, 145] extracellular [44, 60] mitochondrion ( p38 MAPK [145]) [145] nuclear matrix [139] nucleus ( ERK1, ERK2 [4]; cytoplasmic MAPKs, e.g. ERK3, translocate to the nucleus subsequent to their phosphorylation by their activating MAPK kinases, EC 2.7.11.25 [143]; ERK localization is controlled by the cytoplasmic ERK anchoring proteins that have a nuclear export signal, ERK forms complexes with MEK, EC 2.7.11.25, in the cytoplasm, in response to activation ERK dissociates from MEK and is translocated to the nucleus, mechanism [137]) [4, 117, 137, 139, 141, 143] protoplast [148] synaptosome ( from midbrain [142]) [142] Additional information ( CAD occurs in the cytoplasm and the nucleus, but is phosphorylated only in the nucleus, CAD translocation is induced by EGF stimulation [139]; multifunctional protein CAD occurs in the cytoplasm and the nucleus, but is phosphorylated only in the nucleus, CAD translocation is induced by EGF stimulation [139]; subcellular localization of wild-type and mutant enzymes, overview, ERK3 translocates from cytoplasm to the nucleus in a temporally regulated exit from a membraneous organelle, nuclear translocation is cell cycle-dependent, mechanism [143]) [139, 143] Purification (recombinant GST-tagged p38 isozyme a from Escherichia coli strain BL21(DE3) by two steps of ion exchange chromatography to homogeneity, the recombinant enzyme is detagged) [134] (recombinant His-tagged p38a MAP kinase from Escherichia coli strain BL21(DE3) by nickel chelate affinity chromatohgraphy, dialysis, and ion exchange chromatography to homogeneity, the His-tag is cleaved off by thrombin) [150] (recombinant His-tagged p38 isozyme a from Escherichia coli strain BL21(DE3) by nickel affinity and ion exchange chromatography to over 98% purity, removal of the His-tag by thrombin is required for propper enzyme purification and activation) [121] (purification of synaptosomes) [142] [3, 35]

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Crystallization (bilobal structure analysis) [5] (ERK2, X-ray diffraction structure analysis) [9] (purified p38 isozyme a bound to several inhibitors pyridinyl imidazoletype inhibitors, X-ray diffraction structure determination and analysis at 2.12.5 A resolution) [147] (purified recombinant p38a MAP kinase free or in complex with inhibitor SB203580, sitting or hanging drop vapour diffusion method at 16-20 C, 16 mg/ml protein in 25 mM Tris-HCl, pH 7.5, 100 mM NaCl, 10 mM MgCl2 , 10 mM DTT, and 5% glycerol is mixed with reservoir solution containing 10-20% PEG 4000, 18% ethylene glycol, 0.1 M cacodylic acid, pH 6.0, at a volume ratio of 3:2, X-ray diffraction structure determination and analysis at 1.9-2.7 A resolution) [150] (crystal structure of p38a, show docking grooves for binding of substrate D-domains, i.e. of MEF2A, and of activating kinases, e.g. of MKK3b, Ile116 and Gln120 play important roles) [117] Cloning (expression of GST-tagged p38 isozyme a in Escherichia coli strain BL21(DE3)) [134] (expression of His-tagged wild-type and mutant p38 isozyme a) [147] (p38a MAP kinase expression in Escherichia coli strain BL21(DE3) as His-tagged protein with a thrombin cleavage site) [150] (expression of ERK in CHO cells, co-expression of serotonin 5-HT2c receptor leads to increased ERK phosphorylation) [119] (expression of His-tagged p38 isozyme a in Escherichia coli strain BL21(DE3)) [121] (expression of GFP-tagged wild-type and mutant ERK3 in human Hela and T98G cells, and in rat 2 cells, fluorescent immunoaffinity subcellular localization study) [143] (expression of p38 MAPK in HEK293 cells) [142] (phylogenetic tree of kinases derived from the kinase core sequence, overview, overexpression as GST-fusion protein under control of the galactose-inducible GAL1 promotor in Escherichia coli, determination of 5’-end sequences) [120] (gene mpk4, gene expression profiling, overexpression of mpk4 leads to increased expression of the genes PR1 and PR2, encoding plant defense proteins, and of the ICS1 gene, encoding a salicylic acid biosynthetic enzyme) [132] (expression of wild-type MAP kinase and mutants in embryos by microinjection) [131] [20, 21, 22, 23] [28] (expressed in COS7 cells) [35] [40, 42] (expressed in Escherichia coli as a glutathione S-transferase fusion protein) [43]

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(isolation of cDNA) [44] [52] [52] (characterization of cDNA) [44] (heterogeneous expression in different tissues) [45] (heterogeneous expression in different tissues) [45] [57] [60] [65] [68] [77] [79] (expression in Escherichia coli) [80] [81] (overexpressed in Escherichia coli) [83] [21, 89] [91, 92] (expression in Escherichia coli) [93] (expression in Escherichia coli) [93] [94] [94] [94] [94] [94] [97] (expression in Escherichia coli as a fusion protein with glutathione-Stransferase) [96] (expression in Escherichia coli as a fusion protein with glutathione-Stransferase) [96] (expression in Escherichia coli as a fusion protein with glutathione-Stransferase) [96] [99] [102] (expression in COS-7 cells) [100] (isolation of cDNA) [24] [109] (expression in COS-7 cells) [100] [110] (gene gpmk1) [129] (gene tmkA, cDNA library construction, DNA and amino acid sequence determination and analysis, subcloning and expression in Escherichia coli strain XL-1 Blue, expression in protoplasts by particle bombardement) [133] Engineering D546V ( site-directed mutagenesis, the mutant enzyme is exclusively localized in the nucleus and especially in the Golgi apparatus, not in the cytoplasm, in contrast to the wild-type enzyme [143]) [143]

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G110A ( site-directed mutagenesis of isozyme a, the mutant shows a slightly decreased Km value for ATP, but unaltered activity compared to the wild-type enzyme, decreased sensitivity for inhibitors compared to the wildtype enzyme [147]) [147] G110D ( site-directed mutagenesis of isozyme a, the mutant shows a decreased Km value for ATP, but unaltered activity compared to the wild-type enzyme, decreased sensitivity for inhibitors compared to the wild-type enzyme [147]) [147] K717S ( site-directed mutagenesis, the mutant enzyme is exclusively localized in the nucleus and Golgi apparatus, not in the cytoplasm, in contrast to the wild-type enzyme [143]) [143] Additional information ( Tyr-215 mutant shows no autophosphorylation and no phosphorylation of myelin basic protein [83]; Construction of several truncation mutants [143]; effects of overexpression of substrate Smad1 mutant S187A/S195A/S205A/S213A compared to overexpression of Smad1 wild-type, ventralizing of embryos, overview [131]; enzyme-deficient mutant mice show defects in growth arrest and increased tumorigenesis [136]; Gpmk1 MAP kinase disruption mutants of Fusarium graminearum are fully viable in vitro but are unable to infect wheat due to lack of secreted lipolytic enzymes, amylolytic and pectinolytic enzymes are not affected by gpmk1 gene disruption, apathogenic phenotype [129]; isolation of several MTK loss-of-function mutants of TmkA, effects of wild-type and mutant enzymes on host growth, morphology, and conidiation, overview [133]; overexpression of MPK4 substrate MSK1 in wild-type plants leads to activated salicylic-dependent resistance, but does not interfere with induction of a defense gene by jasmonate [132]) [83, 129, 131, 132, 133, 136, 143] Application analysis ( development of a protein chip consisting of a silicone elastomer microwell array with recombinant enzyme covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker for large scale activity assay, overview [120]) [120] drug development ( MAPKs are targets for drug development [144]) [144] medicine ( MAPKs are a molecular targets for pharmacological treatment of inflammatory lung diseases [130]; MAPKs are therapeutic targets in cardiac pathology [144]) [130, 144] pharmacology ( MAPKs are targets for inhibitors and pharmacological drug development [144]) [144]

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[148] Jonak, C.; Nakagami, H.; Hirt, H.: Heavy metal stress. Activation of distinct mitogen-activated protein kinase pathways by copper and cadmium. Plant Physiol., 136, 3276-3283 (2004) [149] Uddin, S.; Ah-Kang, J.; Ulaszek, J.; Mahmud, D.; Wickrema, A.: Differentiation stage-specific activation of p38 mitogen-activated protein kinase isoforms in primary human erythroid cells. Proc. Natl. Acad. Sci. USA, 101, 147-152 (2004) [150] Bukhtiyarova, M.; Northrop, K.; Chai, X.; Casper, D.; Karpusas, M.; Springman, E.: Improved expression, purification, and crystallization of p38a MAP kinase. Protein Expr. Purif., 37, 154-161 (2004)

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1 Nomenclature EC number 2.7.11.25 Systematic name ATP:protein phosphotransferase (MAPKKKK-activated) Recommended name mitogen-activated protein kinase kinase kinase Synonyms (JNK)/stress-activated protein kinase-associated protein 1 [3] ASK1 [23, 25, 30, 43] B-Raf [33, 44] B-Raf kinase [33] C-Raf [44] COT [20, 22] COT30-397 [20] COT30-467 [20] DLK [38] dual leucine zipper bearing kinase HsNIK JSAP1 [3] Jun N-terminal kinase kinase kinase [26] Jun N-terminal protein kinase [3] leucine-zipper protein kinase M3Ka [24] MAP kinase kinase kinase [24, 43, 44] MAP kinase kinase kinase 1 [19] MAP kinase kinase kinase 3 [22] MAP kinase kinase kinase SSK2 [12] MAP kinase kinase kinase mkh1 [2, 17] MAP kinase kinase kinase win1 [2, 9] MAP kinase kinase kinase wis4 [2, 6, 7, 8] MAP3K [20, 22, 29, 37] MAP3Ka [28] MAPK kinase kinase [20, 31] MAPK-upstream kinase MAPK/ERK kinase kinase 1 [23] MAPKK kinase [45]

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MAPKKK [1, 22, 24, 25, 26, 27, 30, 31, 35, 42, 43, 44, 45] MAPKKK6 [10] MAPKKKa [28] MEK kinase 1 [41] MEKK1 [19, 21, 23, 27, 32, 34, 35, 41, 43] MEKK2 [21, 27, 29, 37, 39, 43] MEKK3 [21, 22, 29, 36, 37, 39, 40, 43] MEKK4 [21, 22, 43] MLK [43] MLK-like mitogen-activated protein triple kinase [31] MLK2 [26] MLTKa [31] MTK1 [43] MUK Mek kinase [18] Mkh1 [17] Mos [43, 44] NF-kb-inducing kinase NSY-1 [25] OMTK1 [35] Raf [43] serine/threonine protein kinase NIK Ste11 [42] TAK1 [22, 43] TAO [43] TAO2-1 [37] YODA [45] ZPK apoptosis signal-regulated kinase 1 [23] apoptosis signal-regulating kinase 1 [25] c-mos cancer osaka thyroid [20] dual leucine zipper-bearing kinase [38] extracellular signal-regulated kinase kinase kinase-1 [19] mitogen-activated protein kinase kinase kinase 1 [3, 16] mitogen-activated protein kinase kinase kinase 4 [4, 5] mitogen-activated protein kinase kinase kinase 6 [10] mitogen-activated protein kinase kinase kinase-1 [19] mitogen-activated protein kinase/extracellular-regulated kinase kinase kinase-3 [36] mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase kinase 1 [23] oxidative stress-activated MAP triple-kinase 1 [35] protein kinase byr2 [2, 14, 15] putative mitogen-activated protein kinase 1 [35] serine/threonine-protein kinase STE11 [11, 13]

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Additional information ( MAPKKKa belongs to the A2 subgroup of the MEKK enzyme family [28]; MEKK2 and MEKK3 belong to the MEKK/Ste11 subfamily of the MAP3K family of enzymes [29]; the enzyme belongs to the MEK family [30]; the enzyme belongs to the MLK family of mitogen activated protein kinase kinase kinases [26]) [26, 28, 29, 30] CAS registry number 146702-84-3

2 Source Organism eukaryota (no sequence specified) [1] Mus musculus (no sequence specified) [21, 25, 27, 29, 32, 34, 39, 41] Homo sapiens (no sequence specified) [19, 20, 25, 31, 33, 36, 37, 38, 40, 41, 43] Rattus norvegicus (no sequence specified) [23] Saccharomyces cerevisiae (no sequence specified) [18,42] Arabidopsis thaliana (no sequence specified) [45] Xenopus laevis (no sequence specified) [26,44] Caenorhabditis elegans (no sequence specified) [25] Podospora anserina (no sequence specified) [30] Mus musculus (UNIPROT accession number: O08648) [4, 5] Schizosaccharomyces pombe (UNIPROT accession number: O14299) [2, 6, 7, 8] Schizosaccharomyces pombe (UNIPROT accession number: O74304) [2, 9] Homo sapiens (UNIPROT accession number: O95382) [10] Saccharomyces cerevisiae (UNIPROT accession number: P23561) [11, 13] Schizosaccharomyces pombe (UNIPROT accession number: P28829) [2, 14, 15] Mus musculus (UNIPROT accession number: P53349) [3, 16] Saccharomyces cerevisiae (UNIPROT accession number: P53599) [12] Schizosaccharomyces pombe (UNIPROT accession number: Q10407) [2, 17] Lotus japonicus (UNIPROT accession number: Q75PK5) [24] Nicotiana benthamiana (UNIPROT accession number: Q6RFY4) [28] Lycopersicon esculentum (UNIPROT accession number: Q6RFY3) [28] Medicago sativa (UNIPROT accession number: Q7XTK4) [35] Homo sapiens (UNIPROT accession number: Q6VABC) [22]

3 Reaction and Specificity Catalyzed reaction ATP + a protein = ADP + a phosphoprotein ( Lys391 is the catalytic residue [40]; mechanism of ASK1 [25]; molecular mechanism of MEKK2 and MEKK3 [29]; structure-function relationship of MAPKKKs

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and MAPKKs, K1371 is the catalytic residue of MTK1, MTK1, TAK1, and MEKK1 also possess lysine as catalytic residues [43]) Natural substrates and products S ATP + ERK ( i.e. extracellular signal-regulated kinase [19]; PI3K/PKC/Raf-1-independent activation of the MEK/ERK signaling pathway [41]) (Reversibility: ?) [19, 41] P ADP + phosphorylated ERK S ATP + ERK5 ( substrate of MEKK2 and MEKK3, activation of the ERK-dependent signaling pathway [37]) (Reversibility: ?) [37] P ADP + phosphorylated ERK5 S ATP + JNK ( i.e. Jun amino terminal kinase [19]) (Reversibility: ?) [19] P ADP + phosphorylated JNK S ATP + MAPKK ( MAPKK activation [1]) (Reversibility: ?) [1] P ADP + phosphorylated MAPKK S ATP + MEK ( PI3K/PKC/Raf-1-independent activation of the MEK/ERK signaling pathway [41]) (Reversibility: ?) [20, 41] P ADP + phosphorylated MEK S ATP + MEK1 ( activation by MEKK3 of MAPK signaling pathways [22]; MEK1 activates the ERK2 signaling pathway [27]; Ras-induced activation of the MAPK signaling cascade [44]) (Reversibility: ?) [22, 27, 44] P ADP + phosphorylated MEK1 S ATP + MEK2 ( activation by MEKK3 of MAPK signaling pathways [22]) (Reversibility: ?) [22] P ADP + phosphorylated MEK2 S ATP + MEK5 ( activated MEK5 activates ERK5 [21]) (Reversibility: ?) [21] P ADP + phosphorylated MEK5 S ATP + MKK ( induction of the JNK pathway activation [39]) (Reversibility: ?) [39] P ADP + phosphorylated MKK S ATP + MKK1 ( MKK1 activates the ERK2 signaling pathway [32]) (Reversibility: ?) [32] P ADP + phosphorylated MKK1 S ATP + MKK3 ( a MAPKK, OMTK1 channels oxidative stress signaling through direct interaction with MAPK MMK3 increasing the cell death rate, OMTK1 and MMK3 form a complex in vivo [35]; activation of the p38 MAP kinase signaling pathway [31]; activation of the p38 MAP kinase signaling pathway leading to apoptosis [25]) (Reversibility: ?) [25, 31, 35] P ADP + phosphorylated MKK3 S ATP + MKK4 ( a MAPKK [21]; activation of the Jun Nterminal kinase, JNK, pathway leading to apoptosis [25]; MKK4 activates the JNK signaling pathway [27,32,34]) (Reversibility: ?) [21, 25, 27, 32, 34]

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P ADP + phosphorylated MKK4 S ATP + MKK6 ( activation by MEKK3 of MAPK signaling pathways [22]; activation of the p38 MAP kinase signaling pathway [31]; activation of the p38 MAP kinase signaling pathway leading to apoptosis [25]; substrate of stress-activated MAPKKKs ASK1 and MTK1 [43]) (Reversibility: ?) [22, 25, 31, 40, 43] P ADP + phosphorylated MKK6 S ATP + MKK7 ( activation by MEKK3 of MAPK signaling pathways [22]; activation of the Jun N-terminal kinase, JNK, signaling pathway leading to apoptosis [25]) (Reversibility: ?) [22, 25] P ADP + phosphorylated MKK7 S ATP + a protein (Reversibility: ?) [1, 18] P ADP + a phosphoprotein S ATP + p42 MAPK ( Ras-induced activation of the MAPK signaling cascade [44]) (Reversibility: ?) [44] P ADP + phosphorylated p42 MAPK S ATP + protein ( required for activation of the MAPK homologue Spc1, and integrity of the Wis1-Spc1 pathway is required for survival in extreme conditions of heat, osmolarity, oxidation or limited nutrition. Phosphorylates Wis1 in vitro and activates it in vivo [6]; capable of partial suppression of the ras1 mutant phenotype [15]; selectively regulates the c-Jun amino terminal kinase pathway [4]; enzyme is involved in the response of haploid yeast cells to peptide mating pheromones [11]; phosphorylates and activates Wis1 MAP kinase kinase in response to high osmolarity [9]; ste8 gene product functions in the signal transduction pathway [14]; the enzyme is required for cell-type-specific transcription and signal transduction [13]; Mkh1 regulates cell morphology, cell wall integrity, salt resistance, cell cycle reentry from stationary-phase arrest, and filamentous growth in response to stress [17]; JSAP1 functions as a scaffold protein in the JNK3 cascade [3]) (Reversibility: ?) [3, 4, 6, 9, 11, 13, 14, 15, 17] P ADP + phosphoprotein S Additional information ( enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regulation mechanism, overview [1]; activation mechanism of ASK1, overview, ASK1 is involved in oxidative stress-induced cell death and adaptation processes to various stresses, the enzyme is required for induction of apoptosis by e.g. Fas or TNF-a, or by the endoplasmic reticulum, mechanism [25]; activation mechanism of ASK1, overview, ASK1 is involved in oxidative stress-induced cell death and adaptation processes to various stresses, the enzyme is required for induction of apoptosis by e.g. Fas or TNF-a, or by the endoplasmic reticulum, mechanism, ASK1 plays an important role in neuropathological alterations in polyQ diseases [25]; alterations of the intracellular milieu induced by methylglyoxal through a MEKK1-mediated and PI3K/PKC/Raf-1-independent pathway results in the modification of cell response to IGF-I for

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Mitogen-activated protein kinase kinase kinase

the cyclin-dependent kinase inibitor p21Waf1/Cip1-mediated growth arrest [41]; alterations of the intracellular milieu induced by methylglyoxal through a MEKK1-mediated and PI3K/PKC/Raf-1-independent pathway results in the modification of cell response to IGF-I for the cyclin-dependent kinase inibitor p21_Waf1/Cip1-mediated growth arrest, which may be one of the crucial mechanisms for methylglyoxal to promote the development of chronic clinical complications in diabetes in humans [41]; B-Raf and C-Raf, but not Mos, are required for Ras-induced MEK1 and p42 MAPK activation [44]; COT is a proto-oncogene, the enzyme is essential for the lipopolysaccharide activation of the ERK MAPK cascade in macrophages [20]; Cot plays an important role in inflammation and oncogenesis, MEKK3 mediates the activation of JNK and ERK in the MAP kinase pathway and of the NF-kB pathway and mediates the interleukin-8 production, MEKK3 and Cot are negatively regulated by hKSR-2 [22]; DLK acts as a key regulator of keratinocyte terminal differentiation, and is involved in activation of the JNK signaling pathway, DLK activity is required for transglutaminase activation and induction of keratinocyte cornification [38]; MAPKKKa is responsible for hypersensitive response and resistance to pathogen infection, the enzyme also regulates cell death in susceptible leaves after infection, overview [28]; MAPKKKa is responsible for hypersensitive response and resistance to Pseudomonas syringae infection, the enzyme also regulates cell death in susceptible, infected leaves, identification of MAPKKKa-induced signal cascades, regulation, overview [28]; MEKK1 and ASK1 might play opposing roles in oxidative stress-induced activation of apoptosis [23]; MEKK2 and MEKK3 are involved in activation of signal transduction pathways via toll-like receptor TLR, mitogen-activated protein kinases MAPK, and NF-kB, overview [29]; MEKK2 induces the JNK signaling pathway, overview [21]; MEKK3 is involved in activation of MAPKs e.g. p38 and JNK [40]; MEKK3 is involved in activation of NF-kB and increased expression of cell survival factors which confers resistance to apoptosis [36]; MLK2 plays a tissue specific role and is required for cement gland development and nephritic tubule formation, MLK2 mediates the response of Jun N-terminal kinase JNK, i.e. stress-activated protein kinase 1 SAPK1, to UV irradiation [26]; MLTKa activates the p38g MAPK-dependent signaling pathway, which is regulated by the serine/threonine kinase PKNa [31]; NSY-1 functions in the control of asymmetric expression of odor receptor gene str-2, odor discrimination, and odor chemotaxis, thus possibly in functional differentiation of the nervous system, the enzyme functions downstream of UNC-43 CaMKII [25]; regulation, overview, Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein1- and nuclear factor-kB-mediated gene expression in airway epithelial cells, the enzyme is involved in activation of the signaling cascades via activator protein AP-1 and NF-kB [19]; Ste11 is involved in MAPK pathway signal transduction governing mating, osmoregulation, and nitrogen starvation by direct interaction with the sterile a motif domains,

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Mitogen-activated protein kinase kinase kinase

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SAM, of Ste50 and Ste11 [42]; stomatal development and pattern is controlled by YODA [45]; the enzyme is involved in cell signaling and controls cell degeneration and cell differentiation and thus regulating development and pathogenicity sensing the external conditions [30]; the enzyme is part of the MAPK signaling cascades, overview [39]; the MAPKKKs are part of the MAPK signaling cascade, overview, MEKK1 regulates calpain-dependent cell migration via regulation of th ERK2-dependent signaling pathway and binding to focal adhesions, actinin, and FAK, overview [27]; the MAPKKKs are part of the MAPK signaling cascade, several structurally diverse MAPKKK families exist, overview [43]; the natural enzyme mutant V599E induces cell transformation in NIH3T3 cells, the B-Raf/MEK/ERK pathway regulates cell cycle proteins, overview [33]; the OMTK1 kinase domain is involved in activation of signaling pathways in case of oxidative stress to induce cell death playing a MAPK scaffolding role, OMTK1 shows low constitutive activity [35]) (Reversibility: ?) [1, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 33, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45] P ? Substrates and products S ATP + ERK ( i.e. extracellular signal-regulated kinase [19]; PI3K/PKC/Raf-1-independent activation of the MEK/ERK signaling pathway [41]) (Reversibility: ?) [19, 41] P ADP + phosphorylated ERK S ATP + ERK5 ( substrate of MEKK2 and MEKK3, activation of the ERK-dependent signaling pathway [37]; substrate of MEKK2 and MEKK3, no substrate of TAO2-1 [37]) (Reversibility: ?) [37] P ADP + phosphorylated ERK5 S ATP + JNK ( i.e. Jun amino terminal kinase [19]) (Reversibility: ?) [19] P ADP + phosphorylated JNK S ATP + MAPKK ( MAPKK activation [1]) (Reversibility: ?) [1] P ADP + phosphorylated MAPKK S ATP + MEK ( PI3K/PKC/Raf-1-independent activation of the MEK/ERK signaling pathway [41]; substrate is a MAPKK, usage of inactivated GST-tagged mutant MEK [20]) (Reversibility: ?) [20, 41] P ADP + phosphorylated MEK S ATP + MEK1 ( activation by MEKK3 of MAPK signaling pathways [22]; MEK1 activates the ERK2 signaling pathway [27]; Ras-induced activation of the MAPK signaling cascade [44]; substrate is a MAPKK [22,27]; the substrate of B-Raf and C-Raf is a MAPKK, no substrate of Mos, recombinant GST-MEK1 substrate [44]) (Reversibility: ?) [22, 27, 44] P ADP + phosphorylated MEk1 S ATP + MEK2 ( activation by MEKK3 of MAPK signaling pathways [22]; substrate is a MAPKK [22]) (Reversibility: ?) [22] P ADP + phosphorylated MEK2

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S ATP + MEK5 ( a MAPKK [21]; activated MEK5 activates ERK5 [21]) (Reversibility: ?) [21] P ADP + phosphorylated MEK5 S ATP + MKK ( a MAPKK [39]; induction of the JNK pathway activation [39]) (Reversibility: ?) [39] P ADP + phosphorylated MKK S ATP + MKK1 ( MKK1 activates the ERK2 signaling pathway [32]; a MAPKK, recombinant GST-tagged MKK1 [32]) (Reversibility: ?) [32] P ADP + phosphorylated MKK1 S ATP + MKK3 ( a MAPKK [25,31,35]; a MAPKK, OMTK1 channels oxidative stress signaling through direct interaction with MAPK MMK3 increasing the cell death rate, OMTK1 and MMK3 form a complex in vivo [35]; activation of the p38 MAP kinase signaling pathway [31]; activation of the p38 MAP kinase signaling pathway leading to apoptosis [25]) (Reversibility: ?) [25, 31, 35, 43] P ADP + phosphorylated MKK3 S ATP + MKK4 ( a MAPKK [21,41]; activation of the Jun N-terminal kinase, JNK, pathway leading to apoptosis [25]; MKK4 activates the JNK signaling pathway [27,32,34]; a MAPKK, activity of wild-type and mutant MEKK1 with wild-type and mutant MKK4, determination of the MKK4 binding site of MEKK1, overview [34]; a MAPKK, recombinant GST-tagged MKK4 [32]; i.e. SEK1, a MAPKK [25]; substrate is a MAPKK [27]; substrate of MEKK1 mutant Q1254E and of MTK1 mutant E1372Q [43]) (Reversibility: ?) [21, 25, 27, 32, 34, 41, 43] P ADP + phosphorylated MKK4 S ATP + MKK6 ( a MAPKK [25,31]; activation by MEKK3 of MAPK signaling pathways [22]; activation of the p38 MAP kinase signaling pathway [31]; activation of the p38 MAP kinase signaling pathway leading to apoptosis [25]; substrate of stressactivated MAPKKKs ASK1 and MTK1 [43]; phosphorylation in the activation loop, substrate of stress-activated MAPKKKs ASK1 and MTK1, no activity with MKK6 mutants E318P, F327D, I331D, and V328G, but reduced activity with MKK6 mutants V324G and V328A [43]; substrate is a MAPKK [22]) (Reversibility: ?) [22, 25, 31, 40, 43] P ADP + phosphorylated MKK6 S ATP + MKK7 ( a MAPKK [25]; activation by MEKK3 of MAPK signaling pathways [22]; activation of the Jun N-terminal kinase, JNK, signaling pathway leading to apoptosis [25]; substrate is a MAPKK [22]) (Reversibility: ?) [22, 25] P ADP + phosphorylated MKK7 S ATP + Mek1 (Reversibility: ?) [18] P ADP + phospho-Mek1 S ATP + SEK ( recombinant GST-tagged inactive KR-mutant SEK, i.e. SAPK/ERK or stress-activated protein kinase/extracellular-signalregulated kinase, substrate [23]) (Reversibility: ?) [23]

285

Mitogen-activated protein kinase kinase kinase

P S P S P S P S P S

P S

P S

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ADP + phosphorylated SEK ATP + Wis1 (Reversibility: ?) [6, 9] ADP + phosphorylated Wis1 [9] ATP + a protein (Reversibility: ?) [1, 18] ADP + a phosphoprotein ATP + histone H1 (Reversibility: ?) [44] ADP + phosphorylated histone H1 ATP + myelin basic protein (Reversibility: ?) [38] ADP + phosphorylated myelin basic protein ATP + p42 MAPK ( Ras-induced activation of the MAPK signaling cascade [44]; the substrate of B-Raf and C-Raf, no substrate of Mos, recombinant His6-p42 MAPK substrate [44]) (Reversibility: ?) [44] ADP + phosphorylated p42 MAPK ATP + protein ( required for activation of the MAPK homologue Spc1, and integrity of the Wis1-Spc1 pathway is required for survival in extreme conditions of heat, osmolarity, oxidation or limited nutrition. Phosphorylates Wis1 in vitro and activates it in vivo [6]; capable of partial suppression of the ras1 mutant phenotype [15]; selectively regulates the c-Jun amino terminal kinase pathway [4]; enzyme is involved in the response of haploid yeast cells to peptide mating pheromones [11]; phosphorylates and activates Wis1 MAP kinase kinase in response to high osmolarity [9]; ste8 gene product functions in the signal transduction pathway [14]; the enzyme is required for cell-type-specific transcription and signal transduction [13]; Mkh1 regulates cell morphology, cell wall integrity, salt resistance, cell cycle reentry from stationary-phase arrest, and filamentous growth in response to stress [17]; JSAP1 functions as a scaffold protein in the JNK3 cascade [3]) (Reversibility: ?) [3, 4, 6, 9, 11, 13, 14, 15, 17] ADP + phosphoprotein Additional information ( MEKK4 binds to Cdc42 and Rac [4]; enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regulation mechanism, overview [1]; activation mechanism of ASK1, overview, ASK1 is involved in oxidative stress-induced cell death and adaptation processes to various stresses, the enzyme is required for induction of apoptosis by e.g. Fas or TNF- a, or by the endoplasmic reticulum, mechanism [25]; activation mechanism of ASK1, overview, ASK1 is involved in oxidative stress-induced cell death and adaptation processes to various stresses, the enzyme is required for induction of apoptosis by e.g. Fas or TNF- a, or by the endoplasmic reticulum, mechanism, ASK1 plays an important role in neuropathological alterations in polyQ diseases [25]; alterations of the intracellular milieu induced by methylglyoxal through a MEKK1-mediated and PI3K/PKC/Raf-1-independent pathway results in the modification of cell response to IGF-I for the cyclin-dependent kinase inibitor p21Waf1/ Cip1-mediated growth arrest [41]; alterations of the intracellular milieu induced by methylglyoxal through a MEKK1-mediated and PI3K/

2.7.11.25

Mitogen-activated protein kinase kinase kinase

PKC/Raf-1-independent pathway results in the modification of cell response to IGF-I for the cyclin-dependent kinase inibitor p21_Waf1/Cip1mediated growth arrest, which may be one of the crucial mechanisms for methylglyoxal to promote the development of chronic clinical complications in diabetes in humans [41]; B-Raf and C-Raf, but not Mos, are required for Ras-induced MEK1 and p42 MAPK activation [44]; COT is a proto-oncogene, the enzyme is essential for the lipopolysaccharide activation of the ERK MAPK cascade in macrophages [20]; Cot plays an important role in inflammation and oncogenesis, MEKK3 mediates the activation of JNK and ERK in the MAP kinase pathway and of the NF-kB pathway and mediates the interleukin-8 production, MEKK3 and Cot are negatively regulated by hKSR-2 [22]; DLK acts as a key regulator of keratinocyte terminal differentiation, and is involved in activation of the JNK signaling pathway, DLK activity is required for transglutaminase activation and induction of keratinocyte cornification [38]; MAPKKKa is responsible for hypersensitive response and resistance to pathogen infection, the enzyme also regulates cell death in susceptible leaves after infection, overview [28]; MAPKKKa is responsible for hypersensitive response and resistance to Pseudomonas syringae infection, the enzyme also regulates cell death in susceptible, infected leaves, identification of MAPKKKa-induced signal cascades, regulation, overview [28]; MEKK1 and ASK1 might play opposing roles in oxidative stress-induced activation of apoptosis [23]; MEKK2 and MEKK3 are involved in activation of signal transduction pathways via toll-like receptor TLR, mitogen-activated protein kinases MAPK, and NF-kB, overview [29]; MEKK2 induces the JNK signaling pathway, overview [21]; MEKK3 is involved in activation of MAPKs e.g. p38 and JNK [40]; MEKK3 is involved in activation of NF-kB and increased expression of cell survival factors which confers resistance to apoptosis [36]; MLK2 plays a tissue specific role and is required for cement gland development and nephritic tubule formation, MLK2 mediates the response of Jun N-terminal kinase JNK, i.e. stress-activated protein kinase 1 SAPK1, to UV irradiation [26]; MLTKa activates the p38g MAPK-dependent signaling pathway, which is regulated by the serine/threonine kinase PKNa [31]; NSY-1 functions in the control of asymmetric expression of odor receptor gene str-2, odor discrimination, and odor chemotaxis, thus possibly in functional differentiation of the nervous system, the enzyme functions downstream of UNC-43 CaMKII [25]; regulation, overview, Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein-1- and nuclear factor-kBmediated gene expression in airway epithelial cells, the enzyme is involved in activation of the signaling cascades via activator protein AP-1 and NF-kB [19]; Ste11 is involved in MAPK pathway signal transduction governing mating, osmoregulation, and nitrogen starvation by direct interaction with the sterile a motif domains, SAM, of Ste50 and Ste11 [42]; stomatal development and pattern is controlled by YODA [45]; the enzyme is involved in cell signaling and controls cell degeneration and

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cell differentiation and thus regulating development and pathogenicity sensing the external conditions [30]; the enzyme is part of the MAPK signaling cascades, overview [39]; the MAPKKKs are part of the MAPK signaling cascade, overview, MEKK1 regulates calpain-dependent cell migration via regulation of th ERK2-dependent signaling pathway and binding to focal adhesions, actinin, and FAK, overview [27]; the MAPKKKs are part of the MAPK signaling cascade, several structurally diverse MAPKKK families exist, overview [43]; the natural enzyme mutant V599E induces cell transformation in NIH3T3 cells, the B-Raf/ MEK/ERK pathway regulates cell cycle proteins, overview [33]; the OMTK1 kinase domain is involved in activation of signaling pathways in case of oxidative stress to induce cell death playing a MAPK scaffolding role, OMTK1 shows low constitutive activity [35]; no phosphorylation/activation of IkB kinase [19]; Ste50 binds the MAPKKK Ste11 through a head-to-tail sterile interaction via both a motif SAM domains, NMR binding study, very tight and stable binding between the two mutants Ste50 L69R and Ste11 L72R, overview [42]; substrate specificities of MAPKKKs with wild-type and mutant MAPKKs, overview, no activity with MKK7 by MEKK1 mutant Q1254E, wild-type MTK1, and MTK1 mutant E1372Q, the enzyme docks at the DVD docking site of MAPKK, a stretch of about 20 amino acids immediately on the C-terminal side of the catalytic domain, MAPKK with mutated DVD docking sites are inhibitory for the MAPKKK, overview [43]; the enzyme docks at the DVD docking site of MAPKK, a stretch of about 20 amino acids immediately on the C-terminal side of the catalytic domain, MAPKK with mutated DVD docking sites are inhibitory for the MAPKKK [27]) (Reversibility: ?) [1, 4, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 33, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45] P ? Inhibitors EGTA ( negative regulation of COT [20]) [20] glutathione ( binding to glutathione inhibits MEKK1 in vitro [23]) [23] menadione ( i.e. 2-methyl-1,4-naphthoquinone, oxidative stress caused by menadione inhibits MEKK1, which can be reversed by DTT and glutathione, inhibition is thus caused by a reversible Cys1238 oxidation mechanism followed by binding to glutathione, no inhibition of MEKK1 mutant C1238V [23]) [23] N-ethymaleimide ( MEKK1 inhibition through Cys1238 alkylation, Cys1238 is located in the ATP binding domain, no inhibition of MEKK1 mutant C1238V [23]) [23] PD98059 [41] U0126 ( inhibits MEKK2/MEKK3-dependent ERK5 phosphorylation/activation in vitro and in vivo [37]) [37] farnesylthiosalicylic acid ( a Ras antagonist, inhibits the wild-type and V599E mutant enzyme in vivo and in vitro [33]) [33]

288

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Mitogen-activated protein kinase kinase kinase

hKSR-2 ( i.e. human kinase suppressor of ras 2, selectively inhibits MEKK3-activated MAP kinase and NF-kB pathways in inflammation, selectively inhibits Cot, no inhibition of MEKK4, TAK1, and Ras-Raf [22]) [22] p105 ( inhibition of COT activity, but binding of p105 increases the solubility and stability of COT [20]) [20] thioredoxin ( the reduced form binds to the N-terminus [25]) [25] Additional information ( MAPKK with mutated DVD docking sites are inhibitory for the MAPKKK, as well as synthetic DVD sequence oligopeptides in vitro and in vivo, overview [27]; MAPKK with mutated DVD docking sites are inhibitory for the MAPKKK, as well as synthetic DVD sequence oligopeptides of e.g. MKK6, in vitro and in vivo, overview [43]; no inhibition by LY294002 or bisindolylmaleimide [41]; no interaction with Cdc42 and RhoA by MLK2 [26]; ubiquitinylation of MEKK1 inhibits the enzyme in vitro and in vivo [32]) [26, 27, 32, 41, 43] Cofactors/prosthetic groups ATP [1, 18, 19, 20, 21, 22, 23, 25, 27, 31, 32, 33, 34, 35, 37, 38, 40, 41, 42, 43, 44] Activating compounds GTPAse Rac1 ( interacts with MLK2, the enzyme contains a G-protein binding domain, i.e. a CRIB domain [26]) [26] H2 O2 ( oxidative stress activates OMTK1 [35]) [35] Methylglyoxal ( induces the PI3K/PKC/Raf-1-independent MEK/ ERK signaling pathway by activation of MEKK1, accumulates in case of diabetes [41]) [41] N-ethymaleimide ( ASK1 activation at lower concentrations [23]) [23] NaCl [35] Ras ( activates C-Raf and B-Raf [44]; required for maximal activity in ERK and JNK phosphorylation/activation and for activation of AP-1 pathway [19]) [19, 44] Ste50 ( Ste50 binding of the MAPKKK Ste11 through a head-to-tail sterile interaction via both a motif SAM domains is required for Ste11 activity and cell viability, NMR binding study, very tight and stable binding between the two mutants Ste50 L69R and Ste11 L72R, molecular modeling, overview [42]) [42] TNF-a ( treatment with TNF-a dissociates the inhibitor thioredoxin from the enzymes N-terminus [25]) [25] reactive oxygene species ( the enzyme is oxidative stress-induced [25]) [25] Additional information ( a functional DVD docking site of MAPKK substrates is absolutely required for activity [43]; dimerization through the catalytic domain is essential for MEKK2 activation [39]; MEKK1 forms complexes with FAK involved in regulation of cell migration, overview [27]; MEKK2 and MEKK3 are phosphorylated and thereby ac-

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Mitogen-activated protein kinase kinase kinase

2.7.11.25

tivated by kinase WNK1 [37]; MG115 induces OMTK1 [35]; MLTKa is activated by phosphorylation through PKNa [31]; no effect on enzyme activity by RAF-1 [41]; phosphorylation at Ser526 and Thr530 in the activation loop is required for MEKK3 activation, dephosphorylation is blocked by binding to protein 14-3-3 [40]; polymerization and phosphorylation activates the enzyme after dissociation of thioredoxin due to TNF-a treatment [25]; TNF-a induces MEKK1 and Ras activation [19]; UV irradiation increases the enzyme activity, no interaction with Cdc42 and RhoA by MLK2 [26]) [19, 25, 26, 27, 31, 35, 37, 39, 40, 41, 43] Metals, ions Mg2+ [1, 18, 19, 20, 22, 23, 32, 35, 38, 39, 40, 41, 44] Mn2+ ( preferred divalent cation as ATP metal cofactor [20]) [20] Additional information ( no or nearly no activity with Ni2+ , Zn2+ , Co2+, and Cu2+ [20]) [20] Turnover number (min–1) 0.005 (ATP, recombinant COT30-467/p105DN, pH 7.5, 22 C, with 10 mM Mg2+ [20]) [20] 0.005 (MEK, recombinant COT30-467/p105DN, pH 7.5, 22 C, with 10 mM Mg2+ [20]) [20] 0.006 (ATP, recombinant COT30-467/p105DN, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] 0.006 (MEK, recombinant COT30-467/p105DN, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] 0.0328 (ATP, recombinant COT30-397/p105DN, pH 7.5, 22 C, with 10 mM Mg2+ [20]) [20] 0.0328 (MEK, recombinant COT30-397/p105DN, pH 7.5, 22 C, with 10 mM Mg2+ [20]) [20] 0.033 (ATP, recombinant COT30-397/p105DN, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] 0.033 (MEK, recombinant COT30-397/p105DN, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] 0.245 (ATP, recombinant COT30-397, pH 7.5, 22 C, with 10 mM Mn2+ [20]) [20] 0.245 (MEK, recombinant COT30-397, pH 7.5, 22 C, with 10 mM Mg2+ [20]) [20] 0.26 (ATP, recombinant COT30-397, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] 0.26 (MEK, recombinant COT30-397, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] Specific activity (U/mg) Additional information ( large scale activity assay with recombinant enzyme in a protein chip consisting of a microwell array with protein covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker, overview [18]) [18]

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Mitogen-activated protein kinase kinase kinase

Km-Value (mM) 0.00016 (MEK, recombinant COT30-467/p105DN, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] 0.00019 (MEK, recombinant COT30-397, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] 0.0003 (MEK, recombinant COT30-397/p105DN, pH 7.5, 22 C, with 10 mM Mg2+ [20]; recombinant COT30-397/p105DN, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] 0.00031 (MEK, recombinant COT30-467/p105DN, pH 7.5, 22 C, with 10 mM Mg2+ [20]) [20] 0.00036 (MEK, recombinant COT30-397, pH 7.5, 22 C, with 10 mM Mg2+ [20]) [20] 0.02 (ATP, recombinant COT30-397, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] 0.03 (ATP, recombinant COT30-397/p105DN and recombinant COT30-467/p105DN, pH 7.5, 22 C, with 5 mM Mn2+ [20]) [20] 0.31 (ATP, recombinant COT30-397/p105DN, pH 7.5, 22 C, with 10 mM Mg2+ [20]) [20] 0.39 (ATP, recombinant COT30-397, pH 7.5, 22 C, with 10 mM Mn2+ [20]) [20] 0.394 (ATP, recombinant COT30-467/p105DN, pH 7.5, 22 C, with 10 mM Mg2+ [20]) [20] Additional information ( kinetics of binding between wild-type and mutant Ste11 and wild-type and mutant Ste50, overview [42]) [42] pH-Optimum 7.3 ( assay at [44]) [44] 7.4 ( assay at [23,35,38,41]) [23, 35, 38, 41] 7.4-7.5 ( assay at [40]) [40] 7.5 ( assay at [19,20,31,32]) [19, 20, 31, 32] 7.6 ( assay at [39]) [39] 7.9 ( assay at [21]) [21] Temperature optimum ( C) 22 ( assay at room temperature [20,23,35]) [20, 23, 35] 25 ( assay at [31]) [31] 30 ( assay at [19,21,32,37,38,40,41,44]) [19, 21, 32, 37, 38, 40, 41, 44]

4 Enzyme Structure Molecular weight 45000 ( recombinant single COT30-397, gel filtration [20]) [20] 180000 [4, 9] 200000 ( about, recombinant aggregated COT30-397, gel filtration [20]) [20]

291

Mitogen-activated protein kinase kinase kinase

2.7.11.25

600000 ( about, recombinant aggregated, p105DN-complexed COT30-467 [20]) [20] Subunits dimer ( dimerization through the catalytic domain is essential for MEKK2 activation, the dimerization motif is in the catalytic domain, the Nterminal domain is not required for dimerization, overview [39]) [39] Additional information ( COT30-467 forms very tightly bound complexes with p105DN which remain intact at 2-4 M urea [20]; DLK is a dual leucine zipper-bearing protein [38]; MEKK1 forms complexes with FAK involved in regulation of cell migration, overview [27]; structural analysis of the sterile a motif, SAM, domain of Ste11 MAPKKK and of Ste50 effector, several hydrophobic secondary structures and amino acids are required for effective binding, overview [42]; subdomain VIII is a specificity-determining region in MEKK1 [34]; the C-terminus contains the kinase domain, two ubiquitin interaction motifs, a region of interaction with small GTPases, and a caspase 3-like cleavage site [32]; the large enzyme possesses several domains including a proline-rich region, indispensable for activity, and a 60-amino acid-long polyglutamine stretch, which is not necessary for full activity [30]; the MLTKa C-terminus possesses an a-motif in vicinity to the leucine zipper, the a-motif is supposed to be a regulatory and phosphorylation site [31]; the subdomain X is required for phosphorylation and activation of MAPKKs in vivo [21]) [20, 21, 27, 30, 31, 32, 34, 38, 42] Posttranslational modification phosphoprotein ( activation by phosphorylation [1]; the enzyme performs autophosporylation [18]; MEKK2 and MEKK3 are activated by phosphorylation, determination of phosphorylation sites, S519 is a key regulator phosphorylation site in MEKK2, other sites are Thr521 and Thr523 [29]; MEKK2 and MEKK3 are phosphorylated at the N-terminus and thereby activated by kinase WNK1, residues K385 and K391, respectively, are involved [37]; MLTKa is phosphorylated by PKNa, probably at the C-terminal a-motif [31]; phosphorylation activates the enzyme [25]; phosphorylation at Ser526 and Thr530 in the activation loop is required for MEKK3 activation, dephosphorylation is blocked by binding to protein 14-3-3 [40]) [1, 18, 25, 29, 31, 37, 40] proteolytic modification ( cleavage by caspase-3 at a specific Cterminal cleavage site generates a 91 kDa, catalytically active enzyme fragment [32]) [32] Additional information ( the active MEKK1 stimulates its own ubiquitinylation in vivo which has a negatively regulating function [32]) [32]

292

2.7.11.25

Mitogen-activated protein kinase kinase kinase

5 Isolation/Preparation/Mutation/Application Source/tissue 16HBE14o cell ( bronchial epithelial cell line [19]) [19] HEK-293 cell ( embryonic kidney cell line [41]) [37, 41] HeLa cell [37] MKT-BR cell ( choroidal cancer cell line, expresses V599E mutant enzyme [33]) [33] NIH-3T3 cell ( fibroblast cell line [41]; cutaneous melanoma cell line, expresses V599E mutant enzyme [33]) [33, 41] OCM-1 cell ( choroidal cancer cell line, expresses V599E mutant enzyme [33]) [33] SP-6.5 cell ( choroidal cancer cell line, expresses V599E mutant enzyme [33]) [33] brain [25, 26] breast [36] breast cancer cell ( high expression level of MEKK3 [36]) [36] bronchus [19] cement gland ( MLK2 expression correlates with cell elongation and the onset of an apoptotic phase [26]) [26] egg ( no changes in B-Raf activity after fertilization [44]) [44] embryo ( no changes in B-Raf activity in the first embryonic cell cycles [44]) [44] epidermis ( gard cells of leaf and shoot epidermis [45]) [45] epithelial cell ( bronchial [19]) [19] epithelium ( of skin [38]) [38] fibroblast [27] guard cell [45] keratinocyte ( DLK acts as a key regulator of keratinocyte terminal differentiation and cornification [38]) [38] leaf [28, 45] macrophage [20] melanocyte [33] mycelium [30] neuroglioma cell [36] neuron [25] olfactory neuron [25] oocyte ( no changes in B-Raf activity during progesterone-induced maturation [44]) [44] ovarian cancer cell ( high expression level of MEKK3 [36]) [36] ovary [36] pancreas [26] pronephros ( embryo, MLK2 expression correlates with the differentiation and opening of the nephritic tubules, but not with apoptosis [26]) [26] root ( constitutive expression [24]) [24] root nodule ( constitutive expression [24]) [24]

293

Mitogen-activated protein kinase kinase kinase

2.7.11.25

seedling [45] shoot ( constitutive expression [24]) [24, 45] skin [38] spleen [26] zygote ( MLK2 expression from late gastrula stage/early neurula stage on [26]) [26, 44] Additional information ( stomatal development and pattern is controlled by YODA [45]; the enzyme is ubiquitously expressed [24]; tissue-specific expression of MLK2, no or very low expression in liver, lung, heart, muscle, and kidney [26]) [24, 26, 45] Localization Golgi apparatus ( activation of MEK1 by C-Raf [44]) [44] kinetochore ( activation of p42 MAPK [44]) [44] protoplast ( basal activity level of OMTK1 [35]) [30, 35] Additional information ( localized to perinuclear, vesicular compartment similar to the Golgi [4]; ectopic expression of B-Raf in cutaneous melanoma cells [33]; the enzyme colocalizes with focal adhesions [27]) [4, 27, 33] Purification (purification of recombinant wild-type and mutant COT30-397s, free or complexed to p105DN, and of p105DN-complexed recombinant COT30-467 from Sf9 insect cells by anti-Flag immunoaffinity chromatography, the purification of free COT30-467 is not possible due to its extremely low expression level in absence of p105DN) [20] (purification of recombinant MEKK1 and ASK1 by chitin affinity chromatography, endogenous MEKK1 by protein A affinity chromatography) [23] (recombinant His6- and GST-tagged wild-type and mutants enzymes from Escherichia coli by affinity chromatography and gel filtration, the tags are cleaved off) [42] (partial purification of Mos and B-Raf from egg extracts by heparin affinity chromatography and/or ion exchange chromatography, and GST-MEK1 affinity chromatography, recombinant His6-tagged B-Raf by nickel affinity chromatography) [44] Cloning (MEKK2, DNA and amino acid sequence determination, expression of wild-type and mutant MEKK2 by reticulocyte lysate TnT T7 mixture, expression of wild-type and mutant MEKK2 and MEKK1 in COS-1 cells and in HeLa cells, coexpression with ERK5 in COS-1 cells) [21] (expression of GST-tagged full length MEKK2 and MEKK2 C-terminal and N-terminal fragments, i.e. of residues 1-619, 342-619, and 342-424, in COS-1 cells) [39] (expression of HA-tagged active MEKK2 and inactive S519A MEKK2 mutant catalytic sites, expression of wild-type and mutant full length MEKK2s and of wild-type and mutant MEKK3s) [29]

294

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(expression of His6-tagged MEKK1 subdomain VIII, comprising residues 1174-1493, His6-tagged wild-type, full-length enzyme, and His6-tagged mutant enzymes F1443A, I1394/L1402A, Q1405R/Q1406R, and L1402A/F1443A in HeLa and COS-1 cells) [34] (transient co-expression of MEKK1 and FAK in HEK293 cells) [27] (wild-type and mutant enzyme) [32] (co-expression of FLAG-tagged MTK1 and wild-type and mutant HAtagged MKK6 in COS-7 cells, direct and immunoprecipitation study) [43] (expression of DLK in cultured keratinocytes using the adenovirus transfection method) [38] (expression of FLAG-tagged COT30-467 and COT30-397 in a stable and soluble form when co-expressed with the C-terminal part of p105, complex formation with p105 reduces the kcat value of COT30-397 but increases the expression level, expression of wild-type and mutant COT30-397s in Spodoptera frugiperda Sf9 cells using the baculovirus infection system) [20] (expression of His- or FLAG-tagged wild-type and mutant MEKK3s in HEK293 EBNA cells, co-expression of substrate GST-HA-tagged MKK6 substrate) [40] (expression of wild-type and inactive mutant enzymes in HEK293T cells and in COS-7 cells as HA-tagged proteins) [31] (expression of wild-type and mutant MAP3Ks, MEKK1-4 and TAO2-1, in HEK293 cells, co-expression of ERK5 and WNK1) [37] (overexpression of the mutant enzyme V599E in COS cells leading to 10.7fold increased activity) [33] (stable expression of HA-tagged MEKK3 in HEK293, U373, and Hep3B cells, the expression of MEKK3 blocks the TRAIL-mediated activation of the apoptosis pathway and increases cell resistance to cytotoxic agents such as doxorubicin, daunorubicin, camptothecin, and paclitaxel, overview, TRAIL is a TNF-related apoptosis-inducing ligand) [36] (expression of MEKK1 and ASK1 in CV-1 cells using a vaccinia virus transfection system) [23] (overexpression of His6- and GST-tagged wild-type and mutants enzymes in Escherichia coli) [42] (phylogenetic tree of kinases derived from the kinase core sequence, overview, overexpression as GST-fusion protein under control of the galactose-inducible GAL1 promotor in Escherichia coli, determination of 5’-end sequences) [18] (gene YDA, transcriptome analysis of seedlings with wild-type and altered YODA activity, overview) [45] (B-RAf, DNA and amino acid sequence determination and analysis, expression of His6-tagged B-Raf in bacteria, expression of His6-tagged and FLAG-tagged C-Raf in insect cells) [44] (expression in embryos by microinjection in the two-cell stage, overexpression of MLK2 in COS-7 cells leading to a SEK1/MKK4-dependent hyperactivation of Jun N-terminal kinase) [26]

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(DNA and amino acid sequence determination and analysis, overexpression of the enzyme can complement the defective mutant and results in increase crippled growth after infection) [30] [4] (isolation and characterization) [11] [3] (gene M3Ka, DNA and amino acid sequence determination and analysis) [24] (DNA and amino acid sequence determination and analysis, sequence comparisons, overview, MAPKKKa overexpression in leaves using the Agrobacterium tumefaciens transfection system) [28] (DNA and amino acid sequence determination and analysis, sequence comparisons, overview) [28] (OMTK1, DNA and amino acid sequence determination, expression as GST-fusion protein, transient co-expression of Myc-tagged OMTK1 and HAtagged MMK3 in Arabidopsis thaliana protoplasts, in vitro trabscription and translation of wild-type and mutant OMTK1 by reticulocyte lysate) [35] (expression of FLAG-tagged MEKK3 in HEK293T and HeLa cells, coexpression of NF-kB) [22] Engineering A62D ( site-directed mutagenesis, no binding of Ste50 [42]) [42] C441A ( site-directed mutagenesis, the mutant enzyme is not ubiquitinylated and thus shows a higher ERK activating activity [32]) [32] D169A ( site-directed mutagenesis, the kinase-dead mutation of TAO2-1 does not influence the ERK5 activation level [37]) [37] D270A ( site-directed mutagenesis of COT30-397, inactive mutant [20]) [20] E1372Q ( site-directed mutagenesis, the MTK1 mutant shows altered substrate specificity comapred to the wild-type enzyme [43]) [43] F1443A ( site-directed mutagenesis of MEKK1, the mutation abolishes the in vitro interaction with MKK4, but retains the in vivo activity [21]; site-directed mutagenesis, subdomain X mutation, the mutant shows reduced activity compared to the wild-type enzyme [34]) [21, 34] F571A ( site-directed mutagenesis of MEKK2, inactive mutant [21]) [21] I1394/L1402A ( site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme [34]) [34] I1445A ( site-directed mutagenesis of MEKK1, the mutation has a deleterious effect on MEKK1 function [21]) [21] I1454A ( site-directed mutagenesis of MEKK1, the mutation abolishes the in vitro interaction with MKK4, but retains the in vivo activity [21]) [21] I573A ( site-directed mutagenesis of MEKK2, inactive mutant [21]) [21] I59R ( site-directed mutagenesis, no binding of Ste50 [42]) [42]

296

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Mitogen-activated protein kinase kinase kinase

K1371D ( site-directed mutagenesis, MTK1 mutant catalytic site mutant, inactive mutant, no interaction with substrate MKK6 docking site mutants [43]) [43] K1371E ( site-directed mutagenesis, MTK1 mutant catalytic site mutant, inactive mutant, no interaction with substrate MKK6 docking site mutants [43]) [43] K1371G ( site-directed mutagenesis, MTK1 mutant catalytic site mutant, inactive mutant, no interaction with substrate MKK6 docking site mutants [43]) [43] K1371R ( site-directed mutagenesis, MTK1 mutant catalytic site mutant, inactive mutant, no interaction with substrate MKK6 docking site mutants [43]) [43] K385M ( site-directed mutagenesis of MEKK2, inactive mutant enzyme [37]) [37] K391A ( site-directed mutagenesis of MEKK3, the mutant shows highly reduced activity compared to the wild-type enzyme [40]) [40] K391M ( site-directed mutagenesis of MEKK3, inactive mutant enzyme [37]) [37] L1402A/F1443A ( site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme [34]) [34] L1458A ( site-directed mutagenesis of MEKK1, the mutation has a deleterious effect on MEKK1 function [21]) [21] L582A/P583A ( site-directed mutagenesis of MEKK2, inactive mutant [21]) [21] L72R ( site-directed mutagenesis, highly increased tight binding of Ste50 wild-type compared to the Ste11 wild-type enzyme [42]) [42] P1452A ( site-directed mutagenesis of MEKK1, the mutation has a deleterious effect on MEKK1 function [21]) [21] P1455A ( site-directed mutagenesis of MEKK1, the mutation has a deleterious effect on MEKK1 function [21]) [21] P580A ( site-directed mutagenesis of MEKK2, the mutant shows 82% of wild-type activity [21]) [21] P584A ( site-directed mutagenesis of MEKK2, the mutant shows activity similar to the wild-type enzyme [21]) [21] Q1254E ( site-directed mutagenesis, the MEKK1 mutant shows altered substrate specificity comapred to the wild-type enzyme [43]) [43] Q1405R/Q1406R ( site-directed mutagenesis C-terminal to the subdomain VIII, creation of an optimal recognition site for protease furin, the mutant binds MKK4 more tightly than the wild-type enzyme, MKK4 binding protects the mutant enzyme from proteolytic cleavage [34]) [34] S1459A ( site-directed mutagenesis of MEKK1, the mutation abolishes the in vitro interaction with MKK4, but retains the in vivo activity [21]) [21] S519A ( site-directed mutagenesis, MEKK2 phosphorylation site mutant, inactive mutant [29]) [29] S526A ( site-directed mutagenesis of MEKK3, the mutant shows highly reduced activity compared to the wild-type enzyme [40]; site-di-

297

Mitogen-activated protein kinase kinase kinase

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rected mutagenesis, MEKK3 phosphorylation site mutant, inactive mutant [29]) [29, 40] S526D ( site-directed mutagenesis of MEKK3, the mutant shows reduced activity compared to the wild-type enzyme [40]) [40] S526E ( site-directed mutagenesis of MEKK3, the mutant shows reduced activity compared to the wild-type enzyme [40]) [40] T521A ( site-directed mutagenesis, MEKK2 phosphorylation site mutant, the mutant shows slightly reduced activity compared to the wild-type enzyme [29]) [29] T523A ( site-directed mutagenesis, MEKK2 phosphorylation site mutant, the mutant shows slightly reduced activity compared to the wild-type enzyme [29]) [29] T530A ( site-directed mutagenesis of MEKK3, the mutant shows highly reduced activity compared to the wild-type enzyme [40]) [40] T530D ( site-directed mutagenesis of MEKK3, the mutant shows highly reduced activity compared to the wild-type enzyme [40]) [40] T530E ( site-directed mutagenesis of MEKK3, the mutant shows highly reduced activity compared to the wild-type enzyme [40]) [40] T575A/Q576A/P577A ( site-directed mutagenesis of MEKK2, inactive mutant [21]) [21] V586A ( site-directed mutagenesis of MEKK2, the mutant shows activity similar to the wild-type enzyme [21]) [21] V599E ( naturally occurring mutation of cancer cells, the mutation leads to 10fold increased enzyme activity compared to the wild-type enzyme, and constitutive, Ras-independent activation, siRNA-mediated depletion of the mutant enzyme diminishes the enzyme activity and also cell proliferation [33]) [33] Y54R ( site-directed mutagenesis, no binding of Ste50 [42]) [42] Additional information ( an OMTK1 mutant reduced in MMK3 complex formation shows decreased MMK3 and cell death activation [35]; construction of a kinase-defective MTLKa mutant, expression of a kinase-defective PKNa mutant results in inhibition of MLTKa activity and p38 kinase induction [31]; construction of mutant plants for identification of genes and pathway functioning in hypersensitive response and resistance by MAPKKKa silencing, co-expression of tomato resistance R gene Cf9 and the Cladosporium fulvum avirulence gene avr9, a multicomponent transgenic construct, overexpression of the full length Lycopersicon esculentum enzyme or the isolated tomato enzyme kinase domain in leaves leads to pathogen-independent cell death induction, overview [28]; enzyme inactivation by antisense expression method and expression of dominant negative MLK2 defective in the ATP binding site, which impairs the UV irradiation sensitivity, overview [26]; enzyme-defective mutant strains AS4-44 and AS65 are impaired in the development of crippled growth after infection causing a cell degenerative process, and are defective in mycelium pigmentation, aerial hyphae differentiation, and making of fruiting bodies showing female sterility, construction of mutants lacking the proline-riche region or the polyglutamine stretch, mutant phenotypes, overview [30]; inhibition of heterodimeric

298

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Mitogen-activated protein kinase kinase kinase

association of Ste11 and Ste50 in yeast strains leads to defects in mating and activation of high-osmolarity growth pathways [42]; MEKK3 overexpression confers resistance to apoptosis through activation of NF-kB [36]; mutations in the MEKK subdomain X differentially affect MEKK2 and MEKK1 activity, overview [21]; overexpression of DLK in cultured keratinocytes results in altered features of the cell concerning suprabasal localization, cell shape, compacted cytoplasm, DNA fragmentation, and regulation of filaggrin expression, which is upregulated, terminally differentiated phenotype, the transglutaminase activity is increased leading to cornified cell envelope formation, overview [38]; overexpression of the full length enzyme or the isolated tomato enzyme kinase domain in Nicotiana benthiana leaves leads to pathogen-independent cell death induction, overview [28]; overexpression of WNK1 in HEK293 cells leads to increased enzyme activity, a kinasedead mutation of MEKK1 does not influence the ERK5 activation level [37]; the BRAF gene is mutated in several cancers, especially in cutaneous melanoma [33]; YODA null mutation leads to excess stomata, whereas constittive activation of YODA eliminated stomata [45]) [21, 26, 28, 30, 31, 33, 35, 36, 37, 38, 42, 45] Application analysis ( development of a protein chip consisting of a silicone elastomer microwell array with recombinant enzyme covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker for large scale activity assay, overview [18]) [18]

6 Stability General stability information , binding of p105 increases the solubility and stability of COT, but decreases catalytic activity [20]

References [1] Hunter, T.: Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell, 80, 225-236 (1995) [2] Wood, V.; Gwilliam, R.; Rajandream, M.A.; Lyne, M.; Lyne, R.; et al.: The genome sequence of Schizosaccharomyces pombe. Nature, 415, 871-880 (2002) [3] Ito, M.; Yoshioka, K.; Akechi, M.; Yamashita, S.; Takamatsu, N.; Sugiyama, K.; Hibi, M.; Nakabeppu, Y.; Shiba, T.; Yamamoto, K.I.: JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway. Mol. Cell. Biol., 19, 7539-7548 (1999) [4] Gerwins, P.; Blank, J.L.; Johnson, G.L.: Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. J. Biol. Chem., 272, 8288-8295 (1997)

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[5] Schweifer, N.; Valk, P.J.; Delwel, R.; Cox, R.; Francis, F.; Meier-Ewert, S.; Lehrach, H.; Barlow, D.P.: Characterization of the C3 YAC contig from proximal mouse chromosome 17 and analysis of allelic expression of genes flanking the imprinted Igf2r gene. Genomics, 43, 285-297 (1997) [6] Samejima, I.; Mackie, S.; Fantes, P.A.: Multiple modes of activation of the stress-responsive MAP kinase pathway in fission yeast. EMBO J., 16, 61626170 (1997) [7] Shieh, J.C.; Wilkinson, M.G.; Buck, V.; Morgan, B.A.; Makino, K.; Millar, J.B.: The Mcs4 response regulator coordinately controls the stress-activated Wak1-Wis1-Sty1 MAP kinase pathway and fission yeast cell cycle. Genes Dev., 11, 1008-1022 (1997) [8] Shiozaki, K.; Shiozaki, M.; Russell, P.: Mcs4 mitotic catastrophe suppressor regulates the fission yeast cell cycle through the Wik1-Wis1-Spc1 kinase cascade. Mol. Biol. Cell, 8, 409-419 (1997) [9] Samejima, I.; Mackie, S.; Warbrick, E.; Weisman, R.; Fantes, P.A.: The fission yeast mitotic regulator win1+ encodes an MAP kinase kinase kinase that phosphorylates and activates Wis1 MAP kinase kinase in response to high osmolarity. Mol. Biol. Cell, 9, 2325-2335 (1998) [10] Wang, X.S.; Diener, K.; Tan, T.H.; Yao, Z.: MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5. Biochem. Biophys. Res. Commun., 253, 33-37 (1998) [11] Cairns, B.R.; Ramer, S.W.; Kornberg, R.D.: Order of action of components in the yeast pheromone response pathway revealed with a dominant allele of the STE11 kinase and the multiple phosphorylation of the STE7 kinase. Genes Dev., 6, 1305-1318 (1992) [12] Maeda, T.; Takekawa, M.; Saito, H.: Activation of yeast PBS2 MAPKK by MAPKKKs or by binding of an SH3-containing osmosensor. Science, 269, 554-558 (1995) [13] Rhodes, N.; Connell, L.; Errede, B.: STE11 is a protein kinase required for cell-type-specific transcription and signal transduction in yeast. Genes Dev., 4, 1862-1874 (1990) [14] Styrkarsdottir, U.; Egel, R.; Nielsen, O.: Functional conservation between Schizosaccharomyces pombe ste8 and Saccharomyces cerevisiae STE11 protein kinases in yeast signal transduction. Mol. Gen. Genet., 235, 122-130 (1992) [15] Wang, Y.; Xu, H.P.; Riggs, M.; Rodgers, L.; Wigler, M.: Byr2, a Schizosaccharomyces pombe gene encoding a protein kinase capable of partial suppression of the ras1 mutant phenotype. Mol. Cell. Biol., 11, 3554-3563 (1991) [16] Lange-Carter, C.A.; Pleiman, C.M.; Gardner, A.M.; Blumer, K.J.; Johnson, G.L.: A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science, 260, 315-319 (1993) [17] Sengar, A.S.; Markley, N.A.; Marini, N.J.; Young, D.: Mkh1, a MEK kinase required for cell wall integrity and proper response to osmotic and temperature stress in Schizosaccharomyces pombe. Mol. Cell. Biol., 17, 35083519 (1997)

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[18] Zhu, H.; Klemic, J.F.; Chang, S.; Bertone, P.; Casamayor, A.; Klemic, K.G.; Smith, D.; Gerstein, M.; Reed, M.A.; Snyder, M.: Analysis of yeast protein kinases using protein chips. Nat. Genet., 26, 283-289 (2000) [19] Zhou, L.; Tan, A.; Iasvovskaia, S.; Li, J.; Lin, A.; Hershenson, M.B.: Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein-1- and nuclear factor-kB-mediated gene expression in airway epithelial cells. Am. J. Respir. Cell Mol. Biol., 28, 762-769 (2003) [20] Jia, Y.; Quinn, C.M.; Bump, N.J.; Clark, K.M.; Clabbers, A.; Hardman, J.; Gagnon, A.; Kamens, J.; Tomlinson, M.J.; Wishart, N.; Allen, H.: Purification and kinetic characterization of recombinant human mitogen-activated protein kinase kinase kinase COT and the complexes with its cellular partner NF-kB1 p105. Arch. Biochem. Biophys., 441, 64-74 (2005) [21] Huang, J.; Tu, Z.; Lee, F.S.: Mutations in protein kinase subdomain X differentially affect MEKK2 and MEKK1 activity. Biochem. Biophys. Res. Commun., 303, 532-540 (2003) [22] Channavajhala, P.L.; Rao, V.R.; Spaulding, V.; Lin, L.L.; Zhang, Y.G.: hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kB pathways in inflammation. Biochem. Biophys. Res. Commun., 334, 1214-1218 (2005) [23] Cross, J.V.; Templeton, D.J.: Oxidative stress inhibits MEKK1 by site-specific glutathionylation in the ATP-binding domain. Biochem. J., 381, 675-683 (2004) [24] Kinoshita, N.; Ooki, Y.; Deguchi, Y.; Chechetka, S.A.; Kouchi, H.; Umehara, Y.; Izui, K.; Hata, S.: Cloning and expression analysis of a MAPKKK gene and a novel nodulin gene of Lotus japonicus. Biosci. Biotechnol. Biochem., 68, 1805-1807 (2004) [25] Takeda, K.; Matsuzawa, A.; Nishitoh, H.; Ichijo, H.: Roles of MAPKKK ASK1 in stress-induced cell death. Cell Struct. Funct., 28, 23-29 (2003) [26] Poitras, L.; Bisson, N.; Islam, N.; Moss, T.: A tissue restricted role for the Xenopus Jun N-terminal kinase kinase kinase MLK2 in cement gland and pronephric tubule differentiation. Dev. Biol., 254, 200-214 (2003) [27] Cuevas, B.D.; Abell, A.N.; Witowsky, J.A.; Yujiri, T.; Johnson, N.L.; Kesavan, K.; Ware, M.; Jones, P.L.; Weed, S.A.; DeBiasi, R.L.; Oka, Y.; Tyler, K.L.; Johnson, G.L.: MEKK1 regulates calpain-dependent proteolysis of focal adhesion proteins for rear-end detachment of migrating fibroblasts. EMBO J., 22, 3346-3355 (2003) [28] del Pozo, O.; Pedley, K.F.; Martin, G.B.: MAPKKKa is a positive regulator of cell death associated with both plant immunity and disease. EMBO J., 23, 3072-3082 (2004) [29] Zhang, D.; Facchinetti, V.; Wang, X.; Huang, Q.; Qin, J.; Su, B.: Identification of MEKK2/3 serine phosphorylation site targeted by the Toll-like receptor and stress pathways. EMBO J., 25, 97-107 (2006) [30] Kicka, S.; Silar, P.: PaASK1, a mitogen-activated protein kinase kinase kinase that controls cell degeneration and cell differentiation in Podospora anserina. Genetics, 166, 1241-1252 (2004) [31] Takahashi, M.; Gotoh, Y.; Isagawa, T.; Nishimura, T.; Goyama, E.; Kim, H.S.; Mukai, H.; Ono, Y.: Regulation of a mitogen-activated protein kinase kinase kinase, MLTK by PKN. J. Biochem., 133, 181-187 (2003)

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[32] Witowsky, J.A.; Johnson, G.L.: Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways. J. Biol. Chem., 278, 1403-1406 (2003) [33] Calipel, A.; Lefevre, G.; Pouponnot, C.; Mouriaux, F.; Eychene, A.; Mascarelli, F.: Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK Pathway. J. Biol. Chem., 278, 42409-42418 (2003) [34] Tu, Z.; Lee, F.S.: Subdomain VIII is a specificity-determining region in MEKK1. J. Biol. Chem., 278, 48498-48505 (2003) [35] Machida, N.; Umikawa, M.; Takei, K.; Sakima, N.; Myagmar, B.E.; Taira, K.; Uezato, H.; Ogawa, Y.; Kariya, K.: Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase. J. Biol. Chem., 279, 15711-15714 (2004) [36] Samanta, A.K.; Huang, H.J.; Bast, R.C., Jr.; Liao, W.S.: Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkB. J. Biol. Chem., 279, 7576-7583 (2004) [37] Xu, B.E.; Stippec, S.; Lenertz, L.; Lee, B.H.; Zhang, W.; Lee, Y.K.; Cobb, M.H.: WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. J. Biol. Chem., 279, 7826-7831 (2004) [38] Robitaille, H.; Proulx, R.; Robitaille, K.; Blouin, R.; Germain, L.: The mitogen-activated protein kinase kinase kinase dual leucine zipper-bearing kinase (DLK) acts as a key regulator of keratinocyte terminal differentiation. J. Biol. Chem., 280, 12732-12741 (2005) [39] Cheng, J.; Yu, L.; Zhang, D.; Huang, Q.; Spencer, D.; Su, B.: Dimerization through the catalytic domain is essential for MEKK2 activation. J. Biol. Chem., 280, 13477-13482 (2005) [40] Fritz, A.; Brayer, K.J.; McCormick, N.; Adams, D.G.; Wadzinski, B.E.; Vaillancourt, R.R.: Phosphorylation of serine 526 is required for MEKK3 activity and association with 14-3-3 blocks dephosphorylation. J. Biol. Chem., 281, 6236-6245 (2006) [41] Du, J.; Cai, S.; Suzuki, H.; Akhand, A.A.; Ma, X.; Takagi, Y.; Miyata, T.; Nakashima, I.; Nagase, F.: Involvement of MEKK1/ERK/p21Waf1/Cip1 signal transduction pathway in inhibition of IGF-I-mediated cell growth response by methylglyoxal. J. Cell. Biochem., 88, 1235-1246 (2003) [42] Kwan, J.J.; Warner, N.; Maini, J.; Chan Tung, K.W.; Zakaria, H.; Pawson, T.; Donaldson, L.W.: Saccharomyces cerevisiae Ste50 binds the MAPKKK Ste11 through a head-to-tail SAM domain interaction. J. Mol. Biol., 356, 142-154 (2006) [43] Takekawa, M.; Tatebayashi, K.; Saito, H.: Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Mol. Cell, 18, 295-306 (2005) [44] Yue, J.; Xiong, W.; Ferrell, J.E.: B-Raf and C-Raf are required for Ras-stimulated p42 MAP kinase activation in Xenopus egg extracts. Oncogene, 1, 1-9 (2006) [45] Bergmann, D.C.; Lukowitz, W.; Somerville, C.R.: Stomatal development and pattern controlled by a MAPKK kinase. Science, 304, 1494-1497 (2004)

302

tau-Protein kinase

2.7.11.26

1 Nomenclature EC number 2.7.11.26 Systematic name [tau-protein] O-phosphotransferase Recommended name tau-protein kinase Synonyms AtK-1 [40] CDK5/p25 [71] Cdk5 [59, 70, 71] GSK-3 [12, 20, 42, 63, 65, 68, 69] GSK-3 a GSK-3 b GSK-3/shaggy-like protein kinase [22] GSK-3b [14, 63, 72, 75] GSK3b [57, 61, 66, 67] Gasket protein MCK1 [26] NtK-4 [41] PKA [65, 69] SGK1 [74] SHAGGY-related protein kinase [34] TPK [5, 49] TPK I [57] TPKI [5, 46] TPKI/GSK-3b [48, 54] TPKI/GSK-3b/FA [45] TPKII [5] TTK [54] t-tubulin kinase 1 [75] brain proteinkinase PK40erk [44] cAMP-dependent protein kinase A [65, 69] cyclin-dependent kinase 5 [70, 73] cyclin-dependent kinase 5/p39 [59] cyclin-dependent kinase-5 [71] glycogen synthase kinase glycogen synthase kinase 3 b [66, 67]

303

tau-Protein kinase

2.7.11.26

glycogen synthase kinase 3b [14, 20, 57, 61] glycogen synthase kinase-3 [21, 42, 63, 65, 68, 69] glycogen synthase kinase-3 a [6, 12, 13] glycogen synthase kinase-3 homolog [36] glycogen synthase kinase-3 homolog MsK-1 [37] glycogen synthase kinase-3 homolog MsK-2 [37] glycogen synthase kinase-3 homolog MsK-3 [37] glycogen synthase kinase-3ab [73] glycogen synthase kinase-3b [60, 72, 75] p25-Cdk5 kinase complex [62] protein kinase 1 [74] protein kinase MCK1 [24, 25, 26, 27, 28] protein kinase shaggy [11] protein kinase skp1 [7, 38] protein kinase-A [69] protein tau kinase serine/threonine-protein kinase MDS1/RIM11 [29, 30, 31, 32] serine/threonine-protein kinase MRK1 [35] serum- and glucocorticoid-induced protein kinase 1 [74] shaggy-related protein kinase NtK-1 [41] shaggy-related protein kinase a [4, 33] shaggy-related protein kinase b [9, 22, 23] shaggy-related protein kinase d [39] shaggy-related protein kinase h [8, 34] shaggy-related protein kinase g [9, 33, 34] shaggy-related protein kinase i [2] shaggy-related protein kinase k [2, 40] shaggy-related protein kinase q [8, 22, 34] tau factor protein kinase (phosphorylating) tau kinase [72] tau protein kinase tau protein kinase I tau protein kinase I/GSK-3b/kinaseFA [45] tau protein kinase I/glycogen synthase kinase 3b [48, 51] tau protein kinase II (cdk5/p20) [53] tau protein kinase II system [50] t-protein kinase I [47, 57] t-protein kinase II [47] t-tubulin kinase [47, 54] zeste-white3 [18, 19] Additional information ( CDK5 is a unique member of the CDK family, see also EC 2.7.11.22 [71]; see also EC 2.7.11.1 [57, 60, 61, 63, 66, 67]; see also EC 2.7.11.1 and EC 2.7.11.11 [65, 69]; see also EC 2.7.11.1 and EC 2.7.11.22 [73]; see also EC 2.7.11.22 [59, 62, 70]; cf. EC 2.7.11.1 [75]) [57, 59, 60, 61, 62, 63, 65, 66, 67, 69, 70, 71, 73, 75]

304

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tau-Protein kinase

CAS registry number 111694-09-8

2 Source Organism Mus musculus (no sequence specified) [54, 55, 58, 59, 64, 71, 72, 73] Homo sapiens (no sequence specified) ( gene ACL5-1 [45, 48, 49, 51, 52, 53, 55, 56]) [45, 48, 49, 51, 52, 53, 55, 56, 57, 61, 62, 63, 66, 67, 69, 72, 73, 74, 75] Rattus norvegicus (no sequence specified) [43, 44, 46, 48, 49, 50, 54, 55, 65, 68, 70] Bos taurus (no sequence specified) ( fragment CYP153A11 [5, 47, 54]) [5, 47, 54, 60] Drosophila melanogaster (UNIPROT accession number: P18431) [3, 10, 11, 12, 15, 17, 18, 19] Homo sapiens (UNIPROT accession number: P49841) [6,14,16,20,42] Rattus norvegicus (UNIPROT accession number: P18265) [1,12] Rattus norvegicus (UNIPROT accession number: P18266) [12,13,21] Brassica napus (UNIPROT accession number: O04160) [22] Arabidopsis thaliana (UNIPROT accession number: O23145) [9, 22, 23] Saccharomyces cerevisiae (UNIPROT accession number: P21965) [24, 25, 26, 27, 28] Saccharomyces cerevisiae (UNIPROT accession number: P38615) [29, 30, 31, 32] Arabidopsis thaliana (UNIPROT accession number: P43288) [4, 33] Arabidopsis thaliana (UNIPROT accession number: P43289) [9, 33, 34] Saccharomyces cerevisiae (UNIPROT accession number: P50873) [35] Dictyostelium discoideum (UNIPROT accession number: P51136) [36] Medicago sativa (UNIPROT accession number: P51137) [37] Medicago sativa (UNIPROT accession number: P51138) [37] Medicago sativa (UNIPROT accession number: P51139) [37] Schizosaccharomyces pombe (UNIPROT accession number: Q10452) [7, 38] Arabidopsis thaliana (UNIPROT accession number: Q39010) [2, 39] Arabidopsis thaliana (UNIPROT accession number: Q39011) [8, 34] Arabidopsis thaliana (UNIPROT accession number: Q39012) [2] Arabidopsis thaliana (UNIPROT accession number: Q39019) [2, 40] Nicotiana tabacum (UNIPROT accession number: Q40518) [41] Arabidopsis thaliana (UNIPROT accession number: Q96287) [8, 34] Mus musculus (UNIPROT accession number: Q924U8) [54]

3 Reaction and Specificity Catalyzed reaction ATP + [tau-protein] = ADP + O-phospho-[tau-protein] ( activation loop structure, substrate binding structure, and catalytic site structure and me-

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tau-Protein kinase

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chanism [57]; glycogen synthase kinase-3b also performs serine/threonine protein kinase reaction, EC 2.7.11.1, with other substrates than tau, e.g. it phosphorylates the glycogen synthase [60]; GSK-3 and PKA catalyze tau phosphorylation in the brain, while GSK-3 performs phosphorylation of glycogen synthase, EC 2.7.11.1, and other proteins in different tissues, and PKA performs phosphorylation of other proteins in different tissues [65]) Reaction type phospho group transfer Natural substrates and products S ATP + SC35 ( substrate prephosphorylated SC35, SC35 is a member of the SR family of serine/arginine-rich splicing factors [63]) (Reversibility: ?) [63] P ADP + phosphorylated SC35 S ATP + [tau-protein] ( 14-3-3 connects glycogen synthase kinase-3 b to tau within a brain microtubule-associated tau phosphorylation complex [60]; abnormal hyperphosphorylation of tau by PKA and GSK-3 is associated with Alzheimers disease and other tauopaties leading to neuronal degeneration [65]; activity in organisms with mutated APP and tau, not in wild-type, overview [73]; cdk5 associated with p25 [62]; cdk5 substrate in brain, cdk5 associated with p39, tau is a microtubule-associated and developmentally regulated protein involved in axonal development in neurons, tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules [59]; hyperphosphorylation of tau by CDK5 is involved in apoptosis and neurodegeneration in Alzheimers disease, overview [71]; phosphorylation of tau, especially at the primed epitope T231 negatively regulates t-microtubule interactions, different effects of phosphorylation on primed T231 and unprimed S396/S404 epitopes of tau, overview [66]; protein 14-3-3 mediates phosphorylation of microtubule-associated protein tau by serum- and glucocorticoid-induced protein kinase 1 SGK1, which forms an activated ternary complex with protein 14-3-3q [74]; regulation, overview [58]; tau is microtubule-associated, phopshorylation at T231 by CDK5 causes its release into the cytoplasm [70]; tau is primarily found in neurons, regulation of tau phosphorylation by GSK3b via interaction with FRAT-1 and FRAT-2, i.e. frequently rearranged in advanced T-cell lymphoma proteins [67]; tau phosphorylation by GSK-3b is involved in development of neurodegenerative Alzheimers disease, the tau phosphorylation activity by GSK-3b is further increased by soluble toxic b-amyloid oligomers, overview [72]; tau phosphorylation in vivo is stimulated by extracellular signal-regulated kinase Erk phosphorylation and apolipoprotein isozyme E4, to a lesser extent by isozyme apoE3, overview [64]) (Reversibility: ?) [58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74] P ADP + O-phospho-[tau-protein]

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tau-Protein kinase

S ATP + protein tau ( prior phosphorylation of tau by isoenzyme TPKII strongly enhances the action of TPKI [49]; regulates PDH and participates in energy metabolism and acetylcholine synthesis [48]; microtubule-associated protein [43]) (Reversibility: ?) [5, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56] P ADP + protein tau phosphate [5, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56] S ATP + tau protein ( tau in Alzheimer disease brain is highly phosphorylated and aggregates into paired helical filaments comprising characteristic neurofibrillary tangles, overview [75]) (Reversibility: ?) [75] P ADP + phosphorylated tau protein S Additional information ( enzyme is involved in the cellular response to insulin, the enzyme is highly phosphorylated on tyrosine and thus active in resting cells [12]; possible role of the sgg protein in a signal transduction pathway necessary for intercellular communication at different stages of development [11]; implicated in cell-fate determination and differentiation, phosphorylates several regulatory proteins that are activated by dephosphorylation in response to hormones or growth factors [20]; enzyme of the lithiumsensitive wnt signaling pathway [16]; enzyme acts as a repressor of engrailed autoregulation [19]; enzyme forms part of the wingless signalling pathway. GSK-3b activity is negatively regulated by phosphorylation on serine 9 and positively regulated by phosphorylation on tyrosine 216. Enzyme may also be regulated at the transcriptional level [14]; implicated in the hormonal control of several regulatory proteins including glycogen synthase and the transcription factor c-jun [21]; MDS1 is not essential during normal vegetative growth but appears to be required for meiosis [30]; enzyme regulates cell fate in Dictyostelium [36]; enzyme is involved in the induction of meiosis [24]; MCK1 encodes a positive regulator of meiosis and spore formation. MCK1 is required in vegetative cells for basal IME1 expression, it is also required for efficient ascus maturation. MCK1 plays a role in governing centromere function during vegetative growth as well as sporulation [27]; AtK-1 kinase is involved in reproduction-specific processes [2]; abnormal phosphorylation of tau in dividing cells leads to its accumulation in the cytosol as microtubule-free form, Cdk5 is involved in neurodegenerative mechanisms [62]; activation and deregulation of GSK-3, e.g. by wortmannin or GF-109203X, induces Alzheimer-like tau hyperphosphorylation in hippocampus, the hyperphosphorylated tau forms neurofibrillary tangle [68]; CDK5-dependent clustering of endoplasmic reticulum ER and mitochondria during ceramide-mediated neuronal death: neurotoxic calcium transfer from ER to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau, inhibition of the process leads to cell death [70]; glycogen synthase kinase-3b also performs serine/threonine protein kinase reaction, EC 2.7.11.1, with other substrates than tau, e.g. it phosphorylates the glycogen synthase [60]; GSK-3 affects the t-mRNA splicing of

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exon 10 via phosphorylation of the splicing factors of the serine/argininerich splicing factor SR family, e.g. SC35, leading to priming and dislocation of the splicing factor, aberrant tau splicing contributes to tauopathies including Alzheimers disease, overview [63]; GSK3b and PKA work coordinatedly on tau phosphorylation [69]; naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of mutants leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2 -terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of mutants leads to age-dependent memory deficits [73]; naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of organisms with Alzheimers disease leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2- terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of patients suffering from Alzheimers disease leads to age-dependent memory deficits [73]; phosphorylated tau is important in cytoskeleton assembly [61]; protein 14-3-3 facilitates tau phosphorylation by SGK1 and regulates its subcellular localization in the nucleus or cytoplasm, overview [74]; rapid, reversible cold-water stress-induced hyperphosphorylation of tau S199, S202, T205, T231, and S235 in hippocampal and cerebral region of the brain, hyperphosphorylation of tau is associated to the Alzheimers disease [58]; tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain, inhibition of tau hyperphosphorylation inhibits an associated loss in spatial memory [65]; the enzyme participates in Alzheimers disease [57]) (Reversibility: ?) [2, 11, 12, 14, 16, 19, 20, 21, 24, 27, 30, 36, 57, 58, 60, 61, 62, 63, 65, 68, 69, 70, 73, 74] P ? Substrates and products S ATP + DIWKKFELLPTPPLSPSRRSG ( c-Myc [42]) (Reversibility: ?) [42] P ADP + DIWKKFELLP(P)TPPL(P)SPSRRSG [42] S ATP + DIWKKFELVPSPPTSPPWGL ( l-myc [42]) (Reversibility: ?) [42] P ADP + DIWKKFELVP(P)SPPT(P)SPPWGL [42] S ATP + EEPQTVPEMPGETPPLSPIDMESQER ( c-Jun [42]) (Reversibility: ?) [42] P ADP + EEPQTVPEMPGE(P)TPPL(P)SPIDMESQER [42] S ATP + FITC-GSRSRTPSLP ( synthetic fluorescence-labeled peptide substrate derived from residues 207-216 of tau protein, phosphorylation of S214 by SGK1 [74]) (Reversibility: ?) [74] P ADP + FITC-GSRSRTP-phosphoserine-LP S ATP + FXVEXTPXCFSRXSSLSSLS (Reversibility: ?) [42]

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P ADP + ? S ATP + KAUSSPTVSRKTD ( synthetic peptide p25/F3 [47]) (Reversibility: ?) [47] P ADP + KAUSSPTVSRKTD phosphate S ATP + LLNASGSTSTPAPSRTASFSESR ( ATP-citrate lyase [42]) (Reversibility: ?) [42] P ADP + LLNASGSTS(P)TPAP(P)SRTASFSESR [42] S ATP + MADSRPKPANKTPPK ( synthetic peptide F5f [47]) (Reversibility: ?) [47] P ADP + MADSRPKPANKTPPK phosphate S ATP + MAP2 ( isoenzyme TPKII [49]; isoenzyme TPKI and TPKII [5]) (Reversibility: ?) [5, 47, 49] P ADP + MAP2 phosphate S ATP + MARSRPK ( synthetic peptide F5h [47]) (Reversibility: ?) [47] P ADP + MARSRPK phosphate S ATP + PANKTPPKSPGEPAKDPAAK ( synthetic peptide p25/F5a [47]) (Reversibility: ?) [47] P ADP + PANKTPPKSPGEPAKDPAAK phosphate S ATP + RADSRPK ( synthetic peptide F5g [47]) (Reversibility: ?) [47] P ADP + RADSRPK phosphate S ATP + RKRSRAE ( synthetic peptide 8659 [47]) (Reversibility: ?) [47] P ADP + RKRSRAE phosphate S ATP + RKRSRKE ( synthetic peptide 8655 [47]) (Reversibility: ?) [47] P ADP + RKRSRKE phosphate S ATP + RRREEETEEE ( synthetic peptide CKII substrate [47]) (Reversibility: ?) [47] P ADP + RRREEETEEE phosphate S ATP + RSRSRSRSRSRSPPPVSK ( SC35-derived peptide 180-197, recombinant GSK-3b [63]) (Reversibility: ?) [63] P ADP + phosphorylated RSRSRSRSRSRSPPPVSK S ATP + SC35 ( substrate prephosphorylated SC35, SC35 is a member of the SR family of serine/arginine-rich splicing factors [63]; substrate prephosphorylated SC35, SC35 is a member of the SR family of serine/arginine-rich splicing factors, recombinant GSK-3b [63]) (Reversibility: ?) [63] P ADP + phosphorylated SC35 S ATP + SPPLSPIDMETQER ( JunD [42]) (Reversibility: ?) [42] P ADP + (P)SPPLSPIDME(P)TQER [42] S ATP + SPVVSGDT(P)SPR (Reversibility: ?) [42] P ADP + ? S ATP + TPPKSPSAAK ( protein tau [42]) (Reversibility: ?) [42] P ADP + TPPK(P)SPSAAK [42]

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S ATP + [FRAT-2 protein] ( i.e. frequently rearranged in advanced T-cell lymphoma protein 2, phosphorylation by GSK3b [67]) (Reversibility: ?) [67] P ADP + phosphorylated [FRAT-2 protein] S ATP + [tau-protein] ( 14-3-3 connects glycogen synthase kinase-3 b to tau within a brain microtubule-associated tau phosphorylation complex [60]; abnormal hyperphosphorylation of tau by PKA and GSK-3 is associated with Alzheimers disease and other tauopaties leading to neuronal degeneration [65]; activity in organisms with mutated APP and tau, not in wild-type, overview [73]; cdk5 associated with p25 [62]; cdk5 substrate in brain, cdk5 associated with p39, tau is a microtubule-associated and developmentally regulated protein involved in axonal development in neurons, tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules [59]; hyperphosphorylation of tau by CDK5 is involved in apoptosis and neurodegeneration in Alzheimers disease, overview [71]; phosphorylation of tau, especially at the primed epitope T231 negatively regulates t-microtubule interactions, different effects of phosphorylation on primed T231 and unprimed S396/S404 epitopes of tau, overview [66]; protein 14-3-3 mediates phosphorylation of microtubule-associated protein tau by serum- and glucocorticoid-induced protein kinase 1 SGK1, which forms an activated ternary complex with protein 14-3-3q [74]; regulation, overview [58]; tau is microtubule-associated, phopshorylation at T231 by CDK5 causes its release into the cytoplasm [70]; tau is primarily found in neurons, regulation of tau phosphorylation by GSK3b via interaction with FRAT-1 and FRAT-2, i.e. frequently rearranged in advanced T-cell lymphoma proteins [67]; tau phosphorylation by GSK-3b is involved in development of neurodegenerative Alzheimers disease, the tau phosphorylation activity by GSK-3b is further increased by soluble toxic b-amyloid oligomers, overview [72]; tau phosphorylation in vivo is stimulated by extracellular signal-regulated kinase Erk phosphorylation and apolipoprotein isozyme E4, to a lesser extent by isozyme apoE3, overview [64]; cdk5 associated with p25, recombinant bacterially expressed human tau protein as substrate, phosphorylation of the AT8 and AT180 epitopes, and at T231 of the Alzheimers mitotic epitope TG-3 [62]; phosphorylation at T231, no activity with tau mutant T231A [70]; phosphorylation at the Cterminus, lower activity with C-terminally truncated tau D421 compared to the wild-type tau, the truncated tau protein forms sarcosyl-insoluble aggregates [61]; phosphorylation by PKA at Ser214, and by GSK-3 at Ser404, Ser396, Ser198, Ser199, and Ser202 [65]; phosphorylation of primed and unprimed sites by GSK3b, wild-type and recombinant tau, recombinant GSK3b S9A [67]; phosphorylation of S214 by SGK1, recombinant tau S214A is no substrate [74]; phosphorylation of the PHF-1 epitope at Ser396 and Ser404 by CDK5 [71]; preferred substrate of cdk5 associated with p39, recombinant bacterially expressed human tau protein as substrate, phosphorylation at Ser202 and Thr205 [59])

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P S P S P S P S P S P S P S P S P S P S

P S

P S

tau-Protein kinase

(Reversibility: ?) [57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74] ADP + O-phospho-[tau-protein] ATP + a-casein ( isoenzyme TPKI [5]) (Reversibility: ?) [5, 47] ADP + a-casein phosphate ATP + b-casein ( isoenzyme TPKII [5]) (Reversibility: ?) [5] ADP + b-casein phosphate ATP + b-tubulin ( isoenzyme t-tubulin kinase [47]) (Reversibility: ?) [47] ADP + b-tubulin phosphate ATP + glycogen synthase (Reversibility: ?) [36] ADP + phosphorylated glycogen synthase ATP + histone H1 ( isoenzyme TPKII [5,49]) (Reversibility: ?) [5, 49] ADP + histone H1 phosphate ATP + histone H2a ( isoenzyme TPKII [5]) (Reversibility: ?) [5] ADP + histone H2a phosphate ATP + histone H2b ( isoenzyme TPKII [5]) (Reversibility: ?) [5] ADP + histone H2b phosphate ATP + histone H3 ( isoenzyme TPKII [5]) (Reversibility: ?) [5] ADP + histone H3 phosphate ATP + protein ( autophosphorylation at Tyr and Ser [28]) (Reversibility: ?) [28] ADP + phosphoprotein ATP + protein tau ( microtubule-associated protein, enzyme can also phosphorylate human tau [43]; enzyme can also phosphorylate bovine tau [45]; phosphorylates tau and forms paired helical filament epitopes, tau/K1, K2, K3 and tau/4 repeat [47]; phosphorylates tau protein into Alzheimer disease-like forms, resulting in neuronal death [48]; when a b-mediated aggregated tau is used as a substrate for TPKII, an 8fold increase in the rate of TPKII-mediated tau phosphorylation is observed [56]; 6 isoforms of human tau expressed in adult human brain [53]; prior phosphorylation of tau by isoenzyme TPKII strongly enhances the action of TPKI [49]; regulates PDH and participates in energy metabolism and acetylcholine synthesis [48]; microtubule-associated protein [43]) (Reversibility: ?) [5, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56] ADP + protein tau phosphate [5, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56] ATP + pyruvate dehydrogenase ( PDH is phosphorylated and inactivated in vitro and also in bA-treated hippocampal cultures, resulting in mitochondrial dysfunction which will contribute to neuronal death [48]) (Reversibility: ?) [48] ADP + pyruvate dehydrogenase phosphate ATP + tau protein ( tau in Alzheimer disease brain is highly phosphorylated and aggregates into paired helical filaments comprising characteristic neurofibrillary tangles, overview [75]; determination

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tau-Protein kinase

P S P S

P S

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of several phosphorylation sites, e.g. Ser258, Ser289, Ser262, and Ser356 within the microtubule-binding repeats or at Ser184 and Ser185 of the central region, for casein kinase I, casein kinase 2, and glycogen synthase kinase-3b in insoluble tau, PHF-tau, extracted from Alzheimer brain and of tau from control healthy brain by mass spectrometry, overview [75]) (Reversibility: ?) [75] ADP + phosphorylated tau protein glycogen synthase + ATP ( proline-directed kinase [14]) (Reversibility: ?) [6, 12, 13, 14, 21] phosphorylated glycogen synthase + ADP protein tau + ATP ( the microtubule-associated protein tau is the principal component of the paired helical filaments - PHFs - found in the brains of patients with Alzheimer disease, and PHF-tau is hyperphosphorylated [14]) (Reversibility: ?) [14] phosphorylated protein tau + ADP Additional information ( TPKI cannot phosphorylate K1, K2 and K3 peptides, histones H1, H2A, H2B and H3 and b casein [5]; novel isoenzyme, distinct from TPKI, TPKII CKI and CKII, no activity toward b-casein and neurofilament, no reaction with synthetic peptides F5a PANKTPPKSPGEPAKDPAAK, F5n MADSRPK, F5d MADSRKPAN, F5e MADSRPAE and 8656 RKRARKE, only weak activity with histones H1, H2a and H2b as substrates [47]; enzyme is involved in the cellular response to insulin, the enzyme is highly phosphorylated on tyrosine and thus active in resting cells [12]; possible role of the sgg protein in a signal transduction pathway necessary for intercellular communication at different stages of development [11]; implicated in cell-fate determination and differentiation, phosphorylates several regulatory proteins that are activated by dephosphorylation in response to hormones or growth factors [20]; enzyme of the lithium-sensitive wnt signaling pathway [16]; enzyme acts as a repressor of engrailed autoregulation [19]; enzyme forms part of the wingless signalling pathway. GSK-3b activity is negatively regulated by phosphorylation on serine 9 and positively regulated by phosphorylation on tyrosine 216. Enzyme may also be regulated at the transcriptional level [14]; implicated in the hormonal control of several regulatory proteins including glycogen synthase and the transcription factor c-jun [21]; MDS1 is not essential during normal vegetative growth but appears to be required for meiosis [30]; enzyme regulates cell fate in Dictyostelium [36]; enzyme is involved in the induction of meiosis [24]; MCK1 encodes a positive regulator of meiosis and spore formation. MCK1 is required in vegetative cells for basal IME1 expression, it is also required for efficient ascus maturation. MCK1 plays a role in governing centromere function during vegetative growth as well as sporulation [27]; AtK-1 kinase is involved in reproduction-specific processes [2]; abnormal phosphorylation of tau in dividing cells leads to its accumulation in the cytosol as microtubule-free form, Cdk5 is involved in neurodegenerative mechanisms [62]; activation and deregulation

2.7.11.26

tau-Protein kinase

of GSK-3, e.g. by wortmannin or GF-109203X, induces Alzheimer-like tau hyperphosphorylation in hippocampus, the hyperphosphorylated tau forms neurofibrillary tangle [68]; CDK5-dependent clustering of endoplasmic reticulum ER and mitochondria during ceramide-mediated neuronal death: neurotoxic calcium transfer from ER to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau, inhibition of the process leads to cell death [70]; glycogen synthase kinase-3b also performs serine/threonine protein kinase reaction, EC 2.7.11.1, with other substrates than tau, e.g. it phosphorylates the glycogen synthase [60]; GSK-3 affects the t-mRNA splicing of exon 10 via phosphorylation of the splicing factors of the serine/arginine-rich splicing factor SR family, e.g. SC35, leading to priming and dislocation of the splicing factor, aberrant tau splicing contributes to tauopathies including Alzheimers disease, overview [63]; GSK3b and PKA work coordinatedly on tau phosphorylation [69]; naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of mutants leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2 -terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of mutants leads to age-dependent memory deficits [73]; naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of organisms with Alzheimers disease leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2 -terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of patients suffering from Alzheimers disease leads to age-dependent memory deficits [73]; phosphorylated tau is important in cytoskeleton assembly [61]; protein 14-3-3 facilitates tau phosphorylation by SGK1 and regulates its subcellular localization in the nucleus or cytoplasm, overview [74]; rapid, reversible cold-water stress-induced hyperphosphorylation of tau S199, S202, T205, T231, and S235 in hippocampal and cerebral region of the brain, hyperphosphorylation of tau is associated to the Alzheimers disease [58]; tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain, inhibition of tau hyperphosphorylation inhibits an associated loss in spatial memory [65]; the enzyme participates in Alzheimers disease [57]; cdk5 also performs the kinase reaction of EC 2.7.11.22 [59]; GSK3b catalyzes tau phosphorylation in brain, but phosphorylation of glycogen synthase and other proteins, EC 2.7.11.1, in different tissues [61,66,67]; GSK3b, EC 2.7.11.1, and PKA, EC 2.7.11.11, catalyze tau phosphorylation in brain, but phosphorylation of glycogen synthase and other proteins in different tissues [69]; substrate specificity of GSK3b [57]) (Reversibility: ?) [2, 5, 11, 12, 14, 16, 19, 20, 21, 24, 27, 30, 36, 47, 57, 58, 59, 60, 61, 62, 63, 65, 66, 67, 68, 69, 70, 73, 74] P ?

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Inhibitors AMP-PNP ( ATP analogue adenosine 5-(b,g-imino)triphosphate [57]) [57] ATP ( strongly inhibited by elevated concentrations of ATP uncomplexed with magnesium [5,44]) [5, 44] butyrolactone ( cdk5 inhibitor, isoenzyme TPKII [50]) [50] Ca2+ [43] LiCl ( slight inhibition of T231 phosphorylation by p25-Cdk5 kinase complex [62]) [62] Rp-adenosine 3’,5’-cyclic monophosphorothionate triethyl ammonium salt ( inhibitor of PKA [65]) [65] lithium ( after inhibition of GSK-3 in cortical neurons, the splicing factor SC35 is nuclearly redistributed and enriched in nuclear speckles and colocalizes with the kinase [63]) [63] roscovitine ( complete inhibition of T231 phosphorylation by 25Cdk5 kinase complex [62]; inhibition of CDK5 [70]) [62, 70] Additional information ( no inhibition of the p25-Cdk5 kinase complex by PD98059 and SB203580 [62]; phosphorylation of GSK3b at S9 inhibits the enzyme [61,66,67]; phosphorylation of GSK3b at S9 inhibits the enzyme, the phosphorylation at Ser9 is inhibited by wortmannin or GF- 109203X, this inhibition is eliminated by inhibition of GSK-3 by a different inhibitor [68]) [61, 62, 66, 67, 68] Cofactors/prosthetic groups ATP ( binding site structure [57]) [57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75] Activating compounds FRAT-2 ( i.e. frequently rearranged in advanced T-cell lymphoma protein 2, activates phosphorylation of primed sites of tau protein about 8fold, no effect on unprimed site phosphorylation [67]) [67] heparin [45] cAMP ( required for PKA activation [69]; required for PKA activity [65]) [65, 69] carbonyl cyanide p-trifluoromethoxyphenylhydrazone [44] forskolin ( activates PKA [65]; forskolin specifically induces tau hyperphosphorylation by PKA at Ser214 resulting in increased phosphorylation at Ser199, Ser22, Ser396, and Ser404 in N2a/tau441 cells, forskolin has no effect on GSK-3 [69]) [65, 69] p25 ( activator required for CDK5 activity, activation of CDK5 by p25 which is activated by cleavage of p35 to p25 [70]; cyclin activator, dependent on, over 10fold increase in activity of CDK5 [71]; inducible cytotoxic expression factor required for Cdk5 activity, formation of a complex with Cdk5, p25 overexpression increases tau phosphorylation rate [62]) [62, 70, 71] p35 ( tightly bound neuronal activator of cdk5, required for activity with regulatory function, p39 activates to a greater extent compared to p35 in vitro [59]) [59]

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tau-Protein kinase

p39 ( tightly bound neuronal activator of cdk5, required for activity with regulatory function, p39 activates to a greater extent compared to p35 in vitro, p39 is the activator activator in vivo [59]) [59] protein 14-3-3 ( a dimeric scaffold protein, protein is absolutely required for connection by simultaneous binding of glycogen synthase kinase-3 b to tau within a brain microtubule-associated tau phosphorylation complex [60]; protein 14-3-3 facilitates tau phosphorylation by SGK1 and regulates its subcellular localization [74]) [60, 74] soluble b-amyloid oligomers ( activate GSK-3b mediated tau phosphorylation and increase toxicity, reduced content of soluble, not insoluble, amyloid oligomers reduces the tau phosphorylation activity, specific antibodies can inhibit the activation, overview [72]) [72] tubulin ( stimulates phosphorylation of tau under the condition of microtubile formation [43]) [5, 43, 47] Additional information ( not activated by cyclic nucleotides cAMP and cGMP, calmodulin or phospholipide [43]; activation loop structure [57]; mechanism transitory activation of tau phosphorylation by PKA in Alzheimers disease, effects of durative incubation with activators, overview [69]; starvation- and cold-water stress-induced reversible hyperphosphorylation of tau at S199, S202, T205, T231, and S235 in the brain [58]; tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain [65]; tau phosphorylation in vivo is stimulated by extracellular signal-regulated kinase Erk phosphorylation and apolipoprotein E4, Erk phosphorylation is stinulated by Zn2+ and inhibited by MEK-inhibitor U0126 [64]; treatment of the hippocampus cells with phosphoinositol 3-kinase inhibitor wortmannin or protein kinase C inhibitor GF-109203X leads to tau hyperphosphorylation both at Ser396/404 and at Ser199/202, with both inhibitors acting synergistically to each other, resulting in Alzheimers disease-like tau accumulation, overview, wortmannin or GF-109203X decrease the phosphorylation of GSK-3 at Ser9, inhibition of the GSK-3 eliminates the effects of wortmannin and GF-109203X leads to tau hyperphosphorylation both at Ser396/404 and at Ser199/202, with both inhibitors acting synergistically with each other, resulting in Alzheimers disease-like tau accumulation, overview, wortmannin or GF-109203X [68]) [43, 57, 58, 64, 65, 68, 69] Metals, ions Mg2+ ( binding site structure [57]) [57, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, 73, 74, 75] Mn2+ [74] Specific activity (U/mg) 0.001 ( isoenzyme TPKI, optimum conditions [5]) [5] 0.01325 ( activity towards tubulin [47]) [47] 0.01665 ( activity towards tau [47]) [47] 0.056 ( isoenzyme TPKI [5]) [5] Additional information [63]

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pH-Optimum 7.2 ( assay at [62,70,74]) [62, 70, 74] 7.4 ( assay at [59,63,65,68,69]) [59, 63, 65, 68, 69] 7.5 ( assay at [61,66,67,71,75]) [61, 66, 67, 71, 75] Temperature optimum ( C) 30 ( assay at [59, 61, 65, 66, 67, 68, 69, 70, 71, 74, 75]) [59, 61, 65, 66, 67, 68, 69, 70, 71, 74, 75] 37 ( assay at [62,63]) [62, 63]

4 Enzyme Structure Molecular weight 30000 ( gel filtration [43]; isoenzyme TPKII, SDS-PAGE [5]; recombinant TPKII, SDS-PAGE [52]) [5, 43, 52] 32000 ( gel filtration, SDS-PAGE [47]) [47] 36000 ( calculated from cDNA sequence [54]) [54] 45000 ( SDS-PAGE [45]; isoenzyme TPKI, SDS-PAGE [5,49]) [5, 45, 49] Subunits heterodimer ( 1 * 30000 + 1 * 23000, catalytic and regulatory subunit, SDS-PAGE [49]) [49] Additional information ( 14-3-3 connects glycogen synthase kinase3 b to tau within a brain microtubule-associated tau phosphorylation complex [60]) [60] Posttranslational modification phosphoprotein ( phosphorylated in vitro at Ser9 by p70 S6 kinase and p90rsk-1, resulting in its inhibition [20]; regulation of Rim11 by Tyr phosphorylation during sporulation. Rim11 is phosphorylated on Tyr199, and the Tyr phosphorylation is essential for its in vivo function [29]; autophosphorylation, phosphorylation on a conserved tyrosine residue is required for efficient activity. Phosphorylated at a Ser225 is likely to inhibit its function [38]; phosphorylation of GSK3b at S9 inhibits the enzyme [61,66,67]; phosphorylation of GSK3b by a different protein kinase, e.g. phosphoinositol 3-kinase or protein kinase C, at Ser9 inhibits the enzyme [68]) [20, 29, 38, 61, 66, 67, 68]

5 Isolation/Preparation/Mutation/Application Source/tissue CN1.4 cell ( immortilized embryonic brain cortex cell line [71]) [71] HTAU cell ( immortilized embryonic brain cortex cell line overexpressing the human tau protein [71]) [71]

316

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Neuro-2A cell ( cell line stably expressing human apolipoprotein apoE4 [64]) [64, 69] SH-SY5Y cell ( neuroblastoma cell line [72]) [72] brain ( developing postnatal and embryonic [59]; distribution in brain regions, overview [73]; hyperphosphorylation in hippocampal and cerebral regions, weak in the cerebellum [58]; from Alzheimer patients, isozyme CKId [75]) [5, 43, 44, 45, 46, 47, 48, 49, 52, 54, 55, 56, 57, 58, 59, 60, 61, 63, 64, 65, 66, 67, 68, 69, 71, 73, 75] brain cortex [63, 71] brain stem [59] cell culture ( HeLa cells [20]; primary midbrain mesencephalonic cells [70]) [20, 70] central nervous system [71] cerebellum [59] cerebral cortex ( cold-water stress-induced tau phosphorylation pattern [58]) [58, 59] commercial preparation ( purified recombinant GSK-3b [63]) [63] embryo [46, 48, 49, 50, 55, 71] fetus [48, 49] heart [54] hippocampus ( tau phosphorylation pattern [58]) [58, 64, 65, 68] muscle [54] neuroblastoma cell [62] neuron ( neurofibrillary tangles [44]) [43, 44, 49, 50, 51, 52, 53, 62, 63, 64, 67, 68, 70, 72] spinal cord [59] Additional information ( expression pattern during brain development [59]) [59] Localization cytoplasm [70] cytoskeleton [60] cytosol ( low activity [73]) [62, 73] membrane ( mainly [73]) [73] microtubule [43, 61, 62, 63, 65, 66, 69, 70, 73] nucleus ( GSK-3 after cell treatment with lithium [63]) [63] Additional information ( CDK5-dependent clustering of endoplasmic reticulum ER and mitochondria and translocation to the centrosome during ceramide-mediated neuronal death [70]) [70] Purification [45, 51] (recombinant Leu-Glu-His6-tagged GSK3b from Escherichia coli) [57] (recombinant isoenzyme TPHII) [52] [43] (2 isoenzymes, TPKI and TPKII) [5, 54] (3 isoenzymes, tau protein kinase I and II and t-tubulin kinase) [47] [28]

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Crystallization (hanging drop vapour-diffusion method, prismatic crystals, orthorhombic space group P2(1)2(1)2(1), unit cell parameters a = 82.9, b = 86.1, c = 178.1 A) [51] (purified recombinant Leu-Glu-His6-tagged GSK3b in complex with ATP or ATP analogue AMP-PNP, 10 mg/ml protein, 2 mM ATP or AMP-PNP, 1214% w/v PEG 6000, 100 mM NaCl, 5 mM MgCl2 , 10% v/v glycerol, in 100 mM HEPES-NaOH, pH 7.5, hanging drop vapor diffusion method, 4 C, several days, soaking in 0.1 mM ethylmercuric thiosalicylate at pH 7.5 for 1 h, cryoprotection by 30% w/v d-sorbitol, X-ray diffraction structure determination and analysis at 1.7-2.6 A resolution) [57] Cloning (alternative splicing isoform of tau protein kinase I/glycogen synthase kinase 3b, by RT-PCR also found in rat and human brains, transient expression in COS-7 cells) [55] (mouse TTK cDNA isolated using amino acid sequences of purified bovine brain TTK) [54] [56] (TPKI/GSK-3b-interacting proteins from a human brain cDNA library in a yeast two-hybrid system) [48] (after cloning and cDNA analysis TPKI is found to be identical with glycogen synthase kinase 3b, the catalytic subunit of TPKII is identical with cdc2-related kinase, PSSALRE/Cdk5) [49] (cDNA cloned and expressed in Escherichia coli BL21(DE3)) [51] (expression of GSK3b in Escherichia coli in fusion with a Leu-Glu-His6tag at the C-terminus) [57] (expression of GST-fusion SGK1 in COS-1 cells in the cytoplasm, coexpression with protein 14-3-3 or addition of serum leads to relocation of the enzyme in the nucleus) [74] (recombinant TPKII cdk5/p20) [53] (tau protein kinase II, full length human cdk5 gene inserted into baculovirus genome) [52] (transient co-expression of human tau long isoform, HA-tagged GSK3b, and GST-tagged GFP-fusion FRAT-2 protein in HEK-293 cells) [67] (transient expression of HA-tagged wild-type and mutant enzymes in CHO cells) [61, 66] (co-expression of dominant negative EGFP-tagged CDK5 and p25 in PC12 cells) [70] (co-expression of glycogen synthase kinase-3 b, tau, and 14-3-3 in COS-7 cells and in HEK-293 cells) [60] [21] (expression of a and b protein in COS cells) [21] (isolation of cDNA) [22] (isolation of cDNA) [22] [24] (expression in Escherichia coli) [33]

318

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(expression in Escherichia coli) [33] [36] [38] [54]

Engineering R96A ( site-directed mutagenesis of GSK3b, the mutant shows reduced phosphorylation activity at primed epitopes and increased activity at unprimed epitopes of tau protein substrate compared to the wild-type GSK3b [66]) [66] S9A ( site-directed mutagenesis, mutant cannot be inhibited by phosphorylation at position 9 and is thus constitutively active [61,66,67]) [61, 66, 67] Additional information ( a cdk-deficient mouse mutant lacks tau phosphorylation activity [59]; naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of organisms with Alzheimers disease leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2 -terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of patients suffering from Alzheimers disease leads to age-dependent memory deficits [73]) [59, 73] Application medicine ( TPKI/GSK-3b plays a key role in the pathogenesis of Alzheimer disease, tau protein kinases I and II are candidate enzymes responsible for hyperphosphorylation of tau to induce formation of paired helical filaments [48,49]; brain pathology in investigation of Alzheimerss disease, human tau phosphorylated by the kinase carries an epitope of the paired helical filaments that accumulate in the brain [43,44,45,46,47]; PKA and GSK-3 are targets for the therpeutical treatement of Alzheimers disease and other tauopathies [65]) [43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 65] pharmacology ( anti-bodies highly specific for toxic amyloid oligomer subspecies may reduce toxicity via reduction of GSK-3b amount in Alzheimers disease therapeutic strategy [72]) [72]

6 Stability Temperature stability 95 ( 10 min, inactivation [74]) [74]

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tau-Protein kinase

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[54]

tau-Protein kinase

protein kinase homologous to shaggy/glycogen synthase kinase-3. Biochim. Biophys. Acta, 1260, 315-319 (1995) Ali, A.; Hoeflich, K.P.; Woodgett, J.R.: Glycogen synthase kinase-3: properties, functions, and regulation. Chem. Rev., 101, 2527-2540 (2001) Ishiguro, K.; Ihara, Y.; Uchida, T.; Imahori, K.: A novel tubulin-dependent protein kinase forming a paired helical filament epitope on tau. J. Biochem., 104, 319-321 (1988) Bush, M.L.; Miyashiro, J.S.; Ingram, V.M.: Activation of a neurofilament kinase, a tau kinase, and a tau phosphatase by decreased ATP levels in nerve growth factor-differentiated PC-12 cells. Proc. Natl. Acad. Sci. USA, 92, 1861-1865 (1995) Song, J.-S.; Yang, S.-D.: tau Protein kinase I/GSK-3b/kinase FA in heparin phosphorylates Tau on Ser199, Thr231, Ser235, Ser262, Ser369, and Ser400 sites phosphorylated in Alzheimer disease brain. J. Protein Chem., 14, 95105 (1995) Takahashi, M.; Tomizawa, K.; Ishiguro, K.; Takamatsu, M.; Fujita, S.C.; Imahori, K.: Involvement of tau protein kinase I in paired helical filament-like phosphorylation of the juvenile tau in rat brain. J. Neurochem., 64, 17591768 (1995) Takahashi, M.; Tomizawa, K.; Sato, K.; Ohtake, A.; Omori, A.: A novel ttubulin kinase from bovine brain. FEBS Lett., 372, 59-64 (1995) Hoshi, M.; Takashima, A.; Noguchi, K.; Murayama, M.; Sato, M.; Kondo, S.; Saitoh, Y.; Ishiguro, K.; Hoshino, T.; Imahori, K.: Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3b in brain. Proc. Natl. Acad. Sci. USA, 93, 2719-2723 (1996) Imahori, K.; Uchida, T.: Physiology and pathology of tau protein kinases in relation to Alzheimer’s disease. J. Biochem., 121, 179-188 (1997) Alvarez, A.; Toro, R.; Caceres, A.; Maccioni, R.B.: Inhibition of tau phosphorylating protein kinase cdk5 prevents b-amyloid-induced neuronal death. FEBS Lett., 459, 421-426 (1999) Aoki, M.; Iwamoto-Sugai, M.; Sugiura, I.; Sasaki, C.; Hasegawa, T.; Okumura, C.; Sugio, S.; Kohno, T.; Matsuzaki, T.: Expression, purification and crystallization of human t-protein kinase I/glycogen synthase kinase-3b. Acta Crystallogr. Sect. D, 56, 1464-1465 (2000) Evans, D.B.; Rank, K.B.; Bhattacharya, K.; Thomsen, D.R.; Gurney, M.E.; Sharma, S.K.: tau Phosphorylation at serine 396 and serine 404 by human recombinant tau protein kinase II inhibits tau’s ability to promote microtubule assembly. J. Biol. Chem., 275, 24977-24983 (2000) Lund, E.T.; McKenna, R.; Evans, D.B.; Sharma, S.K.; Mathews, W.R.: Characterization of the in vitro phosphorylation of human tau by tau protein kinase II (cdk5/p20) using mass spectrometry. J. Neurochem., 76, 12211232 (2001) Tomizawa, K.; Omori, A.; Ohtake, A.; Sato, K.; Takahashi, M.: t-Tubulin kinase phosphorylates tau at Ser-208 and Ser-210, sites found in paired helical filament-tau. FEBS Lett., 492, 221-227 (2001)

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[68] Li, X.; Lu, F.; Tian, Q.; Yang, Y.; Wang, Q.; Wang, J.Z.: Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture. J. Neural Transm., 113, 93-102 (2006) [69] Zhang, Y.; Li, H.L.; Wang, D.L.; Liu, S.J.; Wang, J.Z.: A transitory activation of protein kinase-A induces a sustained tau hyperphosphorylation at multiple sites in N2a cells-imply a new mechanism in Alzheimer pathology. J. Neural Transm., 2, 1-11 (2006) [70] Darios, F.; Muriel, M.P.; Khondiker, M.E.; Brice, A.; Ruberg, M.: Neurotoxic calcium transfer from endoplasmic reticulum to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau. J. Neurosci., 25, 4159-4168 (2005) [71] Shelton, S.B.; Krishnamurthy, P.; Johnson, G.V.: Effects of cyclin-dependent kinase-5 activity on apoptosis and tau phosphorylation in immortalized mouse brain cortical cells. J. Neurosci. Res., 76, 110-120 (2004) [72] Ma, Q.L.; Lim, G.P.; Harris-White, M.E.; Yang, F.; Ambegaokar, S.S.; Ubeda, O.J.; Glabe, C.G.; Teter, B.; Frautschy, S.A.; Cole, G.M.: Antibodies against bamyloid reduce ab oligomers, glycogen synthase kinase-3b activation and tau phosphorylation in vivo and in vitro. J. Neurosci. Res., 83, 374-384 (2006) [73] Lambourne, S.L.; Sellers, L.A.; Bush, T.G.; Choudhury, S.K.; Emson, P.C.; Suh, Y.H.; Wilkinson, L.S.: Increased tau phosphorylation on mitogen-activated protein kinase consensus sites and cognitive decline in transgenic models for Alzheimer’s disease and FTDP-17: evidence for distinct molecular processes underlying tau abnormalities. Mol. Cell. Biol., 25, 278-293 (2005) [74] Chun, J.; Kwon, T.; Lee, E.J.; Kim, C.H.; Han, Y.S.; Hong, S.K.; Hyun, S.; Kang, S.S.: 14-3-3 Protein mediates phosphorylation of microtubule-associated protein tau by serum- and glucocorticoid-induced protein kinase 1. Mol. Cells, 18, 360-368 (2004) [75] Hanger, D.P.; Byers, H.L.; Wray, S.; Leung, K.Y.; Saxton, M.J.; Seereeram, A.; Reynolds, C.H.; Ward, M.A.; Anderton, B.H.: Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J. Biol. Chem., 282, 23645-23654 (2007)

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[Acetyl-CoA carboxylase] kinase

2.7.11.27

1 Nomenclature EC number 2.7.11.27 Systematic name ATP:[acetyl-CoA carboxylase] phosphotransferase Recommended name [acetyl-CoA carboxylase] kinase Synonyms 5’-AMP activated protein kinase ( a-2 isoform [12]) [12, 13] ACK2 ACK3 AMPK [15, 17, 18, 20] AMPKa [21] I-peptide kinase ( highly specific for acetyl-CoA carboxylase, binds selectively to the dimeric form [11,14]) [11, 14] acetyl coenzyme A carboxylase kinase (phosphorylating) acetyl-CoA carboxylase bound kinase [10] acetyl-CoA carboxylase kinase acetyl-CoA carboxylase kinase (cAMP-independent) acetyl-CoA carboxylase kinase-2 acetyl-CoA carboxylase kinase-3 (AMP-activated) acetyl-coenzyme A carboxylase kinase Additional information ( cAMP-dependent protein kinase identified, that phosphorylates and inactivates acetyl-CoA carboxylase in vitro, but appears not to be involved in regulation in vivo [8]; phosphorylation by cAMP-dependent protein kinase has the same effect on acetyl-CoA carboxylase activity then phosphorylation with acetyl-CoA carboxylase kinase-2 [6,7]; two other cAMP-independent kinases found, that phosphorylate but do not effect acetyl-CoA carboxylase kinase activity [6]) [6, 7, 8] CAS registry number 77000-06-7

326

2.7.11.27

[Acetyl-CoA carboxylase] kinase

2 Source Organism Homo sapiens (no sequence specified) [15, 16, 21] Rattus norvegicus (no sequence specified) [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 19, 20] Spermophilus tridecemlineatus (no sequence specified) [18]

3 Reaction and Specificity Catalyzed reaction ATP + [acetyl-CoA carboxylase] = ADP + [acetyl-CoA carboxylase] phosphate Reaction type phospho group transfer Natural substrates and products S ATP + [acetyl-CoA carboxylase] ( involved in insulin dependent regulation of acetyl-CoA carboxylase in vivo [11]; phosphorylates and inactivates acetyl-CoA carboxylase, (EC 6.4.1.2), and is therefore involved in regulation of long chain fatty acid synthesis [1, 2, 3, 4, 5, 6, 7, 8]; acetyl-CoA carboxylase bound kinase involved in regulation in vivo [10]; most likely candidate for acetyl-CoA carboxylase inactivation in vivo [9]; ACK3 and not ACK2 appears to be responsible for acetyl-CoA carboxylase inactivation in lactating mammary gland [8]; regulation of acetyl-CoA carboxylase in muscle at metabolic stress conditions [12, 13]; acetyl-CoA carboxylase from skeletal muscle is more potently inhibited by palmitoyl-CoA after having been phosphorylated by AMPK. This may contribute to low muscle malonyl-CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated [20]; AMPK causes phosphorylation and inhibition of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA [15]; AMPKa negatively regulates activity of acetyl-CoA carboxylase and hepatic lipid content [21]; changes in activity of acetyl-CoA carboxylase could be coordinated by AMPK [17]; covalent activation of heart AMP-activated protein kinase in response to physiological concentrations of long-chain fatty acids, activation by an unknown fatty acid-driven signalling process [19]) (Reversibility: ?) [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21] P ADP + [acetyl-CoA carboxylase] phosphate [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14] Substrates and products S ATP + ATP-citrate lyase (Reversibility: ?) [6] P ADP + (ATP-citrate lyase) phosphate

327

[Acetyl-CoA carboxylase] kinase

2.7.11.27

S ATP + [acetyl-CoA carboxylase] ( no increase in acetyl-CoA carboxylase activity [11,14]; phosphorylates Ser77 and Ser1200 [10]; inactivation of carboxylase [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]; incorporates 0.6 mol phosphate per mol of carboxylase [5,14]; incorporates 1.5 mol phosphate per mol of carboxylase [6]; incorporates 0.45 mol phosphate per mol of carboxylase [2]; involved in insulin dependent regulation of acetyl-CoA carboxylase in vivo [11]; phosphorylates and inactivates acetyl-CoA carboxylase, (EC 6.4.1.2), and is therefore involved in regulation of long chain fatty acid synthesis [1, 2, 3, 4, 5, 6, 7, 8]; acetyl-CoA carboxylase bound kinase involved in regulation in vivo [10]; most likely candidate for acetyl-CoA carboxylase inactivation in vivo [9]; ACK3 and not ACK2 appears to be responsible for acetylCoA carboxylase inactivation in lactating mammary gland [8]; regulation of acetyl-CoA carboxylase in muscle at metabolic stress conditions [12,13]; acetyl-CoA carboxylase from skeletal muscle is more potently inhibited by palmitoyl-CoA after having been phosphorylated by AMPK. This may contribute to low muscle malonyl-CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated [20]; AMPK causes phosphorylation and inhibition of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA [15]; AMPKa negatively regulates activity of acetylCoA carboxylase and hepatic lipid content [21]; changes in activity of acetyl-CoA carboxylase could be coordinated by AMPK [17]; covalent activation of heart AMP-activated protein kinase in response to physiological concentrations of long-chain fatty acids, activation by an unknown fatty acid-driven signalling process [19]) (Reversibility: ?) [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21] P ADP + [acetyl-CoA carboxylase] phosphate [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14] S ATP + casein (Reversibility: ?) [4, 6] P ADP + phosphocasein S ATP + glycogen synthase (Reversibility: ?) [6] P ADP + (glycogen synthase) phosphate S ATP + histone ( histone H1 and H2B, very high activity with histone H2B [6]) (Reversibility: ?) [3, 4, 6] P ADP + phosphohistone S ATP + phosphorylase kinase ( poor substrate [6]) (Reversibility: ?) [6] P ADP + (phosphorylase kinase) phosphate S ATP + phosvitin (Reversibility: ?) [6] P ADP + phosvitin phosphate S ATP + protamine (Reversibility: ?) [3, 4] P ADP + protamine phosphate S ATP + pyruvate kinase L ( very poor substrate [6]) (Reversibility: ?) [6] P ADP + (pyruvate kinase L) phosphate

328

2.7.11.27

[Acetyl-CoA carboxylase] kinase

S Additional information ( no activity with phosphorylase b and 3-hydroxy-3-methylglutaryl-CoA reductase [3]; no activity with phosphorylase b [6]) (Reversibility: ?) [3, 6] P ? Inhibitors AMP ( 7% inhibition at 0.8 mM [6]) [6] citrate [10] CoA ( 16% inhibition at 0.1 mM [6]) [6] insulin [13] a-d-glucose 6-phosphate [14] a-glycerophosphate [14] b-glycerophosphate [11, 14] Activating compounds AMP ( no effect [10]; activates ACK3, no effect on ACK2 [8]; activation of ACK3 with Ka: 0.5 mM [9]) [8, 9, 10, 13] ATP ( required [1]) [1, 4] CoA ( required [5]; no effect [10]; inhibitory [6]; most effective at 0.1 mM [3]; required, activates exclusively activity towards acetyl-CoA carboxylase, Ka : 0.025 mM, binds to carboxylase not to kinase [4]) [3, 4, 5, 6, 10] deamino-CoA [4] insulin [11, 14] oxidized CoA [4] cAMP-dependent protein kinase ( phosphorylates and activates carboxylase kinase [5]) [5] dephospho-CoA [4] Additional information ( cAMP independent [1,3,10]; covalent activation of heart AMP-activated protein kinase in response to physiological concentrations of long-chain fatty acids, activation by an unknown fatty aciddriven signalling process [19]) [1, 3, 10, 19] Metals, ions Mg2+ ( required [1]) [1, 4] Specific activity (U/mg) 0.008 ( purified enzyme [6]) [6] 0.5 ( purified enzyme [1]) [1] Km-Value (mM) 0.000045 (acetyl-CoA carboxylase, phosphorylated enzyme [5]) [5] 0.00009 (acetyl-CoA carboxylase) [3] 0.000093 (acetyl-CoA carboxylase) [5] 0.0003 (acetyl-CoA carboxylase) [10] 0.0008 (protamine) [3] 0.005 (histone) [3] 0.02 (ATP) [3] 0.03 (ATP) [10]

329

[Acetyl-CoA carboxylase] kinase

2.7.11.27

Ki-Value (mM) 10 (b-glycerophosphate) [11, 14] 20 (a-glycerophosphate) [14] 30 (a-d-glucose 6-phosphate) [14]

4 Enzyme Structure Molecular weight 40000 ( SDS-PAGE [10]) [10] 53000 ( SDS-PAGE, two bands [11,14]) [11, 14] 65000 ( SDS-PAGE, two bands [11,14]) [11, 14] 76000 ( gel filtration [6,8]; ACK2 [8]) [6, 8] 90000 ( SDS-PAGE, two lighter bands at 40000 and 60000 Da detected [1]) [1] 105000 ( gel filtration ACK3 [8]) [8] 130000 ( gel filtration [14]) [14] 160000-200000 ( gel filtration [1]) [1] 170000 ( SDS-PAGE [3]) [3] Subunits Additional information ( high molecular weight aggregates, gel filtration [10]) [10]

5 Isolation/Preparation/Mutation/Application Source/tissue adipose tissue [11, 14, 18] epididymis [11, 14] heart [13, 15, 19] liver [1, 2, 3, 10, 17, 20] mammary gland [6, 7, 8, 9] muscle [12] skeletal muscle [16] Localization cytosol [1, 6] Purification [1, 2, 3, 4, 5, 6, 7, 10, 11, 14] (partial purification of ACK2 and ACK3) [8]

330

2.7.11.27

[Acetyl-CoA carboxylase] kinase

6 Stability Storage stability , -20 C, 10 mM phosphate buffer, pH 7, 2 mM EDTA, 10 mM 2-mercaptoethanol, 20% glycerol, 4 weeks, no loss of activity [3] , -70 C, partially purified kinase preparation, stable for several months, highly purified kinase is very labile and loses activity within 5 days [1]

References [1] Shiao, M.S.; Drong, R.F.; Porter, J.W.: The purification and properties of a protein kinase and the partial purification of a phosphoprotein phosphatase that inactivate and activate acetyl-CoA carboxylase. Biochem. Biophys. Res. Commun., 98, 80-87 (1981) [2] Jamil, H.; Madsen, N.B.: Phosphorylation state of acetyl-coenzyme A carboxylase. I. Linear inverse relationship to activity ratios at different citrate concentrations. J. Biol. Chem., 262, 630-637 (1987) [3] Lent, B.A.; Kim, K.-H.: Purification and properties of a kinase which phosphorylates and inactivates acetyl-CoA carboxylase. J. Biol. Chem., 257, 1897-1901 (1982) [4] Lent, B.A.; Kim, K.-H.: Requirement of acetyl-coenzyme A carboxylase kinase for coenzyme A. Arch. Biochem. Biophys., 225, 964-971 (1983) [5] Lent, B.A.; Kim, K.-H.: Phosphorylation and activation of acetyl-coenzyme A Carboxylase kinase by the catalytic subunit of cyclic AMP-dependent protein kinase. Arch. Biochem. Biophys., 225, 972-978 (1983) [6] Munday, M.R.; Hardie, D.G.: Isolation of three cyclic-AMP-independent acetyl-CoA carboxylase kinases from lactating rat mammary gland and characterization of their effects on enzyme activity. Eur. J. Biochem., 141, 617-627 (1984) [7] Munday, M.R.; Campbell, D.G.; Carling, D.; Hardie, D.G.: Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur. J. Biochem., 175, 331-338 (1988) [8] Ottey, K.A.; Takhar, S.; Munday, M.R.: Comparison of two cyclic-nucleotide-independent acetyl-CoA carboxylase kinase from lactating rat mammary gland: identification of the kinase responsible for acetyl-CoA inactivation in vivo. Biochem. Soc. Trans., 17, 349-350 (1989) [9] Ottey, K.A.; Munday, M.R.; Calvert, D.T.; Clegg, R.A.: Effect of anoxia on acetyl-CoA carboxylase activity: possible role for an AMP-activated protein kinase. Biochem. Soc. Trans., 17, 350-351 (1989) [10] Mohamed, A.H.; Huang, W.-Y.; Huang, W.; Venkatachalam, K.V.; Wakil, S.J.: Isolation and characterization of a novel acetyl-CoA carboxylase kinase from rat liver. J. Biol. Chem., 269, 6859-6865 (1994) [11] Heesom, K.J.; Moule, S.K.; Denton, R.M.: Purification of an insulin-stimulated acetyl-CoA carboxylase kinase from rat epididymal adipose tissue. Biochem. Soc. Trans., 23, 180S (1995)

331

[Acetyl-CoA carboxylase] kinase

2.7.11.27

[12] Vavvas, D.; Apazidis, A.; Saha, A.K.; Gamble, J.; Patel, A.; Kemp, B.E.; Witters, L.A.; Ruderman, N.B.: Contraction-induced changes in acetyl-CoA carboxylase and 5’-AMP-activated kinase in skeletal muscle. J. Biol. Chem., 272, 13255-13261 (1997) [13] Gamble, J.; Lopaschuk, G.D.: Insulin inhibition of 5’ adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation. Metabolism, 46, 1270-1274 (1997) [14] Heesom, K.J.; Moule, S.K.; Denton, R.M.: Purification and characterisation of an insulin-stimulated protein-serine kinase which phosphorylates acetylCoA carboxylase. FEBS Lett., 422, 43-46 (1998) [15] Hopkins, T.A.; Dyck, J.R.B.; Lopaschuk, G.D.: AMP-activated protein kinase regulation of fatty acid oxidation in the ischaemic heart. Biochem. Soc. Trans., 31, 207-212 (2003) [16] Wojtaszewski, J.F.; MacDonald, C.; Nielsen, J.N.; Hellsten, Y.; Hardie, D.G.; Kemp, B.E.; Kiens, B.; Richter, E.A.: Regulation of 5’-AMP-activated protein kinase activity and substrate utilization in exercising human skeletal muscle. Am. J. Physiol., 284, E813-822 (2003) [17] Assifi, M.M.; Suchankova, G.; Constant, S.; Prentki, M.; Saha, A.K.; Ruderman, N.B.: AMP-activated protein kinase and coordination of hepatic fatty acid metabolism of starved/carbohydrate-refed rats. Am. J. Physiol., 289, E794-800 (2005) [18] Horman, S.; Hussain, N.; Dilworth, S.M.; Storey, K.B.; Rider, M.H.: Evaluation of the role of AMP-activated protein kinase and its downstream targets in mammalian hibernation. Comp. Biochem. Physiol. B, 142, 374-382 (2005) [19] Clark, H.; Carling, D.; Saggerson, D.: Covalent activation of heart AMP-activated protein kinase in response to physiological concentrations of longchain fatty acids. Eur. J. Biochem., 271, 2215-2224 (2004) [20] Rubink, D.S.; Winder, W.W.: Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase. J. Appl. Physiol., 98, 1221-1227 (2005) [21] Zang, M.; Zuccollo, A.; Hou, X.; Nagata, D.; Walsh, K.; Herscovitz, H.; Brecher, P.; Ruderman, N.B.; Cohen, R.A.: AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J. Biol. Chem., 279, 47898-47905 (2004)

332

Tropomyosin kinase

2.7.11.28

1 Nomenclature EC number 2.7.11.28 Systematic name ATP:tropomyosin O-phosphotransferase Recommended name tropomyosin kinase Synonyms tropomyosin kinase (phosphorylating) CAS registry number 90804-56-1

2 Source Organism Gallus gallus (no sequence specified) [1, 2, 3] Oryctolagus cuniculus (no sequence specified) [1]

3 Reaction and Specificity Catalyzed reaction ATP + tropomyosin = ADP + O-phosphotropomyosin Reaction type phospho group transfer Natural substrates and products S ATP + a-tropomyosin ( involved in phosphorylation of embryonal skeletal muscle proteins [3]) (Reversibility: ?) [3] P ADP + O-phosphotropomyosin Substrates and products S ATP + KLKYKAISEELDHALNDITS(P)L ( peptide b[264-284] [3]) (Reversibility: ?) [3] P ? S ATP + KLKYKAISEELDHALNDMTS(P)I ( peptide a[264-284] [3]) (Reversibility: ?) [3] P ?

333

Tropomyosin kinase

2.7.11.28

S ATP + KLKYKAISEELDNALNDITS(P)I ( peptide Ile-284-b[264284] [3]) (Reversibility: ?) [3] P ? S ATP + KLKYKAISEELDNALNDITS(P)L ( peptide His-276-b[264284] [3]) (Reversibility: ?) [3] P ? S ATP + KLKYKAISEELDNALNDMTS(P)L ( peptide Met-281b[264-284] [3]) (Reversibility: ?) [3] P ? S ATP + a-tropomyosin ( involved in phosphorylation of embryonal skeletal muscle proteins [3]) (Reversibility: ?) [3] P ADP + O-phosphotropomyosin S ATP + casein (Reversibility: ?) [1] P ADP + phosphocasein S ATP + histone II- A (Reversibility: ?) [1] P ADP + phosphohistone II-A S ATP + phosphorylase b (Reversibility: ?) [1] P ADP + phosphophosphorylase b S ATP + phosvitin (Reversibility: ?) [1] P ADP + phosphophosvitin S ATP + tropomyosin ( b-tropomyosin from turkey gizzard [1]; other poor substrates are b-tropomyosin from chicken leg muscle, rabbit skeletal muscle [2]; the phosphorylation site is a single serine-residue close to COOH- terminus, i.e Ser-283 [2]; a-tropomyosin subunit preferred over b-tropomyosin subunit [1,2]) (Reversibility: ?) [1, 2, 3] P ADP + O-phosphotropomyosin [2] S ATP + troponin complex ( from rabbit skeletal muscle [1]) (Reversibility: ?) [1] P ADP + phosphotroponin complex S aa-tropomyosin + ATP (Reversibility: ?) [3] P ? S bb-tropomyosin + ATP (Reversibility: ?) [3] P ? S Additional information ( no substrates are smooth muscle myosin light chain from turkey gizzard, tropomyosin from platelet and erythrocyte from chicken gizzard and smooth muscle [1,2]; no substrates are g- or b-tropomyosin from smooth muscle from chicken gizzard [2]) (Reversibility: ?) [1, 2] P ? Inhibitors Ca2+ ( 3 mM [2]) [2] KCl ( high concentrations [2]) [2] Additional information ( no inhibition by heparin [1]) [1]

334

2.7.11.28

Tropomyosin kinase

Cofactors/prosthetic groups Additional information ( no activation by cAMP or calmodulin [1,2]) [1,2] Activating compounds DTT ( requirement [1]) [1] Metals, ions Mg2+ ( requirement [1,2]) [1, 2] Additional information ( no activation by Ca2+ [1,2]) [1, 2] Specific activity (U/mg) 0.0004 [2] 0.0594 [1] Km-Value (mM) 0.047 (aa-tropomyosin, 37 C, pH 7.5 [3]) [3] 0.05 (a-tropomyosin, 37 C, pH 7.5, skeletal a-tropomyosin [1]) [1] 0.2 (ATP, 37 C, pH 7.5 [1]) [1] 0.264 (bb-tropomyosin, 37 C, pH 7.5 [3]) [3] 0.33 (Met-281-b[264-284], 37 C, pH 7.5 [3]) [3] 0.5 (a[264-284], 37 C, pH 7.5 [3]) [3] 0.66 (b[264-284], 37 C, pH 7.5 [3]) [3] 1.36 (Ile-284-b[264-284], 37 C, pH 7.5 [3]) [3] 1.48 (His-276-b[264-284], 37 C, pH 7.5 [3]) [3] pH-Optimum 7.5 [1] pH-Range 6.2-9.5 ( about half-maximal activity at pH 6.2 and 9.5 [1]) [1] Temperature optimum ( C) 37 ( about [1]) [1] Temperature range ( C) 22-40 ( about 10% of maximal activity at 22 C and about 60% of maximal activity at 40 C [1]) [1]

4 Enzyme Structure Molecular weight 252000 ( gel filtration [1]) [1]

335

Tropomyosin kinase

2.7.11.28

5 Isolation/Preparation/Mutation/Application Source/tissue embryo [1, 2, 3] muscle ( thigh and leg [1,2,3]) [1, 2, 3] Additional information ( not in adult chicken or adult rabbit skeletal muscle [1]) [1] Purification (partial) [1, 2]

6 Stability General stability information , highly purified enzyme is very unstable upon further purification [1] Storage stability , 4 C, in 10% sucrose at least 2 weeks [1]

References [1] deBelle, I.; Mak, A.S.: Isolation and characterization of tropomyosin kinase from chicken embryo. Biochim. Biophys. Acta, 925, 17-26 (1987) [2] Montgomery, K.; Mak, A.S.: In vitro phosphorylation of tropomyosin by a kinase from chicken embryo. J. Biol. Chem., 259, 5555-5560 (1984) [3] Watson, M.H.; Taneja, A.K.; Hodges, R.S.; Mak, A.S.: Phosphorylation of aaand bb-tropomyosin and synthetic peptide analogues. Biochemistry, 27, 4506-4512 (1988)

336

Low-density-lipoprotein receptor kinase

2.7.11.29

1 Nomenclature EC number 2.7.11.29 Systematic name ATP:[low-density-lipoprotein receptor]-l-serine O-phosphotransferase Recommended name low-density-lipoprotein receptor kinase Synonyms LDL receptor kinase low-density lipoprotein receptor kinase low-density-lipoprotein receptor kinase (phosphorylating) CAS registry number 107445-00-1

2 Source Organism Bos taurus (no sequence specified) [1, 2]

3 Reaction and Specificity Catalyzed reaction ATP + [low-density-lipoprotein receptor]-l-serine = ADP + [low-density-lipoprotein receptor]-O-phospho-l-serine Reaction type phospho group transfer Natural substrates and products S ATP + low-density lipoprotein receptor (Reversibility: ?) [1, 2] P ? Substrates and products S ATP + casein ( phosphorylated by catalytic subunit, activator subunit not required [2]) (Reversibility: ?) [1, 2] P ? S ATP + low-density lipoprotein receptor (Reversibility: ?) [1, 2] P ?

337

Low-density-lipoprotein receptor kinase

2.7.11.29

S ATP + low-density lipoprotein-l-serine ( phosphorylates the Ser833 in the cytoplasmic domain of the low-density lipoprotein receptor [1]; enzyme is composed of a catalytic and an activator subunit, the specificity for low-density lipoprotein receptor is attributable to the latter [2]; GTP can replace ATP to some extent [1]; no substrates are protamine or histamine [1]) (Reversibility: ?) [1, 2] P ADP + low-density lipoprotein O-phospho-l-serine [1, 2] S ATP + phosvitin (Reversibility: ?) [1] P ? S ATP + tubulin (Reversibility: ?) [2] P ? Inhibitors heparin ( strong [1]) [1] low-density lipoprotein receptor ( above 10 nM, spermine protects [1]) [1] polylysine ( strong [1]) [1] trypsin ( inactivation of activator subunit [2]) [2] Additional information ( no inhibition by cAMP, cGMP, Ca2+ /calmodulin, Ca2+ /phosphatidylserine or N-ethylmaleimide [1]) [1] Activating compounds Additional information ( no activation by polylysine [1]) [1] Specific activity (U/mg) 0.00118 ( casein as substrate [2]) [2] 0.0033 [1] Km-Value (mM) 0.000005 (Low-density lipoprotein receptor, 30 C, pH 7.5 [1]) [1] pH-Optimum 7.5 ( assay at [1,2]) [1, 2] Temperature optimum ( C) 30 ( assay at [1,2]) [1, 2]

4 Enzyme Structure Molecular weight 155000-170000 ( gel filtration [2]) [2] Subunits dimer ( ab, 1 * 35000-50000 + 1 * 120000, SDS-PAGE and gel filtration, a catalytic subunit for phosphorylation and an activator subunit, activator subunit not required [2]) [1, 2]

338

2.7.11.29

Low-density-lipoprotein receptor kinase

5 Isolation/Preparation/Mutation/Application Source/tissue adrenal gland ( cortex [1,2]) [1, 2] Localization cytosol [1, 2] soluble [1, 2] Purification [2] (partial) [1]

6 Stability General stability information , high salt concentrations, e.g. 1 mM NaCl, inactivate [1]

References [1] Kishimoto, A.; Brown, M.S.; Slaughter, C.A.; Goldstein, J.L.: Phosphorylation of serine 833 in cytoplasmic domain of low density lipoprotein receptor by a high molecular weight enzyme resembling casein kinase II. J. Biol. Chem., 262, 1344-1351 (1987) [2] Kishimoto, A.; Goldstein, J.L.; Brown, M.S.: Purification of catalytic subunit of low density lipoprotein receptor kinase and identification of heat-stable activator protein. J. Biol. Chem., 262, 9367-9373 (1987)

339

Receptor protein serine/threonine kinase

1 Nomenclature EC number 2.7.11.30 Systematic name ATP:[receptor-protein] phosphotransferase Recommended name receptor protein serine/threonine kinase Synonyms ACTR-IC [4] ALK1 [13, 15] ALK2 [6] ALK4 [9] ALK5 [3, 6, 12, 13, 15, 16] ALK7 [4, 7, 10] BM-PRI [16] BM-PRII [16] BMP type I receptor [16] BMP type II receptor [11, 16] BMPRII [11] ESK2 MIS type II receptor MISRII MRII RSTK [14] SKR1 SKR2 SKR3 SKR4 SKR5 SKR6 serine/threonine-protein kinase receptor R1 serine/threonine-protein kinase receptor R4 serine/threonine-protein kinase receptor R5 serine/threonine-protein kinase receptor R6 SmRK2 [14] TGF-b receptor [8, 11, 15, 18] TGF-b receptor I [1, 4, 6] TGF-b receptor I kinase [3]

340

2.7.11.30

2.7.11.30

Receptor protein serine/threonine kinase

TGF-b receptor II [6] TGF-b receptor kinase [17] TGF-b type I receptor [12, 13] TGF-b type I receptor kinase [5] TGF-b type II receptor TGF-b type-I receptor [3] TRKI [17] TSK-7L TbKI [1] TbR-I [5, 11] TbR-II [11] TbRI [3, 15] TbRI kinase [2] TbRI receptor kinase [2] TbRII [15] activin receptor-like kinase 1 [13, 15] activin receptor-like kinase 2 [6] activin receptor-like kinase 5 [6, 13, 15, 16] activin receptor-like kinase 7 [4, 7] activin receptor-like kinase-7 [10] activin-like kinase receptor 4 [9] bone morphogenetic protein type II receptor [16] receptor serine/threonine kinase [14] serine/threonine receptor kinase [11] transforming growth factor b type-I receptor [3] transforming growth factor-b receptor [8, 11, 13, 15, 18] transforming growth factor-b receptor 1 [4] transforming growth factor-b receptor I [1, 6] transforming growth factor-b receptor II [6] transforming growth factor-b type I receptor [12] transforming growth factor-b type I receptor kinase [5] type I receptor kinase [1] type I serine/threonine kinase [7] type II receptor serine/threonine kinase [14] Additional information ( ALK7 is a type I serine/threonine kinase receptor belonging to the TGF-b family of proteins [10]; the enzyme belongs to the TGF-b superfamily of enzymes [7]; the RSTK belong to the TGF-b family of receptor serine/threonine kinases [14]) [7, 10, 14] CAS registry number 146702-86-5 152060-53-2 154907-75-2

341

Receptor protein serine/threonine kinase

2.7.11.30

2 Source Organism





Gallus gallus (no sequence specified) [6] Mus musculus (no sequence specified) [5, 11, 15] Homo sapiens (no sequence specified) [1, 2, 3, 5, 9, 10, 12, 13, 17, 18] Rattus norvegicus (no sequence specified) [7, 8, 16] Homo sapiens (UNIPROT accession number: Q8NER5) [4] Schistosoma mansoni (UNIPROT accession number: Q6GZL5) [14]

3 Reaction and Specificity Catalyzed reaction ATP + [receptor-protein] = ADP + [receptor-protein] phosphate Natural substrates and products S ATP + Smad ( involved in ALK5 activation of p38 MAPK signaling and of GADDb45 and BGN expression induced by TGF-b [12]) (Reversibility: ?) [12] P ADP + phosphorylated Smad S ATP + Smad1 ( phosphorylation by ALK1 [15]) (Reversibility: ?) [15] P ADP + phosphorylated Smad1 S ATP + Smad2 ( ALK7 is involved in regulation of cell proliferation and apoptosis, regulation, overview [7]; GDF-9-induced phosphorylation [16]; phosphorylation by ALK5 [15]; step in the MAPK signaling pathway via JNK and p38 [10]; TGF-b- or actividin-induced phosphorylation [1]; TGF-b-induced phosphorylation by TbRI receptor kinase at both phosphorylation sites Ser465 and Ser467 leads to release of Smad2 from membrane-anchored protein SARA and signaling co-mediator Smad4, translocation into the nucleus, and regulation of target gene expression [2]; TGF-b-mediated activation of Smad2 by the TGF-b receptor [8,18]) (Reversibility: ?) [1, 2, 7, 8, 10, 11, 15, 16, 18] P ADP + phosphorylated Smad2 S ATP + Smad3 ( ALK7 [7]; GDF-9-induced phosphorylation [16]; phosphorylation by ALK5 [15]; step in the MAPK signaling pathway via JNK and p38 [10]; TGF-b-mediated activation of Smad3 by the TGF-b receptor [8,18]) (Reversibility: ?) [7, 8, 10, 11, 15, 16, 18] P ADP + phosphorylated Smad3 S ATP + Smad5 ( phosphorylation by ALK1 [15]) (Reversibility: ?) [15] P ADP + phosphorylated Smad5 S Additional information ( activin receptor-like kinase-7, ALK7, induces apoptosis through activation of MAPKs, e.g. SEK1, in a Smad3-dependent mechanism in hepatoma cells [10]; ALK4 forms a

342

2.7.11.30

Receptor protein serine/threonine kinase

complex with type II serine/threonine transmembrane receptor ActRIIB or ActRII and activin for initiation of signaling, ALK3 forms a complex with bone morphogenetic protein-2 [9]; ALK7 induces apoptosis of pancreatic b cells and b cell lines via Smad2-caspase3 pathways causing diabetes of type 1 and 2, ALK7 activation suppresses Akt activation [7]; diverse ligand members of the TGF-b family interact with a limited number of receptors in a combinatorial manner to activate two downstream Smad pathways [16]; in TGF-b signaling, phosphorylated Smad2 and Smad3 form a complex with tumor suppressor Smad4, the complex is translocated to the nucleus, nuclear translocation of Smad2 and Smad3 in absence of Smad4 is not sufficient for TGF-b-induced transcriptional responses, Smad4 mutations occur in some human cancers and inactivate the TGF-b signaling, overview [18]; TGF-b is responsible for induction of growth arrest in cells via the transforming growth factor-b receptor I, the inhibition can be blocked by cell treatment with SD-093overview [1]; TGF-b mediates activation of Smad2 and Smad3 in a differentiated way dependent on the developmental and activationstages of the cells, regulation, overview [8]; TGF-b regulates the activation state of endothelium via two opposing type I receptor/Smad pathways: ALK1 induces Smad1/5 phosphorylation leading to increased endothelial cell proliferation and migration, while ALK5 promotes Smad2/3 activation and inhibits both processes, regulation overview [15]; TGF-b signaling is involved in a wide range of cellular processes and various disease states in humans, R-Smad phosphorylation plays a key role [2]; TGF-b signals via its receptor type I and type II, ALK5 mediates most of the TGF-b signaling, misexpression of ALK2, being constitutively active, in nontransforming ventricular, endocardial cells causes epithelialmesenchymal transformation, EMT, which can be inhibited by Smad6, since ALK2 alone is sufficient to cause EMT, overview [6]; the enzyme is involved in p38 MAPK activation [5]; the TGF-b receptor kinase is involved in transforming growth in advanced carcinogenesis and in epithelial-to-mesenchymal cell transition, EMT, overview [17]; the TGF-b type I receptor/ALK5-dependent activation of the GADD45b gene mediates the induction of biglycan expression by TGF-b, th TGF-b type II receptor is required for for TGF-b binding and signaling induction activity, overview [12]) (Reversibility: ?) [1, 2, 5, 6, 7, 8, 9, 10, 12, 15, 16, 17, 18] P ? Substrates and products S ATP + KKVLTQMGSPSIRCS(P)SV(P)S ( Smad3-derived peptide substrate [3]) (Reversibility: ?) [3] P ADP + ? S ATP + KKVLTQMGSPSIRCS(P)SVA ( Smad3-derived peptide substrate [3]) (Reversibility: ?) [3] P ADP + ?

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S ATP + KKVLTQMGSPSIRCS(P)SVS ( Smad3-derived peptide substrate [3]) (Reversibility: ?) [3] P ADP + ? S ATP + KMGSPSVRCS(P)SMS ( TGF-b-induced phosphorylation by TbRI receptor kinase of the Smad2-derived, phosphorylated peptide substrate containing Ser465 phosphorylation site, poor activity with nonphosphorylated peptide substrate [2]) (Reversibility: ?) [2] P ADP + ? S ATP + KVLTQMGSPSIRCS(P)SVS ( Smad3-derived peptide substrate [3]) (Reversibility: ?) [3] P ADP + ? S ATP + KVLTQMGSPSIRCSSV(P)S ( Smad3-derived peptide substrate [3]) (Reversibility: ?) [3] P ADP + ? S ATP + KVLTQMGSPSVRCS(P)SMS ( Smad2-derived peptide substrate [3]) (Reversibility: ?) [3] P ADP + ? S ATP + KVLTQMGSPSVRCSSMS ( Smad2-derived peptide substrate [3]) (Reversibility: ?) [3] P ADP + ? S ATP + KVLTQMGSPSVRCSSMS(P)S ( Smad2-derived peptide substrate [3]) (Reversibility: ?) [3] P ADP + ? S ATP + Smad ( involved in ALK5 activation of p38 MAPK signaling and of GADDb45 and BGN expression induced by TGF-b [12]) (Reversibility: ?) [12] P ADP + phosphorylated Smad S ATP + Smad1 ( phosphorylation by ALK1 [15]) (Reversibility: ?) [15] P ADP + phosphorylated Smad1 S ATP + Smad2 ( ALK7 [7]; ALK7 is involved in regulation of cell proliferation and apoptosis, regulation, overview [7]; GDF-9induced phosphorylation [16]; phosphorylation by ALK5 [15]; step in the MAPK signaling pathway via JNK and p38 [10]; TGF-b- or actividin-induced phosphorylation [1]; TGF-b-induced phosphorylation by TbRI receptor kinase at both phosphorylation sites Ser465 and Ser467 leads to release of Smad2 from membrane-anchored protein SARA and signaling co-mediator Smad4, translocation into the nucleus, and regulation of target gene expression [2]; TGF-b-mediated activation of Smad2 by the TGF-b receptor [8,18]; phosphorylation by ALK7 [10]; phosphorylation by the TGF-b receptor [8]; recombinant GSTfusion Smad2 substrate expressed in Escherichia coli, TGF-b- or actividin-induced phosphorylation of the two C-terminal Ser residues in the Ser-Ser-Xaa-Ser motif [1]; TGF-b-induced phosphorylation by TbRI receptor kinase at two phosphorylation sites Ser465 and Ser467 within the MH2 domain, activity with Smad2 analogues, overview [2]; TGF-b-induced phosphorylation of Arg462 and Cys463 by TbR-I, no activity with

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P S

P S P S

Receptor protein serine/threonine kinase

Smad2 mutant R462I/C463A by TbR-I, Smad2 is no substrate of TbR-II and BMP type II receptor [11]; the substrate is a tumor suppressor [18]) (Reversibility: ?) [1, 2, 7, 8, 10, 11, 15, 16, 18] ADP + phosphorylated Smad2 ATP + Smad3 ( ALK7 [7]; GDF- 9-induced phosphorylation [16]; phosphorylation by ALK5 [15]; step in the MAPK signaling pathway via JNK and p38 [10]; TGF-b-mediated activation of Smad3 by the TGF-b receptor [8,18]; phosphorylation by ALK7 [10]; phosphorylation by the TGF-b receptor [8]; TGF-binduced C-terminal phosphorylation [11]; the substrate is a tumor suppressor [18]) (Reversibility: ?) [7, 8, 10, 11, 15, 16, 18] ADP + phosphorylated Smad3 ATP + Smad5 ( phosphorylation by ALK1 [15]) (Reversibility: ?) [15] ADP + phosphorylated Smad5 Additional information ( activin receptor-like kinase-7, ALK7, induces apoptosis through activation of MAPKs, e.g. SEK1, in a Smad3-dependent mechanism in hepatoma cells [10]; ALK4 forms a complex with type II serine/threonine transmembrane receptor ActRIIB or ActRII and activin for initiation of signaling, ALK3 forms a complex with bone morphogenetic protein-2 [9]; ALK7 induces apoptosis of pancreatic b cells and b cell lines via Smad2-caspase3 pathways causing diabetes of type 1 and 2, ALK7 activation suppresses Akt activation [7]; diverse ligand members of the TGF-b family interact with a limited number of receptors in a combinatorial manner to activate two downstream Smad pathways [16]; in TGF-b signaling, phosphorylated Smad2 and Smad3 form a complex with tumor suppressor Smad4, the complex is translocated to the nucleus, nuclear translocation of Smad2 and Smad3 in absence of Smad4 is not sufficient for TGF-b-induced transcriptional responses, Smad4 mutations occur in some human cancers and inactivate the TGF-b signaling, overview [18]; TGF-b is responsible for induction of growth arrest in cells via the transforming growth factor-b receptor I, the inhibition can be blocked by cell treatment with SD-093overview [1]; TGF-b mediates activation of Smad2 and Smad3 in a differentiated way dependent on the developmental and activationstages of the cells, regulation, overview [8]; TGF-b regulates the activation state of endothelium via two opposing type I receptor/Smad pathways: ALK1 induces Smad1/5 phosphorylation leading to increased endothelial cell proliferation and migration, while ALK5 promotes Smad2/3 activation and inhibits both processes, regulation overview [15]; TGF-b signaling is involved in a wide range of cellular processes and various disease states in humans, R-Smad phosphorylation plays a key role [2]; TGF-b signals via its receptor type I and type II, ALK5 mediates most of the TGF-b signaling, misexpression of ALK2, being constitutively active, in nontransforming ventricular, endocardial cells causes epithelialmesenchymal transformation, EMT, which can be inhibited by Smad6, since ALK2 alone is sufficient to cause EMT, overview [6]; the en-

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zyme is involved in p38 MAPK activation [5]; the TGF-b receptor kinase is involved in transforming growth in advanced carcinogenesis and in epithelial-to-mesenchymal cell transition, EMT, overview [17]; the TGF-b type I receptor/ALK5-dependent activation of the GADD45b gene mediates the induction of biglycan expression by TGF-b, th TGF-b type II receptor is required for for TGF-b binding and signaling induction activity, overview [12]; ALK2 and ALK5 are type I receptors [6]; ALK5 performs autophosphorylation, substrate specificities of recombinant wild-type and mutant T204D ALK5, ALK5 is the intracellular domain of the transforming growth factor b type-I receptor [3]; GDF-9 does not induce phosphorylation of Smad1 [16]; substrate specificity of transforming growth factor-b receptor I [11]) (Reversibility: ?) [1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 17, 18] P ? Inhibitors 4(quinolin-4-yl)-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole derivatives ( IC50 of 0.00005-0.0013 mM [5]; IC50 of 0.000150.0051 mM, overview [5]) [5] 4-phenyl substituted pyrazole inhibitors ( inhibitory potency of 4phenyl substituted pyrazole derivatives, IC50 of 30-555 nM, overview [3]) [3] 4-phenyl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole derivatives ( IC50 of 0.000005-0.0195 mM [5]; IC50 of 0.00011-0.020 mM, overview [5]) [5] LY364947 ( competitive to ATP, noncompetitive to the peptide substrate, IC50 is 175 nM, mechanism [3]; IC50 is 31 nM [5]; IC50 is 51 nM [5]) [3, 5] LY566578 ( competitive to ATP, noncompetitive to the peptide substrate, IC50 is 70 nM, mechanism [3]) [3] LY580276 ( competitive to ATP, noncompetitive to the peptide substrate, IC50 is 580 nM, mechanism [3]) [3] PEG10 ( ancient retroviral/retrotransposon element intergrated as a single copy gene in to human chromosome 7q21, encodes two splicing varaiants PEG10-RF1 and PEG10-RF1/2, gag- and gag-pol-like proteins that interact with TGF-b family proteins, DNA and amino acid sequence deteramination and analysis of PEG10-RF1, PEG10-RF1 inhibits ALK1 and ALK5 signaling by direct interaction, overview [13]) [13] SB-431542 ( specific TGF-b receptor kinase inhibitor, a potent antitumor agent for human cancers, induces anchorage-independent cell growth in TGF-b growth-inhibited cells, and colony formation in growth-induced cells, overview [17]) [17] Smad7 ( inhibits induction of receptor activation/signaling by GDF-9 in vivo [16]) [16] Additional information ( a dominant negative SEK1 mutant abolishes the ALK7-induced apoptosis [10]; ALK1 mediates inhibition of the ALK5/Smad2/3 pathway [15]; no inhibition of GDF-9-induced receptor activation by Smad6 [16]) [10, 15, 16]

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Cofactors/prosthetic groups ATP [1,2,3,5,7,8,9,10,11,12,15,16,17,18] Activating compounds ALK5 ( is important for ALK1/TGF-b signaling [15]) [15] SARA protein ( i.e. Smad anchor for receptor activation protein, binding site for co-modulator Smad4, modulates self-association of partially phosphorylated Smad2 preventing premature release of monophosphorylated substrate, interaction with Smad2 via the Smad2 MH2 domain [2]) [2] TGF-b ( a potent regulator of cell proliferation, differentiation, motility, and apoptosis, binds to and activates serine/threonine receptors that phosphorylate Smad2 and Smad3 [11]; activates the TGF-b receptor by direct binding [18]; activates the TGF-b type I receptor kinase by binding, affects BGN and GADDb45 expression in PANC-1 and M-63 cells via ALK5 and Smad phosphorylation/activation, overview [12]; activates the type II and type I membrane receptors, e.g. ALK1 and ALK5 [15]; binds and activates the TGF-b receptor kinase, promotes transforming growth in advanced carcinogenesis, influences transcription activity of cells [17]; binds and activates the TGF-b receptor, treatment of cells with TGF-b increases the production of matrix proteins [8]; binds and activates the TGF-family receptor kinases of type I and type II, e.g. type I receptor ALK7 [7]; binds to and activates TbRI receptor kinase that phosphorylates Smad2 [2]; i.e. transforming growth factor-b, interacts with and activates type I transforming growth factor-b receptor [1]; interacts with and activates type I actividin receptor-like kinase 5, ALK5 [16]) [1, 2, 5, 6, 7, 8, 10, 11, 12, 15, 16, 17, 18] TGF-b 3 ( binds and activates ALK5 [13]) [13] actividin ( activates Smad2 phosphorylation via type I receptor kinases [1]; binds and activates the type I receptor ALK7 [7]; TGF-b receptor I and ALK7 possess an actividin receptor-binding domain [4]) [1, 4, 7] actividin A ( required for activity in a complex formed with ALK4 and ActRIIB or ActRII, identification of the functional binding site [9]) [9] actividin B ( required for activity in a complex formed with ALK4 and ActRIIB or ActRII, identification of the functional binding site [9]) [9] growth differentiation factor-9 ( i.e. GDF-9, interacts with bone morphogenetic protein type II receptor, and activates type I actividin receptor-like kinase 5, ALK5, GDF-9 belongs to the TGF-b family, no stimulation of receptors ALK1, ALK2, ALK3, and ALKA6 by GDF-9 [16]) [16] nodal [4] Additional information ( increased d-glucose and palmitate concentrations increase the ALK7 enzyme expression in INS-1 cells [7]) [7] Metals, ions Mg2+ [2, 3, 11] Mn2+ [1, 2, 11] Specific activity (U/mg) Additional information [15]

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Km-Value (mM) 0.0057 (ATP, pH 7.5, 30 C, recombinant mutant T204D ALK5 [3]) [3] 0.0088 (ATP, pH 7.5, 30 C, recombinant wild-type ALK5 [3]) [3] 0.26 (KKVLTQMGSPSIRCS(P)SVS, pH 7.5, 30 C, recombinant wildtype ALK5 [3]) [3] 0.331 (KVLTQMGSPSVRCS(P)SMS, pH 7.5, 30 C, recombinant wild-type ALK5 [3]) [3] Ki-Value (mM) 0.000028 (LY364947, pH 7.5, 30 C, recombinant mutant T204D ALK5, inhibition of autophosphorylation [3]) [3] 0.000037 (LY580276, pH 7.5, 30 C, recombinant mutant T204D ALK5, inhibition of autophosphorylation [3]) [3] 0.000038 (LY566578, pH 7.5, 30 C, recombinant mutant T204D ALK5, inhibition of autophosphorylation [3]) [3] pH-Optimum 7.4 ( assay at [11]) [11] 7.5 ( assay at [1,2,3,5]) [1, 2, 3, 5] Temperature optimum ( C) 22 ( assay at [11]) [11] 22-30 ( assay at [2]) [2] 25 ( assay at [1]) [1] 30 ( assay at [3,5]) [3, 5]

4 Enzyme Structure Subunits ? ( x * 55000-72000, different cell sources, SDS-PAGE [7]) [7] Additional information ( ALK3 crystal structure model analysis [9]; ALK5 is the intracellular domain of the transforming growth factor b type-I receptor [3]) [3, 9] Posttranslational modification phosphoprotein ( ALK5 performs autophosphorylation, wild-type and mutant T204D enzymes [3]) [3]

5 Isolation/Preparation/Mutation/Application Source/tissue BxPC-3 cell ( pancreatic Smad4 null cell line, expression of Smad2 and Smad3 [18]) [18] CFPAC-1 cell ( pancreatic Smad4 null cell line, expression of Smad2 and Smad3 [18]) [18]

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Receptor protein serine/threonine kinase

HS776T cell ( pancreatic Smad4 null cell line, expression of Smad2 and Smad3 [18]) [18] Hep-3B cell ( hepatoma cell line [10]) [10] INR1G9 cell ( a-cell line [7]) [7] INS-1 cell ( pancreatic b cell line [7]) [7] MDA-MB-231 cell ( breast carcinoma cell line, derived from malignant pleural effusions [1]) [1] MDA-MB-435 cell ( breast carcinoma cell line, derived from malignant pleural effusions [1]) [1] MDA-MB-468 cell ( breast Smad4 null cell line, expression of Smad2 and Smad3 [18]) [18] MEF cell ( enbryonic fibroblast cell line [11]) [11] MG-63 cell ( osteosarcoma cell line [12]) [12] MIN-6 cell ( pancreatic b cell line [7]) [7] NIH-3T3 cell ( fibroblast cell line [5]) [5] P-19 cell ( granulosa cell line [16]) [16] PANC-1 cell ( pancreatic cancer cell line [12]) [12] VACO cell ( diverse VACO cell lines, Smad4 null cell lines, expression analysis of Smad2, overview [18]) [18] adult ( e.g. on the dorsal surface of male parasites, and on the dorsal and ventral surfaces of female parasites [14]) [14] bone ( ALK3 [9]) [9] brain [4, 7] breast carcinoma cell [1] carcinoma cell [17] endocardium ( ALK2, nontransforming ventricular, misexpression of LAK2 in endocardial cells [6]) [6] endothelium ( embryonic cells [15]) [15] epithelium [6] fibroblast [5, 11] granulosa cell [16] gynecophoral canal [14] heart ( ALK2 and ALK5, atrioventricular cushion of developing heart [6]; low ALK7 expression level [4]) [4, 6] hepatic stellate cell ( primary, differential TGF-b-mediated activation of Smad2 and Smad3 in activated and non-activated cells, overview [8]) [8] hepatoma cell [10] integument ( surface, primary expression of type II receptor serine/ threonine kinase, SmRK2 [14]) [14] kidney ( high ALK7 expression level [4]) [4] liver [4] muscle [4] osteosarcoma cell [12] ovarian follicle ( small antral follicle of estrogen-treated rats [16]) [16] ovary [16]

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Receptor protein serine/threonine kinase

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pancreas [7] pancreatic b cell [7] pancreatic cancer cell [12] pancreatic islet [7] placenta ( high ALK7 expression level, co-expression of nodal in different gestational stages [4]) [4, 13] schistosomulum [14] trophoblast [4] Additional information ( expression analysis of ALK7 in different cells types, overview [7]) [7] Localization membrane ( transmembrane protein [4,9]; the isozymes all possess an extracellular domain [14]; with a cytoplasmic domain [13]; with a large cytoplasmic domain [7]) [1, 2, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18] Purification (recombinant His-tagged transforming growth factor-b type I receptor kinase domain mutant T204D from insect Sf9 cells by nickel affinity chromatography) [5] (recombinant His-tagged wild-type and mutant ALK5 from Spodoptera frugiperda Sf9 cells by nickel affinity chromatography) [3] Cloning (transient expression of ALK2 and ALK5 in C3H10T1/2 cells using the adenovirus transfection system) [6] (expression of ALK1 and ALK5 in 293T cells, Hep-G2 cells, and in COS-7 cells using the adenovirus transfection system) [15] (co-expression and co-localization of ALK1 mutant Q201D and cytoplasmic PEG10-RF1 mutant YFP in COS-1 cells, expression of ALK1 and ALK5 with PEG10-RF1 in a two-hydrid system in Saccharomyces cerevisiae, overview) [13] (expression of HA-tagged wild-type ALK7 in rat FaO hepatoma cells and transiently of HA-tagged ALK mutant T194D in human Hep3B hepatoma cells using the adenovirus infection method, expression leads in both cases to an apoptosis-positive phenotype, expression of inactive ALK7 mutant K222R dos not cause an altered phenotype) [10] (expression of His-tagged transforming growth factor-b type I receptor kinase domain mutant T204D in Spodoptera frugiperda Sf9 cells using the baculovirus infection system) [5] (expression of His-tagged wild-type and mutant ALK5 in Spodoptera frugiperda Sf9 cells using the baculovirus infection system) [3] (functional co-expression of TGF-b and the soluble intracellular domain of the TGF-b type I receptor in murine mammary gland epithelial cells and in mink lung epithelial cells inducing growth inhibition) [1]

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(surface expression of wild-type and mutant ALK4 type I receptors in HEK293T cells, expression of wild-type and mutant ALK4 type I receptors in mink lung epithelial cells, Mv1Lu cells) [9] (expression of ALK7 in COS cells, native expression analysis of ALK7 in different cells types) [7] (ALK7, DNA and amino acid sequence determination and analysis, genetic organization, determination of several isoforms by alternative splicing of ALK7) [4] (DNA and amino acid sequence determination and analysis of type II receptor serine/threonine kinase, SmRK2, which is expressed in three different transcripts: one encoding a full-length receptor with 5’- and 3’-UTRs, a second one encoding a longer form containing no 3’-UTR and no stop codon, and a third truncated version encoding the first 53 amino acids of the Nterminus, phylogenetic tree, expression of GST-tagged SmRK2 in Escherichia coli strain BL21(DE3)) [14] Engineering A78G ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] D89A ( site-directed mutagenesis, the mutation does not affect binding of actividin [9]) [9] E74A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] E88A ( site-directed mutagenesis, the mutation does not affect binding of actividin [9]) [9] F82A ( site-directed mutagenesis, the mutation slightly affects binding of actividin [9]) [9] G79A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] I70A ( site-directed mutagenesis, the mutation of a residue from the ALK4 extracellular domain affects the binding of activin and the substantial effects of the dominant negative truncated ALK4 mutant [9]) [9] K222R ( inactive mutant [10]) [10] K72A ( site-directed mutagenesis, the mutation does not affect binding of actividin [9]) [9] K80A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] L40A ( site-directed mutagenesis, the mutation of a residue from the ALK4 extracellular domain affects the binding of activin and the substantial effects of the dominant negative truncated ALK4 mutant [9]) [9] L75A ( site-directed mutagenesis, the mutation of a residue from the ALK4 extracellular domain affects the binding of activin and the substantial effects of the dominant negative truncated ALK4 mutant [9]) [9] L85A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] L90A ( site-directed mutagenesis, the mutation does not affect binding of actividin [9]) [9]

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M53A ( site-directed mutagenesis, the mutation slightly affects binding of actividin [9]) [9] P71A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] P77A ( site-directed mutagenesis, the mutation of a residue from the ALK4 extracellular domain affects the binding of activin and the substantial effects of the dominant negative truncated ALK4 mutant [9]) [9] P81A ( site-directed mutagenesis, the mutation does not affect binding of actividin [9]) [9] Q201D ( constitutively active ALK1 mutant [13]) [13] R91A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] S38A ( site-directed mutagenesis, the mutation slightly affects binding of actividin [9]) [9] S55A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] S86A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] S87A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] T194D ( constitutive active ALK7 mutant [10]) [10] T204D ( constitutively active ALK5 mutant [3]) [3] T93A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] V73A ( site-directed mutagenesis, the mutation of a residue from the ALK4 extracellular domain affects the binding of activin and the substantial effects of the dominant negative truncated ALK4 mutant [9]) [9] V76A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] Y83A ( site-directed mutagenesis, the mutation affects binding of actividin [9]) [9] Additional information ( conferring of responsiveness to GDF-9-mediated stimulation of ALK5 and Smad3 phosphorylation in normally unresponsive COS-7 cells by overexpression of the three proteins, no responsiveness by co-expression with BMPRII receptor, expression of GDF-9 in a CAGA-luciferase reporter construct in P19 cells reveals that GDF-9 binds to BMP-activated type II receptors but its downstream actions are mediated by the type I receptor ALK5, overview, expression of ALK5 siRNA inhibits GDF-9-induced stimulation in granulosa cells [16]; construction of a truncated dominant negative ALK4 mutant [9]; construction of a truncated mutant ALK7 [4]; expression of HA-tagged wild-type ALK7 in rat FaO hepatoma cells and transiently of HA-tagged ALK mutant T194D in human Hep3B hepatoma cells using the adenovirus infection method, expression leads in both cases to an apoptosis-positive phenotype, expression of inactive ALK7 mutant K222R dos not cause an altered phenotype [10]; functional co-expression of TGF-b and the soluble intracellular domain of the TGF-b type I receptor in murine mammary gland epithelial cells induces

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transdifferentiation of epithelial cells to mesenchymal cells, overview [1]; knockdown of ALK5 expression in embryonic endothelial cells by antisense oligonucleotides results in inhibition of both TGF-b-induced Smad 2 and Smad1/5 phosphorylation, an ALk5mutant defective in Smad activation rescues TGF-b/ALK1-induced signaling in ALK5 null mutant endothelial cells [15]; misexpression of ALK2 in nontransforming ventricular, endocardial cells causes epithelial-mesenchymal transformation, EMT, which can be decreased by overexpression of inhibitor Smad6 [6]) [1, 4, 6, 9, 10, 15, 16]

References [1] Ge, R.; Rajeev, V.; Subramanian, G.; Reiss, K.A.; Liu, D.; Higgins, L.; Joly, A.; Dugar, S.; Chakravarty, J.; Henson, M.; McEnroe, G.; Schreiner, G.; Reiss, M.: Selective inhibitors of type I receptor kinase block cellular transforming growth factor-b signaling. Biochem. Pharmacol., 68, 41-50 (2004) [2] Ottesen, J.J.; Huse, M.; Sekedat, M.D.; Muir, T.W.: Semisynthesis of phosphovariants of Smad2 reveals a substrate preference of the activated TbRI kinase. Biochemistry, 43, 5698-5706 (2004) [3] Peng, S.B.; Yan, L.; Xia, X.; Watkins, S.A.; Brooks, H.B.; Beight, D.; Herron, D.K.; Jones, M.L.; Lampe, J.W.; McMillen, W.T.; Mort, N.; Sawyer, J.S.; Yingling, J.M.: Kinetic characterization of novel pyrazole TGF-b receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition. Biochemistry, 44, 2293-2304 (2005) [4] Roberts, H.J.; Hu, S.; Qiu, Q.; Leung, P.C.; Caniggia, I.; Gruslin, A.; Tsang, B.; Peng, C.: Identification of novel isoforms of activin receptor-like kinase 7 (ALK7) generated by alternative splicing and expression of ALK7 and its ligand, Nodal, in human placenta. Biol. Reprod., 68, 1719-1726 (2003) [5] Sawyer, J.S.; Beight, D.W.; Britt, K.S.; Anderson, B.D.; Campbell, R.M.; Goodson, T., Jr.; Herron, D.K.; Li, H.Y.; McMillen, W.T.; Mort, N.; Parsons, S.; Smith, E.C.; Wagner, J.R.; Yan, L.; Zhang, F.; Yingling, J.M.: Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-b type I receptor kinase domain. Bioorg. Med. Chem. Lett., 14, 3581-3584 (2004) [6] Desgrosellier, J.S.; Mundell, N.A.; McDonnell, M.A.; Moses, H.L.; Barnett, J.V.: Activin receptor-like kinase 2 and Smad6 regulate epithelial-mesenchymal transformation during cardiac valve formation. Dev. Biol., 280, 201210 (2005) [7] Zhang, N.; Kumar, M.; Xu, G.; Ju, W.; Yoon, T.; Xu, E.; Huang, X.; Gaisano, H.; Peng, C.; Wang, Q.: Activin receptor-like kinase 7 induces apoptosis of pancreatic b cells and b cell lines. Diabetologia, 49, 506-518 (2006) [8] Liu, C.; Gaca, M.D.; Swenson, E.S.; Vellucci, V.F.; Reiss, M.; Wells, R.G.: Smads 2 and 3 are differentially activated by transforming growth factor-b (TGF-b) in quiescent and activated hepatic stellate cells. Constitutive nuclear localization of Smads in activated cells is TGF-b-independent. J. Biol. Chem., 278, 11721-11728 (2003)

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[9] Harrison, C.A.; Gray, P.C.; Koerber, S.C.; Fischer, W.; Vale, W.: Identification of a functional binding site for activin on the type I receptor ALK4. J. Biol. Chem., 278, 21129-21135 (2003) [10] Kim, B.C.; van Gelder, H.; Kim, T.A.; Lee, H.J.; Baik, K.G.; Chun, H.H.; Lee, D.A.; Choi, K.S.; Kim, S.J.: Activin receptor-like kinase-7 induces apoptosis through activation of MAPKs in a Smad3-dependent mechanism in hepatoma cells. J. Biol. Chem., 279, 28458-28465 (2004) [11] Yakymovych, I.; Heldin, C.H.; Souchelnytskyi, S.: Smad2 phosphorylation by type I receptor. Contribution of arginine 462 and cysteine 463 In the C terminus of Smad2 for specificity. J. Biol. Chem., 279, 35781-35787 (2004) [12] Ungefroren, H.; Groth, S.; Ruhnke, M.; Kalthoff, H.; Fandrich, F.: Transforming growth factor-b (TGF-b) type I receptor/ALK5-dependent activation of the GADD45b gene mediates the induction of biglycan expression by TGF-b. J. Biol. Chem., 280, 2644-2652 (2005) [13] Lux, A.; Beil, C.; Majety, M.; Barron, S.; Gallione, C.J.; Kuhn, H.M.; Berg, J.N.; Kioschis, P.; Marchuk, D.A.; Hafner, M.: Human retroviral gag- and gag-pol-like proteins interact with the transforming growth factor-b receptor activin receptor-like kinase 1. J. Biol. Chem., 280, 8482-8493 (2005) [14] Forrester, S.G.; Warfel, P.W.; Pearce, E.J.: Tegumental expression of a novel type II receptor serine/threonine kinase (SmRK2) in Schistosoma mansoni. Mol. Biochem. Parasitol., 136, 149-156 (2004) [15] Goumans, M.J.; Valdimarsdottir, G.; Itoh, S.; Lebrin, F.; Larsson, J.; Mummery, C.; Karlsson, S.; ten Dijke, P.: Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFb/ALK5 signaling. Mol. Cell, 12, 817-828 (2003) [16] Mazerbourg, S.; Klein, C.; Roh, J.; Kaivo-Oja, N.; Mottershead, D.G.; Korchynskyi, O.; Ritvos, O.; Hsueh, A.J.: Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5. Mol. Endocrinol., 18, 653-665 (2004) [17] Halder, S.K.; Beauchamp, R.D.; Datta, P.K.: A specific inhibitor of TGF-b receptor kinase, SB-431542, as a potent antitumor agent for human cancers. Neoplasia, 7, 509-521 (2005) [18] Fink, S.P.; Mikkola, D.; Willson, J.K.V.; Markowitz, S.: TGF-b-induced nuclear localization of Smad2 and Smad3 in Smad4 null cancer cell lines. Oncogene, 22, 1317-1323 (2003)

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[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

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1 Nomenclature EC number 2.7.11.31 Systematic name ATP:[hydroxymethylglutaryl-CoA reductase (NADPH)] phosphotransferase Recommended name [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase Synonyms 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase 3-hydroxy-3-methylglutaryl-CoA reductase kinase AMP-activated protein kinase [39, 40, 42, 43] AMP-activated protein kinase a [41] AMP-activated protein kinase a1 [41] AMPK [39, 40, 41, 42, 43] AMPK1 [41] [hydroxymethylglutaryl-CoA reductase (NADPH2 )] kinase b-hydroxy-b-methylglutaryl-CoA reductase kinase hydroxymethylglutaryl coenzyme A reductase kinase hydroxymethylglutaryl coenzyme A reductase kinase (phosphorylating) reductase kinase CAS registry number 172522-01-9

2 Source Organism Cricetulus griseus (no sequence specified) [31] Mus musculus (no sequence specified) [16, 38, 43] Homo sapiens (no sequence specified) ( gene ACL5-1 [4, 18, 19, 20, 24, 36]) [4, 18, 19, 20, 24, 30, 33, 35, 36, 39, 41, 42] Rattus norvegicus (no sequence specified) [1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 21, 22, 23, 25, 26, 27, 28, 29, 32, 34, 37, 40, 41, 43] Sus scrofa (no sequence specified) [4] Brassica oleracea (no sequence specified) [2,13]

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[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

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3 Reaction and Specificity Catalyzed reaction ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] = ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate Reaction type phospho group transfer Natural substrates and products S ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] ( activated AMPK acts to down-regulate ATP-consuming pathways such as fatty acid synthesis by phosphorylating and inactivating acetyl-CoA carboxylase and protein synthesis by promoting the phosphorylationof eukaryotic elongation factor-2, in heart AMPK activation stimulates glycolysis by increasing glucose uptake [37]; bicyclic phosporylation system, enzyme is believed to be involved in protecting cells against ATP depletion due to environmental stress by inactivating several key biosynthetic enzymes [25]; inactivates EC 1.1.1.34 by phosphorylation [2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 14]) (Reversibility: ?) [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 25, 32, 37] P ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 25, 32, 37] S ATP + acetyl-CoA carboxylase ( the enzyme is involved in the regulation of hepatic lipids via its downstream effector acetyl-CoA carboxylase, enzyme inhibition leads to an increased level of triacylglycerols and accumulation of lipids, metformin decreases lipid accumulation, induced by high d-glucose levels, by activating the enzyme, the enzyme functions as energy intracellular sensor [39]) (Reversibility: ?) [39, 41] P ADP + phosphorylated acetyl-CoA carboxylase S ATP + acetyl-CoA carboxylase 1 (Reversibility: ?) [41] P ADP + phosphorylated acetyl-CoA carboxylase 1 S ATP + eukaryotic elongation factor 2 kinase ( phosphorylation at Ser398, the enzyme plays a regulatory role in eEF2 kinase activity, overview [42]) (Reversibility: ?) [42] P ADP + phosphorylated eukaryotic elongation factor 2 kinase S ATP + hormone-sensitive lipase ( HSL is a key enzyme in controlling lipolysis in adipocytes, phosphorylation at Ser565 by AMPK reduces its translocation toward lipid droplets [43]) (Reversibility: ?) [43] P ADP + phosphorylated hormone-sensitive lipase S Additional information ( AMPK regulation, AMPK mediates the autophagy suppression of okadaic acid and other protein phosphatase-inhibitory toxins, overview [40]; mechanism of lipolytic enzyme activity modulation, regulation, overview [43]) (Reversibility: ?) [40, 43] P ?

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Substrates and products S ATP + HGRSAMSGLHLVKRR ( SAMS-containing peptide as substrate [2]) (Reversibility: ?) [2] P ADP + ? S ATP + HMGSAMSGLHLVKRR ( SAMS-containing peptide as substrate [2]) (Reversibility: ?) [2] P ADP + ? S ATP + HMKSAMSGLHLVKRR ( synthetic SAMS-containing peptide as substrate [2]) (Reversibility: ?) [2] P ADP + ? S ATP + HMRSAGSGLHLVKRR ( SAMS-containing peptide as substrate [2]) (Reversibility: ?) [2] P ADP + ? S ATP + HMRSAMSGLHGGKRR ( SAMS-containing peptide as substrate [2]) (Reversibility: ?) [2] P ADP + ? S ATP + HMRSAMSGLHGVKRR ( SAMS-containing peptide as substrate [2]) (Reversibility: ?) [2] P ADP + ? S ATP + HMRSAMSGLHLGKRR ( SAMS-containing peptide as substrate [2]) (Reversibility: ?) [2] P ADP + ? S ATP + HMRSAMSGLHLVKRR ( SAMS-containing peptide as substrate [2]; synthetic SAMS-containing peptide as substrate [35]; acetyl-CoA carboxylase-derived synthetic peptide substrate [41]) (Reversibility: ?) [2, 16, 35, 41] P ADP + ? S ATP + HMRSAMTGLHLVKRR ( SAMS-containing peptide as substrate [2]) (Reversibility: ?) [2] P ADP + ? S ATP + HMRSAMYGLHLVKRR ( SAMS-containing peptide as substrate [2]) (Reversibility: ?) [2] P ADP + ? S ATP + MAP-2 ( relative kinase activity for low-MW kinase 14%, high MW-kinase 566% [11]) (Reversibility: ?) [11] P ADP + MAP-2 phosphate S ATP + RNA-binding protein HUR ( inhibits the protein by phosporylation [18,20]) (Reversibility: ?) [18, 2] P ADP + ? S ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] ( 2 isoforms, major form A and minor form B, both phosphorylates mammalian HMG-CoA reductase [2]; activated AMPK acts to down-regulate ATP-consuming pathways such as fatty acid synthesis by phosphorylating and inactivating acetyl-CoA carboxylase and protein synthesis by promoting the phosphorylation of eukaryotic elongation factor-2, in heart AMPK activation stimulates glycolysis by increasing glucose uptake [37]; bicyclic phosporylation system, enzyme is believed to be involved in protect-

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[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

P S P S P S

P S

P S P S P S P S P S P S P S

P

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ing cells against ATP depletion due to environmental stress by inactivating several key biosynthetic enzymes [25]; inactivates EC 1.1.1.34 by phosphorylation [2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 14]) (Reversibility: ?) [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 32, 37] ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 25, 32, 37] ATP + [malonylCoAdecarboxylase] (Reversibility: ?) [17] ADP + [malonylCoAdecarboxylase]phosphate ATP + [sn-glycerol-3-phosphate acyltransferase] (Reversibility: ?) [17, 29] ADP + [sn-glycerol-3-phosphate acyltransferase]phosphate ATP + acetyl-CoA carboxylase ( AMPK plays an important role in regulating malonyl-CoA levels through the phosphorylation of acetyl-CoA carboxylase [19]; substrate Rattus norvegicus hepatic acetyl-CoA carboxylase, enzyme phosphorylates Ser-residues 79, 1200 and 1215 [13]) (Reversibility: ?) [4, 13, 17, 19, 30, 33] ADP + [acetyl-CoA carboxylase] phosphate [4, 13, 17, 19, 30, 33] ATP + acetyl-CoA carboxylase ( the enzyme is involved in the regulation of hepatic lipids via its downstream effector acetyl-CoA carboxylase, enzyme inhibition leads to an increased level of triacylglycerols and accumulation of lipids, metformin decreases lipid accumulation, induced by high d-glucose levels, by activating the enzyme, the enzyme functions as energy intracellular sensor [39]; phosphorylation at Ser79 [40]; phosphorylation at Ser79, phosphorylation inhibits the acetyl-CoA carboxylase [39]) (Reversibility: ?) [39, 40, 41] ADP + phosphorylated acetyl-CoA carboxylase ATP + acetyl-CoA carboxylase 1 (Reversibility: ?) [41] ADP + phosphorylated acetyl-CoA carboxylase 1 ATP + adipose hormone-sensitive lipase (Reversibility: ?) [30] ADP + adipose hormone-sensitive lipase phosphate ATP + adipose hormone-sensitive lipase (Reversibility: ?) [4, 13] ADP + [adipose hormone-sensitive lipase] phosphate ATP + a,b-tubulin ( relative kinase activity high MW-kinase 15% [11]) (Reversibility: ?) [11] ADP + [a,b-tubulin] phosphate ATP + bovine serum albumin ( fraction V [9]) (Reversibility: ?) [9] ADP + [bovine serum albumin] phosphate ATP + casein ( relative kinase activity for low-MW kinase 8%, high MW-kinase 48% [11]) (Reversibility: ?) [11] ADP + casein phosphate ATP + eukaryotic elongation factor 2 kinase ( phosphorylation at Ser398, the enzyme plays a regulatory role in eEF2 kinase activity, overview [42]; phosphorylation at Ser398 activates the eukaryotic elongation factor 2 kinase, no activity with the substrate mutant S398A [42]) (Reversibility: ?) [42] ADP + phosphorylated eukaryotic elongation factor 2 kinase

2.7.11.31

[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

S ATP + glycogen synthase ( relative kinase activity for low-MW kinase 7%, high MW-kinase 87% [11]) (Reversibility: ?) [11] P ADP + [glycogen synthase] phosphate S ATP + heavy meromyosin ( relative kinase activity for low-MW kinase 2%, high MW-kinase 100% [11]) (Reversibility: ?) [11] P ADP + [heavy meromyosin] phosphate S ATP + histone 2A (Reversibility: ?) [37] P ? S ATP + histone H1 (IIIS) ( histones are better substrates for highMW kinase than hydroxymethylglutaryl-CoA reductase, relative kinase activity for low-MW kinase 275%, high MW-kinase 103% [11]) (Reversibility: ?) [11] P ADP + [histone H1 (IIIS)] phosphate S ATP + histone II-S ( relative kinase activity for low-MW kinase 38%, high MW-kinase 159% [11]) (Reversibility: ?) [11] P ADP + [histone II-S] phosphate S ATP + histone VIIIS ( relative kinase activity for low-MW kinase 65%, high MW-kinase 141% [11]) (Reversibility: ?) [11] P ADP + [histone VIIIS] phosphate S ATP + hormone-sensitive lipase ( HSL is a key enzyme in controlling lipolysis in adipocytes, phosphorylation at Ser565 by AMPK reduces its translocation toward lipid droplets [43]) (Reversibility: ?) [43] P ADP + phosphorylated hormone-sensitive lipase S ATP + myelin basic protein ( moderate substrate for low-MW kinase, better than hydroxymethylglutaryl-CoA reductase for high-MW kinase, relative kinase activity for low-MW kinase 36%, high MW-kinase 238% [11]) (Reversibility: ?) [11] P ADP + [myelin basic protein] phosphate S ATP + myosin mixed light chains ( relative kinase activity for low-MW kinase 4%, high MW-kinase 27% [11]) (Reversibility: ?) [11] P ADP + [myosin mixed light chains] phosphate S ATP + phosphorylase B ( relative kinase activity high MW-kinase 12% [11]) (Reversibility: ?) [11] P ADP + [phosphorylase B] phosphate S ATP + phosvitin ( relative kinase activity for low-MW kinase 2%, high MW-kinase 2% [11]) (Reversibility: ?) [11] P ADP + phosvitin phosphate S ATP + protamine ( relative kinase activity for low-MW kinase 24%, high MW-kinase 38% [11]) (Reversibility: ?) [11] P ADP + protamine phosphate S ATP + rabbit muscle glycogen synthase ( rabbit muscle glycogen synthase [13]) (Reversibility: ?) [13] P ADP + [rabbit muscle glycogen synthase] phosphate S ATP + synapsin 1 ( as good substrate as hydroxymethylglutarylCoA reductase, relative kinase activity for low-MW kinase 151%, high MW-kinase 103% [11]) (Reversibility: ?) [11] P ADP + [synapsin 1] phosphate

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S CTP + [hydroxymethylglutaryl-CoA reductase (NADPH)] (Reversibility: ?) [12] P CDP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate S GTP + [hydroxymethylglutaryl-CoA reductase (NADPH)] ( phosphorylation at about 30% the rate of ATP [9]) (Reversibility: ?) [9, 12] P GDP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate S ITP + [hydroxymethylglutaryl-CoA reductase (NADPH)] ( phosphorylation at about 10% the rate of ATP [9]) (Reversibility: ?) [9, 12] P IDP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate S UTP + [hydroxymethylglutaryl-CoA reductase (NADPH)] ( phosphorylation at about 5% the rate of ATP [9]) (Reversibility: ?) [9, 12] P UDP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate S dATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] ( phosphorylation at about 90% the rate of ATP [9]) (Reversibility: ?) [9] P dADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate S Additional information ( autophosphorylation in absence of substrate [8,11]; protein kinase C and Ca2+ /calmodulin dependent reductase kinases are no substrates [12]; incorporates 0.5 mol phosphate/mol MW 53000 enzyme substrate fragment, 2 mol phosphate/mol native enzyme substrate [11]; conditions that elevate the AMP:ATP ratio in cells, such as growth factor depletion, hypoglycemia, ischemia in heart muscle, exercise in skeletal muscle, as well as treatment with arsenite, azide, oxidative agents and the pharmacological agent AICAR, which mimics the effect of AMP can cause activation of AMPK [20]; acetyl-CoA carboxylase kinase EC 2.7.1.128 and hydroxymethylglutarylCoA reductase kinase activity are catalyzed by the same enzyme [3]; enzyme functions as a metabolic sensor that monitors cellular AMP and ATP levels [31]; regulates triacylglycerolsynthesis and fatty acid oxidation in liver and muscle reciprocally [29]; phosphorylates key target proteins that control flux through metabolic pathways of hepatic ketogenesis, cholesterol synthesis, adipocyte lipolysis and skeletal muscle fatty acid oxidation [30]; AMPK regulation, AMPK mediates the autophagy suppression of okadaic acid and other protein phosphatase-inhibitory toxins, overview [40]; mechanism of lipolytic enzyme activity modulation, regulation, overview [43]; the enzyme is regulated by the nucleoside diphosphate kinase, complex formation in vivo, e.g. between isozyme a1 and NDPK-H1, inhibits the enzyme, overview [41]) (Reversibility: ?) [3, 8, 11, 12, 20, 29, 30, 31, 40, 41, 43] P ? Inhibitors 2’-deoxy-ATP [15] 5’-fluorosulfonylbenzoyladenosine [2, 3] 8-bromo-AMP [34] ADP [3] adenosine [3]

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adenosine-5’-tetraphospho-5’-adenosine ( i.e. AP4A, inhibits in the presence of AMP [22]) [22] Ara-ATP [15] EGTA [11] glycerol ( 25% v/v, reversible inhibition [8]) [8] inhibitor W-7 ( specific Ca2+ /calmodulin-dependent kinase inhibitor [11]) [11] naringin ( inhibits enzyme phosphorylation [40]) [40] protein phosphatase [24] trifluperazine ( specific Ca2+ /calmodulin-dependent kinase inhibitor [11]) [11] adenine-9-b-d-arabinofuranoside [34] hydroxymethylglutaryl-CoA ( only with hydroxymethylglutaryl-CoA reductase as substrate [14]) [14] iodotubercidin [34] mammalian protein phosphatase 2C [2] protein phosphatase C [1] Additional information ( no inhibition by adenosine-5-pentaphospho-5-adenosine [12]; complex formation between isozyme a1 and NDPK-H1 inhibits the AMPK activity, inhibition by NDPK is reduced by addition of ADP or GTP, overview [41]; insulin-resistance caused by high levels of d-glucose in the cell decreases the enzyme activity [39]) [12, 39, 41] Cofactors/prosthetic groups 2’-dAMP ( activation, can replace AMP or ADP [12]) [12] ATP [39,40,41,42,43] calmodulin ( requirement, Ca2+ /calmodulin dependent kinase, no phosphorylation of substrate observed in absence [11]) [11] Activating compounds 2’-AMP [10] 2’-AMP [10] 3’-AMP [10, 12] 5’-AMP ( regulated by allosteric activation [25]) [3, 4, 10, 12, 13, 15, 17, 18, 19, 20, 25, 26, 27, 31, 33, 34, 36, 37, 38] 5-amino-4-imidazolecarboxamide ribotide [15, 16, 20] 5-amino-4-imidazolecarboxamide ribonucleoside [31, 34, 36, 37] 5-amino-4-imidazolecarboxamide riboside [42] 5-aminoimidazole-4-carboxamide riboside ( stimulation of activating AMPK phosphorylation at Thr172 [40]) [40] ADP ( requirement [9]) [9, 10, 12] AMP ( dependent on [39]) [39] adenosine [12] CDP ( allosteric activator [9,12]) [9, 12] CMP [10, 12] GMP [10, 12] IDP [12] IMP [12]

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[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

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reductase kinase kinase ( EC 2.7.1.110, activation in presence of MgATP2- [6]; activation, i.e. EC 2.7.1.110, in the presence of MgATP2[1, 21, 22, 23, 24]) [1, 6, 21, 22, 23, 24] ribose 5’-phosphate [12] UDP ( allosteric activator [9,12]) [9, 12] UMP [10, 12] adiponectin [37] a,b-methylene-ADP ( allosteric activator, can replace ADP, with 66% efficiency with bovine serum albumin as substrate [9]) [9] cAMP ( dependent on, stimulates [42]) [12, 42] calyculin A ( stimulation of activating AMPK phosphorylation at Thr172, independent of narigin [40]) [40] cantharidin ( stimulation of activating AMPK phosphorylation at Thr172, independent of narigin [40]) [40] leptin [37] metformin ( antidiabetic drug [37]; increases the activating phosphorylation of the enzyme at Thr172 of the a-subunit by 3.6fold [39]) [37, 39] microcystin-LR ( stimulation of activating AMPK phosphorylation at Thr172 [40]) [40] okadaic acid ( stimulation of activating AMPK phosphorylation at Thr172, activation is antagonized by naringin [40]) [40] ribose 5’-phosphate [12] rosiglitazone ( antidiabetic drug [37]) [37] tautomycin ( stimulation of activating AMPK phosphorylation at Thr172, independent of narigin [40]) [40] Additional information ( no activation by cGMP [1]; no activation by cAMP [1,21]; not activated by cAMP [3,9]; no activation by cIMP, cCMP [1]; activated by phosphorylation by upstream protein kinases AMPKK and CaMKIK [25]; AMPK can also be activated by hyperosmotic stress [37]; phosphorylation activates the enzyme [39]; ATP depletion activates the enzyme [42]; stimulation by protein phosphatase-inhibitory toxins [40]) [1, 3, 9, 21, 25, 37, 39, 40, 42] Metals, ions Ca2+ [11] Mg2+ ( requirement, actual substrate: MgATP2- [1, 6, 21, 22, 23, 24]) [1, 6, 8, 12, 21, 22, 23, 24, 42] Specific activity (U/mg) 0.0102 [14] 0.069 [3] 0.292 [11] 3.281 ( major form B [2]) [2] 13.1 ( major form A [2]) [2] Additional information ( 3.130 nU/mg [9]; autophagic activity under different conditions [40]) [9, 40]

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[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

Km-Value (mM) 0.00085 (hydroxymethylglutaryl-CoA reductase, pH 6.5, 30 C, lowMW kinase [11]) [11] 0.0029 (histone H1, pH 6.5, 30 C, low-MW kinase [11]) [11] 0.013 (HMRSAMSGLHGVKRR, pH 7.0, 30 C, kinase A [2]) [2] 0.028 (ATP, pH 6.5, 30 C, low-MW kinase [11]) [11] 0.034 (HMRSAMTGLHGVKRR, pH 7.0, 30 C, kinase A [2]) [2] 0.038 (HMRSAMSGLHLGKRR, pH 7.0, 30 C, kinase A [2]) [2] 0.0404 (HGRSAMSGLHLVKRR, pH 7.0, 30 C, kinase A [2]) [2] 0.042 (HMRSAMSGLHLGKRR, pH 7.0, 30 C, kinase B [2]) [2] 0.046 (ATP, in absence of AMP [15]) [15] 0.049 (HMRSAMSGLHGGKRR, pH 7.0, 30 C, kinase A [2]) [2] 0.0498 (HMRSAMSGLHLVKRR, pH 7.0, 30 C, kinase A [2]) [2] 0.065 (HMRSAMTGLHGVKRR, pH 7.0, 30 C, kinase B [2]) [2] 0.069 (HMRSAGSGLHLVKRR, pH 7.0, 30 C, kinase B [2]) [2] 0.07 (HMRSAGSGLHLVKRR, pH 7.0, 30 C, kinase A [2]) [2] 0.091 (HMRSAMSGLHLVKRR, pH 7.0, 30 C, kinase B [2]) [2] 0.096 (HMRSAMSGLHGVKRR, pH 7.0, 30 C, kinase B [2]) [2] 0.111 (HMKSAMSGLHLVKRR, pH 7.0, 30 C, kinase B [2]) [2] 0.117 (ATP, in presence of ZMP [15]) [15] 0.118 (HMHSAMSGLHLVKRR, pH 7.0, 30 C, kinase A [2]) [2] 0.123 (ATP, in presence of AMP [15]) [15] 0.133 (HMKSAMSGLHLVKRR, pH 7.0, 30 C, kinase A [2]) [2] 0.14 (ATP, pH 7.5, 37 C [9]) [9] 0.295 (ATP, pH 7.5, 37 C [12]) [12] 0.315 (ATP, pH 7.5, 37 C, in presence of AMP [12]) [12] 0.428 (HMHSAMSGLHLVKRR, pH 7.0, 30 C, kinase B [2]) [2] 0.573 (HMGSAMSGLHLVKRR, pH 7.0, 30 C, kinase A [2]) [2] 2.316 (HMGSAMSGLHLVKRR, pH 7.0, 30 C, kinase B [2]) [2] pH-Optimum 6.5 ( low-MW kinase [11]) [11] 7 ( assay at [42]) [42] 7.4 ( assay at [43]) [43] Additional information ( pI: 5.6 [21]) [21] pH-Range 5.5-7 ( about half-maximal activity at pH 5.5 and 7.0, low-MW kinase [11]) [11] Temperature optimum ( C) 30 ( assay at [22,24,41,42]) [22, 24, 41, 42] 37 ( assay at [1,21,23]) [1, 21, 23]

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4 Enzyme Structure Molecular weight 30000 ( b-subunit, predicted protein sequence [27]) [27] 45000 ( major form B, gel filtration [2]) [2] 110000-125000 ( low-MW kinase, gel filtration [11]) [11] 150000 ( major form A, electrophoresis in non-denaturing gels [2]) [2] 160000 ( major form A, PAGE [2]) [2] 190000 [26] 200000 ( major form A, gel filtration [2]) [2] 205000 ( gel filtration [8]) [8] 380000 ( gel filtration [21]) [21] 560000-600000 ( high-MW kinase, gel filtration [11]) [11] Subunits ? ( x * 180000, SDS-PAGE [41]; x * 56000, SDS-PAGE [9]; x * 58000, catalytic subunit [2]; x * 58000, SDS-PAGE [21]) [2, 9, 21, 41] dimer ( 2 * 105000, SDS-PAGE [8]) [8] heterotrimer ( 1 * 63000 + 1 * 38000 + 1 * 35000, 3 subunits a, b and g, SDS-PAGE [26]; 1 * 63000 + 1 * 40000 + ?, a and b subunit, SDS-PAGE [37]; 1 * 63000 * ? + 1 * 38000 + 1 * 36000, a, b, g, SDS-PAGE [27]) [26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38] Additional information ( heterotrimeric serine/threonine kinase consists of a catalytic a-subunit and 2 regulatory subunits b and g, each subunit exists as multiple isoforms, a1, a2, b1, b2, g1, g2 and g3, giving 12 different possible combinantions of holoenzyme with different tissue distribution and subcellular localization [31,33,37]) [31, 33, 37, 38] Posttranslational modification phosphoprotein ( the enzyme is activated by phosporylation at Thr172, which is inhibited by naringin [40]; the enzyme is phosphorylated at Thr172 of its a-subunit, phosphorylation activates the enzyme, metformin increases the enzyme phosphorylation [39]) [39, 40]

5 Isolation/Preparation/Mutation/Application Source/tissue 3T3-L1 cell [43] HEK-293 cell [35] Hep-G2 cell ( hepatoma cell line [39]) [39] IDH4 cell [20] IMR-90 cell [20] KB cell ( oral epidermoid carcinoma cell line [42]) [42] RKO cell [18]

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WI-38 cell [20] adipocyte ( primary [43]) [43] adipose tissue [17] aorta [36] aorta endothelium [36] brain [4, 11] endothelium [36] fibroblast [20] heart [4, 19, 38] hepatocyte [15, 29, 40] inflorescence [2, 13] kidney [4] liver [1, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 15, 17, 21, 22, 23, 24, 27, 29, 30, 32, 37, 39, 41] lung [4, 41] ovary [31] pancreas [30] skeletal muscle [4, 16, 17, 30, 34, 38, 39] Localization cytoplasm [18] cytosol ( predominant [1]) [1, 6, 7, 8, 9, 10, 11, 12, 21, 22, 23, 24, 41] microsome [3, 5, 6, 7, 8, 12, 21, 23, 24] Purification (from KB cells by several steps including immunoprecipitation) [42] (partial) [24] (recombinant His-tagged isozymes a1 and a2 from Escherichia coli by nickel affinity chromatography) [41] [7, 8, 9, 12, 15, 17, 32] (catalytic subunit a) [4] (isozymes a1 and a2 from liver homogenates by subcellular fractionation and immunoprecipitation) [41] (low-MW kinase) [11] (partial) [3, 6, 21, 22, 23, 26, 27] (wild-type and mutant enzymes, expressed in bacteria) [37] (2 isoformes, major form A and major form B) [2] Cloning (expression of a dominant-negative mutant or of a constitutively active mutant of AMPK in adipocytes via adenovirus transfection) [43] (transgenic mouse constructed by injection of Rattus norvegicus a2 subunit cDNA) [38] (AMPK heterotrimer expressed in COS7 cells) [33] (cDNA identified with porcine cDNA) [4] (expression of His-tagged isozymes a1 and a2 in Escherichia coli) [41]

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[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

2.7.11.31

(expression of mutant enzymes in Escherichia coli and, via adenovirus transfection, in Hep-G2 cells) [39] (cDNA identified with porcine cDNA) [4] (expression of a dominant-negative mutant or of a constitutively active mutant of AMPK in adipocytes via adenovirus transfection) [43] (sequence analysis of cDNA clones encoding the subunits) [27] (transfection of CCL13 cells) [37] (transfections of COS7 cells) [28] (cDNA encoding porcine AMPK a1 isolated) [4] Engineering D157A ( site-directed mutagenesis [32]) [32] K45R ( site-directed mutagenesis, a dominant-negative mutant, expression leads to accumulation of lipids in cells [39]) [39] R70Q ( site-directed mutagenesis, marked increase in activity, largely AMP-independent [33]) [33] S108A ( site-directed mutagenesis, reduces enzyme activity by 60% [35]) [35] S182A ( site-directed mutagenesis, no effect on enzyme activity [18]) [18] S485A ( site-directed mutagenesis, non-phosphorylatable mutant [37]) [37] S485D ( site-directed mutagenesis [37]) [37] T172A ( site-directed mutagenesis [28,32]) [28, 32] T172D ( site-directed mutagenesis [32]; site-directed mutagenesis, constitutively active mutant of AMPK, insensitive to metformin [39]) [32, 39] T172E ( site-directed mutagenesis [37]) [37] T258A ( site-directed mutagenesis, non-phosphorylatable mutant [37]) [37] T258D ( site-directed mutagenesis [37]) [37] Additional information ( lipolysis is reduced in mutant with expression of a dominant-negative AMPK of in a null-mutant [43]) [43] Application medicine ( compounds that would cause activation of enzyme in skeletal muscle promise to be attractive agents for therapeutic intervention [16]; decreasing the ischaemic-induced activation of AMPK may be a therapeutic approach to treating ischaemic heart disease, AMPK may be an important pharmacological target for improving cardiac efficiency following ischaemia [19]; defects or disuse of the AMPK signaling system would be predicted to result in many of the metabolic perturbations observed in type 2 diabetes mellitus [30]) [16, 19, 30]

366

2.7.11.31

[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

6 Stability Temperature stability 37 ( 2 h, inactivation, MgATP2- in a low, not high salt buffer restores activity, not cAMP or in phosphate buffer [6]) [6] General stability information , about 10% decrease of activity after each freeze-thawing [8] , highly labile enzyme [7, 11] , protease inhibitors stabilizes enzyme [11] , very stable at either 4 C or -20 C when in microsomes [8] Storage stability , -196 C, stored in liquid nitrogen, stable for several months [9] , -20 C, can be stored in buffer containing 50% glycerol for up to a month [26] , -20 C, in 0.05 M Tris-HCl, pH 7.5, 0.05 M NaF, 0.005 M diphosphate, 1 mM EDTA, 1 mM EGTA and 1 mM DTT, 0.1 mM PMSF, soybean trypsin inhibitor, benzamidine, Brij-35, 50% w/v glycerol, stable for at least 2 months [3] , -80 C, in 0.05 M Tris-HCl buffer, pH 7.4, 0.05 M NaF, 0.003 M EDTA, 0.002 M EGTA, 0.005 M DTT, 0.5 mM PMSF, 10% v/v glycerol, remains stable for at least 3 months [8] , -80 C, partially purified preparation, stable to freezing [6] , 4 C, unstable when solubilized, loses 90% activity within 3 days [8] , -70 C, 0.5 mg protein/ml, frozen in liquid nitrogen, an be stored with no loss of activity [2]

References [1] Ingebritsen, T.S.; Parker, R.A.; Gibson, D.M.: Regulation of liver hydroxymethylglutaryl-CoA reductase by a bicyclic phosphorylation system. J. Biol. Chem., 256, 1138-1144 (1981) [2] Ball, K.L.; Dale, S.; Weekes, J.; Hardie, D.G.: Biochemical characterization of two forms of 3-hydroxy-3-methylglutaryl-CoA reductase kinase from cauliflower (Brassica oleracea). Eur. J. Biochem., 219, 743-750 (1994) [3] Carling, D.; Clarke, P.R.; Hardie, D.G.: Adenosine monophosphate-activated protein kinase: hydroxymethylglutaryl-CoA reductase kinase. Methods Enzymol., 200, 362-371 (1991) [4] Stapleton, D.; Mitchelhill, K.I.; Gao, G.; Widmer, J.; Michell, B.J.; Teh, T.; House, C.M.; Fernandez, C.S.; Cox, T.; Witters, L.A.; Kemp, B.E.: Mammalian AMP-activated protein kinase subfamily. J. Biol. Chem., 271, 611-614 (1996) [5] Beg, Z.H.; Stonik, J.A.; Brewer, H.B.: 3-Hydroxy-3-methylglutaryl coenzyme A reductase: regulation of enzymatic activity by phosphorylation and dephosphorylation. Proc. Natl. Acad. Sci. USA, 75, 3678-3682 (1978)

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[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

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[6] Ingebritsen, T.S.; Lee, H.-S.; Parker, R.A.; Gibson, D.M.: Reversible modulation of the activities of both liver microsomal hydroxymethylglutaryl coenzyme A reductase and its inactivating enzyme. Evidence for regulation by phosphorylation-dephosphorylation. Biochem. Biophys. Res. Commun., 81, 1268-1277 (1978) [7] Beg, Z.H.; Stonik, J.A.: Reversible inactivation of 3-hydroxy-3-methylglutaryl coenzyme A reductase: reductase kinase and mevalonate kinase are separate enzymes. Biochem. Biophys. Res. Commun., 108, 559-566 (1982) [8] Ferrer, A.; Hegardt, F.G.: Phosphorylation of 3-hydroxy-3-methylglutaryl coenzyme A reductase by microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase. Arch. Biochem. Biophys., 230, 227-237 (1984) [9] Harwood, H.J.; Brandt, K.G.; Rodwell, V.W.: Allosteric activation of rat liver cytosolic 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase by nucleoside diphosphates. J. Biol. Chem., 259, 2810-2815 (1984) [10] Ferrer, A.; Caelles, C.; Massot, N.; Hegardt, F.G.: Activation of rat liver cytosolic 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase by adenosine 5-monophosphate. Biochem. Biophys. Res. Commun., 132, 497-504 (1985) [11] Beg, Z.H.; Stonik, J.A.; Brewer, H.B.: Phosphorylation and modulation of the enzymic activity of native and protease-cleaved purified hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase by a calcium/calmodulindependent protein kinase. J. Biol. Chem., 262, 13228-13240 (1987) [12] Ferrer, A.; Caelles, C.; Massot, N.; Hegardt, F.G.: Allosteric activation of rat liver microsomal [hydroxymethylglutaryl-CoA reductase (NADPH)]kinase by nucleoside phosphates. Biol. Chem. Hoppe-Seyler, 368, 249-257 (1987) [13] Weekes, J.; Ball, K.L.; Caudwell, F.B.; Hardie, D.G.: Specificity determinants for the AMP-activated protein kinase and its plant homologue analysed using synthetic peptides. FEBS Lett., 334, 335-339 (1993) [14] Omkumar, R.V.; Darnay, B.G.; Rodwell, V.W.: Modulation of syrian hamster 3-hydroxy-3-methylglutaryl-CoA reductase activity by phosphorylation. Role of serine 871 [published erratum appears in J Biol Chem 1994 Jun 10;269(23):16518]. J. Biol. Chem., 269, 6810-6814 (1994) [15] Henin, N.; Vincent, M.F.; Van den Berghe, G.: Stimulation of rat liver AMPactivated protein kinase by AMP analogues. Biochim. Biophys. Acta, 1290, 197-203 (1996) [16] Fryer, L.G.; Foufelle, F.; Barnes, K.; Baldwin, S.A.; Woods, A.; Carling, D.: Characterization of the role of the AMP-activated protein kinase in the stimulation of glucose transport in skeletal muscle cells. Biochem. J., 363, 167174 (2002) [17] Park, H.; Kaushik, V.K.; Constant, S.; Prentki, M.; Przybytkowski, E.; Ruderman, N.B.; Saha, A.K.: Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. J. Biol. Chem., 277, 32571-32577 (2002)

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[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

[18] Wang, W.; Fan, J.; Yang, X.; Furer-Galban, S.; Lopez de Silanes, I.; von Kobbe, C.; Guo, J.; Georas, S.N.; Foufelle, F.; Hardie, D.G.; Carling, D.; Gorospe, M.: AMP-activated kinase regulates cytoplasmic HuR. Mol. Cell. Biol., 22, 3425-3436 (2002) [19] Hopkins, T.A.; Dyck, J.R.B.; Lopaschuk, G.D.: AMP-activated protein kinase regulation of fatty acid oxidation in the ischaemic heart. Biochem. Soc. Trans., 31, 207-212 (2003) [20] Wang, W.; Yang, X.; Lopez de Silanes, I.; Carling, D.; Gorospe, M.: Increased AMP:ATP ratio and AMP-activated protein kinase activity during cellular senescence linked to reduced HuR function. J. Biol. Chem., 278, 2701627023 (2003) [21] Beg, Z.H.; Stonik, J.A.; Brewer, B.: Characterization and regulation of reductase kinase, a protein kinase that modulates the enzymic activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proc. Natl. Acad. Sci. USA, 76, 4375-4379 (1979) [22] Weekes, J.; Hawley, S.A.; Corton, J.; Shugar, D.; Hardie, D.G.: Activation of rat liver AMP-activated protein kinase by kinase kinase in a purified, reconstituted system. Effects of AMP and AMP analogues. Eur. J. Biochem., 219, 751-757 (1994) [23] Beg, Z.H.; Stonik, J.A.; Brewer, B.: In vivo modulation of rat liver 3-hydroxy-3-methylglutaryl-coenzyme A reductase, reductase kinase, and reductase kinase kinase by mevalonolactone. Proc. Natl. Acad. Sci. USA, 81, 7293-7297 (1984) [24] Beg, Z.H.; Stonik, J.A.; Brewer, B.: Human hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: evidence for the regulation of enzymic activity by a bicyclic phosphorylation cascade. Biochem. Biophys. Res. Commun., 119, 488-498 (1984) [25] Hawley, S.A.; Selbert, M.A.; Goldstein, E.G.; Edelman, A.M.; Carling, D.; Hardie, D.G.: 5’-AMP activates the AMP-activated protein kinase cascade, and Ca2+ /calmodulin activates the calmodulin-dependent protein kinase I cascade, via three independent mechanisms. J. Biol. Chem., 270, 2718627191 (1995) [26] Hawley, S.A.; Davison, M.; Woods, A.; Davies, S.P.; Beri, R.K.; Carling, D.; Hardie, D.G.: Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J. Biol. Chem., 271, 2787927887 (1996) [27] Woods, A.; Cheung, P.C.; Smith, F.C.; Davison, M.D.; Scott, J.; Beri, R.K.; Carling, D.: Characterization of AMP-activated protein kinase b and g subunits. Assembly of the heterotrimeric complex in vitro. J. Biol. Chem., 271, 10282-10290 (1996) [28] Crute, B.E.; Seefeld, K.; Gamble, J.; Kemp, B.E.; Witters, L.A.: Functional domains of the a1 catalytic subunit of the AMP-activated protein kinase. J. Biol. Chem., 273, 35347-35354 (1998) [29] Muoio, D.M.; Seefeld, K.; Witters, L.A.; Coleman, R.A.: AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation

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[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

[30] [31]

[32] [33] [34] [35]

[36]

[37]

[38]

[39]

[40] [41]

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in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem. J., 338, 783-791 (1999) Winder, W.W.; Hardie, D.G.: AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am. J. Physiol., 277, E1-10 (1999) Kishi, K.; Yuasa, T.; Minami, A.; Yamada, M.; Hagi, A.; Hayashi, H.; Kemp, B.E.; Witters, L.A.; Ebina, Y.: AMP-activated protein kinase is activated by the stimulations of G(q)-coupled receptors. Biochem. Biophys. Res. Commun., 276, 16-22 (2000) Stein, S.C.; Woods, A.; Jones, N.A.; Davison, M.D.; Carling, D.: The regulation of AMP-activated protein kinase by phosphorylation. Biochem. J., 345, 437-443 (2000) Hamilton, S.R.; Stapleton, D.; O’Donnell, J.B.; Kung, J.T.; Dalal, S.R.; Kemp, B.E.; Witters, L.A.: An activating mutation in the g1 subunit of the AMPactivated protein kinase. FEBS Lett., 500, 163-168 (2001) Musi, N.; Hayashi, T.; Fujii, N.; Hirshman, M.F.; Witters, L.A.; Goodyear, L.J.: AMP-activated protein kinase activity and glucose uptake in rat skeletal muscle. Am. J. Physiol., 280, E677-684 (2001) Warden, S.M.; Richardson, C.; O’Donnell, J., Jr.; Stapleton, D.; Kemp, B.E.; Witters, L.A.: Post-translational modifications of the b-1 subunit of AMPactivated protein kinase affect enzyme activity and cellular localization. Biochem. J., 354, 275-283 (2001) Morrow, V.A.; Foufelle, F.; Connell, J.M.; Petrie, J.R.; Gould, G.W.; Salt, I.P.: Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells. J. Biol. Chem., 278, 3162931639 (2003) Woods, A.; Vertommen, D.; Neumann, D.; Tuerk, R.; Bayliss, J.; Schlattner, U.; Wallimann, T.; Carling, D.; Rider, M.H.: Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis. J. Biol. Chem., 278, 28434-28442 (2003) Xing, Y.; Musi, N.; Fujii, N.; Zou, L.; Luptak, I.; Hirshman, M.F.; Goodyear, L.J.; Tian, R.: Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative a2 subunit of AMP-activated protein kinase. J. Biol. Chem., 278, 28372-28377 (2003) Zang, M.; Zuccollo, A.; Hou, X.; Nagata, D.; Walsh, K.; Herscovitz, H.; Brecher, P.; Ruderman, N.B.; Cohen, R.A.: AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J. Biol. Chem., 279, 47898-47905 (2004) Samari, H.R.; Moeller, M.T.N.; Holden, L.; Asmyhr, T.; Seglen, P.O.: Stimulation of hepatocytic AMP-activated protein kinase by okadaic acid and other autophygy-suppressive toxins. Biochem. J., 386, 237-244 (2005) Crawford, R.M.; Treharne, K.J.; Best, O.G.; Muimo, R.; Riemen, C.E.; Mehta, A: A novel physical and functional association between nucleoside diphosphate kinase A and AMP-activated protein kinase a1 in liver and lung. Biochem. J., 392, 201-209 (2005)

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[Hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

[42] Browne, G.J.; Finn, S.G.; Proud, C.G.: Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398. J. Biol. Chem., 279, 1222012231 (2004) [43] Daval, M.; Diot-Dupuy F.; Bazin, R.; Hainault, I.; Viollet, B.; Vaulont, S.; Hajduch, E.; Ferre, P.; Foufelle, F.: Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes. J. Biol. Chem., 280, 25250-25257 (2005)

371

Dual-specificity kinase

2.7.12.1

1 Nomenclature EC number 2.7.12.1 Systematic name ATP:protein phosphotransferase (Ser/Thr- and Tyr-phosphorylating) Recommended name dual-specificity kinase Synonyms BVR [57] Clik1 Clk/Sty protein kinase [26] DPK [56] DYRK [36, 41] DYRK1A [21] DYRK1B [42, 51] Esk kinase [45] MNB protein [37] PTK2 [50] RPK1 [48] Rad53 protein kinase [6, 7, 8] STY protein [29] STY protein kinase [52, 55] STYK [54] Ser/Thr/Tyr kinase [54] TTK [43] Yak1p protein kinase [23] biliverdin reductase [57] cdc2/CDC28-like protein kinase [32] dual specificity protein kinase [53] dual specificity protein kinase TTK [43, 44, 45] dual specificity tyrosine phosphorylated and regulated kinase 1B [51] dual-specificity protein kinase [56] dual-specificity tyrosine-phosphorylation regulated kinase 1A [21, 34, 35, 36, 37, 39, 41] dual-specificity tyrosine-phosphorylation regulated kinase 1B [42]

372

2.7.12.1

Dual-specificity kinase

dual-specificity tyrosine-phosphorylation regulated kinase 2 [21] dual-specificity tyrosine-phosphorylation regulated kinase 3 [20, 21] non-receptor tyrosine kinase spore lysis A [3, 4] protein kinase AFC1 [14, 49] protein kinase AFC2 [12, 49] protein kinase AFC3 [12, 49] protein kinase CLK1 [26, 27, 28, 29, 30, 32] protein kinase CLK2 [17, 19, 28, 33] protein kinase CLK3 [19, 28, 40] protein kinase CLK4 [19] protein kinase Doa [2, 17] protein kinase KNS1 [15] protein kinase SPK1 [6, 7, 8, 9, 10, 11, 13] protein kinase YAK1 [22, 23, 24, 25] protein kinase gene DYRK3 [20] protein kinase lkh1 [5, 15] protein tyrosine kinase 2 [50] serine/threonine protein kinase MPS1 [46, 47, 48] serine/threonine protein kinase minibrain [31] serine/threonine/tyrosine kinase [57] serine/threonine/tyrosine protein kinase [52, 55] Additional information ( the enzyme belongs to the insulin receptor substrate family [57]) [57] CAS registry number 134549-83-0

2 Source Organism











eukaryota (no sequence specified) [1] Homo sapiens (no sequence specified) [51, 57] Saccharomyces cerevisiae (no sequence specified) [50] Bradyrhizobium japonicum (no sequence specified) [54] Arabidopsis thaliana (no sequence specified) [54] Pseudomonas aeruginosa (no sequence specified) [54] Pseudomonas putida (no sequence specified) [54] Thermoplasma acidophilum (no sequence specified) [54] Nitrosomonas europaea (no sequence specified) [54] Arachis hypogaea (no sequence specified) [52, 55] Mycobacterium tuberculosis (no sequence specified) [54] Streptomyces coelicolor (no sequence specified) [54] Pseudomonas syringae (no sequence specified) [54] Sulfolobus solfataricus (no sequence specified) [54] Clostridium acetobutylicum (no sequence specified) [54] Methanococcus jannaschii (no sequence specified) [54] Nostoc sp. (no sequence specified) [54]

373

Dual-specificity kinase





























374

2.7.12.1

Deinococcus radiodurans (no sequence specified) [54] Clostridium thermocellum (no sequence specified) [54] Thermobifida fusca (no sequence specified) [54] Streptomyces avermitilis (no sequence specified) [54] Halobacterium salinarium (no sequence specified) [54] Chlamydia sp. (no sequence specified) [54] Mesorhizobium loti (no sequence specified) [54] Leptospira interrogans (no sequence specified) [54] Nostoc punctiforme (no sequence specified) [54] Methanosarcina mazei (no sequence specified) [54] Sulfolobus tokodaii (no sequence specified) [54] Dictyostelium discoideum (UNIPROT accession number: P18160) [3, 4] Saccharomyces cerevisiae (UNIPROT accession number: P22216) [6, 7, 8, 9, 10, 11, 13] Schizosaccharomyces pombe (UNIPROT accession number: Q10156) [5, 15] Saccharomyces cerevisiae (UNIPROT accession number: P32350) [15, 16, 17, 18] Homo sapiens (UNIPROT accession number: Q9Z188) [42] Mus musculus (UNIPROT accession number: O35491) [19] Mus musculus (UNIPROT accession number: O35492) [19] Mus musculus (UNIPROT accession number: O35493) [19] Homo sapiens (UNIPROT accession number: O43781) [20, 21] Saccharomyces cerevisiae (UNIPROT accession number: P14680) [22, 23, 24, 25] Mus musculus (UNIPROT accession number: P22518) [26, 27, 28, 29, 30] Drosophila melanogaster (UNIPROT accession number: P49657) [31] Homo sapiens (UNIPROT accession number: P49759) [28, 32] Homo sapiens (UNIPROT accession number: P49760) [17, 28, 33] Homo sapiens (UNIPROT accession number: P49761) [28] Homo sapiens (UNIPROT accession number: Q13627) [34, 35, 36, 37, 38] Mus musculus (UNIPROT accession number: Q61214) [36, 39] Rattus norvegicus (UNIPROT accession number: Q63117) [40] Rattus norvegicus (UNIPROT accession number: Q63470) [21, 41] Homo sapiens (UNIPROT accession number: Q92630) [21] Homo sapiens (UNIPROT accession number: Q9Y463) [42] Homo sapiens (UNIPROT accession number: P33981) [43,44] Mus musculus (UNIPROT accession number: P35761) [45] Saccharomyces cerevisiae (UNIPROT accession number: P54199) [46, 47, 48] Drosophila melanogaster (UNIPROT accession number: P49762) [2,17] Arabidopsis thaliana (UNIPROT accession number: P51566) [14,49] Arabidopsis thaliana (UNIPROT accession number: P51567) [12,49] Arabidopsis thaliana (UNIPROT accession number: P51568) [12,49] Gloeobacter violaceus (no sequence specified) [54] Methanothermobacter thermoautotrophicus (no sequence specified) [54] Pirellula sp. (no sequence specified) [54] Mus musculus (UNIPROT accession number: Q9Z188) [51]

2.7.12.1









Dual-specificity kinase

Methanosarcina acetovirans (no sequence specified) [54] Thermoplasma volcanum (no sequence specified) [54] Mycobacterium bovis ssp. bovis AF2 (no sequence specified) [54] Mycobacterium avium ssp. paratuberculosis (no sequence specified) [54] Thermospora curvatum (no sequence specified) [54] Thermodesmium erythraeum (no sequence specified) [54] Chloroflexus aurantia (no sequence specified) [54] Cucumis sativus (UNIPROT accession number: Q7XJ65) [53] Oryza sativa (UNIPROT accession number: Q8GV30) [56] Oryza sativa (UNIPROT accession number: Q8GV28) [56] Oryza sativa (UNIPROT accession number: Q8GV29) [56] Oryza sativa (UNIPROT accession number: Q84U74) [56]

3 Reaction and Specificity Catalyzed reaction ATP + a protein = ADP + a phosphoprotein Reaction type phospho group transfer Natural substrates and products S ATP + SR protein ( enzyme is involved in the regulation of nuclear functions [42]; DYRK may be involved in the abnormal neurogenesis found in Down syndrome [36]; functions as a negative regulator of the cell cycle in Saccharomyces cerevisiae, acting downstream of the cAMP-dependent protein kinase [23]; might be a component of a signaling pathway regulating nuclear functions [41]; enzyme may be involved in cell cycle control [30]; the enzyme is required in distinct neuroblast proliferation centers during postembryonic neurogenesis [31]; enzyme is a good candidate to mediate some of the pleiotropic effects of Down syndrome [39]; Yak1 acts downstream from, or on a parallel pathway to, the kinase step in the Ras/cAMP pathway [25]; MNB protein may play a significant role in a signaling pathway regulating nuclear functions of neuronal cell proliferation, contributing to certain features of Down syndrome [37,38]; enzyme regulates a predominately testicular function [40]; Yak1p and Pop2p are part of a novel glucose-sensing system in yeast that is involved in growth control in response to glucose availability [22]; enzyme may be constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing [19]; the enzyme phosphorylates SR splicing factors and regulates their intranuclear distribution [26]) (Reversibility: ?) [19, 22, 23, 25, 26, 30, 31, 35, 36, 37, 38, 39, 40, 41, 42] P ADP + ? S ATP + a protein (Reversibility: ?) [1, 5] P ADP + a phosphoprotein

375

Dual-specificity kinase

2.7.12.1

S ATP + insulin receptor kinase substrate 1 ( phosphorylation at serine residues, overview, the enzyme is involved in the insulin signaling pathway [57]) (Reversibility: ?) [57] P ADP + phosphorylated insulin receptor kinase substrate 1 S Additional information ( a role for tyrosine phosphorylation in controlling Dictyostelium development [4]; regulates the differentiation of spore cells [3]; required for the execution of checkpoint arrest at multiple stages of the cell cycle. Rad53 modulates the lagging strand replication apparatus by controlling phosphorylation of the DNA polymerase a-primase complex in response to intra-S DNA damage [7]; Rad53 exerts its role in checkpoint control through regulation of the Polo kinase Cdc5 [6]; the SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast [10]; the enzyme is not essential for cell growth and a variety of other cellular processes in yeast [18]; negative regulation of filamentous growth and flocculation [15]; Esk kinase may play some role in the control of cell proliferation or differentiation [45]; the enzyme is associated with cell proliferation [43]; may function in a checkpoint control which couples DNA replication to mitosis. The level of the RPK1 transcript is extremely low and constant throughout the mitotic cycle. However it is regulated during cellular differentiation, being decreased in afactor-treated cells and increased late in meiosis in a diploids. Rpk1 is involved in a pathway that coordinates cell proliferation and differentiation [48]; the enzyme is associated to ubiquinone biosynthesis [54]; the enzyme is associated with nitrate dissimilation involving the NirV domain [54]; the enzyme is developmentally regulated [52,55]; the enzyme is involved in regulation of Mg-chelatase and chlorophyll biosynthesis [54]; the enzyme is involved in response to plant abiotic and biotic stresses [56]) (Reversibility: ?) [3, 4, 6, 7, 10, 15, 18, 43, 45, 48, 52, 54, 55, 56] P ? Substrates and products S ATP + Pop2p (Reversibility: ?) [22] P ADP + phosphorylated Pop2p S ATP + SR protein ( enzyme is involved in the regulation of nuclear functions [42]; DYRK may be involved in the abnormal neurogenesis found in Down syndrome [36]; functions as a negative regulator of the cell cycle in Saccharomyces cerevisiae, acting downstream of the cAMP-dependent protein kinase [23]; might be a component of a signaling pathway regulating nuclear functions [41]; enzyme may be involved in cell cycle control [30]; the enzyme is required in distinct neuroblast proliferation centers during postembryonic neurogenesis [31]; enzyme is a good candidate to mediate some of the pleiotropic effects of Down syndrome [39]; Yak1 acts downstream from, or on a parallel

376

2.7.12.1

P S P S P S P S P S

P S P S

P S

P S P S P S

Dual-specificity kinase

pathway to, the kinase step in the Ras/cAMP pathway [25]; MNB protein may play a significant role in a signaling pathway regulating nuclear functions of neuronal cell proliferation, contributing to certain features of Down syndrome [37,38]; enzyme regulates a predominately testicular function [40]; Yak1p and Pop2p are part of a novel glucose-sensing system in yeast that is involved in growth control in response to glucose availability [22]; enzyme may be constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing [19]; the enzyme phosphorylates SR splicing factors and regulates their intranuclear distribution [26]) (Reversibility: ?) [19, 22, 23, 25, 26, 30, 31, 35, 36, 37, 38, 39, 40, 41, 42] ADP + ? ATP + SR protein ( i.e. serine-rich and argininerich proteins [19]) (Reversibility: ?) [19] ADP + hyperphosphorylated SR protein [19] ATP + Ser/Arg-rich splicing factors (Reversibility: ?) [26] ADP + phosphorylated Ser/Arg-rich splicing factor ATP + a protein (Reversibility: ?) [1, 5] ADP + a phosphoprotein ATP + casein (Reversibility: ?) [57] ADP + phosphorylated casein ATP + histone ( recombinant glutathione S-transferase-Dyrk/ fusion protein catalyzes histone phosphorylation on tyrosine and Ser/Thr residues [41]) (Reversibility: ?) [41] ADP + phosphorylated histone ATP + histone H1 (Reversibility: ?) [52, 55] ADP + phosphorylated histone H1 ATP + insulin receptor kinase substrate 1 ( phosphorylation at serine residues, overview, the enzyme is involved in the insulin signaling pathway [57]; phosphorylation at serine residues leading to blockage of insulin action, overview [57]) (Reversibility: ?) [57] ADP + phosphorylated insulin receptor kinase substrate 1 ATP + myelin basic protein ( phosphorylation on a Cterminal Ser residue [23]; phosphorylation on serine, threonine, and tyrosine residues [45]) (Reversibility: ?) [23, 45, 57] ADP + phosphorylated myelin basic protein ATP + peptide DYRKtide ( synthetic peptide substrate [51]) (Reversibility: ?) [51] ADP + phosphorylated peptide DYRKtide ATP + poly-(Tyr-Glu) ( tyrosine kinase substrate [50]) (Reversibility: ?) [50] ADP + phospho-poly-(Tyr-Glu) ATP + protein ( autophosphorylation [17,19,21,23,41]; the enzyme phosphorylates proteins on serine, threonine, and tyrosine [11]; Rad53 autophosphorylation activity depends on trans phosphorylation mediated by Mec1 and does not require physical association with

377

Dual-specificity kinase

P S P S

378

2.7.12.1

other proteins [7]; autophosphorylates on Ser/Thr and Tyr residues [17]; autophosphorylation on Tyr residues [23]; recombinant glutathione S-transferase-Dyrk fusion protein catalyzed autophosphorylation on tyrosine and serine/threonine residues [40]; when expressed in E. coli the enzyme catalyzes autophosphorylation on Tyr residues [21]; autophosphorylation on serine, threonine, and tyrosine residues [45]; can phosphorylate serine, threonine, and tyrosine hydroxyamino acids [43]; kinase can phosphorylate serine, threonine and tyrosine residues [47]) (Reversibility: ?) [7, 11, 17, 19, 21, 23, 40, 41, 43, 45, 47] ADP + phosphoprotein ATP + protein tyrosine ( autophosphorylated on Ser and Thr residues [3]) (Reversibility: ?) [3] ADP + protein tyrosine phosphate Additional information ( autophosphorylation [17]; activity is dependent on tyrosine residues between subdomains VII and VIII [41]; a glutathione S-transferase fusion protein of Clk3 catalyzes autophosphorylation of the kinase but not phosphorylation of the exogenous substrates histone or casein [40]; the enzyme activates STE12-dependent processes in Saccharomyces cerevisiae [49]; a role for tyrosine phosphorylation in controlling Dictyostelium development [4]; regulates the differentiation of spore cells [3]; required for the execution of checkpoint arrest at multiple stages of the cell cycle. Rad53 modulates the lagging strand replication apparatus by controlling phosphorylation of the DNA polymerase a-primase complex in response to intra-S DNA damage [7]; Rad53 exerts its role in checkpoint control through regulation of the Polo kinase Cdc5 [6]; the SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast [10]; the enzyme is not essential for cell growth and a variety of other cellular processes in yeast [18]; negative regulation of filamentous growth and flocculation [15]; Esk kinase may play some role in the control of cell proliferation or differentiation [45]; the enzyme is associated with cell proliferation [43]; may function in a checkpoint control which couples DNA replication to mitosis. The level of the RPK1 transcript is extremely low and constant throughout the mitotic cycle. However it is regulated during cellular differentiation, being decreased in afactor-treated cells and increased late in meiosis in a diploids. Rpk1 is involved in a pathway that coordinates cell proliferation and differentiation [48]; the enzyme is associated to ubiquinone biosynthesis [54]; the enzyme is associated with nitrate dissimilation involving the NirV domain [54]; the enzyme is developmentally regulated [52,55]; the enzyme is involved in regulation of Mg-chelatase and chlorophyll biosynthesis [54]; the enzyme is involved in response to plant abiotic and biotic stresses [56]; the enzyme of strain PCC 7120 contains a pectinesterase domain catalyzing the

2.7.12.1

Dual-specificity kinase

hydrolysis of pectin, the enzyme probably interacts with chaperonic proteins via tetratrico peptide repeats TPR [54]; the enzyme performs autophosphorylation at Thr202, Tyr72 and Tyr83, the enzyme also shows biliverdin reductase activity [57]; the enzyme probably interacts with chaperonic proteins via tetratrico peptide repeats TPR [54]) (Reversibility: ?) [3, 4, 6, 7, 10, 15, 17, 18, 40, 41, 43, 45, 48, 49, 52, 54, 55, 56, 57] P ? Inhibitors genistein ( protein tyrosine kinase inhibitor [1]; competitive inhibition versus ATP, uncompetitive inhibition versus histone H1 [52]) [1, 52, 57] N6 -dimethylaminopurine ( unspecific inhibitor of protein kinases [1]) [1] staurosporine ( unspecific inhibitor of protein kinases [1]; competitive versus ATP, mixed inhibition versus histone H1 [52]) [1, 52] Zn2+ ( inhibits the autophosphoylation, which cannot be reversed by Mn2+ addition [57]) [57] tyrphostin ( competitive versus ATP, mixed inhibition versus histone H1 [52]) [52] Additional information ( drought stress decreased the expression level [53]; molecular docking with tyrosine kinase inhibitors, recombinant His-tagged wild-type and mutant enzymes [52]) [52, 53] Cofactors/prosthetic groups ATP ( binding site residue Tyr317 is important [55]) [1, 50, 51, 52, 55, 57] Activating compounds abscisic acid ( induces the expression of isozymes DPK1-DPK3 in seedlings [56]) [56] Additional information ( activation of Rad53 in response to DNA damage in G(1) requires the Rad9, Mec3, Ddc1, Rad17 and Rad24 checkpoint factors, while this dependence is greatly reduced in S phase cells. Furthermore, during recovery from checkpoint activation, Rad53 activity decreases through a process that does not require protein synthesis [7]; cold stress increased the expression level [53]; high salinity, drought, and blast by fungus Magnaporthe grisea induce the expression of isozymes DPK1-DPK3 in seedlings [56]; the enzyme is induced by abiotic stresses, the activation loop is located between subdomains VII and VIII, phosphorylation at Tyr317, Tyr297, and Tyr148 activates the enzyme [55]) [7, 53, 55, 56] Metals, ions Mg2+ ( required for kinase activity [57]) [1, 50, 51, 52, 57] Mn2+ ( essential for autophosposphorylation activity, cannot be substituted by Mg2+ , Ca2+ , or Zn2+ [57]) [51, 57]

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Additional information ( the expression level of the enzyme is not influenced by high salinity stress [53]) [53] Turnover number (min–1) 0.26 (ATP, recombinant mutant Y317F [55]) [55] 0.54 (ATP, recombinant mutant Y297F [55]) [55] 1.02 (ATP, recombinant mutant Y148F [55]) [55] 3.09 (histone H1, recombinant mutant Y148F [55]) [55] 3.3 (histone H1, recombinant mutant Y317F [55]) [55] 3.71 (histone H1, recombinant mutant Y297F [55]) [55] 5.25 (ATP, recombinant wild-type enzyme [55]) [55] 14.5 (ATP, recombinant mutant Y213F [55]) [55] 18.4 (histone H1, recombinant mutant Y213F [55]) [55] Specific activity (U/mg) Additional information ( large scale activity assay with recombinant enzyme in a protein chip consisting of a microwell array with protein covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker, overview [50]) [50] Km-Value (mM) 0.006 (histone H1, recombinant mutant Y213F [55]) [55] 0.007 (histone H1, recombinant wild-type enzyme [55]) [55] 0.009 (histone H1, recombinant wild-type enzyme [55]) [55] 0.011 (histone H1, recombinant mutants Y148F and Y297F [55]) [55] 0.012 (histone H1, recombinant mutant Y317F [55]) [55] 0.019 (ATP, recombinant mutant Y213F [55]) [55] 0.034 (ATP, recombinant wild-type enzyme [55]) [55] 0.059 (ATP, recombinant mutant Y317F [55]) [55] 0.081 (ATP, recombinant mutant Y297F [55]) [55] 0.107 (ATP, recombinant mutant Y148F [55]) [55] Additional information ( kinetics [52]) [52] Ki-Value (mM) 0.000014 (tyrphostin, versus ATP, pH 7.5, 30 C, recombinant mutant Y213F [52]) [52] 0.000017 (genistein, versus ATP, pH 7.5, 30 C, recombinant mutant Y213F [52]) [52] 0.000018 (tyrphostin, versus ATP, pH 7.5, 30 C, recombinant wild-type enzyme [52]) [52] 0.00002 (genistein, versus ATP, pH 7.5, 30 C, recombinant wildtype enzyme [52]) [52] 0.000055 (tyrphostin, versus ATP, pH 7.5, 30 C, recombinant mutant Y317F [52]) [52] 0.000056 (staurosporine, pH 7.5, 30 C, recombinant mutant Y213F [52]) [52] 0.000059 (genistein, versus ATP, pH 7.5, 30 C, recombinant mutant Y317F [52]) [52]

380

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0.000069 (staurosporine, versus ATP, pH 7.5, 30 C, recombinant wild-type enzyme [52]) [52] 0.000112 (staurosporine, pH 7.5, 30 C, recombinant mutant Y317F [52]) [52] 0.000186 (tyrphostin, versus ATP, pH 7.5, 30 C, recombinant mutant Y297F [52]) [52] 0.000187 (tyrphostin, versus ATP, pH 7.5, 30 C, recombinant mutant Y148F [52]) [52] 0.000191 (genistein, versus ATP, pH 7.5, 30 C, recombinant mutant Y148F [52]) [52] 0.000194 (genistein, versus ATP, pH 7.5, 30 C, recombinant mutant Y297F [52]) [52] 0.000202 (tyrphostin, versus histone H1, pH 7.5, 30 C, recombinant wild-type enzyme [52]) [52] 0.000426 (genistein, versus histone H1, pH 7.5, 30 C, recombinant wild-type enzyme [52]) [52] 0.000455 (staurosporine, versus histone H1, pH 7.5, 30 C, recombinant wild-type enzyme [52]) [52] 0.000464 (staurosporine, pH 7.5, 30 C, recombinant mutant Y297F [52]) [52] 0.000549 (staurosporine, versus histone H1, pH 7.5, 30 C, recombinant mutant Y213F [52]) [52] 0.000571 (staurosporine, pH 7.5, 30 C, recombinant mutant Y148F [52]) [52] 0.000599 (staurosporine, versus histone H1, pH 7.5, 30 C, recombinant mutant Y317F [52]) [52] 0.000621 (staurosporine, versus histone H1, pH 7.5, 30 C, recombinant mutant Y148F [52]) [52] 0.000694 (staurosporine, versus histone H1, pH 7.5, 30 C, recombinant mutant Y297F [52]) [52] Additional information ( inhibition kinetics of tyrosine kinase inhibitors, recombinant His-tagged wild-type and mutant enzymes [52]) [52] pH-Optimum 7.4 ( assay at [51]) [51] 7.5 ( assay at [52]) [52] 8.4 ( assay at [57]) [57] Temperature optimum ( C) 30 ( assay at [51,52,57]) [51, 52, 57]

4 Enzyme Structure Molecular weight 55000 ( recombinant His-tagged wild-type enzyme, gel filtration [52]) [52]

381

Dual-specificity kinase

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Subunits ? ( x * 65000, splicing variant 1, SDS-PAGE, x * 70000, splicing variant 2, SDS-PAGE, x * 75000, splicing variant 3 from skeletal muscle, SDS-PAGE [51]) [51] Additional information ( analysis of sequence motifs [55]; enzyme domain determination and analysis, modular organization, the enzyme contains a C-terminal NirV domain and a TPR domain, an N-terminal protein kinase domain, overview [54]; enzyme domain determination and analysis, modular organization, the enzyme contains a O-sialoglycoprotein endopeptidase, OSGP, domain at the N-terminus [54]; enzyme domain determination and analysis, modular organization, the enzyme contains a O-sialoglycoprotein endopeptidase, OSGP, domain at the N-terminus, the enzyme contains an N-terminal ABC1 kinase domain and a putative transmembrane spanning segment at the C-terminus [54]; enzyme domain determination and analysis, modular organization, the enzyme contains a PP2C-like domain at the N-terminus [54]; enzyme domain determination and analysis, modular organization, the enzyme contains a PP2C-like domain at the N-terminus, and 11 STYK-like sequences, overview [54]; enzyme domain determination and analysis, modular organization, the enzyme contains an N-terminal ABC1 kinase domain and a putative transmembrane spanning segment at the C-terminus [54]; enzyme domain determination and analysis, modular organization, the enzyme contains an N-terminal protein kinase domain and a hydrophobin-like region at the C-terminus, the latter plays a role in the recognition of d-alanyl-d-alanine dipeptides [54]; enzyme domain determination and analysis, modular organization, the enzyme contains an universal stress induced protein associated domain, USPA [54]; enzyme domain determination and analysis, modular organization, the enzyme contains an universal stress induced protein associated domain, USPA, and a Cterminal GUN4 domain, the latter binds magnesium-protoporphyrin IX [54]; enzyme domain determination and analysis, modular organization, the enzyme contains an universal stress induced protein associated domain, USPA, the enzyme contains an N-terminal ABC1 kinase domain and a putative transmembrane spanning segment at the C-terminus [54]; enzyme domain determination and analysis, modular organization, the enzyme contains N-terminal TPR repeats, followed by a GGDEF domain at the C-terminus, overview [54]; enzyme domain determination and analysis, modular organization, the enzyme contains PQQ family repeats, which form bpropeller-like structures and can serve as sites for the interaction with target proteins [54]; enzyme domain determination and analysis, modular organization, the enzyme contains PQQ family repeats, which form b-propellerlike structures and can serve as sites for the interaction with target proteins, the enzyme also contains three to six NHL repeats, following the kinase domain, which are known to serve as protein interaction surfaces and might possess enzymic activity [54]; enzyme domain determination and analysis, modular organization, the enzyme contains several tetratrico

382

2.7.12.1

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peptide repeats [54]; enzyme domain determination and analysis, modular organization, the enzyme contains several tetratrico peptide repeats and a C-terminal GUN4 domain, the latter binds magnesium-protoporphyrin IX, the enzyme of strain PCC 7120 contains a pectinesterase domain catalyzing the hydrolysis of pectin, and WD repeats [54]; enzyme domain determination and analysis, modular organization, the enzyme contains several tetratrico peptide repeats, and three to six NHL repeats, following the kinase domain, which are known to serve as protein interaction surfaces and might possess enzymic activity, the enzyme also contains an N-terminal protein kinase domain and a hydrophobin-like region at the C-terminus, the latter plays a role in the recognition of d-alanyl d-alanine dipeptides [54]; enzyme domain determination and analysis, modular organization, the enzyme contains several tetratrico peptide repeats, the enzyme contains an N-terminal ABC1 kinase domain and a putative transmembrane spanning segment at the C-terminus [54]; enzyme domain determination and analysis, modular organization, the enzyme contains several tetratrico peptide repeats, the enzyme contains PQQ family repeats, which form b-propeller-like structures and can serve as sites for the interaction with target proteins [54]; enzyme domain determination and analysis, modular organization, the enzyme contains WD repeats [54]; enzyme domain determination and analysis, unique modular organization, the enzyme contains an N-terminal protein kinase domain, a central transmembrane domain, and a C-terminal peptidyl-prolyl cis-trans isomerase domain [54]; structure modeling of wild-type and mutant enzymes based on the X-ray structure of homologous sequences, computational docking and molecular dynamics simulations, overview [52]) [52, 54, 55] Posttranslational modification glycoprotein ( the enzyme contains a O-sialoglycoprotein endopeptidase, OSGP, domain at the N-terminus, and is thus probably sialo-glycosylated [54]) [54] phosphoprotein ( autophosphorylation [17, 19, 21, 23, 41]; autophosphorylated on serine and threonine residues [3]; dual specificity protein kinase that is regulated by tyrosine phosphorylation in the activation loop [41]; autophosphorylation on serine, threonine, and tyrosine residues [45]; the enzyme performs autophosporylation [50]; MALDI-MS phosphorylation site mapping, the enzyme performs autophosphorylation within the ATP binding site at Tyr148 and Tyr317, at Tyr213 of the activation loop, and at Tyr297 in the C-terminus [55]; the enzyme autophosphorylates at Thr202, Tyr72 and Tyr83, the insulin-activated insulin receptor kinase phosphorylates Y198 in the YMKM motif, Y228 in the YLSF motif, and Y291 [57]; the enzyme performs autophosphorylation, mechanism and phosphorylation sites, overview [52]) [3, 17, 19, 21, 23, 41, 45, 50, 52, 55, 57]

383

Dual-specificity kinase

2.7.12.1

5 Isolation/Preparation/Mutation/Application Source/tissue brain ( fetal and adult [37]; expressed in the neuronal regions affected in Down syndrome [38]; overexpression in Down syndrome [34]; expression pattern in frontal brain nuclei during murine embryogenesis [39]) [34, 37, 38, 39, 41, 51] cell culture ( most malignant tumors assessed express TTK mRNA, as well, all rapidly proliferating cell lines tested express TTK mRNA [43]; embryonal carcinoma cell line [45]) [43, 45] embryonic carcinoma cell line [29] erythroleukemia cell [30] heart [51] leaf ( low expression level [53]; high expression of DPK1 [56]; low expression of DPK4 [56]; moderate expression of DPK2 [56]; moderate expression of DPK3 [56]) [53, 56] lung [51] muscle ( predominately expressed in muscle and testis [42]) [20, 42] neuroblast [31] root ( low expression of DPK4 [56]; moderate expression of DPK3 [56]) [53, 56] seedling [56] shoot [53] skeletal muscle [51] spike ( high expression of DPK1 in immature spikes [56]; low expression of DPK4 [56]) [56] spleen [51] stem ( low expression of DPK2 [56]; low expression of DPK4 [56]) [56] stomach [51] testis ( predominately expressed in muscle and testis [42]; predominately expressed in testis [21,40]) [20, 21, 40, 42, 43, 51] thymus [43] Additional information ( tissue-specific expression of isozymes [56]; the enzyme is expressed in most tissues [51]) [51, 56] Localization membrane [45, 54] nucleus ( enzyme contains a nuclear targeting signal sequence [36]) [36] Additional information ( nuclear localization of DYRK1A is mediated by its nuclear targeting signal, amino acids 105-139, but ist charac-

384

2.7.12.1

Dual-specificity kinase

teristic subnuclear distribution depends on additional N-terminal elements, amino acids 1-104 [21]; STY protein contains a putative nuclear localization signal [29]) [21, 29] Purification (recombinant GST-fusion protein from Escherichia coli strain DH5a by glutathione affinity chromatography) [57] (recombinant His-tagged wild-type and mutant enzymes from Escherichia coli strain BL21(DE3) by nickel affinity chromatography) [52, 55] Cloning (DNA and amino acid sequence determination and analysis, the enzyme occurs in several splicing variants, expression in human fibroblast 3T3-L1 cell line) [51] (expression in Escherichia coli strain DH5a as GST-fusion protein, expression in 293A cells) [57] (phylogenetic tree of kinases derived from the kinase core sequence, overview, overexpression as GST-fusion protein under control of the galactose-inducible GAL1 promotor in Escherichia coli, determination of 5’-end sequences) [50] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (expression of His-tagged wild-type and mutant enzymes in Escherichia coli strain BL21(DE3)) [52] (overexpression of His-tagged wild-type and mutant enzymes in Escherichia coli strain BL21(DE3)) [55] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54]

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Dual-specificity kinase

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[15] (green fluorescent protein fusion protein of DYRK1B is found mainly in the nucleus of transfected COS-7 cells) [42] [19] [19] [19] [20] [29] [32] [28] [28] [36, 37] [40] [41] (fusion protein of DYRK1A accumulates in the nucleus of transfected COS-7 and HEK293 cells, expression in Escherichia coli) [21] (green fluorescent protein fusion protein of DYRK1B is found mainly in the nucleus of transfected COS-7 cells) [42] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (DNA and amino acid sequence determination and analysis, the enzyme occurs in several splicing variants, analysis overview, expression in murine hypothalamic GT1-7 cell line, expression of splicing variants in COS-7 cells and in Escherichia coli) [51] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (sequence analysis for enzyme domain determination) [54] (single-copy gene, DNA and amino acid sequence determination and analysis, comparison of subdomain sequences with those of Arabidopsis thaliana) [53] (isozyme DPK1, DNA and amino acid sequence determination and analysis, gene mapping, expression analysis under stress conditions) [56] (isozyme DPK3, DNA and amino acid sequence determination and analysis, gene mapping, expression analysis under stress conditions) [56] (isozyme DPK2, DNA and amino acid sequence determination and analysis, gene mapping, expression analysis under stress conditions) [56] (isozyme DPK4, DNA and amino acid sequence determination and analysis, gene mapping, expression analysis under stress conditions) [56]

386

2.7.12.1

Dual-specificity kinase

Engineering K160R ( site-directed mutagenesis, inactive mutant enzyme [52]) [52] Y148F ( site-directed mutagenesis, ATP binding site residue, the mutant is unable to phosphorylate histone and is not phosphorylated itself [55]; site-directed mutagenesis, the mutant enzyme shows altered inhibition kinetics with tyrosine kinase inhibitors compared to the wild-type enzyme [52]) [52, 55] Y213F ( site-directed mutagenesis, TEY motif residue, the mutant shows 4fold increased autophosphorylation and 2.8fold increased activity with ATP and histone compared to the wild-type enzyme [55]; site-directed mutagenesis, the mutant enzyme shows altered inhibition kinetics with tyrosine kinase inhibitors compared to the wild-type enzyme [52]) [52, 55] Y297F ( site-directed mutagenesis, inactive mutant enzyme [55]; site-directed mutagenesis, the mutant enzyme shows altered inhibition kinetics with tyrosine kinase inhibitors compared to the wild-type enzyme [52]) [52, 55] Y317F ( site-directed mutagenesis, ATP binding site residue, the mutant is unable to phosphorylate histone and is not phosphorylated itself [55]; site-directed mutagenesis, the mutant enzyme shows altered inhibition kinetics with tyrosine kinase inhibitors compared to the wild-type enzyme [52]) [52, 55] Additional information ( exchange of two Tyr residues in the activation loop between subdomains VII and VIII for Phe almost completely suppresses the activity and Tyr autophosphorylation of Dyrk. Tyr autophosphorylation is also reduced by exchange of Tyr219 in a tyrosine phosphorylation consensus motif [41]; enzyme knock-out leads to increased dglucose uptake in response to insulin [57]) [41, 57] Application analysis ( development of a protein chip consisting of a silicone elastomer microwell array with recombinant enzyme covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker for large scale activity assay, overview [50]) [50]

References [1] MacKintosh, C.; MacKintosh, R.W.: Inhibitors of protein kinases and phosphatases. Trends Biochem. Sci., 19, 444-448 (1994) [2] Adams, M.D.; Celniker, S.E.; Holt, R.A.; Evans, C.A.; Gocayne, J.D.; et al.: The genome sequence of Drosophila melanogaster. Science, 287, 2185-2195 (2000) [3] Nuckolls, G.H.; Osherov, N.; Loomis, W.F.; Spudich, J.A.: The Dictyostelium dual-specificity kinase splA is essential for spore differentiation. Development, 122, 3295-3305 (1996) [4] Tan, J.L.; Spudich, J.A.: Developmentally regulated protein-tyrosine kinase genes in Dictyostelium discoideum. Mol. Cell. Biol., 10, 3578-3583 (1990)

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[5] Wood, V.; Gwilliam, R.; Rajandream, M.A.; Lyne, M.; Lyne, R.; et al.: The genome sequence of Schizosaccharomyces pombe. Nature, 415, 871-880 (2002) [6] Sanchez, Y.; Bachant, J.; Wang, H.; Hu, F.; Liu, D.; Tetzlaff, M.; Elledge, S.J.: Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms. Science, 286, 1166-1171 (1999) [7] Pellicioli, A.; Lucca, C.; Liberi, G.; et al.: Activation of Rad53 kinase in response to DNA damage and its effect in modulating phosphorylation of the lagging strand DNA polymerase. EMBO J., 18, 6561-6572 (1999) [8] Liao, H.; Byeon, I.J.; Tsai, M.D.: Structure and function of a new phosphopeptide-binding domain containing the FHA2 of Rad53. J. Mol. Biol., 294, 1041-1049 (1999) [9] Purnelle, B.; Coster, F.; Goffeau, A.: The sequence of 55 kb on the left arm of yeast chromosome XVI identifies a small nuclear RNA, a new putative protein kinase and two new putative regulators. Yeast, 12, 1483-1492 (1996) [10] Allen, J.B.; Zhou, Z.; Siede, W.; Friedberg, E.C.; Elledge, S.J.: The SAD1/ RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast. Genes Dev., 8, 2401-2415 (1994) [11] Stern, D.F.; Zheng, P.; Beidler, D.R.; Zerillo, C.: Spk1, a new kinase from Saccharomyces cerevisiae, phosphorylates proteins on serine, threonine, and tyrosine. Mol. Cell. Biol., 11, 987-1001 (1991) [12] Mayer, K.; Schuller, C.; Wambutt, R.; Murphy, G.; et al.: Sequence and analysis of chromosome 4 of the plant Arabidopsis thaliana. Nature, 402, 769777 (1999) [13] Bussey, H.; Storms, R.K.; Ahmed, A.; Albermann, K.; et al.: The nucleotide sequence of Saccharomyces cerevisiae chromosome XVI. Nature, 387, 103105 (1997) [14] Salanoubat, M.; Lemcke, K.; Rieger, M.; Ansorge, W.; Unseld, M.; et al.: Sequence and analysis of chromosome 3 of the plant Arabidopsis thaliana. Nature, 408, 820-822 (2000) [15] Kim, K.H.; Cho, Y.M.; Kang, W.H.; Kim, J.H.; Byun, K.H.; Park, Y.D.; Bae, K.S.; Park, H.M.: Negative regulation of filamentous growth and flocculation by Lkh1, a fission yeast LAMMER kinase homolog. Biochem. Biophys. Res. Commun., 289, 1237-1242 (2001) [16] Purnelle, B.; Goffeau, A.: The sequence of 32b on the left arm of yeast chromosome XII reveals six known genes, a new member of the seripauperins family and a new ABS transporter homologous to the human multidrug resistance protein. Yeast, 13, 183-188 (1997) [17] Lee, K.; Du, C.; Horn, M.; Rabinow, L.: Activity and autophosphorylation of LAMMER protein kinases. J. Biol. Chem., 271, 27299-27303 (1996) [18] Padmanabha, R.; Gehrung, S.; Snyder, M.: The KNS1 gene of Saccharomyces cerevisiae encodes a nonessential protein kinase homologue that is distantly related to members of the CDC28/cdc2 gene family. Mol. Gen. Genet., 229, 1-9 (1991) [19] Nayler, O.; Stamm, S.; Ullrich, A.: Characterization and comparison of four serine- and arginine-rich (SR) protein kinases. Biochem. J., 326, 693-700 (1997)

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[20] Xia, J.; Yang, X.; Ruan, Q.; Pan, Q.; Liu, C.; Xie, W.; Deng, H.: Molecular cloning and characterization of novel protein kinase gene DYRK3. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 15, 327-332 (1998) [21] Becker, W.; Weber, Y.; Wetzel, K.; Eirmbter, K.; Tejedor, F.J.; Joost, H.G.: Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J. Biol. Chem., 273, 25893-25902 (1998) [22] Moriya, H.; Shimizu-Yoshida, Y.; Omori, A.; Iwashita, S.; Katoh, M.; Sakai, A.: Yak1p, a DYRK family kinase, translocates to the nucleus and phosphorylates yeast Pop2p in response to a glucose signal. Genes Dev., 15, 12171228 (2001) [23] Kassis, S.; Melhuish, T.; Annan, R.S.; Chen, S.L.; Lee, J.C.; Livi, G.P.; Creasy, C.L.: Saccharomyces cerevisiae Yak1p protein kinase autophosphorylates on tyrosine residues and phosphorylates myelin basic protein on a C-terminal serine residue. Biochem. J., 348, 263-272 (2000) [24] Katsoulou, C.; Tzermia, M.; Tavernarakis, N.; Alexandraki, D.: Sequence analysis of a 40.7 kb segment from the left arm of yeast chromosome X reveals 14 known genes and 13 new open reading frames including homologues of genes clustered on the right arm of chromosome XI. Yeast, 12, 787-797 (1996) [25] Garrett, S.; Broach, J.: Loss of Ras activity in Saccharomyces cerevisiae is suppressed by disruptions of a new kinase gene, YAKI, whose product may act downstream of the cAMP-dependent protein kinase. Genes Dev., 3, 1336-1348 (1989) [26] Colwill, K.; Pawson, T.; Andrews, B.; Prasad, J.; Manley, J.L.; Bell, J.C.; Duncan, P.I.: The Clk/Sty protein kinase phosphorylates SR splicing factors and regulates their intranuclear distribution. EMBO J., 15, 265-275 (1996) [27] Duncan, P.I.; Howell, B.W.; Marius, R.M.; Drmanic, S.; Douville, E.M.; Bell, J.C.: Alternative splicing of STY, a nuclear dual specificity kinase. J. Biol. Chem., 270, 21524-21531 (1995) [28] Hanes, J.; von der Kammer, H.; Klaudiny, J.; Scheit, K.H.: Characterization by cDNA cloning of two new human protein kinases. Evidence by sequence comparison of a new family of mammalian protein kinases. J. Mol. Biol., 244, 665-672 (1994) [29] Howell, B.W.; Afar, D.E.; Lew, J.; Douville, E.M.; Icely, P.L.; Gray, D.A.; Bell, J.C.: STY, a tyrosine-phosphorylating enzyme with sequence homology to serine/threonine kinases. Mol. Cell. Biol., 11, 568-572 (1991) [30] Ben-David, Y.; Letwin, K.; Tannock, L.; Bernstein, A.; Pawson, T.: A mammalian protein kinase with potential for serine/threonine and tyrosine phosphorylation is related to cell cycle regulators. EMBO J., 10, 317-325 (1991) [31] Tejedor, F.; Zhu, X.R.; Kaltenbach, E.; Ackermann, A.; Baumann, A.; Canal, I.; Heisenberg, M.; Fischbach, K.F.; Pongs, O.: Minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila. Neuron, 14, 287-301 (1995) [32] Johnson, K.W.; Smith, K.A.: Molecular cloning of a novel human cdc2/ CDC28-like protein kinase. J. Biol. Chem., 266, 3402-3407 (1991)

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Dual-specificity kinase

2.7.12.1

[33] Winfield, S.L.; Tayebi, N.; Martin, B.M.; Ginns, E.I.; Sidransky, E.: Identification of three additional genes contiguous to the glucocerebrosidase locus on chromosome 1q21: implications for Gaucher disease. Genome Res., 7, 1020-1026 (1997) [34] Guimera, J.; Casas, C.; Estivill, X.; Pritchard, M.: Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome. Genomics, 57, 407-418 (1999) [35] Dahmane, N.; Ghezala, G.A.; Gosset, P.; Chamoun, Z.; et al.: Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome. Genomics, 48, 12-23 (1998) [36] Song, W.J.; Sternberg, L.R.; Kasten-Sportes, C.; et al.: Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome “critical region“. Genomics, 38, 331-339 (1996) [37] Shindoh, N.; Kudoh, J.; Maeda, H.; Yamaki, A.; Minoshima, S.; Shimizu, Y.; Shimizu, N.: Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from “the Down syndrome critical region“ of chromosome 21. Biochem. Biophys. Res. Commun., 225, 92-99 (1996) [38] Guimera, J.; Casas, C.; Pucharcos, C.; et al.: A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region. Hum. Mol. Genet., 5, 1305-1310 (1996) [39] Song, W.J.; Chung, S.H.; Kurnit, D.M.: The murine Dyrk protein maps to chromosome 16, localizes to the nucleus, and can form multimers. Biochem. Biophys. Res. Commun., 231, 640-644 (1997) [40] Becker, W.; Kentrup, H.; Heukelbach, J.; Joost, H.G.: cDNA cloning and characterization of rat Clk3, a LAMMER kinase predominately expressed in testis. Biochim. Biophys. Acta, 1312, 63-67 (1996) [41] Kentrup, H.; Becker, W.; Heukelbach, J.; Wilmes, A.; Schurmann, A.; Huppertz, C.; Kainulainen, H.; Joost, H.G.: Dyrk, a dual specificity protein kinase with unique structural features whose activity is dependent on tyrosine residues between subdomains VII and VIII. J. Biol. Chem., 271, 34883495 (1996) [42] Leder, S.; Weber, Y.; Altafaj, X.; Estivill, X.; Joost, H.G.; Becker, W.: Cloning and characterization of DYRK1B, a novel member of the DYRK family of protein kinases. Biochem. Biophys. Res. Commun., 254, 474-479 (1999) [43] Mills, G.B.; Schmandt, R.; McGill, M.; Amendola, A.; Hill, M.; Jacobs, K.; May, C.; Rodricks, A.M.; Campbell, S.; Hogg, D.: Expression of TTK, a novel human protein kinase, is associated with cell proliferation. J. Biol. Chem., 267, 16000-16006 (1992) [44] Hanks, S.K.; Quinn, A.M.: Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol., 200, 38-62 (1991) [45] Douville, E.M.; Afar, D.E.; Howell, B.W.; Letwin, K.; Tannock, L.; Ben-David, Y.; Pawson, T.; Bell, J.C.: Multiple cDNAs encoding the esk kinase predict

390

2.7.12.1

[46]

[47] [48]

[49] [50] [51]

[52]

[53] [54] [55]

[56]

[57]

Dual-specificity kinase

transmembrane and intracellular enzyme isoforms. Mol. Cell. Biol., 12, 2681-2689 (1992) Saren, A.M.; Laamanen, P.; Lejarcegui, J.B.; Paulin, L.: The sequence of a 36.7 kb segment on the left arm of chromosome IV from Saccharomyces cerevisiae reveals 20 non-overlapping open reading frames (ORFs) including SIT4, FAD1, NAM1, RNA11, SIR2, NAT1, PRP9, ACT2 and MPS1 and 11 new ORFs. Yeast, 13, 65-71 (1997) Lauze, E.; Stoelcker, B.; Luca, F.C.; Weiss, E.; Schutz, A.R.; Winey, M.: Yeast spindle pole body duplication gene MPS1 encodes an essential dual specificity protein kinase. EMBO J., 14, 1655-1663 (1995) Poch, O.; Schwob, E.; de Fraipont, F.; Camasses, A.; Bordonne, R.; Martin, R.P.: RPK1, an essential yeast protein kinase involved in the regulation of the onset of mitosis, shows homology to mammalian dual-specificity kinases. Mol. Gen. Genet., 243, 641-653 (1994) Bender, J.; Fink, G.R.: AFC1, a LAMMER kinase from Arabidopsis thaliana, activates STE12-dependent processes in yeast. Proc. Natl. Acad. Sci. USA, 91, 12105-12109 (1994) Zhu, H.; Klemic, J.F.; Chang, S.; Bertone, P.; Casamayor, A.; Klemic, K.G.; Smith, D.; Gerstein, M.; Reed, M.A.; Snyder, M.: Analysis of yeast protein kinases using protein chips. Nat. Genet., 26, 283-289 (2000) Leder, S.; Czajkowska, H.; Maenz, B.; De Graaf, K.; Barthel, A.; Joost, H.G.; Becker, W.: Alternative splicing variants of dual specificity tyrosine phosphorylated and regulated kinase 1B exhibit distinct patterns of expression and functional properties. Biochem. J., 372, 881-888 (2003) Rudrabhatla, P.; Rajasekharan, R.: Functional characterization of peanut serine/threonine/tyrosine protein kinase: molecular docking and inhibition kinetics with tyrosine kinase inhibitors. Biochemistry, 43, 12123-12132 (2004) Jang, J.Y.; Kwak, K.J.; Kang, H.: Molecular cloning and characterization of a cDNA encoding a kinase in Cucumis sativus and its expression by abiotic stress treatments. Biochim. Biophys. Acta, 1679, 74-79 (2004) Krupa, A.; Srinivasan, N.: Diversity in domain architectures of Ser/Thr kinases and their homologues in prokaryotes. BMC Genet., 6, 1-20 (2005) Rudrabhatla, P.; Rajasekharan, R.: Mutational analysis of stress-responsive peanut dual specificity protein kinase. Identification of tyrosine residues involved in regulation of protein kinase activity. J. Biol. Chem., 278, 17328-17335 (2003) Gu, Z.; Wang, J.; Huang, J.; Zhang, H.: Cloning and characterization of a novel rice gene family encoding putative dual-specificity protein kinases, involved in plant responses to abiotic and biotic stresses. Plant Sci., 169, 470-477 (2005) Lerner-Marmarosh, N.; Shen, J.; Torno, M.D.; Kravets, A.; Hu, Z.; Maines, M.D.: Human biliverdin reductase: A member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity. Proc. Natl. Acad. Sci. USA, 102, 7109-7114 (2005)

391

Mitogen-activated protein kinase kinase

1 Nomenclature EC number 2.7.12.2 Systematic name ATP:protein phosphotransferase (MAPKKK-activated) Recommended name mitogen-activated protein kinase kinase Synonyms ASK1 [16, 67] CaSTE7 [42] Cdc7p kinase [38] ERK [77, 79, 80, 82, 84] ERK 1 [78] ERK 2 [78] ERK1 [85] ERK2 [85] HEP protein [55] JNKK2 [15] MAP kinase kinase MKK1/SSP32 [4, 32] MAP kinase kinase MKK2/SSP33 [5, 32] MAP kinase kinase homologue [83] MAP kinase kinase skh1/pek1 [3, 74, 75] MAPK kinase [1] MAPK kinase-1 [2] MAPK/ERK kinase 5 [9] MAPK/Erk kinase [30] MAPKK [1] MAPKK1 [31] MAPKK2 [31] MAPKKK5 [67] MEK [30, 77, 78, 80, 82, 84] MEK 1 [81] MEK 2 [81] MEK kinase 1 [59] MEK kinase 2 [71] MEK-2 [54] MEK1 [1, 34, 61, 76, 79, 85] MEK2 [1, 60, 64, 79, 85]

392

2.7.12.2

2.7.12.2

Mitogen-activated protein kinase kinase

MEK5 [9, 58] MEKK 2 [57] MEKK3 [69] MKK homologue [83] MKK1 [52] MKK2 [34, 35] MKK4 [40] MKK6 [47, 49] MKK7 [12] PK4 [83] PTK2 [76] SAPK/ERK kinase-1 [45] SAPKK3 [46] TUB4 [76] apoptosis signal-regulating kinase 1 [16] cdc7 protein kinase [37] cell division control protein 7 [37, 38] dual specificity mitogen-activated protein kinase kinase 1 [14, 25, 26, 27, 28, 29, 30, 31, 34, 36, 50, 51, 52, 53, 61] dual specificity mitogen-activated protein kinase kinase 2 [14, 30, 31, 34, 35, 36, 60, 63, 64] dual specificity mitogen-activated protein kinase kinase 3 [6, 8, 11, 43, 44] dual specificity mitogen-activated protein kinase kinase 4 [8, 14, 39, 40, 45] dual specificity mitogen-activated protein kinase kinase 5 [9, 58] dual specificity mitogen-activated protein kinase kinase 6 [14, 43, 46, 47, 48, 49] dual specificity mitogen-activated protein kinase kinase 7 [10, 12, 13, 14, 15] dual specificity mitogen-activated protein kinase kinase dSOR1 [56] dual specificity mitogen-activated protein kinase kinase hemipterous [55] dual specificity mitogen-activated protein kinase kinase mek-2 [54] dual specificity protein kinase FUZ7 [65] extracellular signal-regulated kinase [84] extracellular-signal-regulated kinase [79, 82, 85] extracellular-signal-regulated kinase 1 [78] extracellular-signal-regulated kinase 2 [78] mammalian MAP kinase kinase [61] mitogen-activated protein kinase kinase [82] mitogen-activated protein kinase kinase 1 [79, 81] mitogen-activated protein kinase kinase 2 [79, 81, 85] mitogen-activated protein kinase kinase 4 [83] mitogen-activated protein kinase kinase homologue [83] mitogen-activated protein kinase kinase kinase 1 [59] mitogen-activated protein kinase kinase kinase 2 [57, 71]

393

Mitogen-activated protein kinase kinase

2.7.12.2

mitogen-activated protein kinase kinase kinase 3 [57, 69] mitogen-activated protein kinase kinase kinase 4 [72, 73] mitogen-activated protein kinase kinase kinase 5 [16, 66, 67, 68] mitogen-activated protein kinase kinase type 2 [64] mitogen-activated protein kinase/ERK kinase kinase 3 [69] mitogen-activated protein/ERK kinase kinases [57] p120cdc7 protein kinase [37] p21cdc42/rac1 binding protein [62] polymyxin B resistance protein kinase [7, 21, 22, 23] protein kinase byr1 [3, 24] protein kinase wis1 [3, 33] serine/threonine protein kinase STE7 [17, 18, 19, 20] serine/threonine protein kinase STE7 homolog [41, 42] serine/threonine-protein kinase PAK 2 [62] serine/threonine-protein kinase PAK 7 [70] wis1 protein kinase [33] CAS registry number 142805-58-1

2 Source Organism













394

eukaryota (no sequence specified) [1, 2] Mus musculus (no sequence specified) [84] Homo sapiens (no sequence specified) [77, 80, 81] Rattus norvegicus (no sequence specified) [78, 79, 82] Saccharomyces cerevisiae (no sequence specified) [76] Mesocricetus auratus (no sequence specified) [85] Mus musculus (UNIPROT accession number: O09110) [6,11] Homo sapiens (UNIPROT accession number: O14733) [10,12,13,14,15] Mus musculus (UNIPROT accession number: O35099) [16] Saccharomyces cerevisiae (UNIPROT accession number: P06784) [17, 18, 19, 20] Saccharomyces cerevisiae (UNIPROT accession number: P08018) [7, 21, 22, 23] Schizosaccharomyces pombe (UNIPROT accession number: P10506) [3, 24] Oryctolagus cuniculus (UNIPROT accession number: P29678) [25, 26, 27, 28] Mus musculus (UNIPROT accession number: P31938) [29, 30, 31] Saccharomyces cerevisiae (UNIPROT accession number: P32490) [4, 32] Saccharomyces cerevisiae (UNIPROT accession number: P32491) [5, 32] Schizosaccharomyces pombe (UNIPROT accession number: P33886) [3, 33] Rattus norvegicus (UNIPROT accession number: P36506) [34, 35] Homo sapiens (UNIPROT accession number: P36507) [14, 31, 36]

2.7.12.2

Mitogen-activated protein kinase kinase

Schizosaccharomyces pombe (UNIPROT accession number: P41892) [37, 38] Homo sapiens (UNIPROT accession number: P45985) [8, 14, 39, 40] Candida albicans (UNIPROT accession number: P46599) [41, 42] Homo sapiens (UNIPROT accession number: P46734) [8, 11, 43, 44] Mus musculus (UNIPROT accession number: P47809) [45] Homo sapiens (UNIPROT accession number: P52564) [14, 43, 46, 47, 48, 49] Mus musculus (UNIPROT accession number: P70236) [46] Rattus norvegicus (UNIPROT accession number: Q01986) [34, 50, 51] Homo sapiens (UNIPROT accession number: Q02750) [14, 20, 31, 36, 52] Xenopus laevis (UNIPROT accession number: Q05116) [53] Caenorhabditis elegans (UNIPROT accession number: Q10664) [54] Homo sapiens (UNIPROT accession number: Q13163) [9] Drosophila melanogaster (UNIPROT accession number: Q23977) [55] Drosophila melanogaster (UNIPROT accession number: Q24324) [56] Mus musculus (UNIPROT accession number: Q61083) [57] Mus musculus (UNIPROT accession number: Q61084) [57] Rattus norvegicus (UNIPROT accession number: Q62862) [58] Rattus norvegicus (UNIPROT accession number: Q62925) [59] Mus musculus (UNIPROT accession number: Q63932) [30, 60] Cricetulus griseus (UNIPROT accession number: Q63980) [61] Rattus norvegicus (UNIPROT accession number: Q64303) [62] Cyprinus carpio (UNIPROT accession number: Q90321) [63] Gallus gallus (UNIPROT accession number: Q90891) [64] Ustilago maydis (UNIPROT accession number: Q99078) [65] Homo sapiens (UNIPROT accession number: Q99683) [66, 67, 68] Homo sapiens (UNIPROT accession number: Q99759) [69] Homo sapiens (UNIPROT accession number: Q9P286) [70] Homo sapiens (UNIPROT accession number: Q9Y2U5) [71] Homo sapiens (UNIPROT accession number: Q9Y6R4) [72, 73] Schizosaccharomyces pombe (UNIPROT accession number: Q9Y884) [3, 74, 75] Leishmania mexicana (UNIPROT accession number: Q9GRT1) [83]

3 Reaction and Specificity Catalyzed reaction ATP + a protein = ADP + a phosphoprotein Natural substrates and products S ATP + ERK ( ERK phosphorylation by MEK1/2 [81]; phosphorylation by MEK activates ERK, which plays a role in pain induction modulating the A-type currents of potassium channels in neurons, ERK plays a central role in nocireceptive sensitization in the spinal cord [84]) (Reversibility: ?) [81, 84]

395

Mitogen-activated protein kinase kinase

2.7.12.2

P ADP + phosphorylated ERK S ATP + MAP kinase ( the enzyme is involved in the mitogenactivated protein kinase signaling pathway important for e.g. flagellar length control, the enzyme is involved in differentiation of the parasite and is important for virulence and infection of human peritoneal macrophages [83]) (Reversibility: ?) [83] P ADP + phosphorylated MAP kinase S ATP + MAPK ( MAPK activation [1]) (Reversibility: ?) [1] P ADP + phosphorylated MAPK S ATP + a protein (Reversibility: ?) [1, 2, 76] P ADP + a phosphoprotein S ATP + protein ( Pek1, in its unphosphorylated form, acts as a potent negative regulator of Pmk1 MAPK signalling. Mkh1, an upstream MAPKK kinase, converts Pek1 from being an inhibitor to an activator. Pek1 has a dual stimulatory and inhibitory function which depends on its phosphorylation state [75]; enzyme is involved in independent human MAP-kinase signal transduction pathway [8]; enzyme plays a key role in initiation of septum formation and cytokinesis in fission yeast, p120cdc7 interacts with the cdc11 protein in the control of septation [37]; the enzyme renders the cell resistant to polymyxin B [21]; possible role for ASK1 in tissue development during embryogenesis as well as cytokine-induced apoptosis [16]; MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2. The enzyme is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins, additional role for MKK4 in tumor suppression [40]; the enzyme is an activator of the c-Jun NH2 -terminal kinase, the enzyme is a component of the JNK signal transduction pathway [10]; dosagedependent regulator of mitosis in Schizosaccharomyces pombe [33]; Spg1p is a key element in controlling the onset of septum formation that acts through the Cdc7p kinase [38]; MKK1 and MKK2 function in a signal transduction pathway involving the protein kinases encoded by PKC1, BCK1, and MPK1. The site of action for MKK1 and MKK2 is between BCK1 and MPK1 [32]; enzyme is the major activator for p38 [11]; enzyme is involved on MAPK signal transduction pathway [31]; enzyme is involved in the response of haploid yeast cells to peptide mating pheromones [17]; Hst7 activates the mating pathway even in the absence of upstream signaling components including the Ste7 regulator Ste11, elevates the basal level of the pheromone-inducible FUS1 gene, and amplifies the pseudohyphal growth response in diploid cells [41]; byr1 is an important gene in the sexual differentiation pathway and at least part of ras1 function is to act directly or indirectly through byr1 to modulate protein phosphorylation [24]; the enzyme functions in a novel Drosophila MAPK pathway, controlling puckered expression and morphogenetic activity of the dorsal epidermis [55]; MEKK 2 preferentially activates JNK [57];

396

2.7.12.2

Mitogen-activated protein kinase kinase

MEKK 3 preferentially activates p42/44MAPK [57]; the enzyme is the major activator of RK/p38 [46]; mek-2 acts between lin-45 raf and sur-1/mpk-1 in a signal transduction pathway used in the control of vulval differentiation and other developmental events [54]; the enzyme is involved in the mitogenic growth factor signal transduction pathway in vertebrates [64]; the enzyme is a component of the mkh1 signaling pathway. Mkh1, Skh1 and Spm1 constitute a MAPK cascade in Schizosaccharomyces pombe [74]; MEKK3 regulates the SAPK and the ERK pathway directly [69]; the enzyme is required for locusdependent and locus-independent steps in the fungal life cycle. Necessary for locus-dependent processes, such as conjugation tube formation, filament formation, and maintenance of filamentous growth, and for locusindependent processes, such as tumor induction and teliospore germination [65]; ASK1 may be a key element in the mechanism of stressinduced and cytokine-induced apoptosis [67]; MEK6 is a member of the p38 kinase cascade and efficiently phosphorylates p38, induces phosphorylation of ATF2 by p38 but does not phosphorylate ATF2 directly [49]; MAPKKK5 may be an upstream activator of MKK4 in the cJun N-terminal kinase pathway [68]; the enzyme functions as a direct upstream activator for a presumed MAP kinase homolog in each signal transduction pathway involved in the regulation of cell cycle progression or cellular responses to extracellular signals [53]; sequences located in the N-terminus of MEK5 may be important in coupling GTPase signaling molecules to the MEK5 protein kinase cascade [9]) (Reversibility: ?) [8, 9, 10, 11, 16, 17, 21, 24, 31, 32, 33, 37, 38, 40, 41, 46, 49, 53, 54, 55, 57, 62, 64, 65, 67, 68, 69, 74, 75] P ADP + phosphoprotein S Additional information ( enzyme is part of mitogenactivated protein kinase pathways, crosstalk and regulation mechanism, overview [1]; MEK1/2 are involved in the mitogen-activated protein kinase signaling pathway and in cancer tumorigenesis [81]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway [78]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway regulating cell dissociation of cancer cells, MEK2 is an invasion-metastasis related factor between highly and weakly invasive cells, occludin acts as antagonist [85]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway, pathway induction by neurotrophin stabilizes the axonal growth cone, pathway inhibitor semaphorin 3F induces growth cone collaps in sympathetic neurons and reduction of axonal growth [82]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is involved in e.g. activation of Egr-1 and subsequently of c-Fos and cyclin D1 after mechanic injury for induction/regulation of regrowth of smooth vascular cells, vascular smooth muscle cell proliferation plays an important role in pathogenesis of atherosclerosis and post-angioplasty restenosis, overview [79]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is involved in e.g. formalin-induced inflamma-

397

Mitogen-activated protein kinase kinase

2.7.12.2

tory pain and thermal hyperalgesia, overview [84]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is linked to the cell cycle machinery, constitutive phosphorylation and activation of the enzyme leads to cell proliferation in choroidal melanoma cells [80]) (Reversibility: ?) [1, 78, 79, 80, 81, 82, 84, 85] P ? Substrates and products S ATP + ERK ( ERK phosphorylation by MEK1/2 [81]; phosphorylation by MEK activates ERK, which plays a role in pain induction modulating the A-type currents of potassium channels in neurons, ERK plays a central role in nocireceptive sensitization in the spinal cord [84]; ERK phosphorylation by MEK [84]) (Reversibility: ?) [81, 84] P ADP + phosphorylated ERK S ATP + ERK1 ( MEK2 protein stimulates Thr and Tyr phosphorylation on ERK1 and concomitantly activates ERK1 kinase activity more than 100-fold [36]) (Reversibility: ?) [36] P ADP + phosphorylated ERK1 S ATP + Erk-1 gene product ( phosphorylation primarily on a tyrosine residue and, to a lesser extent, on a threonine [30]) (Reversibility: ?) [30] P ADP + phosphorylated Erk-1 gene product [30] S ATP + JNK (Reversibility: ?) [10] P ADP + phosphorylated JNK S ATP + JNK1 (Reversibility: ?) [12] P ADP + phosphorylated JNK1 S ATP + MAP kinase ( the enzyme is involved in the mitogenactivated protein kinase signaling pathway important for e.g. flagellar length control, the enzyme is involved in differentiation of the parasite and is important for virulence and infection of human peritoneal macrophages [83]; docking site for the substrate is located close to the Nterminal Lys4 and consists of 2 basic amino acid residues separated by a spacer of 2-6 variable residues from an L/I/V-X-L/I/V sequence [83]) (Reversibility: ?) [53, 83] P ADP + phosphorylated MAP kinase S ATP + MAP kinase ERK1 (Reversibility: ?) [54] P ADP + ? S ATP + MAPK ( MAPK activation [1]) (Reversibility: ?) [1] P ADP + phosphorylated MAPK S ATP + MKK4 (Reversibility: ?) [68] P ADP + phosphorylated MKK4 S ATP + Red1 ( substrate of Mek1 [76]) (Reversibility: ?) [76] P ADP + phospho-Red1 S ATP + a protein ( MKK1 phosphorylates and activates the MAP kinases ERK1 and ERK2 [2]) (Reversibility: ?) [1, 2, 76] P ADP + a phosphoprotein S ATP + myelin basic protein (Reversibility: ?) [83]

398

2.7.12.2

P S P S P S P S

P S P S P S

Mitogen-activated protein kinase kinase

ADP + phosphorylated myelin basic protein ATP + myelin basic protein kinase (Reversibility: ?) [30] ADP + phosphorylated myelin basic protein kinase ATP + p38 (Reversibility: ?) [49] ADP + ? ATP + p38 MAP kinase ( phosphorylates and activates p38 MAP kinase [43]) (Reversibility: ?) [43] ADP + ? ATP + p38/MPK2 kinase ( phosphorylates and specifically activates the p38/MPK2 subgroup of the mitogen-activated protein kinase superfamily [48]) (Reversibility: ?) [48] ADP + ? ATP + p42 MAP kinase (Reversibility: ?) [51] ADP + ? ATP + poly-(Tyr-Glu) ( tyrosine kinase substrate [76]) (Reversibility: ?) [76] ADP + phospho-poly-(Tyr-Glu) ATP + protein ( the enzyme undergoes autophosphorylation on Ser, Thr and Tyr [53]; tyrosine/threonine kinase [51]; phosphorylates kinase-inactive Erk-1 protein primarily on a tyrosine residue and, to a lesser extent, on a threonine [30]; Pek1, in its unphosphorylated form, acts as a potent negative regulator of Pmk1 MAPK signalling. Mkh1, an upstream MAPKK kinase, converts Pek1 from being an inhibitor to an activator. Pek1 has a dual stimulatory and inhibitory function which depends on its phosphorylation state [75]; enzyme is involved in independent human MAP-kinase signal transduction pathway [8]; enzyme plays a key role in initiation of septum formation and cytokinesis in fission yeast, p120cdc7 interacts with the cdc11 protein in the control of septation [37]; the enzyme renders the cell resistant to polymyxin B [21]; possible role for ASK1 in tissue development during embryogenesis as well as cytokine-induced apoptosis [16]; MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2. The enzyme is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins, additional role for MKK4 in tumor suppression [40]; the enzyme is an activator of the c-Jun NH2 -terminal kinase, the enzyme is a component of the JNK signal transduction pathway [10]; dosage-dependent regulator of mitosis in Schizosaccharomyces pombe [33]; Spg1p is a key element in controlling the onset of septum formation that acts through the Cdc7p kinase [38]; MKK1 and MKK2 function in a signal transduction pathway involving the protein kinases encoded by PKC1, BCK1, and MPK1. The site of action for MKK1 and MKK2 is between BCK1 and MPK1 [32]; enzyme is the major activator for p38 [11]; enzyme is involved on MAPK signal transduction pathway [31]; enzyme is involved in the response of haploid yeast cells to peptide mating pheromones [17];

399

Mitogen-activated protein kinase kinase

2.7.12.2

Hst7 activates the mating pathway even in the absence of upstream signaling components including the Ste7 regulator Ste11, elevates the basal level of the pheromone-inducible FUS1 gene, and amplifies the pseudohyphal growth response in diploid cells [41]; byr1 is an important gene in the sexual differentiation pathway and at least part of ras1 function is to act directly or indirectly through byr1 to modulate protein phosphorylation [24]; the enzyme functions in a novel Drosophila MAPK pathway, controlling puckered expression and morphogenetic activity of the dorsal epidermis [55]; MEKK 2 preferentially activates JNK [57]; MEKK 3 preferentially activates p42/44MAPK [57]; the enzyme is the major activator of RK/p38 [46]; mek-2 acts between lin-45 raf and sur-1/mpk-1 in a signal transduction pathway used in the control of vulval differentiation and other developmental events [54]; the enzyme is involved in the mitogenic growth factor signal transduction pathway in vertebrates [64]; the enzyme is a component of the mkh1 signaling pathway. Mkh1, Skh1 and Spm1 constitute a MAPK cascade in Schizosaccharomyces pombe [74]; MEKK3 regulates the SAPK and the ERK pathway directly [69]; the enzyme is required for locus-dependent and locus-independent steps in the fungal life cycle. Necessary for locus-dependent processes, such as conjugation tube formation, filament formation, and maintenance of filamentous growth, and for locus-independent processes, such as tumor induction and teliospore germination [65]; ASK1 may be a key element in the mechanism of stress-induced and cytokine-induced apoptosis [67]; MEK6 is a member of the p38 kinase cascade and efficiently phosphorylates p38, induces phosphorylation of ATF2 by p38 but does not phosphorylate ATF2 directly [49]; MAPKKK5 may be an upstream activator of MKK4 in the c-Jun N-terminal kinase pathway [68]; the enzyme functions as a direct upstream activator for a presumed MAP kinase homolog in each signal transduction pathway involved in the regulation of cell cycle progression or cellular responses to extracellular signals [53]; sequences located in the N-terminus of MEK5 may be important in coupling GTPase signaling molecules to the MEK5 protein kinase cascade [9]) (Reversibility: ?) [8, 9, 10, 11, 16, 17, 21, 24, 30, 31, 32, 33, 37, 38, 40, 41, 46, 49, 51, 53, 54, 55, 57, 62, 64, 65, 67, 68, 69, 74, 75] P ADP + phosphoprotein S Additional information ( Pek1, in its unphosphorylated form, acts as a potent negative regulator of Pmk1 MAPK signalling. Mkh1, an upstream MAPKK kinase, converts Pek1 from being an inhibitor to an activator. Pek1 has a dual stimulatory and inhibitory function which depends on its phosphorylation state [75]; MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK respectively [69]; enzyme is part of mitogen-activated protein kinase pathways, crosstalk and regulation mechanism, overview [1]; the enzyme performs autophosphorylation [83]; MEK1/2 are involved in the mitogen-activated protein kinase signaling pathway and in cancer tumorigenesis [81]; the enzyme is involved in the mitogen-activated

400

2.7.12.2

Mitogen-activated protein kinase kinase

protein kinase signaling pathway [78]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway regulating cell dissociation of cancer cells, MEK2 is an invasion-metastasis related factor between highly and weakly invasive cells, occludin acts as antagonist [85]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway, pathway induction by neurotrophin stabilizes the axonal growth cone, pathway inhibitor semaphorin 3F induces growth cone collaps in sympathetic neurons and reduction of axonal growth [82]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is involved in e.g. activation of Egr-1 and subsequently of c-Fos and cyclin D1 after mechanic injury for induction/regulation of regrowth of smooth vascular cells, vascular smooth muscle cell proliferation plays an important role in pathogenesis of atherosclerosis and post-angioplasty restenosis, overview [79]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is involved in e.g. formalin-induced inflammatory pain and thermal hyperalgesia, overview [84]; the enzyme is involved in the mitogen-activated protein kinase signaling pathway, which is linked to the cell cycle machinery, constitutive phosphorylation and activation of the enzyme leads to cell proliferation in choroidal melanoma cells [80]) (Reversibility: ?) [1, 69, 74, 75, 78, 79, 80, 81, 82, 83, 84, 85] P ? Inhibitors 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-one ( selective anthranilic acid type inhibitors, residues K97, I141, M143, F129, V127, I126, L118, F209, V211, and S212 of MEK1/2 are important for interaction with the inhibitor, noncompetitive to ATP, inhibition of ERK phosphorylation by MEK1/2 by the derivatives with IC50 values of 6.8-124 nM, low cytotoxic effects, overview [81]) [81] berberine ( suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits vascular smooth muscle cell regrowth after mechanical injury in vitro [79]) [79] U0126 ( MEK inhibitor [84,85]; specific MEK inhibitor [79]) [79, 84, 85] Additional information ( inactivated by the serine/threonine phosphatase 2A but not by the protein-tyrosine phosphatase 1B [30]; occludin acts as antagonist of the MEK and ERK signaling pathway inducing cell aggregation of pancreatic cancer cells [85]) [30, 85] Cofactors/prosthetic groups ATP ( dependent on [2]; subdomain II with an invariable lysine residue is responsible for ATP binding [83]) [1,2,76,81,83,84] Activating compounds CD40 ( activated by ligation of CD40, the B-cell antigen receptor [12]) [12] anisomycin ( activates [49]) [49]

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Mitogen-activated protein kinase kinase

2.7.12.2

growth factor interleukin-3 ( activates [12]) [12] Additional information ( enzyme is activated by environmental stress and physiological stimuli. In hematopoietic cells, endogenous MKK7 is activated by treatment with the growth factor interleukin-3, or by ligation of CD40, the B-cell antigen receptor, or the receptor for the Fc fragment of immunoglobulin. MKK7 is also activated when cells are exposed to heat, UV irradiation, anisomycin, hyperosmolarity or the pro-inflammatory cytokine tumor necrosis factor-a [12]; Pbs2p is activated by MAP kinase kinase kinases Ssk2p and Ssk22p that are under the control of the SLN1-SSK1 two-component osmosensor. Alternatively, Pbs2p is activated by a mechanism that involves the binding of its amino terminal proline-rich motif to the Src homology 3 domain of a putative transmembrane osmosensor Sho1p [23]; activation in vivo in response to serum, phosphorylation and activation by the v-Raf protein in vitro [35]; activated by GTP-Cdc42 or GTP-Rac1 in vitro [62]; MEK6 is strongly activated by UV, anisomycin, and osmotic shock [49]; the enzyme is activated in cells treated with tumor necrosis factor-a [67]; activation is induced by epidermal growth factor tyrosine protein kinase and nucelar growth factor tyrosine protein kinase [1]; dissociation factor DF induces MEK1/2 and ERK1/2 expression [85]; ERK and MEK are activated by phosphorylation, ERK is induced by formalin [84]; MEK and ERK are activated by phosphorylation [79]; MEK, ERK-1 and ERK-2 are activated by phosphorylation by B-Raf, the B-Raf mutant V590E activates the enzymes constitutively and independently of Ras, which leads to melanoma cell proliferation [80]; MEK, ERK-1 and ERK-2 are activated by phosphorylation, tetanus toxin or the C-terminal part of the heavy chain induce phosphorylation of ERK-1 and ERK-2 at Thr202 and Tyr204 [78]; neurotrophin induces mitogen-activated protein kinase kinase signaling, which is antagonized by semaphorin 3F, Gab-1, an adaptor protein, is recruited by the TrkA kinase to activate MEK in sympathetic neurons, Gab-1 can reverse semaphorin 3F inhibition of the MEK activation [82]) [1, 12, 23, 35, 49, 62, 67, 78, 79, 80, 82, 84, 85] Metals, ions Cd2+ ( can partially substitue Mg2+ [2]) [2] Co2+ ( can partially substitue Mg2+ [2]) [2] Mg2+ ( dependent on, Mg2+ is the physiologic metal ion, other divalent cations are able to support nucleotide binding, but only Mn2+ , Co2+, and Cd2+ can substitute Mg2+ in supporting the catalytic activity [2]) [1, 2, 76] Mn2+ ( can partially substitue Mg2+ [2]) [2] Specific activity (U/mg) Additional information ( large scale activity assay with recombinant enzyme in a protein chip consisting of a microwell array with protein covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker, overview [76]) [76]

402

2.7.12.2

Mitogen-activated protein kinase kinase

Temperature optimum ( C) 37 ( in vivo assay at [82]) [82] 40 [83]

4 Enzyme Structure Subunits ? ( x * 45000 [53]; x * 37000, calculation from nucleotide sequence [48]; x * 62000 [62]; x * 66000, calculation from nucleotide sequence [33]; x * 71000 [57]; x * 195000, SDS-PAGE [59]; x * 69200 [57]; x * 45000, calculation from nucleotide sequence [34]; x * 77500, calculation from nucleotide sequence [21]; x * 44000, calculation from nucleotide sequence [34]; x * 42000 [27]; x * 43439, MKK1a, calculation from nucleotide sequence [52]; x * 43330, calculation from nucleotide sequence [26]; x * 44500 [60]; x * 40745, MKK1b an alternatively spliced form of the MKK1a gene, calculation from nucleotide sequence [52]; x * 38900, sequence calculation, x * 39000, recombinant enzyme, SDSPAGE [83]) [21, 26, 27, 33, 34, 48, 52, 53, 57, 59, 60, 62, 83] Additional information ( alternative splicing results in a 50000 Da a and a 40000 Da b isoform of MEK5 [58]; the enzyme contains a protein kinase domain, residues L73-I331, with 11 highly conserved subdomains, and a subdomain II with an invariable lysine residue responsible for ATP binding [83]) [58, 83] Posttranslational modification phosphoprotein ( activation by phosphorylation [1]; Pek1 has a dual stimulatory and inhibitory function which depends on its phosphorylation state [75]; Ser218 and Ser222 are the primary sites for phosphorylation [20]; phosphorylation and activation by the v-Raf protein in vitro [35]; STE7 displays several phosphorylation forms and is multiply phosphorylated in response to either pheromone or coexpression of dominant STE11 protein [17]; Ser222 represents one key MAPKKK-dependent phosphorylation site switching on and off the activity of MAPKK, an event crucial for growth control [61]; Ser217 and Ser221 are the sites phosphorylated by p74raf-1. Phosphorylation of either residue is sufficient for maximal activation [25]; the enzyme is phosphorylated and activated in vitro by TAK1 [48]; the enzyme performs autophosphorylation [83]; the enzyme performs autophosporylation [76]; ERK and MEK are activated by phosphorylation [84]; MEK and ERK are activated by phosphorylation [79]; MEK and ERK are phosphorylated by B-Raf, a mitogen-activated protein kinase kinase kinase, the B-Raf mutant V590E activates the enzymes constitutively and independently of Ras, which leads to melanoma cell proliferation [80]; MEK is phosphorylated and activated by the mitogen-activated protein kinase kinase kinase COT, which can be inhibited by p105 [77]; MEK is

403

Mitogen-activated protein kinase kinase

2.7.12.2

phosphorylated at Ser217 and Ser221, activating phosphorylation of ERK-1 and ERK-2 at Thr202 and Tyr204 induced by tetanus toxin or the C-terminal part of the heavy chain [78]) [1, 17, 20, 25, 35, 48, 61, 75, 76, 77, 78, 79, 80, 83, 84]

5 Isolation/Preparation/Mutation/Application Source/tissue AsPC-1 cell ( pancreatic cancer cell line, weakly invasive [85]) [85] CAPAN-2 cell ( pancreatic cancer cell line [85]) [85] KG-1 cell [72] L-5178-Y cell [11] OCM-1 cell ( choroidal melanoma cell line [80]) [80] PC-1.0 cell ( subcutaneous tumor cell line, highly invasive [85]) [85] T-cell [52] adenocarcinoma cell ( pancreatic ductal [85]) [85] brain ( expression at low levels [60]; isoenzyme MEK5 b [58]) [16, 58, 60, 70] brain cortex [78] breast cancer cell line [40] cell culture ( from superior cervical ganglia [82]) [82] colonic cancer cell line ( colorectal cancer cell line [40]) [40] embryo ( 17 days post coitum, expression of ASK1 in developing skin, cartilage and bone [16]) [16] ganglion ( superior cervical [82]) [82] heart ( expression at low levels in adult brain, expression at high levels in neonatal brain [60]) [9, 16, 60, 67] hematopoietic cell [12] kidney [16, 51] liver ( enzyme MEK5 a [58]) [16, 58] lung [16] lung cancer cell line [40] macrophage [68, 77] melanoma cell ( choroidal from eyes, and cutaneous [80]) [80] muscle [46] neuron ( cultured cortical neurons from fetal brain [78]) [78, 84] pancreas [68, 85] pancreatic cancer cell [85] pancreatic cancer cell line [40] promastigote ( and during differentiation to amastigote [83]) [83] skeletal muscle [9, 27, 28] spinal cord [84] testicular cancer cell line ( human pancreatic, lung, breast, testicle, and colorectal cancer cell lines [40]) [40] testis [62] vascular smooth muscle cell ( aortic, cell culture [79]) [79]

404

2.7.12.2

Mitogen-activated protein kinase kinase

Additional information ( isoform MEK5 b is ubiquitously distributed and primarily cytosolic. Isoform MEK5 a is expressed most highly in liver and brain and is particulate [58]; cancer cell growth patterns, overview [85]; the enzyme is developmentally regulated expressed, no expression in the amastigote stage in human host cells [83]) [58, 83, 85] Localization cytoplasm ( MEK1, MEK2 [1]) [1] cytosol ( isoform MEK5 b is primarily cytosolic [58]) [58, 83] extracellular [36] flagellum ( of promastigotes [83]) [83] membrane ( associated with [59]) [59] nucleus [83] particle-bound ( isoform MEK5 a [58]) [58] Purification [27, 28] [30] [46] [62] (recombinant wild-type and mutant GST-fusion enzymes from Escherichia coli by glutathione affinity chromatography) [83] Cloning (phylogenetic tree of kinases derived from the kinase core sequence, overview, expression as GST-fusion protein under control of the galactoseinducible GAL1 promotor in Escherichia coli, determination of 5’-end sequences) [76] (expressed in COS7 cells) [11] [10, 12, 15] [16] [21] [26] (expression in COS cells) [35] (isolation of cDNA) [34] [36] [37] (expressed in COS7 cells) [11] [46, 49] (isolation of cDNA) [47] [46] [51] (isolation of cDNA) [34] [36] (overexpression in COS cells) [52] (bacterial expression) [53] (isolation of cDNA) [9]

405

Mitogen-activated protein kinase kinase

2.7.12.2

[56] (expression in HEK293 cells) [57] (expression in HEK293 cells) [57] [59] [60] [63] [64] (expression in COS and 293 cells) [68] (isolation of cDNA) [69] (DNA and amino acid sequence determination and analysis, expression of wild-type and mutant GST-fusion enzymes in Escherichia coli, expression of a GFP-tagged enzyme in the mutant strain, complementation of the mutant strain by expression of the enzyme from plasmid or by reintegration of the wild-type gene into the genomic DNA locus) [83] Engineering D208N ( mutation abolishes MAPKK activity [61]) [61] K102R ( site-directed mutagenesis, kinase inactive mutant, but slight autophosphorylation activity, the mutant strain shows a phenotype with a proliferation defect after infection of human macrophages and no or delayed lesion development in mice [83]) [83] S222A ( mutation abolishes MAPKK activity, shows a reduction in phosphorylation in response to active MAPKKK and exerts a dominant negative effect on the serum-stimulated endogenous MAPKK [61]) [61] Additional information ( construction of deletion/disruption, null, or loss-of-function mutants, which all show a phenotype with a proliferation defect after infection of human macrophages and no or delayed lesion development in mice, gene replacement method [83]; expression of the neuron-specific dominant negative mitogen activated protein kinase kinase in mutant mice leads to impaired inflammatory pain and thermal hyperalgesia [84]; overexpression of Gab-1 in sympathetic neuronal cells leads to increased MEK and ERK activation [82]) [82, 83, 84] Application analysis ( development of a protein chip consisting of a silicone elastomer microwell array with recombinant enzyme covalently attached to the wells via a 3-glycidoxypropyltrimethoxysilane crosslinker for large scale activity assay, overview [76]) [76]

6 Stability General stability information , proteolytic inactivation by anthrax lethal factor [14, 31]

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2.7.12.2

Mitogen-activated protein kinase kinase

[57] Blank, J.L.; Gerwins, P.; Elliott, E.M.; Sather, S.; Johnson, G.L.: Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3. Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase. J. Biol. Chem., 271, 5361-5368 (1996) [58] English, J.M.; Vanderbilt, C.A.; Xu, S.; Marcus, S.; Cobb, M.H.: Isolation of MEK5 and differential expression of alternatively spliced forms. J. Biol. Chem., 270, 28897-28902 (1995) [59] Xu, S.; Robbins, D.J.; Christerson, L.B.; English, J.M.; Vanderbilt, C.A.; Cobb, M.H.: Cloning of rat MEK kinase 1 cDNA reveals an endogenous membrane-associated 195-kDa protein with a large regulatory domain. Proc. Natl. Acad. Sci. USA, 93, 5291-5295 (1996) [60] Brott, B.K.; Alessandrini, A.; Largaespada, D.A.; Copeland, N.G.; Jenkins, N.A.; Crews, C.M.; Erikson, R.L.: MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues. Cell Growth Differ., 4, 921-929 (1993) [61] Pages, G.; Brunet, A.; L’Allemain, G.; Pouyssegur, J.: Constitutive mutant and putative regulatory serine phosphorylation site of mammalian MAP kinase kinase (MEK1). EMBO J., 13, 3003-3010 (1994) [62] Teo, M.; Manser, E.; Lim, L.: Identification and molecular cloning of a p21cdc42/rac1-activated serine/threonine kinase that is rapidly activated by thrombin in platelets. J. Biol. Chem., 270, 26690-26697 (1995) [63] Huang, C.J.; Lee, M.S.; Chang, G.D.; Huang, F.L.; Lo, T.B.: Molecular cloning and sequencing of a carp cDNA encoding mitogen-activated protein kinase kinase. Biochim. Biophys. Acta, 1220, 223-225 (1994) [64] Wang, H.; Meury, L.; Morais, R.: Cloning and characterization of cDNAs encoding chicken mitogen-activated protein kinase kinase type 2, MEK2: downregulation of MEK2 in response to inhibition of mitochondrial DNA expression. Biochemistry, 36, 15371-15380 (1997) [65] Banuett, F.; Herskowitz, I.: Identification of fuz7, a Ustilago maydis MEK/ MAPKK homolog required for a-locus-dependent and -independent steps in the fungal life cycle. Genes Dev., 8, 1367-1378 (1994) [66] Chang, H.Y.; Nishitoh, H.; Yang, X.; Ichijo, H.; Baltimore, D.: Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science, 281, 1860-1863 (1998) [67] Ichijo, H.; Nishida, E.; Irie, K.; ten Dijke, P.; Saitoh, M.; Moriguchi, T.; Takagi, M.; Matsumoto, K.; Miyazono, K.; Gotoh, Y.: Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science, 275, 90-94 (1997) [68] Wang, X.S.; Diener, K.; Jannuzzi, D.; Trollinger, D.; Tan, T.H.; Lichenstein, H.; Zukowski, M.; Yao, Z.: Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. J. Biol. Chem., 271, 31607-31611 (1996) [69] Ellinger-Ziegelbauer, H.; Brown, K.; Kelly, K.; Siebenlist, U.: Direct activation of the stress-activated protein kinase (SAPK) and extracellular signalregulated protein kinase (ERK) pathways by an inducible mitogen-activated protein kinase/ERK kinase kinase 3 (MEKK) derivative. J. Biol. Chem., 272, 2668-2674 (1997)

411

Mitogen-activated protein kinase kinase

2.7.12.2

[70] Nagase, T.; Ishikawa, K.; Kikuno, R.; Hirosawa, M.; Nomura, N.; Ohara, O.: Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res., 6, 337-345 (1999) [71] Cheng, J.; Yang, J.; Xia, Y.; Karin, M.; Su, B.: Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation. Mol. Cell. Biol., 20, 2334-2342 (2000) [72] Nagase, T.; Seki, N.; Ishikawa, K.; Ohira, M.; Kawarabayasi, Y.; Ohara, O.; Tanaka, A.; Kotani, H.; Miyajima, N.; Nomura, N.: Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Res., 3; 321-329, 341-354 (1996) [73] Takekawa, M.; Posas, F.; Saito, H.: A human homolog of the yeast Ssk2/ Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. EMBO J., 16, 4973-4982 (1997) [74] Loewith, R.; Hubberstey, A.; Young, D.: Skh1, the MEK component of the mkh1 signaling pathway in Schizosaccharomyces pombe. J. Cell Sci., 113, 153-160 (2000) [75] Sugiura, R.; Toda, T.; Dhut, S.; Shuntoh, H.; Kuno, T.: The MAPK kinase Pek1 acts as a phosphorylation-dependent molecular switch. Nature, 399, 479-483 (1999) [76] Zhu, H.; Klemic, J.F.; Chang, S.; Bertone, P.; Casamayor, A.; Klemic, K.G.; Smith, D.; Gerstein, M.; Reed, M.A.; Snyder, M.: Analysis of yeast protein kinases using protein chips. Nat. Genet., 26, 283-289 (2000) [77] Jia, Y.; Quinn, C.M.; Bump, N.J.; Clark, K.M.; Clabbers, A.; Hardman, J.; Gagnon, A.; Kamens, J.; Tomlinson, M.J.; Wishart, N.; Allen, H.: Purification and kinetic characterization of recombinant human mitogen-activated protein kinase kinase kinase COT and the complexes with its cellular partner NF-kB1 p105. Arch. Biochem. Biophys., 441, 64-74 (2005) [78] Gil, C.; Chaib-Oukadour, I.; Aguilera, J.: C-terminal fragment of tetanus toxin heavy chain activates Akt and MEK/ERK signalling pathways in a Trk receptor-dependent manner in cultured cortical neurons. Biochem. J., 373, 613-620 (2003) [79] Liang, K.W.; Ting, C.T.; Yin, S.C.; Chen, Y.T.; Lin, S.J.; Liao, J.K.; Hsu, S.L.: Berberine suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits vascular smooth muscle cell regrowth after in vitro mechanical injury. Biochem. Pharmacol., 71, 806-817 (2006) [80] Calipel, A.; Lefevre, G.; Pouponnot, C.; Mouriaux, F.; Eychene, A.; Mascarelli, F.: Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK Pathway. J. Biol. Chem., 278, 42409-42418 (2003) [81] Wallace, E.M.; Lyssikatos, J.; Blake, J.F.; Seo, J.; Yang, H.W.; Yeh, T.C.; Perrier, M.; Jarski, H.; Marsh, V.; Poch, G.; Livingston, M.G.; Otten, J.; Hingorani, G.; Woessner, R.; Lee, P.; Winkler, J.; Koch, K.: Potent and selective mitogen-activated protein kinase kinase (MEK) 1,2 inhibitors. 4-(4-Bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones. J. Med. Chem., 49, 441-444 (2006)

412

2.7.12.2

Mitogen-activated protein kinase kinase

[82] Atwal, J.K.; Singh, K.K.; Tessier-Lavigne, M.; Miller, F.D.; Kaplan, D.R.: Semaphorin 3F antagonizes neurotrophin-induced phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase signaling: a mechanism for growth cone collapse. J. Neurosci., 23, 7602-7609 (2003) [83] Kuhn, D.; Wiese, M.: LmxPK4, a mitogen-activated protein kinase kinase homologue of Leishmania mexicana with a potential role in parasite differentiation. Mol. Microbiol., 56, 1169-1182 (2005) [84] Karim, F.; Hu, H.J.; Adwanikar, H.; Kaplan, D.R.; Gereau, R.W.T.: Impaired inflammatory pain and thermal hyperalgesia in mice expressing neuronspecific dominant negative mitogen activated protein kinase kinase (MEK). Mol. Pain, 2, 1-10 (2006) [85] Tan, X.; Tamori, Y.; Egami, H.; Ishikawa, S.; Kurizaki, T.; Takai, E.; Hirota, M.; Ogawa, M.: Analysis of invasion-metastasis mechanism in pancreatic cancer: involvement of tight junction transmembrane protein occludin and MEK/ERK signal transduction pathway in cancer cell dissociation. Oncol. Rep., 11, 993-998 (2004)

413

Protein-histidine pros-kinase

2.7.13.1

1 Nomenclature EC number 2.7.13.1 (see EC 2.7.13.3 for detailed, organism-specific information for enzymes lacking information on histidine stereochemistry) Systematic name ATP:protein-l-histidine Npi-phosphotransferase Recommended name protein-histidine pros-kinase Synonyms histidine kinase histidine protein kinase kinase, protein (phosphorylating histidine) protein histidine kinase protein kinase (histidine) Additional information CAS registry number 99283-67-7 (protein-histidine kinases, EC 2.7.13.1, EC 2.7.13.2, and EC 2.7.13.3 an not distinguished in Chemical Abstracts)

2 Source Organism



Escherichia coli (no sequence specified) [3, 10, 11] Rattus norvegicus (no sequence specified) [2, 4, 5] Saccharomyces cerevisiae (no sequence specified) [6, 7, 8, 9] Physarum polycephalum (no sequence specified) [1, 9]

3 Reaction and Specificity Catalyzed reaction ATP + protein l-histidine = ADP + protein Np -phospho-l-histidine Reaction type phospho group transfer Natural substrates and products S ATP + chemotaxis protein CheA ( sensory transduction in chemotaxis [11]) (Reversibility: ?) [11] P ADP + phosphorylated chemotaxis protein CheA

414

2.7.13.1

Protein-histidine pros-kinase

Substrates and products S ATP + chemotaxis protein CheA ( sensory transduction in chemotaxis [11]) (Reversibility: ?) [11] P ADP + phosphorylated chemotaxis protein CheA S ATP + histone H4 (Reversibility: ?) [1, 2, 6, 8, 9] P ADP + phosphohistone H4 ( phosphorylation of His 75 [1,8]; formation of 1-phosphohistidine isomer [1,2]) [1, 2, 8] S ATP + protein l-histidine ( P36, i.e. 36 kDa protein of rat [4,5]; CheA, i.e. chemotaxis protein of E. coli [11]; proteins: OmpR, i.e. regulator protein of E. coli [3]; NRII, i.e. regulatory protein of E. coli [10]) (Reversibility: ?) [3, 4, 5, 10, 11] P ADP + phosphohistidine containing protein [3, 5, 11] Inhibitors Genistein [6] KCl [8] NaCl [8] Activating compounds GTP ( activation [5]) [5] recombinant RAS protein ( activation [5]) [5] Metals, ions Co2+ ( 2 mM, activation [8]) [8] Mg2+ ( 15-20 mM, activation [8]) [8] Mn2+ ( 1.5 mM, activation [8]) [8] Additional information ( not activated by Ca2+ , Zn2+ , Fe2+ , Cu2+ [8]) [8] Specific activity (U/mg) 0.19 [8] Km-Value (mM) 0.00025 (ATP, in presence of activators: GTP or recombinant RAS protein [5]) [5] 0.00125 (ATP, in absence of activators: GTP or recombinant RAS protein [5]) [5] 0.014 (histone H4) [6] 0.017 (histone H4) [8] 0.06 (MgATP2- ) [8] 0.085 (peptide corresponding to residues 70-102 of histone H4) [6] 0.11 (ATP) [6]

4 Enzyme Structure Molecular weight 32000 ( gel filtration [8]) [8] 36000 ( gel filtration [3]) [3] 70000 ( HPLC [4]) [4]

415

Protein-histidine pros-kinase

2.7.13.1

Subunits monomer ( 1 * 32000, SDS-PAGE [8]) [8] Additional information ( after solubilization the enzyme dissociates to proteins of 25000 and 10000 kDa, the 25000 kDa fragment being a dimer [3]) [3]

5 Isolation/Preparation/Mutation/Application Source/tissue liver [2, 4, 5] Localization membrane [3, 4, 5] nucleus [1, 2, 9] Purification (partial) [4] [7, 8]

References [1] Huebner, V.D.; Matthews, H.R.: Phosphorylation of histidine in proteins by a nuclear extract of Physarum polycephalum plasmodia. J. Biol. Chem., 260, 16106-16113 (1985) [2] Fujikati, J.M.; Fung, G.; Oh, E.Y.; Smith, R.A.: Characterization of chemical and enzymatic acid-labile phosphorylation of histone H4 using phosphorus-31 nuclear magnetic resonance. Biochemistry, 20, 3658-3664 (1981) [3] Roberts, D.L.; Bennett, D.W.; Forst, S.A.: Identification of the site of phosphorylation on the osmosensor, EnvZ, of Escherichia coli. J. Biol. Chem., 269, 8728-8733 (1994) [4] Motojima, K.; Goto, S.: Histidyl phosphorylation and dephosphorylation of P36 in rat liver extract. J. Biol. Chem., 269, 9030-9037 (1994) [5] Motojima, K.; Goto, S.: A protein histidine kinase induced in rat liver by peroxisome proliferators. In vitro activation by Ras protein and guanine nucleotides. FEBS Lett., 319, 75-79 (1993) [6] Huang, J.; Nasr, M.; Kim, Y.; Matthews, H.R.: Genistein inhibits protein histidine kinase. J. Biol. Chem., 267, 15511-15515 (1992) [7] Wei, Y.F.; Matthews, H.R.: Identification of phosphohistidine in proteins and purification of protein-histidine kinases. Methods Enzymol., 200, 388414 (1991) [8] Huang, J.; Wei, Y.K.; Osterberg, L.; Matthews, H.R.: Purification of a protein histidine kinase from the yeast Saccharomyces cerevisiae. The first member of this class of protein kinases. J. Biol. Chem., 266, 9023-9031 (1991) [9] Wei, Y.F.; Morgan, J.E.; Matthews, H.R.: Studies of histidine phosphorylation by a nuclear protein histidine kinase show that histidine-75 in histone

416

2.7.13.1

Protein-histidine pros-kinase

H4 is masked in nucleosome core particles and in chromatin. Arch. Biochem. Biophys., 268, 546-550 (1989) [10] Weiss, V.; Magasanik, B.: Phosphorylation of nitrogen regulator I (NRI) of Escherichia coli. Proc. Natl. Acad. Sci. USA, 85, 8919-8923 (1988) [11] Hess, J.F.; Bourret, R.B.; Simon, M.I.: Histidine phosphorylation and phosphoryl group transfer in bacterial chemotaxis. Nature, 336, 139-143 (1988)

417

Protein-histidine tele-kinase

2.7.13.2

1 Nomenclature EC number 2.7.13.2 (see EC 2.7.13.3 for detailed, organism-specific information for enzymes without information on histidine stereochemistry) Systematic name ATP:protein-l-histidine Nt -phosphotransferase Recommended name protein-histidine tele-kinase Synonyms histidine kinase histidine protein kinase kinase, protein (phosphorylating histidine) protein histidine kinase protein kinase (histidine) Additional information CAS registry number 99283-67-7 (protein-histidine kinases, EC 2.7.13.1, EC 2.7.13.2, and EC 2.7.13.3 an not distinguished in Chemical Abstracts)

2 Source Organism Rattus norvegicus (no sequence specified) [1]

3 Reaction and Specificity Catalyzed reaction ATP + protein l-histidine = ADP + protein Nt -phospho-l-histidine Reaction type phospho group transfer Substrates and products S ATP + histone H4 (Reversibility: ?) [1] P ADP + phosphohistone H4 ( a histidine residue is phosphorylated at t-position, yielding 3-phosphohistidine [1]) [1]

418

2.7.13.2

Protein-histidine tele-kinase

5 Isolation/Preparation/Mutation/Application Source/tissue carcinosarcoma cell ( Walker rat 256 cell [1]) [1] Localization nucleus [1]

References [1] Fujikati, J.M.; Fung, G.; Oh, E.Y.; Smith, R.A.: Characterization of chemical and enzymatic acid-labile phosphorylation of histone H4 using phosphorus31 nuclear magnetic resonance. Biochemistry, 20, 3658-3664 (1981)

419

Histidine kinase

2.7.13.3

1 Nomenclature EC number 2.7.13.3 (protein-histidine kinases without information on stereospecificity towards histidine) Systematic name ATP:protein l-histidine N-phosphotransferase Recommended name histidine kinase Synonyms AtBphP1 [283] AtBphP2 [283] BarA protein [8] BarA sensor kinase (sensory histidine kinase) [247, 259] C4-dicarboxylate transport sensor protein dctB [72, 82, 83, 84, 85, 86] C4-dicarboxylate transport sensor protein dctS [156] CheN [142] DctB [72] ENVZ [31] ETR1 [181, 182] ETR1 ethylene receptor [284] FrzE [115, 116] HISTIDIN kinase (histidine protein kinase PlnB, sensor protein) [5, 15, 16, 17] Hik1 [269] Hik16 [285] Hik34 [282, 285] Hik41 [285] HpkA HK [273] HydH [95, 96] LeETR1 [28] NTHK2 [281] NodV protein [97] NreB [279] PRRB [226] PhoR1 [267] RodK [280] SasA [277]

420

2.7.13.3

Histidine kinase

TWO component response regulator transcription regulator protein [243] VncS, histidine kinase [231] aerobic respiration control sensor protein arcB [11, 33, 123, 124, 125, 126, 127, 128, 129, 257, 260, 261] aerobic respiration control sensor protein arcB homolog [174] aerobic respiration control sensor/response regulatory protein [244, 245] alginate biosynthesis sensor protein KINB [25] alkaline phosphatase synthesis sensor protein phoR [7, 22, 132, 133, 242] alrO117 [278] autolysin sensor kinase [241] bacteriophytochrome (phytochrome-like protein) [252, 253] chemotaxis histidine kinase [248] chemotaxis protein [240] chemotaxis protein CheA (sensory transducer kinase) [244, 245] chemotaxis protein cheA [7, 11, 22, 46, 47, 48, 49, 50, 51, 52, 53, 54, 66, 142, 193, 200, 201, 216, 217, 218, 221, 222, 224, 229, 236, 237, 238, 258, 259, 261, 263] chemotaxis-specific histidine autokinase CheA [53] copper resistance, histidine kinase [259] cyanobacterial phytochrome A [265] cyanobacterial phytochrome B [265] drug sensory protein A [118, 119, 120] ethanolamine two-component sensor kinase [241] ethylene receptor [29, 181, 182, 183, 184, 185, 186] ethylene receptor (CS-ETR1) [254] ethylene receptor (MEETR1) (Cm-ETR1) [30] ethylene receptor (PE-ETR1) [256] ethylene receptor 1 (LeETR1) [28, 214] ethylene receptor 2 (LeETR2) [28] ethylene receptor 2 (PhETR2) [255] ethylene receptor12 (PhETR2) [255] gliding motility regulatory protein [115, 116] high-affinity potassium transport system [259] histidine autokinase CheA [48, 53] histidine kinase [231, 246] histidine kinase BA1351 [272] histidine kinase BA1356 [272] histidine kinase BA1478 [272] histidine kinase BA2291 [272] histidine kinase BA2636 [272] histidine kinase BA2644 [272] histidine kinase BA3702 [272] histidine kinase BA4223 [272] histidine kinase BA5029 [272]

421

Histidine kinase

2.7.13.3

histidine kinase CikA [274] histidine kinase DivJ [271] histidine kinase EnvZ [268, 270, 276] histidine kinase Hik10 [275] histidine kinase Hik16 [275] histidine kinase Hik33 [275] histidine kinase Hik34 [275] histidine kinase Hik41 [275] histidine kinase PilS [286] histidine kinase PleC [271] histidine kinase SasA [277] histidine protein kinase [231] histidine protein kinase KinB [25] histidine protein kinase, sensor protein [5] limited host range virA protein(LHR virA) [45] methanol utilization control sensor protein moxY [143] nisin biosynthesis sensor protein nisK [173] nitrate-nitrite sensor protein [245] nitrate/nitrite sensor protein [245] nitrate/nitrite sensor protein narQ [11, 12, 139, 140, 258, 261] nitrate/nitrite sensor protein narX [11, 33, 79, 80, 81, 257, 260, 261, 262] nitrogen regulation protein NR(II) [6, 11, 33, 40, 41, 42, 43, 44, 141, 257, 259, 260] nitrogen regulation protein ntrB [39, 67, 68, 73, 117, 172, 177, 193, 225, 242] nitrogen regulation protein ntrY [205, 242] nitrogen regulation protein ntrY homolog [177] nodulation protein V [97, 98, 99] ornithine decarboxylase antizyme [207] osmolarity sensor protein (protein histidine) [244, 245] osmolarity sensor protein envZ [2, 6, 11, 13, 31, 32, 33, 34, 35, 36, 37, 38, 65, 242, 258, 259, 261] osmolarity two-component system protein SLN1 [168, 169, 170] phosphate regulon sensor protein phoR [7, 11, 58, 59, 60, 134, 135, 174, 176, 242, 244, 245, 261] phosphoglycerate transport system sensor protein pgtB [153, 154, 259] phytochrome-like protein cph1 (light-regulated histidine) [233, 234, 235] positive and negative sensor protein for pho regulon [244, 245] secretion system regulator:sensor component [259] sensor histidine kinase mtrB [192, 223, 264] sensor histidine kinase regB (PrrB protein) [226, 227, 228] sensor kinase citA [187, 188, 258] sensor kinase cusS [11, 196, 261, 262] sensor kinase dpiB [7, 11, 258] sensor kinase dpiB (sensor kinase citA) [197, 261, 262]

422

2.7.13.3

Histidine kinase

sensor protein [259] sensor protein afsQ2 [206, 266] sensor protein atoS [11, 207, 261, 263] sensor protein baeS [11, 144, 261, 263] sensor protein barA [3, 8, 9, 10, 11, 12, 257, 260, 261] sensor protein basS/pmrB [11, 63, 144, 152, 259] sensor protein chvG [112, 114, 210, 242] sensor protein chvG (histidine kinase sensory protein) [193, 194, 195] sensor protein ciaH [230, 231, 232] sensor protein citS [22, 26, 27, 249] sensor protein copS [202] sensor protein cpxA [11, 42, 55, 56, 57, 257, 260] sensor protein creC [11, 61, 62, 63, 64] sensor protein cssS [21, 22, 23, 24] sensor protein cutS [203, 266] sensor protein czcS [215] sensor protein dcuA [33] sensor protein dcuS [11, 33, 63, 96, 157, 158, 159, 257] sensor protein degS [22, 87, 88, 89, 191, 242] sensor protein divL [250, 251] sensor protein evgS precursor [11, 12, 105, 145, 146, 147, 257, 260, 261] sensor protein fixL [75, 76, 77, 78, 99, 130, 131, 137, 138] sensor protein for basR [244, 245] sensor protein gacS [178] sensor protein irlS [20] sensor protein kdpD [11, 121, 122, 198, 199, 261, 262, 264] sensor protein kinase (sensor protein PhoQ) [244, 245] sensor protein luxN [189] sensor protein luxQ [190] sensor protein narQ homolog [174] sensor protein pfeS [135, 204] sensor protein phoQ [11, 136, 242, 261, 262] sensor protein qseC [6, 11, 171, 174, 175, 257, 259, 260, 261] sensor protein rcsC [11] sensor protein rcsC (capsular synthesis regulator) [6, 18, 92, 93, 259, 261, 263] sensor protein resE [7, 22, 150, 151] sensor protein rprX [211] sensor protein rstB [11, 108, 109, 110, 111, 261] sensor protein sphS [164] sensor protein torS [11, 63, 160, 161, 162, 163, 257, 260, 261] sensor protein uhpB [11, 69, 70, 71] sensor protein vanS (vancomycin resistance protein vanS) [209] sensor protein vanSB (vancomycin B-type resistance) [4, 14]

423

Histidine kinase

2.7.13.3

sensor protein yycG [22, 219, 220] sensor protein zraS [6, 11, 94, 95, 96, 155, 257, 259, 261] sensor-like histidine kinase senX3 [19, 192, 264] sensory histidine kinase in two-component regulatory system with ArcA [259] sensory histidine kinase in two-component regulatory system with DcuR, senses fumarate/C4-dicarboxylate [259] sensory histidine kinase in two-component regulatory system with NarP [259] sensory kinase (alternative) in two-component regulatory system with CreB (or alternatively PhoB), senses catabolite repression [259] sensory kinase in multi-component regulatory system with TorR [259] sensory kinase in two-component regulatory system with CpxR, senses misfolded proteins in bacterial envelope [258, 259] sensory kinase in two-component regulatory system with PhoB, regulates pho regulon [259] sensory kinase in two-component regulatory system wtih KdpE, regulates kdp operon [259] sensory transduction histidine kinase [242] sensory transduction protein kinase [7, 240, 241, 242] sensory/regulatory protein rpfC [179, 180] sporulation kinase A (stage II sporulation protein J) [22, 100, 101] sporulation kinase B [22, 212, 213] sporulation kinase C [22, 165, 166, 167] sporulation kinase C (sensor kinase) [239] subtilin biosynthesis sensor protein spaK [1, 7, 148, 149, 262] tetrathionate reductase complex: sensory transduction histidine kinase [259] transmembrane sensor histidine kinase transcription regulator protein [243] tricarboxylic transport: regulatory protein [259] two component sensor kinase/response regulator protein RcsC [244, 245] two component system histidine kinase [240, 241] two-component regulatory protein [245] two-component regulatory protein sensor kinase KdpD [244, 245] two-component sensor kinase [258] two-component sensor kinase czcS [241] two-component sensor kinase yesM [7, 241] two-component system sensor protein [244, 245] virulence sensor protein bvgS precursor [102, 103, 104, 105, 106, 107] virulence sensor protein phoQ [90, 91, 259] wide host range virA protein (WHR virA) [45, 74, 112, 113, 114]

424

2.7.13.3

Histidine kinase

CAS registry number 99283-67-7 (protein-histidine kinases, EC 2.7.13.1, EC 2.7.13.2, and EC 2.7.13.3 are not distinguished in Chemical Abstracts)

2 Source Organism

























Escherichia coli (no sequence specified) [268, 270, 276, 286] Nicotiana tabacum (no sequence specified) [281] Arabidopsis thaliana (no sequence specified) [284] Pseudomonas aeruginosa (no sequence specified) [286] Myxococcus xanthus (no sequence specified) [280] Caulobacter crescentus (no sequence specified) [271] Agrobacterium tumefaciens (no sequence specified) [283] Staphylococcus carnosus (no sequence specified) [279] Anabaena sp. (no sequence specified) [278] Synechocystis sp. (no sequence specified) [275, 282, 285] Thermotoga maritima (no sequence specified) [273] Escherichia coli (UNIPROT accession number: P26607) [3, 8, 9, 10, 11, 12, 257, 260, 261] Enterococcus faecalis (UNIPROT accession number: Q47745) [4, 14] Lactobacillus plantarum (UNIPROT accession number: Q88T93) [5] Lactobacillus plantarum (UNIPROT accession number: Q88S61) [5] Lactobacillus plantarum (UNIPROT accession number: Q88S11) [5] Lactobacillus plantarum (UNIPROT accession number: Q88T19) [5] Lactobacillus plantarum (UNIPROT accession number: Q88VU1) [5] Lactobacillus plantarum (UNIPROT accession number: Q88TB5) [5] Lactobacillus plantarum (UNIPROT accession number: Q88YL2) [5] Lactobacillus plantarum (UNIPROT accession number: Q88UI1) [5] Lactobacillus plantarum (UNIPROT accession number: Q88WS3) [5] Lactobacillus plantarum (UNIPROT accession number: Q890H9) [5] Lactobacillus plantarum (UNIPROT accession number: Q48828) [5, 15, 16, 17] Lactobacillus plantarum (UNIPROT accession number: Q88X78) [5] Lactobacillus plantarum (UNIPROT accession number: Q88ZM9) [5] Salmonella typhi (UNIPROT accession number: Q8Z332) [6] Salmonella typhi (UNIPROT accession number: Q56128) [6, 18, 19] Salmonella typhi (UNIPROT accession number: Q8Z3P2) [6] Salmonella typhi (UNIPROT accession number: P41406) [6, 13, 258] Salmonella typhimurium (UNIPROT accession number: P41788) [6, 258, 259] Clostridium tetani (UNIPROT accession number: Q893H6) [7] Clostridium tetani (UNIPROT accession number: Q893S8) [7] Clostridium tetani (UNIPROT accession number: Q894P4) [7] Clostridium tetani (UNIPROT accession number: Q899l3) [7] Clostridium tetani (UNIPROT accession number: Q896X1) [7] Clostridium tetani (UNIPROT accession number: Q892E7) [7]

425

Histidine kinase



























426

2.7.13.3

Clostridium tetani (UNIPROT accession number: Q893l4) [7] Clostridium tetani (UNIPROT accession number: Q895Y4) [7] Clostridium tetani (UNIPROT accession number: Q899I6) [7] Clostridium tetani (UNIPROT accession number: Q893B1) [7] Clostridium tetani (UNIPROT accession number: Q894W4) [7] Clostridium tetani (UNIPROT accession number: Q897D4) [7] Clostridium tetani (UNIPROT accession number: Q897U6) [7] Clostridium tetani (UNIPROT accession number: Q894l7) [7] Clostridium tetani (UNIPROT accession number: Q893C2) [7] Clostridium tetani (UNIPROT accession number: Q893K0) [7] Clostridium tetani (UNIPROT accession number: Q898N3) [7] Mycobacterium bovis (UNIPROT accession number: O07129) [19] Burkholderia pseudomallei (UNIPROT accession number: O31396) [20] Bacillus subtilis (UNIPROT accession number: O32193) [21,22,23,24] Pseudomonas aeruginosa (UNIPROT accession number: O34206) [25] Bacillus subtilis (UNIPROT accession number: O34427) [22,26,27] Lycopersicon esculentum (UNIPROT accession number: O49187) [28] Brassica oleracea (UNIPROT accession number: O49230) [29] Cucumis melo (UNIPROT accession number: O82436) [30] Escherichia coli (UNIPROT accession number: P02933) [2, 31, 32, 33, 34, 35, 36, 37, 38, 261] Klebsiella pneumoniae (UNIPROT accession number: P06218) [39] Escherichia coli (UNIPROT accession number: P06712) [33, 40, 41, 42, 43, 44, 257, 260] Agrobacterium tumefaciens (UNIPROT accession number: P07167) [45] Agrobacterium tumefaciens (UNIPROT accession number: P07168) [45] Escherichia coli (UNIPROT accession number: P07363) [46, 47, 48, 49, 50, 51, 52, 53, 54, 261, 263] Escherichia coli (UNIPROT accession number: P08336) [11, 42, 55, 56, 57, 257, 260] Escherichia coli (UNIPROT accession number: P08400) [58,59,60,261] Escherichia coli (UNIPROT accession number: P08401) [61,62,63,64] Salmonella typhimurium (UNIPROT accession number: P08982) [65, 259] Salmonella typhimurium (UNIPROT accession number: P09384) [66, 259] Rhodobacter capsulatus (UNIPROT accession number: P09431) [67,68] Escherichia coli (UNIPROT accession number: P09835) [69,70,71] Rhizobium leguminosarum (UNIPROT accession number: p10047) [72] Bradyrhizobium sp. (UNIPROT accession number: P10578) [73] Agrobacterium tumefaciens (UNIPROT accession number: P10799) [74] Rhizobium meliloti (UNIPROT accession number: P10955) [75,76,77,78] Escherichia coli (UNIPROT accession number: P10956) [33, 79, 80, 81, 257, 260, 261, 262] Rhizobium meliloti (UNIPROT accession number: P13633) [82, 83, 84, 85, 86] Bacillus subtilis (UNIPROT accession number: P13799) [22,87,88,89]

2.7.13.3

Histidine kinase

Salmonella typhimurium (UNIPROT accession number: P14147) [90, 91, 259] Escherichia coli (UNIPROT accession number: P14376) [92,93,261,263] Escherichia coli (UNIPROT accession number: P14377) ( large subunit [94]) [94,95,96] Bradyrhizobium japonicum (UNIPROT accession number: P15939) [97, 98, 99] Bacillus subtilis (UNIPROT accession number: P16497) [22,100,101] Bordetella pertussis (UNIPROT accession number: P16575) [102, 103, 104, 105, 106, 107] Escherichia coli (UNIPROT accession number: P18392) [108, 109, 110, 111, 261] Agrobacterium tumefaciens (UNIPROT accession number: P18540) [112, 113, 114] Myxococcus xanthus (UNIPROT accession number: P18769) [115,116] Vibrio alginolyticus (UNIPROT accession number: P19906) [117] Synechocystis sp. (UNIPROT accession number: P20169) [118,119,120] Escherichia coli (UNIPROT accession number: P21865) [121, 122, 261, 262] Escherichia coli (UNIPROT accession number: P22763) [33, 123, 124, 125, 126, 127, 128, 129, 261] Bradyrhizobium japonicum (UNIPROT accession number: P23222) [76, 99, 130, 131] Bacillus subtilis (UNIPROT accession number: P23545) [22,132,133] Pseudomonas aeruginosa (UNIPROT accession number: P23621) [134, 135] Escherichia coli (UNIPROT accession number: P23837) [136,261,262] Azorhizobium caulinodans (UNIPROT accession number: P26489) [137, 138] Bordetella bronchiseptica (UNIPROT accession number: P26762) [103] Salmonella typhimurium (UNIPROT accession number: P27668) [71, 259] Escherichia coli (UNIPROT accession number: P27896) [12,139,140,261] Proteus vulgaris (UNIPROT accession number: P28788) [141] Bacillus subtilis (UNIPROT accession number: P29072) [22,142] Paracoccus denitrificans (UNIPROT accession number: P29905) [143] Escherichia coli (UNIPROT accession number: P30844) [63, 144] Escherichia coli (UNIPROT accession number: P30847) [144, 261, 263] Escherichia coli (UNIPROT accession number: P30855) [12, 105, 145, 146, 147, 261] Bacillus subtilis (UNIPROT accession number: P33113) [1, 148] Pseudomonas aeruginosa (UNIPROT accession number: P33639) [149, 262] Bacillus subtilis (UNIPROT accession number: P35164) [22, 150, 151] Salmonella typhimurium (UNIPROT accession number: P36557) [152, 259]

427

Histidine kinase

2.7.13.3

Salmonella typhimurium (UNIPROT accession number: P37433) [153, 154, 259] Salmonella typhimurium (UNIPROT accession number: P37461) [155, 259] Rhodobacter capsulatus (UNIPROT accession number: P37739) [156] Escherichia coli (UNIPROT accession number: P39272) [63, 96, 157, 158, 159, 257] Escherichia coli (UNIPROT accession number: P39453) [63, 160, 161, 162, 163, 261] Synechococcus sp. (UNIPROT accession number: P39664) [164] Bacillus subtilis (UNIPROT accession number: P39764) [22, 165, 166, 167] Saccharomyces cerevisiae (UNIPROT accession number: P39928) [168, 169, 170] Bordetella parapertussis (UNIPROT accession number: P40330) [103] Escherichia coli (UNIPROT accession number: P40719) [171, 261] Rhizobium leguminosarum (UNIPROT accession number: P41503) [172] Lactococcus lactis (UNIPROT accession number: P42707) ( gene CaDXMT1 [173]) [173] Haemophilus influenzae (UNIPROT accession number: P44578) [174] Haemophilus influenzae (UNIPROT accession number: P44604) [174] Haemophilus influenzae (UNIPROT accession number: P45336) [174, 175] Klebsiella pneumoniae (UNIPROT accession number: P45608) [176] Shigella dysenteriae (UNIPROT accession number: P45609) [176] Azospirillum brasilense (UNIPROT accession number: P45670) [177] Azospirillum brasilense (UNIPROT accession number: P45675) [177] Pseudomonas syringae (UNIPROT accession number: P48027) [178] Xanthomonas campestris (UNIPROT accession number: P49246) [179, 180] Arabidopsis thaliana (UNIPROT accession number: P49333) [181, 182, 183, 184, 185, 186] Klebsiella pneumoniae (UNIPROT accession number: P52687) [187, 188] Vibrio harveyi (UNIPROT accession number: P54301) [189] Vibrio harveyi (UNIPROT accession number: P54302) [190] Bacillus brevis (UNIPROT accession number: P54663) [191] Mycobacterium leprae (UNIPROT accession number: P54883) [192] Escherichia coli (UNIPROT accession number: P58356) [257, 260] Escherichia coli (UNIPROT accession number: P58363) [257, 260] Escherichia coli (UNIPROT accession number: P58402) [257, 260] Salmonella typhimurium (UNIPROT accession number: P58662) [259] Escherichia coli (UNIPROT accession number: P59340) [11] Shigella flexneri (UNIPROT accession number: P59341) [33] Shigella flexneri (UNIPROT accession number: P59342) [33] Haemophilus influenzae (UNIPROT accession number: P71380) [174] Rhizobium meliloti (UNIPROT accession number: P72292) [193, 194, 195]

428

2.7.13.3

Histidine kinase

Escherichia coli (UNIPROT accession number: P77485) [196, 261, 262] Escherichia coli (UNIPROT accession number: P77510) [197, 261, 262] Clostridium acetobutylicum (UNIPROT accession number: P94608) [198, 199] Treponema pallidum (UNIPROT accession number: P96123) [200, 201] Mycobacterium tuberculosis (UNIPROT accession number: P96372) [264] Pseudomonas syringae (UNIPROT accession number: Q02541) [202] Streptomyces coelicolor (UNIPROT accession number: Q03757) [203, 266] Pseudomonas aeruginosa (UNIPROT accession number: Q04804) [135, 204] Azorhizobium caulinodans (UNIPROT accession number: Q04850) [205] Streptomyces coelicolor (UNIPROT accession number: Q04943) [206, 266] Escherichia coli (UNIPROT accession number: Q06067) [207, 261, 263] Enterococcus faecium (UNIPROT accession number: Q06240) [113, 208, 209] Agrobacterium tumefaciens (UNIPROT accession number: Q07737) [112, 114, 210] Bacteroides fragilis (UNIPROT accession number: Q08408) [211] Bacillus subtilis (UNIPROT accession number: Q08430) [22, 212, 213] Mycobacterium tuberculosis (UNIPROT accession number: Q11155) [19, 264] Lycopersicon esculentum (UNIPROT accession number: Q41342) [28, 214] Ralstonia eutropha (UNIPROT accession number: Q44007) [215] Borrelia burgdorferi (UNIPROT accession number: Q44737) [216, 217, 218] Bacillus subtilis (UNIPROT accession number: Q45614) [22, 219, 220] Listeria monocytogenes (UNIPROT accession number: Q48768) [221, 222] Mycobacterium tuberculosis (UNIPROT accession number: Q50496) [223, 264] Rhizobium meliloti (UNIPROT accession number: Q52880) [193, 224] Rhizobium meliloti (UNIPROT accession number: Q52977) [193, 225] Rhodobacter sphaeroides (UNIPROT accession number: Q53068) [226, 227, 228] Rhodobacter sphaeroides (UNIPROT accession number: Q53135) [229] Streptococcus pneumoniae (UNIPROT accession number: Q54955) [230, 231, 232] Synechocystis sp. (UNIPROT accession number: Q55168) [233, 234, 235] Thermotoga maritima (UNIPROT accession number: Q56310) [236, 237, 238] Escherichia coli (UNIPROT accession number: Q8CVU5) [11] Oceanobacillus iheyensis (UNIPROT accession number: Q8CXG3) [239] Streptococcus pneumoniae (UNIPROTaccession number: Q8DMW4) [231]

429

Histidine kinase

































430

2.7.13.3

Streptococcus pneumoniae (UNIPROTaccession number: Q8DN03) [231] Streptococcus pneumoniae (UNIPROTaccession number: Q8DN65) [231] Streptococcus pneumoniae (UNIPROTaccession number: Q8DNC1) [231] Streptococcus pneumoniae (UNIPROTaccession number: Q8DNX7) [231] Streptococcus pneumoniae (UNIPROTaccession number: Q8DPL8) [231] Streptococcus pneumoniae (UNIPROTaccession number: Q8DQN7) [231] Streptococcus pneumoniae (UNIPROTaccession number: Q8DQR9) [231] Streptococcus pneumoniae (UNIPROTaccession number: Q8DR46) [231] Streptococcus pneumoniae (UNIPROTaccession number: Q8DRK0) [231] Escherichia coli (UNIPROT accession number: Q8FA38) [11] Escherichia coli (UNIPROT accession number: Q8FAU6) [11] Escherichia coli (UNIPROT accession number: Q8FB70) [11] Escherichia coli (UNIPROT accession number: Q8FBG6) [11] Escherichia coli (UNIPROT accession number: Q8FBX4) [11] Escherichia coli (UNIPROT accession number: Q8FCU0) [11] Escherichia coli (UNIPROT accession number: Q8FD66) [11] Escherichia coli (UNIPROT accession number: Q8FDJ7) [11] Escherichia coli (UNIPROT accession number: Q8FF85) [11] Escherichia coli (UNIPROT accession number: Q8FFP8) [11] Escherichia coli (UNIPROT accession number: Q8FFP9) [11] Escherichia coli (UNIPROT accession number: Q8FG01) [11] Escherichia coli (UNIPROT accession number: Q8FGP1) [11] Escherichia coli (UNIPROT accession number: Q8FHA9) [11] Escherichia coli (UNIPROT accession number: Q8FHZ2) [11] Escherichia coli (UNIPROT accession number: Q8FIB8) [11] Escherichia coli (UNIPROT accession number: Q8FJ55) [11] Escherichia coli (UNIPROT accession number: Q8FJV6) [11] Escherichia coli (UNIPROT accession number: Q8FJZ9) [11] Escherichia coli (UNIPROT accession number: Q8FK37) [11] Escherichia coli (UNIPROT accession number: Q8FKD0) [11] Methanosarcina mazei (UNIPROT accession number: Q8PSH8) [240] Methanosarcina mazei (UNIPROT accession number: Q8PSI0) [240] Methanosarcina mazei (UNIPROT accession number: Q8PTE2) [240] Methanosarcina mazei (UNIPROT accession number: Q8PTR6) [240] Methanosarcina mazei (UNIPROT accession number: Q8PV00) [240] Methanosarcina mazei (UNIPROT accession number: Q8PVN2) [240] Methanosarcina mazei (UNIPROT accession number: Q8PX97) [240] Methanosarcina mazei (UNIPROT accession number: Q8Q010) [240] Fusobacterium nucleatum (UNIPROT accession number: Q8R5N6) [241] Fusobacterium nucleatum (UNIPROT accession number: Q8R5P0) [241] Fusobacterium nucleatum (UNIPROT accession number: Q8R693) [241] Fusobacterium nucleatum (UNIPROT accession number: Q8R6B2) [241] Fusobacterium nucleatum (UNIPROT accession number: Q8R6B7) [241] Fusobacterium nucleatum (UNIPROT accession number: Q8R6C3) [241] Fusobacterium nucleatum (UNIPROT accession number: Q8R6C4) [241] Brucella melitensis (UNIPROT accession number: Q8YBU4) [242] Brucella melitensis (UNIPROT accession number: Q8YC53) [242]

2.7.13.3

Histidine kinase























Brucella melitensis (UNIPROT accession number: Q8YDX2) [242] Brucella melitensis (UNIPROT accession number: Q8YE43) [242] Brucella melitensis (UNIPROT accession number: Q8YE51) [242] Brucella melitensis (UNIPROT accession number: Q8YER2) [242] Brucella melitensis (UNIPROT accession number: Q8YF74) [242] Brucella melitensis (UNIPROT accession number: Q8YF98) [242] Brucella melitensis (UNIPROT accession number: Q8YFB6) [242] Brucella melitensis (UNIPROT accession number: Q8YFD9) [242] Brucella melitensis (UNIPROT accession number: Q8YG26) [242] Brucella melitensis (UNIPROT accession number: Q8YG34) [242] Brucella melitensis (UNIPROT accession number: Q8YG37) [242] Brucella melitensis (UNIPROT accession number: Q8YH57) [242] Brucella melitensis (UNIPROT accession number: Q8YHD4) [242] Brucella melitensis (UNIPROT accession number: Q8YHD6) [242] Brucella melitensis (UNIPROT accession number: Q8YIF2) [242] Brucella melitensis (UNIPROT accession number: Q8YIR9) [242] Salmonella typhimurium (UNIPROT accession number: Q8ZJU5) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZKD8) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZKZ3) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZLR5) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZLZ9) [259] Salmonella typhimurium (UNIPROTaccession number: Q8ZMM5) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZN78) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZP35) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZPL6) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZPP5) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZPP6) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZQ54) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZQW4) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZR59) [259] Salmonella typhimurium (UNIPROT accession number: Q8ZRE1) [259] Escherichia coli (UNIPROT accession number: Q8X524) [171, 257, 260] Escherichia coli (UNIPROT accession number: Q8X614) [257, 261] Salmonella typhimurium (UNIPROT accession number: Q8XG60) [258, 259] Ralstonia solanacearum (UNIPROT accession number: Q8XVU0) [243] Ralstonia solanacearum (UNIPROT accession number: Q8XVU1) [243] Salmonella typhi (UNIPROT accession number: Q8Z1N4) [258] Salmonella typhi (UNIPROT accession number: Q8Z1P5) [258] Salmonella typhi (UNIPROT accession number: Q8Z4S5) [258] Salmonella typhi (UNIPROT accession number: Q8Z5U8) [258] Salmonella typhi (UNIPROT accession number: Q8Z8I7) [258] Salmonella typhi (UNIPROT accession number: Q8Z9M7) [258] Yersinia pestis (UNIPROT accession number: Q8ZB69) [244, 245] Yersinia pestis (UNIPROT accession number: Q8ZBB0) [244, 245] Yersinia pestis (UNIPROT accession number: Q8ZBM7) [245] Yersinia pestis (UNIPROT accession number: Q8ZC22) [244, 245]









431

Histidine kinase

















2.7.13.3

Yersinia pestis (UNIPROT accession number: Q8ZD99) [244, 245] Yersinia pestis (UNIPROT accession number: Q8ZFN1) [244, 245] Yersinia pestis (UNIPROT accession number: Q8ZGR4) [244, 245] Yersinia pestis (UNIPROT accession number: Q8ZJH0) [244, 245] Listeria innocua (UNIPROT accession number: Q92DW2) [222] Yersinia pestis (UNIPROT accession number: Q93TP8) [244, 245] Klebsiella oxytoca (UNIPROT accession number: Q9APE0) [95] Mycobacterium leprae (UNIPROT accession number: Q9CCV1) [192] Streptococcus pneumoniae (UNIPROT accession number: Q9F2F5) [231, 246] Salmonella typhimurium (UNIPROT accession number: Q9L9E4) [247, 259] Anabaena sp. (UNIPROT accession number: Q9LCC2) [265] Campylobacter jejuni (UNIPROT accession number: Q9PIL2) [248] Anabaena sp. (UNIPROT accession number: Q9R6X3) [265] Bacillus halodurans (UNIPROT accession number: Q9RC53) [249] Caulobacter crescentus (UNIPROT accession number: Q9RQQ9) [250, 251] Deinococcus radiodurans (UNIPROT accession number: Q9RZA4) [252, 253] Cucumis sativus (UNIPROT accession number: Q9SSY6) [254] Cucumis sativus (UNIPROT accession number: Q9XH57) [255] Cucumis sativus (UNIPROT accession number: Q9XH58) [255] Yersinia pestis (UNIPROT accession number: Q9ZC64) [245] Passiflora edulis (UNIPROT accession number: Q9ZWL6) [256] Bacillus anthracis (no sequence specified) [272] Synechococcus elongatus (no sequence specified) [274, 277] Magnaporthe grisea (UNIPROT accession number: Q9C1U1) [269] Myxococcus xanthus (UNIPROT accession number: Q9Z5F5) [267]

3 Reaction and Specificity Catalyzed reaction ATP + protein l-histidine = ADP + protein N-phospho-l-histidine Reaction type phospho group transfer Natural substrates and products S ATP + histidine kinase Hik34 ( histidine kinase Hik34 might negatively regulate the expression of certain heat shock genes that might by related to thermotolerance in Synechocystis [282]) (Reversibility: ?) [282] P ADP + histidine kinase Hik34 N-phospho-l-histidine S ATP + protein l-histidine ( AtBphP1 contains a typical two-component histidine kinase domain at its C-terminus whose activity is repressed after photoconversion to Pfr

432

2.7.13.3

Histidine kinase

[283]; AtBphP2 is repressed after photoconversion to Pr [283]; canonical histidine kinase activity of the transmitter domain of the ETR1 ethylene receptor from Arabidopsis is not required for signal transmission [284]; histidine kinase BA1351 [272]; histidine kinase BA1356 is capable of inducing sporulation [272]; histidine kinase BA1478 [272]; histidine kinase BA2291 acts as a phosphatase on the sporulation phosphorelay [272]; histidine kinase BA2636 [272]; histidine kinase BA2644 [272]; histidine kinase BA3702 [272]; histidine kinase BA4223 is capable of inducing sporulation in Bacillus anthracis [272]; histidine kinase BA5029 [272]; histidine kinase CikA resets the circadian clock [274]; histidine kinases DivJ and PleC initiate signal transduction pathways that regulate an early cell division cycle step and the gain of motility later in the Caulobacter crescentus cell cycle [271]; in Synechocystis sp. PCC 6803 four histidine kinases, Hik16, Hik33, Hik34, and Hik41, perceive and transduce salt signals [285]; in Synechocystis sp. PCC 6803 four histidine kinases, Hik16, Hik33, Hik34, and Hik41, perceive and transduce salt signals. The Hik16/Hik41 system responds only to NaCl [285]; induced by dehydration and CaCl2 . NTHK2 possesses Ser/Thr kinase activity in presence of Mn2+ and histidine kinase activity in presence of Ca2+ [281]; istidine kinases DivJ and PleC initiate signal transduction pathways that regulate an early cell division cycle step and the gain of motility later in the Caulobacter crescentus cell cycle [271]; RodK may regulate multiple temporally separated events during fruiting body formation including stimulation of early developmental gene expression, inhibition of A-signal production and inhibition of the intercellular C-signal transduction pathway [280]; the circadian clock-associated histidine kinase SasA is necessary for rubustness of the circadian rhythm of gene expression and involved in clock output [277]; the gene-disrupted mutant is unable to produce normal mature fruiting bodies and produces fewer spores [267]; the three-component system of histidine kinases and response regulator, His16-Hik41-Rre17, acts as transducer of hyperosmotic stress [275]; the two-component histidine kinase alrO117 is involved in heterocyst development [278]; the two-component system of histidine kinase and response regulator, His10-Rre3, acts as transducer of hyperosmotic stress [275]; the two-component system of histidine kinase and response regulator, His33-Rre31, acts as transducer of hyperosmotic stress [275]; the two-component systes of histidine kinase and response regulator, His34-Rre1, acts as transducer of hyperosmotic stress [275]) (Reversibility: ?) [267, 271, 272, 274, 275, 277, 278, 280, 281, 283, 284, 285] P ADP + protein N-phospho-l-histidine S ArcA + ATP ( ArcB undergoes autophosphorylation at the expense of ATP and subsequently transphosphorylates its cognate response regulator ArcA through a His to Asp to His to Asp phosphorelay pathway [123]; the arcB gene encodes a sensor-regulator protein for anaerobic repression of the arc modulon [125]; the ArcB and ArcA pro-

433

Histidine kinase

P S

P S

434

2.7.13.3

teins constitute a two-component signal transduction system that plays a broad role in transcriptional regulation. Under anoxic or environmentally reducing conditions, the sensor kinase ArcB is stimulated to autophosphorylate at the expense of ATP and subsequently transphosphorylates the response regulator ArcA [124]; phosphoryl group transfer from phosphorylated ArcB to ArcA, signal transmission occurs solely by HisAsp-His-Asp phosphorelay [129]) (Reversibility: ?) [123, 124, 125, 129] ? Rcp1 + ATP ( Cph1 is a light-regulated histidine kinase that mediates red, far-red reversible phosphorylation of the a small response regulator Rcp1 [235]) (Reversibility: ?) [235] ? Additional information ( BarA/UvrY system activated biofilm formation. UvrY resides downstream from csrA in a signaling pathway for csrB and CsrA stimulates UvrY-dependent activation of csrB expression by BarA-dependent and BarA-independent mechanisms [10]; DNA sequences of plnB reveals that the product closely resembles members of bacterial two-component signal transduction systems. The finding that plnABCD are transcribed from a common promoter suggests that the biological role played by the bacteriocin is somehow related to the regulatory function of the two-component system located on the same operon [17]; ompRenvZ is a two component regulatory system that plays an important role in the regulation of Vi polysaccharide synthesis in Salmonella typhi. One of the environmental signals for this regulation may be osmolarity [13]; E. coli BarA-UvrY two-component system is required for efficient switching between glycolytic and gluconeogenic carbon sources [3]; purified BarA protein is able to autophosphorylate when incubated with [g-32 P]ATP but not with [a-32 P]ATP or [g-32 P]GTP. Phosphorylated BarA, in turn, acts as an efficient phosphoryl group donor to UvrY. BarA and UvrY constitute a new two-component system for gene regulation in Escherichia coli [9]; enzyme is involved in adaptive responses in E. coli [8]; the VanR B-VanS B two-component regulatory system activates a promoter located immediately downstream from the vanS B gene [14]; CpxA functions as a transmembrane sensory protein [57]; EnvZ modulates expression of the ompF and ompC genes through phosphotransfer signal transduction in Escherichia coli [37]; enzyme controls the osmoregulated biosynthesis of the porin proteins OmpF and OmpC [31]; the enzyme plays a central role in osmoregulation, a cellular adaptation process involving the His-Asp phosphorelay signal transduction system. Dimerization of the transmembrane protein is essential for its autophosphorylation and phosphorelay signal transduction functions [38]; Cm-ETR1 mRNA is very high in the seeds and placenta. Marked increase of Cm-ETR1 mRNA parallels climacteric ethylene

2.7.13.3

Histidine kinase

production. Cm-ETR1 plays a specific role not only in ripening but also in the early development of melon fruit [30]; the enzyme plays an important role in coupling signals received from membrane-bound receptors to changes in the swimming behavior of the cells in order to respond appropriately to environmental signals [48]; a complex of the proteins CheA (CheAL and CheAS) and CheW constitutes a functional unit that responds to the signaling state of the chemoreceptors. The autophosphorylation rate of CheAL is much greater when CheAL and CheAS are complexed with CheW. Moreover, the presence of mutant chemoreceptors that cause cells to tumble increases this rate. At wild-type levels of expression, the isolated CheAL/CheAS/CheW complex accounts for about 10% of the total number of CheAL, CheAS, and CheW molecules and exists in a 1:1:1 stoichiometry. This complex is also required for CheAL/CheAS and CheW binding to the phosphorylation substrate, CheY [49]; it is proposed that VirA acts as an environmental sensor of plant-derived inducer molecules and transmits this information to the level of vir gene expression [45]; the two-component regulatory system irlR-irlS is involved in invasion of eukaryotic cells and heavy-metal resistance in Burkholderia pseudomallei [20]; two-component regulatory system CssR-CssS, is required for the cell to survive the severe secretion stress caused by a combination of high-level production of the a-amylase AmyQ and reduced levels of the extracytoplasmic folding factor PrsA. The Css system is required to degrade misfolded exported proteins at the membrane-cell wall interface. CssS represents the first identified sensor for extracytoplasmic protein misfolding in a Gram-positive eubacterium [21]; the CitST two-component system regulates the expression of the Mg-citrate transporter in Bacillus subtilis [26]; the protein is involved in osmoregulation of OmpF and OmpC. EnvZ is considered to be an osmosensor which transmits signals across the membrane to OmpR, a transcriptional activator for ompF and ompC [32]; UhpB and perhaps UhpC play both positive and negative roles in the control of uhpT transcription [71]; regulation of nitrogen fixation genes in Rhizobium meliloti is mediated by two proteins, FixL and FixJ, in response to oxygen availability, oxygen sensor [78]; the gene regulates transcription of the nifHDK operon and so limits the expression of nitrogen fixation activity to periods of low environmental concentrations of both oxygen and fixed nitrogen [68]; FixL senses an environmental signal and transduces it to FixJ, a transcriptional activator of nif and fix genes [76]; required for the activation of the C4-dicarboxylate transport structural gene dctA in free-living Rhizobium leguminosarum [72]; during bacterial chemotaxis, the binding of stimulatory ligands to chemoreceptors at the cell periphery leads to a response at the flagellar motor. Three proteins appear to be required for receptor-mediated control of swimming behavior, the products of the cheA, cheW, and cheY genes [66]; enzyme is required for the proper expression of the outer membrane proteins OmpC and OmpF [65]; enzyme has an enhancing effect on the transcription of phoA, primary function may not be con-

435

Histidine kinase

2.7.13.3

nected to the phosphate regulon [64]; membrane-bound sensor of plant signal molecules [74]; FrzE is a second messenger that relays information between the signaling protein FrzCD and the gliding motor [115]; mediates the transfer of phosphate to the Spo0A and Spo0F sporulation regulatory proteins [101]; RcsC is the sensor components of the two-component regulatory system which regulates expression of the slime polysaccharide colanic acid. rcs system is essential for expression of high levels of the group I capsular polysaccharide in lon+ E. coli K30 [92]; the two-component regulatory system phoP/phoQ controls Salmonella typhimurium virulence [91]; colanic acid capsule synthesis in Escherichia coli K-12 is regulated by RcsB and RcsC. RcsC acts as the sensor and RcsB acts as the receiver or effector to stimulate capsule synthesis from cps genes [93]; bvgS and bvgA control the expression of the virulence-associated genes in Bordetella species by a system similar to the two-component systems used by a variety of bacterial species to respond to environmental stimuli [103]; the PhoPPhoQ system exerts a master regulatory function for preventing bacterial overgrowth within fibroblasts [90]; the HydH/G system senses high periplasmic Zn2+ and Pb2+ concentrations and contributes to metal tolerance by activating the expression of zraP [95]; NodV and NodW proteins are members of the family of two-component regulatory systems, NodV responds to an environmental stimulus and, after signal transduction, NodW may be required to positively regulate the transcription of one or several unknown genes involved in the nodulation process [97]; the enzyme is involved in chemical sensing [118]; genes dctB and dctD form a two-component system which responds to the presence of C4-dicarboxylates to regulate expression of a transport protein encoded by dctA [84]; narL and narX mediate nitrate induction of nitrate reductase synthesis and nitrate repression of fumarate reductase synthesis [81]; in free-living cells, the regulatory dctBD genes are absolutely required for the expression of the dctA gene [85]; dctBencoded protein includes a putative periplasmic N-terminal domain that senses the presence of dicarboxylates and a C-terminal cytoplasmic domain that activates the dctD-encoded protein [86]; enzyme is involved in signal transduction [146]; the enzyme is a regulator of chemotaxis [142]; enzyme is responsible for regulation of subtilin biosynthesis [1,148]; enzyme is involved in the regulation of expression of phosphoglycerate transport in Salmonella typhimurium. pgtB and pgtC genes are involved in the induction of the pgtP expression by modulating derepressor activity [154]; moxY is part of the twocomponent regulatory system controlling methanol dehydrogenase synthesis [143]; either of two functionally redundant sensor proteins, NarX and NarQ, is sufficient for nitrate regulation in Escherichia coli K12. NarQ and NarX may have subtle functional differences [140]; activation role for ResD, and to a lesser extent ResE, in global regulation of aerobic and anaerobic respiration in Bacillus subtilis [151]; PgtB and PgtC polypeptides modulate PgtA activity [153]; narQ is a ni-

436

2.7.13.3

Histidine kinase

trate sensor for nitrate-dependent gene regulation in Escherichia coli [139]; the enzyme is a biological oxygen sensors that restricts the expression of specific genes to hypoxic conditions [131]; the twocomponent sensor-effector system KdpD /KdpE controls expression of the kdpABC operon [121,122]; FixL and FixJ proteins are members of the two-component sensor/regulator family [130]; PilS/PilR is a two-component transcriptional regulatory system controlling expression of type 4 fimbriae in Pseudomonas aeruginosa. PilS is a sensor protein which when stimulated by the appropriate environmental signals activates PilR through kinase activity. PilR then activates transcription of pilA, probably by interacting with RNA polymerase containing RpoN [149]; the TorS/TorR two-component system induces the expression of the tor structural operon encoding the trimethylamine N-oxide reductase respiratory system in response to substrate availability. TorS belongs to a sensor subfamily that includes a classical transmitter domain, a receiver, and a C-terminal alternative transmitter domain [161]; ETR1 acts as an ethylene receptor [181, 182, 183, 184, 185]; TorS is a sensor that contains three phosphorylation sites and transphosphorylates TorR via a four-step phosphorelation, His443–Asp723–His850–Asp(TorR) [160]; QseBC is a two-component regulatory system involved in the regulation of flagella and motility by quorum sensing in E. coli strains EHEC and K-12 [171]; TorS mediates the induction of the tor structural genes in response to trimethylamine N-oxide [162]; enzyme is involved in positive regulation of synthesis of extracellular enzymes and polysaccharide in Xanthomonas campestris pathovar campestris [180]; enzyme is involved in regulation of the phosphate regulon [176]; the two-component regulatory system DcuSR of Escherichia coli controls the expression of genes of C4-dicarboxylate metabolism in response to extracellular C4-dicarboxylates such as fumarate or succinate. The phosphoryl group of DcuS is rapidly transferred to the response regulator DcuR. Upon phosphorylation, DcuR binds specifically to dcuB promoter DNA [158]; citrate, Na+ , and oxygen exert their regulatory effects via the CitA/CitB system. In the presence of these signals, the citAB gene products induce their own synthesis. The positive autoregulation occurrs via co-transcription of citAB with citS and oadGAB [187]; the genes encoding the anaerobic fumarate respiratory system are transcriptionally regulated by C4-dicarboxylates. The regulation is effected by a two-component regulatory system, DcuSR, consisting of a sensory histidine kinase DcuS and a response regulator DcuR [159]; periplasmic loop of DcuS serves as a C4-dicarboxylate sensor. The cytosolic region of DcuS contains two domains: a central PAS domain possibly acting as a second sensory domain and a C-terminal transmitter domain [157]; the two-component system regulates an osmosensing MAP kinase cascade [169]; expression of cusC is induced by high concentrations of copper ions, the cusRS two-component signal transduction system is required for copper-induced expression of pcoE, a plasmid-borne gene from the E. coli copper resistance operon pco. The

437

Histidine kinase

2.7.13.3

genes cusRS are also required for the copper-dependent expression of at least one chromosomal gene, designated cusC, which is allelic to the recently identified virulence gene ibeB in E. coli K1. The cus locus may comprise a copper ion efflux system [196]; the antizyme is a bifunctional protein serving as both an inhibitor of polyamine biosynthesis as well as a transcriptional regulator of an as yet unknown set of genes [207]; the enzyme is involved in chemotaxis [201]; twocomponent regulatory system CopR/CopS is required for copper-inducible expression of the copper resistance operon [202]; the two-component regulatory system, NtrY/NtrX is involved in nitrogen fixation and metabolism. NtrY is likely to represent the transmembrane sensor protein element in a two-component regulatory system [205]; the twocomponent regulatory system afsQ1/afsQ2 is involved in secondary metabolism [206]; the two-component systemDpiA/DpiB is involved in regulation of plasmid inheritance [197]; the cutR-cutS operon regulates copper metabolism in Streptomyces [203]; rhe periplasmic domain of the histidine autokinase CitA functions as a highly specific citrate receptor [187]; the ExoS-ChvI two-component regulatory system regulates succinoglycan production. ChvG is the sensor protein of the ChvG-ChvI two-component regulatory system [194]; the enzyme is involved in regulation of density-dependent expression of luminescence in Vibrio harveyi [189,190]; the two-component regulatory system PfeR/PfeS is involved in the expression of the ferric enterobactin receptor PfeA [204]; deletion of PilS results in a non-pilated phenotype [286]) (Reversibility: ?) [1, 3, 8, 9, 10, 13, 14, 17, 20, 21, 26, 30, 31, 32, 37, 38, 45, 48, 49, 57, 64, 65, 66, 68, 71, 72, 74, 76, 78, 81, 84, 85, 86, 90, 91, 92, 93, 95, 97, 101, 103, 115, 118, 121, 122, 130, 131, 139, 140, 142, 143, 146, 148, 149, 151, 153, 154, 157, 158, 159, 160, 161, 162, 169, 171, 176, 180, 181, 182, 183, 184, 185, 187, 189, 190, 194, 196, 197, 201, 202, 203, 204, 205, 206, 207, 286] P ? S Additional information ( the two-component regulatory system CzcS/ CzcR is involved in transcriptional control of heavy-metal homoeostasis in Alcaligenes eutrophus [215]; kinase of the alternate pathway for phosphorylating the SpoOF protein [213]; enzyme is involved in early steps of competence regulation [230]; photosynthesis gene expression in Rhodobacter sphaeroides is controlled in part by the twocomponent regulatory system composed of a membrane-bound sensor kinase PrrB and a response regulator PrrA [227]; regB is part of a two-component system and encodes a sensor kinase involved in the global regulation of both anoxygenic light-dependent- and oxygenic light-independent CO2 fixation as well as anoxygenic photosystem biosynthesis [228]; the tyrosine kinase DivL function in cell cycle and developmental regulation is mediated, at least in part, by the global response regulator CtrA, the enzyme is essential for cell viability and division [251]; enzyme is involved in signal transduction controlling chemotaxis

438

2.7.13.3

Histidine kinase

[221]; the essential two-component regulatory system yycF/yycG modulates expression of the ftsAZ operon in Bacillus subtilis [220]; enzyme is involved in chemotaxis [224,225,229]; Deinococcus radiodurans bacteriophytochrome functions as a light-regulated histidine kinase, which helps protect the bacterium from visible light [252]; PrrB is responsive to the removal of oxygen and functions through the response regulator PrrA. Together, prrB and prrA provide the major signal involved in synthesis of the specialized intracytoplasmic membrane, harboring components essential to the light reactions of photosynthesis. PrrB is a global regulator of photosynthesis gene expression [226]; regulation of the levels of OmpF and OmpC is normally controlled by a multicomponent signal-transducing regulatory pair of proteins, EnvZ and OmpR. The effect RprX and RprY have on OmpF expression is mediated at the level of transcription. Thus, RprX and RprY may be interfering with the normal regulation of OmpF by OmpR and EnvZ [211]; the two-component sensory transduction system chvG/chvI is required for virulence of Agrobacterium tumefaciens [210]; the two-component regulatory system VanS-VanR activates a promoter used for cotranscription of the vanH, vanA, and vanX resistance genes [208]; the two-component signal transduction system yycF/ yycG is essential for growth of Bacillus subtilis [219]) (Reversibility: ?) [208, 210, 211, 213, 215, 219, 220, 221, 224, 225, 226, 227, 228, 229, 230, 251, 252] P ADP + a phosphoprotein Substrates and products S ATP + histidine kinase EnvZ ( autophosphorylation. Probing catalytically essential domain orientation in histidine kinase EnvZ by targeted disulfide crosslinking [276]) (Reversibility: ?) [276] P ADP + histidine kinase EnvZ N-phospho-l-histidine S ATP + histidine kinase Hik34 ( histidine kinase Hik34 might negatively regulate the expression of certain heat shock genes that might by related to thermotolerance in Synechocystis [282]; autophosphorylation, in vitro at physiological temperatures, but not at elevated temperatures, such as 44 C [282]) (Reversibility: ?) [282] P ADP + histidine kinase Hik34 N-phospho-l-histidine S ATP + protein l-histidine ( AtBphP1 contains a typical two-component histidine kinase domain at its C-terminus whose activity is repressed after photoconversion to Pfr [283]; AtBphP2 is repressed after photoconversion to Pr [283]; canonical histidine kinase activity of the transmitter domain of the ETR1 ethylene receptor from Arabidopsis is not required for signal transmission [284]; histidine kinase BA1351 [272]; histidine kinase BA1356 is capable of inducing sporulation [272]; histidine kinase BA1478 [272]; histidine kinase BA2291 acts as a phosphatase on the sporulation phosphorelay [272]; histidine kinase BA2636 [272]; histidine kinase BA2644 [272]; histidine kinase

439

Histidine kinase

2.7.13.3

BA3702 [272]; histidine kinase BA4223 is capable of inducing sporulation in Bacillus anthracis [272]; histidine kinase BA5029 [272]; histidine kinase CikA resets the circadian clock [274]; histidine kinases DivJ and PleC initiate signal transduction pathways that regulate an early cell division cycle step and the gain of motility later in the Caulobacter crescentus cell cycle [271]; in Synechocystis sp. PCC 6803 four histidine kinases, Hik16, Hik33, Hik34, and Hik41, perceive and transduce salt signals [285]; in Synechocystis sp. PCC 6803 four histidine kinases, Hik16, Hik33, Hik34, and Hik41, perceive and transduce salt signals. The Hik16/Hik41 system responds only to NaCl [285]; induced by dehydration and CaCl2 . NTHK2 possesses Ser/Thr kinase activity in presence of Mn2+ and histidine kinase activity in presence of Ca2+ [281]; histidine kinases DivJ and PleC initiate signal transduction pathways that regulate an early cell division cycle step and the gain of motility later in the Caulobacter crescentus cell cycle [271]; RodK may regulate multiple temporally separated events during fruiting body formation including stimulation of early developmental gene expression, inhibition of A-signal production and inhibition of the intercellular C-signal transduction pathway [280]; the circadian clock-associated histidine kinase SasA is necessary for rubustness of the circadian rhythm of gene expression and involved in clock output [277]; the gene-disrupted mutant is unable to produce normal mature fruiting bodies and produces fewer spores [267]; the three-component system of histidine kinases and response regulator, His16-Hik41-Rre17, acts as transducer of hyperosmotic stress [275]; the two-component histidine kinase alrO117 is involved in heterocyst development [278]; the two-component system of histidine kinase and response regulator, His10-Rre3, acts as transducer of hyperosmotic stress [275]; the two-component system of histidine kinase and response regulator, His33-Rre31, acts as transducer of hyperosmotic stress [275]; the two-component systes of histidine kinase and response regulator, His34-Rre1, acts as transducer of hyperosmotic stress [275]) (Reversibility: ?) [267, 271, 272, 274, 275, 277, 278, 280, 281, 283, 284, 285] P ADP + protein N-phospho-l-histidine S ArcA + ATP ( ArcB undergoes autophosphorylation at the expense of ATP and subsequently transphosphorylates its cognate response regulator ArcA through a His to Asp to His to Asp phosphorelay pathway [123]; ArcB undergoes autophosphorylation at the expense of ATP and subsequently transphosphorylates its cognate response regulator ArcA through a His to Asp to His to Asp phosphorelay pathway [123]; the arcB gene encodes a sensor-regulator protein for anaerobic repression of the arc modulon [125]; the ArcB and ArcA proteins constitute a two-component signal transduction system that plays a broad role in transcriptional regulation. Under anoxic or environmentally reducing conditions, the sensor kinase ArcB is stimulated to autophosphorylate at the expense of ATP and subsequently transphosphorylates the response regulator ArcA [124]; phosphoryl group transfer from phos-

440

2.7.13.3

P S

P S

P S P S

P S

P S

P S

P S

Histidine kinase

phorylated ArcB to ArcA, signal transmission occurs solely by His-AspHis-Asp phosphorelay [129]) (Reversibility: ?) [123, 124, 125, 129] ? BvgA + ATP ( the phosphorylated, purified C-terminal domain alone is sufficient for phosphotransfer to BvgA [107]; the cytoplasmic portion of BvgS (BvgS) [106]; one hybrid histidine kinase consisting of the BvgS transmitter and HPt domains and of the EvgS receiver domain BvgS-TO-EvgS-R is able to phosphorylate BvgA but not EvgA. In contrast, the hybrid protein consisting of the BvgS transmitter and the EvgS receiver and HPt domains BvgS-T-EvgS-RO is unable to phosphorylate BvgA but efficiently phosphorylates EvgA [105]) (Reversibility: ?) [105, 106, 107] ? CitB + ATP ( a fusion protein MalE-CitAC is composed of the maltose-binding protein and the CitA kinase domain shows constitutive autokinase activity and transfers the g-phosphate group of ATP to its cognate response regulator CitB [188]) (Reversibility: ?) [188] ? CtrA + ATP (Reversibility: ?) [250] ? DcuR + ATP ( the phosphoryl group of DcuS is rapidly transferred to the response regulator DcuR. Upon phosphorylation, DcuR binds specifically to dcuB promoter DNA [158]) (Reversibility: ?) [158] ? EvgA + ATP ( one hybrid histidine kinase consisting of the BvgS transmitter and HPt domains and of the EvgS receiver domain BvgSTO-EvgS-R is able to phosphorylate BvgA but not EvgA. In contrast, the hybrid protein consisting of the BvgS transmitter and the EvgS receiver and HPt domains BvgS-T-EvgS-RO is unable to phosphorylate BvgA but efficiently phosphorylates EvgA [105]) (Reversibility: ?) [105] ? Rcp1 + ATP ( Cph1 is a light-regulated histidine kinase that mediates red, far-red reversible phosphorylation of the a small response regulator Rcp1 [235]) (Reversibility: ?) [235] ? TorR + ATP ( TorS is a sensor that contains three phosphorylation sites and transphosphorylates TorR via a four-step phosphorelay, His443 to Asp723 to His850 to Asp(TorR). TorS can dephosphorylate phospho-TorR when trimethylamine N-oxide is removed. Dephosphorylation probably occurs by a reverse phosphorelay, Asp(TorR) to His850 to Asp723 [160]) (Reversibility: ?) [160] ? protein + ATP ( the cytoplasmic portion of BvgS autophosphorylates with the g-phosphate from [g-32P]ATP [106]; autophosphorylation [8, 25, 36, 41, 49, 54, 101, 107, 116, 123, 124, 125, 158, 164]; a model of the mechanism of FrzE phosphorylation: autophos-

441

Histidine kinase

P S

P S

442

2.7.13.3

phorylation initially occurs at a conserved His residue within the “CheA“ domain and then, via an intramolecular transphosphorylation, is transferred to a conserved aspartate residue within the “CheY“ domain [116]; DivL protein is homologous to the ubiquitous bacterial histidine protein kinases, it differs from previously studied members of this protein kinase family in that it contains a tyrosine residue Tyr550 in the conserved H-box instead of a histidine residue, which is the expected site of autophosphorylation. DivL is autophosphorylated on Tyr-550 in vitro, and this tyrosine residue is essential for cell viability and regulation of the cell division cycle [251]; H243 is a site of autophosphorylation as well as transphosphorylation to the conserved D55 residue of response regulator OmpR [36]) (Reversibility: ?) [8, 25, 36, 41, 49, 54, 101, 106, 107, 116, 123, 124, 125, 158, 164, 251] ? regulator protein OmpR + ATP ( H243 is the a site of autophosphorylation as well as transphosphorylation to the conserved D55 residue of response regulator OmpR [36]) (Reversibility: ?) [2, 36] ? Additional information ( the two-component regulatory system CzcS/ CzcR is involved in transcriptional control of heavy-metal homoeostasis in Alcaligenes eutrophus [215]; kinase of the alternate pathway for phosphorylating the SpoOF protein [213]; enzyme is involved in early steps of competence regulation [230]; photosynthesis gene expression in Rhodobacter sphaeroides is controlled in part by the twocomponent regulatory system composed of a membrane-bound sensor kinase PrrB and a response regulator PrrA [227]; regB is part of a two-component system and encodes a sensor kinase involved in the global regulation of both anoxygenic light-dependent- and oxygenic light-independent CO2 fixation as well as anoxygenic photosystem biosynthesis [228]; the tyrosine kinase DivL function in cell cycle and developmental regulation is mediated, at least in part, by the global response regulator CtrA, the enzyme is essential for cell viability and division [251]; enzyme is involved in signal transduction controlling chemotaxis [221]; the essential two-component regulatory system yycF/yycG modulates expression of the ftsAZ operon in Bacillus subtilis [220]; enzyme is involved in chemotaxis [224,225,229]; Deinococcus radiodurans bacteriophytochrome functions as a light-regulated histidine kinase, which helps protect the bacterium from visible light [252]; PrrB is responsive to the removal of oxygen and functions through the response regulator PrrA. Together, prrB and prrA provide the major signal involved in synthesis of the specialized intracytoplasmic membrane, harboring components essential to the light reactions of photosynthesis. PrrB is a global regulator of photosynthesis gene expression [226]; regulation of the levels of OmpF and OmpC is normally controlled by a multicomponent signal-transducing regulatory pair of proteins, EnvZ and OmpR. The effect RprX and RprY have on OmpF ex-

2.7.13.3

Histidine kinase

pression is mediated at the level of transcription. Thus, RprX and RprY may be interfering with the normal regulation of OmpF by OmpR and EnvZ [211]; the two-component sensory transduction system chvG/chvI is required for virulence of Agrobacterium tumefaciens [210]; the two-component regulatory system VanS-VanR activates a promoter used for cotranscription of the vanH, vanA, and vanX resistance genes [208]; the two-component signal transduction system yycF/ yycG is essential for growth of Bacillus subtilis [219]) (Reversibility: ?) [208, 210, 211, 213, 215, 219, 220, 221, 224, 225, 226, 227, 228, 229, 230, 251, 252] P ADP + a phosphoprotein S Additional information ( mediates the transfer of phosphate to the Spo0A and Spo0F sporulation regulatory proteins. Spo0F protein is a much better phosphoreceptor for this kinase than Spo0A protein in vitro [101]; BarA/UvrY system activated biofilm formation. UvrY resides downstream from csrA in a signaling pathway for csrB and CsrA stimulates UvrY-dependent activation of csrB expression by BarA-dependent and BarA-independent mechanisms [10]; DNA sequences of plnB reveals that the product closely resembles members of bacterial two-component signal transduction systems. The finding that plnABCD are transcribed from a common promoter suggests that the biological role played by the bacteriocin is somehow related to the regulatory function of the two-component system located on the same operon [17]; ompR-envZ is a two component regulatory system that plays an important role in the regulation of Vi polysaccharide synthesis in Salmonella typhi. One of the environmental signals for this regulation may be osmolarity [13]; E. coli BarA-UvrY two-component system is required for efficient switching between glycolytic and gluconeogenic carbon sources [3]; purified BarA protein is able to autophosphorylate when incubated with [g-32 P]ATP but not with [a-32 P]ATP or [g-32 P]GTP. Phosphorylated BarA, in turn, acts as an efficient phosphoryl group donor to UvrY. BarA and UvrY constitute a new two-component system for gene regulation in Escherichia coli [9]; enzyme is involved in adaptive responses in E. coli [8]; the VanR BVanS B two-component regulatory system activates a promoter located immediately downstream from the vanS B gene [14]; CpxA functions as a transmembrane sensory protein [57]; EnvZ modulates expression of the ompF and ompC genes through phosphotransfer signal transduction in Escherichia coli [37]; enzyme controls the osmoregulated biosynthesis of the porin proteins OmpF and OmpC [31]; the enzyme plays a central role in osmoregulation, a cellular adaptation process involving the His-Asp phosphorelay signal transduction system. Dimerization of the transmembrane protein is essential for its autophosphorylation and phosphorelay signal transduction functions [38];

443

Histidine kinase

2.7.13.3

Cm-ETR1 mRNA is very high in the seeds and placenta. Marked increase of Cm-ETR1 mRNA parallels climacteric ethylene production. Cm-ETR1 plays a specific role not only in ripening but also in the early development of melon fruit [30]; the enzyme plays an important role in coupling signals received from membrane-bound receptors to changes in the swimming behavior of the cells in order to respond appropriately to environmental signals [48]; a complex of the proteins CheA (CheAL and CheAS) and CheW constitutes a functional unit that responds to the signaling state of the chemoreceptors. The autophosphorylation rate of CheAL is much greater when CheAL and CheAS are complexed with CheW. Moreover, the presence of mutant chemoreceptors that cause cells to tumble increases this rate. At wild-type levels of expression, the isolated CheAL/CheAS/CheW complex accounts for about 10% of the total number of CheAL, CheAS, and CheW molecules and exists in a 1:1:1 stoichiometry. This complex is also required for CheAL/CheAS and CheW binding to the phosphorylation substrate, CheY [49]; it is proposed that VirA acts as an environmental sensor of plant-derived inducer molecules and transmits this information to the level of vir gene expression [45]; the two-component regulatory system irlR-irlS is involved in invasion of eukaryotic cells and heavy-metal resistance in Burkholderia pseudomallei [20]; two-component regulatory system CssR-CssS, is required for the cell to survive the severe secretion stress caused by a combination of high-level production of the a-amylase AmyQ and reduced levels of the extracytoplasmic folding factor PrsA. The Css system is required to degrade misfolded exported proteins at the membrane-cell wall interface. CssS represents the first identified sensor for extracytoplasmic protein misfolding in a Gram-positive eubacterium [21]; the CitST two-component system regulates the expression of the Mg-citrate transporter in Bacillus subtilis [26]; the protein is involved in osmoregulation of OmpF and OmpC. EnvZ is considered to be an osmosensor which transmits signals across the membrane to OmpR, a transcriptional activator for ompF and ompC [32]; UhpB and perhaps UhpC play both positive and negative roles in the control of uhpT transcription [71]; regulation of nitrogen fixation genes in Rhizobium meliloti is mediated by two proteins, FixL and FixJ, in response to oxygen availability, oxygen sensor [78]; the gene regulates transcription of the nifHDK operon and so limits the expression of nitrogen fixation activity to periods of low environmental concentrations of both oxygen and fixed nitrogen [68]; FixL senses an environmental signal and transduces it to FixJ, a transcriptional activator of nif and fix genes [76]; required for the activation of the C4-dicarboxylate transport structural gene dctA in free-living Rhizobium leguminosarum [72]; during bacterial chemotaxis, the binding of stimulatory ligands to chemoreceptors at the cell periphery leads to a response at the flagellar motor. Three proteins appear to be required for receptor-mediated control of swimming behavior, the products of the cheA, cheW, and cheY genes [66]; enzyme is required for the proper expression of the outer membrane pro-

444

2.7.13.3

Histidine kinase

teins OmpC and OmpF [65]; enzyme has an enhancing effect on the transcription of phoA, primary function may not be connected to the phosphate regulon [64]; membrane-bound sensor of plant signal molecules [74]; FrzE is a second messenger that relays information between the signaling protein FrzCD and the gliding motor [115]; mediates the transfer of phosphate to the Spo0A and Spo0F sporulation regulatory proteins [101]; RcsC is the sensor components of the two-component regulatory system which regulates expression of the slime polysaccharide colanic acid. rcs system is essential for expression of high levels of the group I capsular polysaccharide in lon+ E. coli K30 [92]; the two-component regulatory system phoP/phoQ controls Salmonella typhimurium virulence [91]; colanic acid capsule synthesis in Escherichia coli K-12 is regulated by RcsB and RcsC. RcsC acts as the sensor and RcsB acts as the receiver or effector to stimulate capsule synthesis from cps genes [93]; bvgS and bvgA control the expression of the virulence-associated genes in Bordetella species by a system similar to the two-component systems used by a variety of bacterial species to respond to environmental stimuli [103]; the PhoP-PhoQ system exerts a master regulatory function for preventing bacterial overgrowth within fibroblasts [90]; the HydH/G system senses high periplasmic Zn2+ and Pb2+ concentrations and contributes to metal tolerance by activating the expression of zraP [95]; NodV and NodW proteins are members of the family of two-component regulatory systems, NodV responds to an environmental stimulus and, after signal transduction, NodW may be required to positively regulate the transcription of one or several unknown genes involved in the nodulation process [97]; the enzyme is involved in chemical sensing [118]; genes dctB and dctD form a two-component system which responds to the presence of C4-dicarboxylates to regulate expression of a transport protein encoded by dctA [84]; narL and narX mediate nitrate induction of nitrate reductase synthesis and nitrate repression of fumarate reductase synthesis [81]; in free-living cells, the regulatory dctBD genes are absolutely required for the expression of the dctA gene [85]; dctB-encoded protein includes a putative periplasmic N-terminal domain that senses the presence of dicarboxylates and a C-terminal cytoplasmic domain that activates the dctD-encoded protein [86]; enzyme is involved in signal transduction [146]; the enzyme is a regulator of chemotaxis [142]; enzyme is responsible for regulation of subtilin biosynthesis [1,148]; enzyme is involved in the regulation of expression of phosphoglycerate transport in Salmonella typhimurium. pgtB and pgtC genes are involved in the induction of the pgtP expression by modulating derepressor activity [154]; moxY is part of the two-component regulatory system controlling methanol dehydrogenase synthesis [143]; either of two functionally redundant sensor proteins, NarX and NarQ, is sufficient for nitrate regulation in Escherichia coli K-12. NarQ and NarX may have subtle functional differences [140]; activation role for ResD, and to a lesser extent ResE, in global regulation of aerobic and anae-

445

Histidine kinase

2.7.13.3

robic respiration in Bacillus subtilis [151]; PgtB and PgtC polypeptides modulate PgtA activity [153]; narQ is a nitrate sensor for nitrate-dependent gene regulation in Escherichia coli [139]; the enzyme is a biological oxygen sensors that restricts the expression of specific genes to hypoxic conditions [131]; the two-component sensor-effector system KdpD /KdpE controls expression of the kdpABC operon [121,122]; FixL and FixJ proteins are members of the two-component sensor/regulator family [130]; PilS/PilR is a two-component transcriptional regulatory system controlling expression of type 4 fimbriae in Pseudomonas aeruginosa. PilS is a sensor protein which when stimulated by the appropriate environmental signals activates PilR through kinase activity. PilR then activates transcription of pilA, probably by interacting with RNA polymerase containing RpoN [149]; the TorS/TorR two-component system induces the expression of the tor structural operon encoding the trimethylamine N-oxide reductase respiratory system in response to substrate availability. TorS belongs to a sensor subfamily that includes a classical transmitter domain, a receiver, and a Cterminal alternative transmitter domain [161]; ETR1 acts as an ethylene receptor [181, 182, 183, 184, 185]; TorS is a sensor that contains three phosphorylation sites and transphosphorylates TorR via a four-step phosphorelation, His443–Asp723–His850–Asp(TorR) [160]; QseBC is a two-component regulatory system involved in the regulation of flagella and motility by quorum sensing in E. coli strains EHEC and K-12 [171]; TorS mediates the induction of the tor structural genes in response to trimethylamine N-oxide [162]; enzyme is involved in positive regulation of synthesis of extracellular enzymes and polysaccharide in Xanthomonas campestris pathovar campestris [180]; enzyme is involved in regulation of the phosphate regulon [176]; the two-component regulatory system DcuSR of Escherichia coli controls the expression of genes of C4-dicarboxylate metabolism in response to extracellular C4-dicarboxylates such as fumarate or succinate. The phosphoryl group of DcuS is rapidly transferred to the response regulator DcuR. Upon phosphorylation, DcuR binds specifically to dcuB promoter DNA [158]; citrate, Na+ , and oxygen exert their regulatory effects via the CitA/CitB system. In the presence of these signals, the citAB gene products induce their own synthesis. The positive autoregulation occurrs via co-transcription of citAB with citS and oadGAB [187]; the genes encoding the anaerobic fumarate respiratory system are transcriptionally regulated by C4-dicarboxylates. The regulation is effected by a two-component regulatory system, DcuSR, consisting of a sensory histidine kinase DcuS and a response regulator DcuR [159]; periplasmic loop of DcuS serves as a C4-dicarboxylate sensor. The cytosolic region of DcuS contains two domains: a central PAS domain possibly acting as a second sensory domain and a C-terminal transmitter domain [157]; the two-component system regulates an osmosensing MAP kinase cascade [169]; expression of cusC is induced by high concentrations of copper ions, the cusRS two-component signal transduction sys-

446

2.7.13.3

Histidine kinase

tem is required for copper-induced expression of pcoE, a plasmid-borne gene from the E. coli copper resistance operon pco. The genes cusRS are also required for the copper-dependent expression of at least one chromosomal gene, designated cusC, which is allelic to the recently identified virulence gene ibeB in E. coli K1. The cus locus may comprise a copper ion efflux system [196]; the antizyme is a bifunctional protein serving as both an inhibitor of polyamine biosynthesis as well as a transcriptional regulator of an as yet unknown set of genes [207]; the enzyme is involved in chemotaxis [201]; two-component regulatory system CopR/CopS is required for copper-inducible expression of the copper resistance operon [202]; the two-component regulatory system, NtrY/NtrX is involved in nitrogen fixation and metabolism. NtrY is likely to represent the transmembrane sensor protein element in a two-component regulatory system [205]; the two-component regulatory system afsQ1/afsQ2 is involved in secondary metabolism [206]; the two-component systemDpiA/DpiB is involved in regulation of plasmid inheritance [197]; the cutR-cutS operon regulates copper metabolism in Streptomyces [203]; the periplasmic domain of the histidine autokinase CitA functions as a highly specific citrate receptor [187]; the ExoS-ChvI two-component regulatory system regulates succinoglycan production. ChvG is the sensor protein of the ChvG-ChvI twocomponent regulatory system [194]; the enzyme is involved in regulation of density-dependent expression of luminescence in Vibrio harveyi [189,190]; the two-component regulatory system PfeR/PfeS is involved in the expression of the ferric enterobactin receptor PfeA [204]; deletion of PilS results in a non-pilated phenotype [286]) (Reversibility: ?) [1, 3, 8, 9, 10, 13, 14, 17, 20, 21, 26, 30, 31, 32, 37, 38, 45, 48, 49, 57, 64, 65, 66, 68, 71, 72, 74, 76, 78, 81, 84, 85, 86, 90, 91, 92, 93, 95, 97, 101, 103, 115, 118, 121, 122, 130, 131, 139, 140, 142, 143, 146, 148, 149, 151, 153, 154, 157, 158, 159, 160, 161, 162, 169, 171, 176, 180, 181, 182, 183, 184, 185, 187, 189, 190, 194, 196, 197, 201, 202, 203, 204, 205, 206, 207, 286] P ? Inhibitors 3,6-diamino-5-cyano-4-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid (4bromo-phenyl)amide ( competitive inhibitor of the coupled reaction of histidine kinase HpkA HK and the cognate response regulator DrrA RR [273]) [273] AMP-PNP [273] Cofactors/prosthetic groups heme ( FixL is an oxygen-binding hemoprotein, the heme domain serves as the dioxygen switch in the FixL/FixJ two-component system [77]; the oxygen-detecting domain is a heme binding region that controls the activity of an attached histidine kinase. In the absence of bound ligand, the heme domain permits kinase activity. In the presence of bound ligand, this domain turns off kinase activity [131]) [77, 131]

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Histidine kinase

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Metals, ions Fe ( enzyme contains 2-labile 1-2 iron-sulphur [4Fe-4S]2+ clusters of the FNR-type [279]) [279] Ki-Value (mM) 0.00062 (3,6-diamino-5-cyano-4-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid (4-bromo-phenyl)amide) [273] 0.1 (AMP-PNP) [273]

4 Enzyme Structure Subunits ? ( x * 99000, SDS-PAGE [142]; x * 50000 [31]; x * 52000 [57]; x * 55290 [136]; x * 66000 [25]; x * 50597, calculation from nucleotide sequence [204]; x * 74500 [118]; x * 99000 [121]; x * 69170 [101]; x * 67275, calculation from nucleotide sequence [79]; x * 102452, calculation from nucleotide sequence [8]; x * 83000 [115]; x * 73000 [66]; x * 46389, calculation from nucleotide sequence [164]; x * 38409, calculation from nucleotide sequence [39]; x * 48846, calculation from nucleotide sequence [165]; x * 49666 [58]; x * 43800 [191]; x * 44600, calculation from nucleotide sequence [148]; x * 47774, calculation from nucleotide sequence [213]; x * 49772, calculation from nucleotide sequence [64]) [8, 25, 31, 39, 57, 58, 64, 66, 79, 101, 115, 118, 121, 136, 142, 148, 164, 165, 191, 204, 213] dimer ( 2 * 79000 [185]; the Cph1 protein forms dimers through the C-terminal region [234]) [185, 234, 236, 276] Additional information ( the periplasmic region of histidine kinase EnvZ(Ala38-Arg162) forms a dimer in solution [268]) [268] Posttranslational modification phosphoprotein ( autophosphorylation [8, 25, 36, 41, 49, 54, 101, 107, 116, 123, 124, 125, 158, 164]; enzyme undergoes phosphorylation in the presence of ATP [8]; the major site at which NRII is autophosphorylated is contained within a peptide consisting of amino acid residues 136-142 of NRII, and thus probably corresponds to H139. A minor site of phosphorylation, accounting for about 2% of the phosphate in NRII-P, is found in a peptide that corresponds to residues 158-169 [41]; in the presence of [g-32 P]ATP, the purified COOH-terminal KinB protein undergoes progressive autophosphorylation in vitro. Substitutions of the residues conserved among histidine protein kinases abolishes KinB autophosphorylation [25]; the phosphotransfer domain, CheA1-134, contains the site of phosphorylation, His48, and two other histidine residues, His26 and His67 [53]; His243 is the a site of autophosphorylation as well as transphosphorylation to the conserved D55 residue of response regulator OmpR [36];

448

2.7.13.3

Histidine kinase

His243 is the major site of phosphorylation on EnvZ [2]; purified BarA protein is able to autophosphorylate when incubated with [g-32 P]ATP but not with [a-32 P]ATP or [g-32 P]GTP. Phosphorylated BarA, in turn, acts as an efficient phosphoryl group donor to UvrY. BarA and UvrY constitute a new two-component system for gene regulation in Escherichia coli [9]) [2, 8, 9, 25, 36, 41, 49, 53, 54, 101, 107, 116, 123, 124, 125, 158, 164]

5 Isolation/Preparation/Mutation/Application Source/tissue floret ( expressed in geranium florets long before they are receptive to pollination and transcript levels remain constant throughout floral development [255]) [255] fruit ( the level of expression of PE-ETR1 does not significantly change over the course of ripening, however, the mRNA levels of PE-ETR1 is much higher in arils than in seeds [256]) [256] petiole ( LeETR2 mRNA expression is down-regulated in senescing leaf petioles [28]) [28] placenta ( Cm-ETR1 mRNA is very high [30]) [30] root [28] seed ( Cm-ETR1 mRNA is very high [30]; LeETR2 mRNA is expressed at low levels throughout the plant but is induced in imbibing seeds prior to germination [28]) [28, 30] seedling ( LeETR2 mRNA expression is down-regulated in elongating seedlings [28]) [28] vegetative cell ( RodK is present in vegetative cells and remains present until the late aggregation stage, after which the level decreases in a manner that depends on the intracellular A-signal [280]) [280] Additional information ( FrzE is clearly present during vegetative growth and at much lower levels during development [116]; LeETR1 is expressed constitutively in all plant tissues examined [28]; mRNA is constitutively expressed in vegetative and reproductive tissues [214]) [28, 116, 214] Localization cytoplasm ( RodK is a soluble cytoplasmic protein, which contains an N-terminal sensor domain, a histidine protein kinase domain and three receiver domains [280]) [66, 280] cytoplasmic membrane ( enzyme is anchored to the cytoplasmic membrane by the amino-terminal region [60]) [60, 204] cytosol [279] endoplasmic reticulum ( ETR1 of Arabidopsis contains transmembrane domains responsible for ethylene binding and membrane localization [182]) [182]

449

Histidine kinase

2.7.13.3

inner membrane ( bound, PilS is retained to the poles of Pseudomonas aeruginosa [286]; the enzyme is distributed evenly about the membrane of Escherichia coli [286]) [286] membrane ( associated with [154]; bound to [2]; transmembrane protein [38,107]; cytoplasmic side of inner membrane [31]; may be a membrane protein [58]; transmembrane regions of EnvZ play roles in transmembrane signaling [37]; FixL has features of a transmembrane protein [76]; EnvZ is a transmembrane protein with histidine kinase activity in its cytoplasmic region. The cytoplasmic region contains two functional domains: domain A, residues 223-289, contains the conserved histidine residue H243, a site of autophosphorylation as well as transphosphorylation to the conserved D55 residue of response regulator OmpR [36]; a large periplasmic domain is lacking and an extended cytoplasmic domain is present besides the kinase domain [59]; N-terminal region may be located in the periplasm and its Cterminal region in the cytoplasm [72]; FixL is a membrane protein containing four possible transmembrane segments [78]; the region between the hydrophobic segments of CpxA is periplasmic, whereas the region carboxy-terminal to the second such segment is cytoplasmic. CpxA functions as a trans-membrane sensory protein [57]; dctB-encoded protein includes a putative periplasmic N-terminal domain that senses the presence of dicarboxylates and a C-terminal cytoplasmic domain that activates the dctDencoded protein [86]; CitA represents a membrane-bound sensor kinase consisting of a periplasmic domain flanked by two transmembrane helices, a linker domain and the conserved kinase or transmitter domain [188]; CitA contains in the N-terminal half, two putative transmembrane helices which enclosed a presumably periplasmic domain of about 130 amino acids [187]; membrane-bound sensor-kinase with two potential membrane-spanning sequences in the N-terminal region [156]; NtrY is likely to represent the transmembrane sensor protein element in the twocomponent regulatory system [205]; DcuS contains two putative transmembrane helices flanking an approximately 140-residue N-terminal domain apparently located in the periplasm [157]; DcuS is a membrane-integral sensor kinase, and the sensory and kinase domains are located on opposite sides of the cytoplasmic membrane [158]; membrane-bound protein comprising at least three cytoplasmic domains [124]; KdpD is anchored to the membrane by four membrane-spanning segments near its middle, with both C-terminal and N-terminal portions in the cytoplasm [121]; EnvZ contained two hydrophobic stretches typical of transmembrane regions [65]; KdpD has four membrane-spanning segments in the middle of the polypeptide chain, whereas N and C terminus are both cytoplasmic [122]; NH2 -terminal periplasmic domain [25]; transmembrane enzyme [276]) [2, 8, 25, 31, 36, 37, 38, 45, 57, 58, 59, 64, 65, 72, 74, 76, 78, 86, 107, 121, 122, 124, 125, 154, 156, 157, 158, 185, 187, 188, 205, 227, 276]

450

2.7.13.3

Histidine kinase

Purification (recombinant periplasmic domain of histidine kinase EnvZ(Ala38Arg162)) [268] (histidine kinase NTHK2) [281] (recombinant) [282] (a KinB derivative containing the COOH terminus of KinB) [25] [66] (cytoplasmic portion of BvgS (’BvgS)) [106] (recombinant FrzE protein is overproduced in Escherichia coli and purified from inclusion bodies) [116] (coexpressed with a bacterial thioredoxin in Escherichia coli) [234] Crystallization (crystal structure at 2.0 A resolution of the complex of the Escherichia coli chemotaxis response regulator CheY and the phosphoacceptor-binding domain P2 of the kinase CheA) [47] (crystal structure, at 2.95 A resolution, of the response regulator of bacterial chemotaxis, CheY, bound to the recognition domain from its cognate histidine kinase, CheA) [52] (crystal structure of the C-terminal HPt domain of ArcB) [127] (crystal structure of the histidine-containing phosphotransfer domain) [128] (crystallization of a complex between a novel C-terminal transmitter, HPt domain, of the anaerobic sensor kinase ArcB and the chemotaxis response regulator CheY) [126] [236] Cloning (expression of the periplasmic domain of histidine kinase EnvZ(Ala38Arg162) in Escherichia coli) [268] (mutant enzymes cloned and expressed in Escherichia coli strain BL21(DE3)) [270] (overexpression in Escherichia coli, histidine kinase Hik34) [282] (heterologous expression of the plnABCD operon in a Lactobacillus sake strain) [15] [18] (cloned from a Salmonella typhi Ty2 cosmid bank and characterized by DNA sequence analysis) [13] (cloned from a root cDNA library) [28] (overexpression of a 36-kDa truncated EnvZ protein, Glu106 to Gly450, that forms inclusion bodies in the cell) [2] [92] [96] (cytoplasmic portion of BvgS (’BvgS) is overexpressed) [106] (subcloning of the entire vir regulon) [113] [116] [118] [130]

451

Histidine kinase

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(phoP-phoQ operon cloned and expressed in Escherichia coli) [136] (kanamycin cartridges are inserted into the cloned fixL gene and recombined into the host genome) [137] [139] (no heterologous expression of NRII in Escherichia coli) [141] [142] [146, 147] [181] [191] [201] [202] [207] (expression of these proteins from a multicopy plasmid vector in Escherichia coli) [211] [28] [234] (isolation of cDNA) [255] (isolation of cDNA) [255] (expression in Bacillus subtilis) [272] (expression of Hik1 can confer fungicide-sensitivity to Saccharomyces cerevisiae. This requires both the histidine kinase and the response response regulator domain of Hik1) [269] [267] Engineering D286C ( t1=2 at room temperature is 16 min, compared to 12 min for wild-type enzyme. 71% of the wild-type phosphatase activity [270]) [270] D56N ( phosphorylation of CitB is inhibited by a D56N exchange. In the presence of ATP, CitB-D56N forms a stable complex with MalE-CitAC [188]) [188] E257C ( t1=2 at room temperature is 30 min, compared to 12 min for wild-type enzyme. 31% of the wild-type phosphatase activity [270]) [270] E261C ( t1=2 at room temperature is 15 min, compared to 12 min for wild-type enzyme. 77% of the wild-type phosphatase activity [270]) [270] E268C ( t1=2 at room temperature is 23 min, compared to 12 min for wild-type enzyme. 45% of the wild-type phosphatase activity [270]) [270] E275C ( t1=2 at room temperature is 28 min, compared to 12 min for wild-type enzyme. 34% of the wild-type phosphatase activity [270]) [270] E276C ( t1=2 at room temperature is 68 min, compared to 12 min for wild-type enzyme. 5% of the wild-type phosphatase activity [270]) [270] E282C ( t1=2 at room temperature is 15 min, compared to 12 min for wild-type enzyme. 77% of the wild-type phosphatase activity [270]) [270] G240C ( t1=2 at room temperature is 10 min, compared to 12 min for wild-type enzyme. 123% of the wild-type phosphatase activity [270]) [270] G264C ( t1=2 at room temperature is 12 min, compared to 12 min for wild-type enzyme. As active as wild-type enzyme [270]) [270]

452

2.7.13.3

Histidine kinase

H1172Q ( mutation abolishes BvgS activity in vivo and eliminates detectable phosphorylation of BvgA in vitro. Activity of BvgS H1172Q can be restored by providing the wild-type C-terminal domain in trans [107]) [107] H243K ( inactive mutant protein [270]) [270] H243N ( inactive mutant protein [270]) [270] H243S ( inactive mutant protein [270]) [270] H243V ( inactive mutant protein [270]) [270] H243X ( the His residue at position 243 of the EnvZ protein is changed by means of site-directed mutagenesis. The mutant EnvZ protein is defective in its in vitro ability not only as to EnvZ-autophosphorylation but also OmpR-phosphorylation and OmpR-dephosphorylation. This particular mutant EnvZ protein seems to exhibit null functions as to the in vivo osmoregulatory phenotype [34]) [34] H243Y ( inactive mutant protein [270]) [270] H350L ( autokinase activity of CitA is abolished by an H350L exchange [188]) [188] K272C ( t1=2 at room temperature is 55 min, compared to 12 min for wild-type enzyme. 10% of the wild-type phosphatase activity [270]) [270] L236C ( t1=2 at room temperature is 25 min, compared to 12 min for wild-type enzyme. 40% of the wild-type phosphatase activity [270]) [270] L254C ( inactive mutant enzyme, t1=2 at room temperature is 90 min, compared to 12 min for wild-type enzyme [270]) [270] N271C ( t1=2 at room temperature is 36 min, compared to 12 min for wild-type enzyme. 23% of the wild-type phosphatase activity [270]) [270] N278C ( t1=2 at room temperature is 45 min, compared to 12 min for wild-type enzyme. 15% of the wild-type phosphatase activity [270]) [270] Q262C ( t1=2 at room temperature is 11 min, compared to 12 min for wild-type enzyme. 111% of the wild-type phosphatase activity [270]) [270] Q283C ( t1=2 at room temperature is 13 min, compared to 12 min for wild-type enzyme. 91% of the wild-type phosphatase activity [270]) [270] R246C ( t1=2 at room temperature is 62 min, compared to 12 min for wild-type enzyme. 7% of the wild-type phosphatase activity [270]) [270] S242C ( t1=2 at room temperature is 39 min, compared to 12 min for wild-type enzyme. 20% of the wild-type phosphatase activity [270]) [270] S260C ( t1=2 at room temperature is 13 min, compared to 12 min for wild-type enzyme. 91% of the wild-type phosphatase activity [270]) [270] S269C ( t1=2 at room temperature is 20 min, compared to 12 min for wild-type enzyme. 54% of the wild-type phosphatase activity [270]) [270] T235C ( t1=2 at room temperature is 14 min, compared to 12 min for wild-type enzyme. 84% of the wild-type phosphatase activity [270]) [270] T247R ( inactive mutant protein [270]) [270] T250C ( t1=2 at room temperature is 23 min, compared to 12 min for wild-type enzyme. 45% of the wild-type phosphatase activity [270]) [270] T256C ( t1=2 at room temperature is 27 min, compared to 12 min for wild-type enzyme. 36% of the wild-type phosphatase activity [270]) [270] Y265C ( t1=2 at room temperature is 20 min, compared to 12 min for wild-type enzyme. 54% of the wild-type phosphatase activity [270]) [270]

453

Histidine kinase

2.7.13.3

Additional information ( cheA mutations leading to defects in chemotaxis are mapped and characterized [51]; the histidine phosphorylation sites of each TorS transmitter domain and the aspartate phosphorylation site of the TorS receiver are individually changed by sitedirected mutagenesis. All three phosphorylation sites proved essential for in vivo induction of the tor structural operon and for in vitro transphosphorylation of the cognate TorR response regulator. The His to Gln change in the classical transmitter domain abolished TorS autophosphorylation, whereas TorS undergoes significant autophosphorylation when the phosphorylation site of its receiver or alternative transmitter is changed [161]; construction of several phoR genes, with various deletions in the 5 regions, which are regulated by the trp-lac hybrid promoter. The PhoR1084 and PhoR1159 proteins that lack the 83 and 158 N-terminal amino acids, respectively, retain the positive function for the expression of phoA that codes for alkaline phosphatase, but lack the negative function. The PhoR1263 protein that lacks the 262 N-terminal amino acids is deficient in both functions [60]) [51, 60, 161]

References [1] Klein, C.; Entian, K.D.: Genes involved in self-protection against the lantibiotic subtilin produced by Bacillus subtilis ATCC 6633. Appl. Environ. Microbiol., 60, 2793-2801 (1994) [2] Roberts, D.L.; Bennett, D.W.; Forst, S.A.: Identification of the site of phosphorylation on the osmosensor, EnvZ, of Escherichia coli. J. Biol. Chem., 269, 8728-8733 (1994) [3] Pernestig, A.K.; Georgellis, D.; Romeo, T.; Suzuki, K.; Tomenius, H.; Normark, S.; Melefors, O.: The Escherichia coli BarA-UvrY two-component system is needed for efficient switching between glycolytic and gluconeogenic carbon sources. J. Bacteriol., 185, 843-853 (2003) [4] Paulsen, I.T.; Banerjei, L.; Myers, G.S.; et al.: Role of mobile DNA in the evolution of vancomycin-resistant Enterococcus faecalis. Science, 299, 2071-2074 (2003) [5] Kleerebezem, M.; Boekhorst, J.; van Kranenburg, R.; et al.: Complete genome sequence of Lactobacillus plantarum WCFS1. Proc. Natl. Acad. Sci. USA, 100, 1990-1995 (2003) [6] Deng, W.; Liou, S.R.; Plunkett, G.; Mayhew, G.F.; Rose, D.J.; Burland, V.; Kodoyianni, V.; Schwartz, D.C.; Blattner, F.R.: Comparative genomics of Salmonella enterica serovar typhi strains Ty2 and CT18. J. Bacteriol., 185, 2330-2337 (2003) [7] Bruggemann, H.; Baumer, S.; Fricke, W.F.; Wiezer, A.; Liesegang, H.; Decker, I.; Herzberg, C.; Martinez-Arias, R.; Merkl, R.; Henne, A.; Gottschalk, G.: The genome sequence of Clostridium tetani, the causative agent of tetanus disease. Proc. Natl. Acad. Sci. USA, 100, 1316-1321 (2003) [8] Nagasawa, S.; Tokishita, S.; Aiba, H.; Mizuno, T.: A novel sensor-regulator protein that belongs to the homologous family of signal-transduction pro-

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[9] [10]

[11]

[12]

[13]

[14] [15] [16] [17]

[18]

[19] [20]

Histidine kinase

teins involved in adaptive responses in Escherichia coli. Mol. Microbiol., 6, 799-807 (1992) Pernestig, A.K.; Melefors, O.; Georgellis, D.: Identification of UvrY as the cognate response regulator for the BarA sensor kinase in Escherichia coli. J. Biol. Chem., 276, 225-231 (2001) Suzuki, K.; Wang, X.; Weilbacher, T.; Pernestig, A.K.; Melefors, O.; Georgellis, D.; Babitzke, P.; Romeo, T.: Regulatory circuitry of the CsrA/CsrB and BarA/UvrY systems of Escherichia coli. J. Bacteriol., 184, 5130-5140 (2002) Welch, R.A.; Burland, V.; Plunkett, G. III; Redford, P.; Roesch, P.; Rasko, D.; Buckles, E.L.; Liou, S.-R.; Boutin, A.; Hackett, J.; Stroud, D.; Mayhew, G.F.; Rose, D.J.; Zhou, S.; Schwartz, D.C.; Perna, N.T.; Mobley, H.L.T.; Donnenberg, M.S.; Blattner, F.R.: Extensive mosaic structure revealed by the complete genome sequence of uropathogenic Escherichia coli. Proc. Natl. Acad. Sci. USA, 99, 17020-17024 (2002) Yamamoto, Y.; Aiba, H.; Baba, T.; Hayashi, K.; et al.: Construction of a contiguous 874-kb sequence of the Escherichia coli -K12 genome corresponding to 50.0-68.8 min on the linkage map and analysis of its sequence features. DNA Res., 4, 91-113 (1997) Pickard, D.; Li, J.; Roberts, M.; Maskell, D.; Hone, D.; Levine, M.; Dougan, G.; Chatfield, S.: Characterization of defined ompR mutants of Salmonella typhi: ompR is involved in the regulation of Vi polysaccharide expression. Infect. Immun., 62, 3984-3993 (1994) Evers, S.; Courvalin, P.: Regulation of VanB-type vancomycin resistance gene expression by the VanS(B)-VanR (B) two-component regulatory system in Enterococcus faecalis V583. J. Bacteriol., 178, 1302-1309 (1996) Diep, D.B.; Havarstein, L.S.; Nes, I.F.: A bacteriocin-like peptide induces bacteriocin synthesis in Lactobacillus plantarum C11. Mol. Microbiol., 18, 631-639 (1995) Diep, D.B.; Havarstein, L.S.; Nes, I.F.: Characterization of the locus responsible for the bacteriocin production in Lactobacillus plantarum C11. J. Bacteriol., 178, 4472-4483 (1996) Diep, D.B.; Havarstein, L.S.; Nissen-Meyer, J.; Nes, I.F.: The gene encoding plantaricin A, a bacteriocin from Lactobacillus plantarum C11, is located on the same transcription unit as an agr-like regulatory system. Appl. Environ. Microbiol., 60, 160-166 (1994) Virlogeux, I.; Waxin, H.; Ecobichon, C.; Lee, J.O.; Popoff, M.Y.: Characterization of the rcsA and rcsB genes from Salmonella typhi: rcsB through tviA is involved in regulation of Vi antigen synthesis. J. Bacteriol., 178, 1691-1698 (1996) Supply, P.; Magdalena, J.; Himpens, S.; Locht, C.: Identification of novel intergenic repetitive units in a mycobacterial two-component system operon. Mol. Microbiol., 26, 991-1003 (1997) Jones, A.L.; DeShazer, D.; Woods, D.E.: Identification and characterization of a two-component regulatory system involved in invasion of eukaryotic cells and heavy-metal resistance in Burkholderia pseudomallei. Infect. Immun., 65, 4972-4977 (1997)

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Histidine kinase

2.7.13.3

[246] Reichmann, P.; Hakenbeck, R.: Allelic variation in a peptide-inducible two-component system of Streptococcus pneumoniae. FEMS Microbiol. Lett., 190, 231-236 (2000) [247] Altier, C.; Suyemoto, M.; Ruiz, A.I.; Burnham, K.D.; Maurer, R.: Characterization of two novel regulatory genes affecting Salmonella invasion gene expression. Mol. Microbiol., 35, 635-646 (2000) [248] Parkhill, J.; Wren, B.W.; Mungall, K.; et al.: The genome sequence of the food-borne pathogen Campylobacter jejuni reveals hypervariable sequences. Nature, 403, 665-668 (2000) [249] Takami, H.; Takaki, Y.; Nakasone, K.; Sakiyama, T.; Maeno, G.; Sasaki, R.; Hirama, C.; Fuji, F.; Masui, N.: Genetic analysis of the chromosome of alkaliphilic Bacillus halodurans C-125. Extremophiles, 3, 227-233 (1999) [250] Nierman, W.C.; Feldblyum, T.V.; Laub, M.T.; et al.: Complete genome sequence of Caulobacter crescentus. Proc. Natl. Acad. Sci. USA, 98, 41364141 (2001) [251] Wu, J.; Ohta, N.; Zhao, J.L.; Newton, A.: A novel bacterial tyrosine kinase essential for cell division and differentiation. Proc. Natl. Acad. Sci. USA, 96, 13068-13073 (1999) [252] Davis, S.J.; Vener, A.V.; Vierstra, R.D.: Bacteriophytochromes: phytochrome-like photoreceptors from nonphotosynthetic eubacteria. Science, 286, 2517-2520 (1999) [253] White, O.; Eisen, J.A.; Heidelberg, J.F.; Hickey, E.K.; et al.: Genome sequence of the radioresistant bacterium Deinococcus radiodurans R1. Science, 286, 1571-1577 (1999) [254] Yamasaki, S.; Fujii, N.; Takahashi, H.: The ethylene-regulated expression of CS-ETR2 and CS-ERS genes in cucumber plants and their possible involvement with sex expression in flowers. Plant Cell Physiol., 41, 608-616 (2000) [255] Dervinis, C.; Clark, D.G.; Barrett, J.E.; Nell, T.A.: Effect of pollination and exogenous ethylene on accumulation of ETR1 homologue transcripts during flower petal abscission in geranium (Pelargonium x hortorum L.H. Bailey). Plant Mol. Biol., 42, 847-856 (2000) [256] Mita, S.; Kawamura, S.; Yamawaki, K.; Nakamura, K.; Hyodo, H.: Differential expression of genes involved in the biosynthesis and perception of ethylene during ripening of passion fruit (Passiflora edulis Sims). Plant Cell Physiol., 39, 1209-1217 (1998) [257] Perna, N.T.; Plunkett, G.; Burland, V.; Mau, B.; Glasner, J.D.; et al.: Genome sequence of enterohaemorrhagic Escherichia coli O157:H7. Nature, 409, 529-533 (2001) [258] Parkhill, J.; Dougan, G.; James, K.D.; Thomson, N.R.; Pickard, D.; Wain, J.; et al.: Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature, 413, 848-852 (2001) [259] McClelland, M.; Sanderson, K.E.; Spieth, J.; Clifton, S.W.; Latreille, P.; et al.: Complete genome sequence of Salmonella enterica serovar typhimurium LT2. Nature, 413, 852-856 (2001) [260] Hayashi, T.; Makino, K.; Ohnishi, M.; Kurokawa, K.; Ishii, K.; et al.: Complete genome sequence of enterohemorrhagic Escherichia coli O157:H7

472

2.7.13.3

[261] [262]

[263] [264] [265] [266] [267] [268] [269] [270] [271] [272] [273]

[274]

Histidine kinase

and genomic comparison with a laboratory strain K-12. DNA Res., 8, 1122 (2001) Blattner, F.R.; Plunkett, G.; Bloch, C.A.; Perna, N.T.; et al.: The complete genome sequence of Escherichia coli K-12. Science, 277, 1453-1474 (1997) Oshima, T.; Aiba, H.; Baba, T.; Fujita, K.; Hayashi, K.; Honjo, A.; et al..: A 718-kb DNA sequence of the Escherichia coli K-12 genome corresponding to the 12.7-28.0 min region on the linkage map. DNA Res., 3, 137-155 (1996) Itoh, T.; Aiba, H.; Baba, T.; Hayashi, K.; Inada, T.; Isono, K.; et al.: A 460-kb DNA sequence of the Escherichia coli K-12 genome corresponding to the 40.1-50.0 min region on the linkage map. DNA Res., 3, 379-392 (1996) Cole, S.T.; Brosch, R.; Parkhill, J.; Garnier, T.; et al.: Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature, 393, 537-544 (1998) Kaneko, T.; Nakamura, Y.; Wolk, C.P.; Kuritz, T.; et al.: Complete genomic sequence of the filamentous nitrogen-fixing cyanobacterium Anabaena sp. strain PCC 7120. DNA Res., 8; 205-213, 227-253 (2001) Bentley, S.D.; Chater, K.F.; Cerdeno-Tarraga, A.M.; et al.: Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature, 417, 141-147 (2002) Martinez-Canamero, M.; Ortiz-Codorniu, C.; Extremera, A.L.; MunozDorado, J.; Arias, J.M.: phoR1, a gene encoding a new histidine protein kinase in Myxococcus xanthus. Antonie Leeuwenhoek, 83, 361-368 (2003) Khorchid, A.; Inouye, M.; Ikura, M.: Structural characterization of Escherichia coli sensor histidine kinase EnvZ: the periplasmic C-terminal core domain is critical for homodimerization. Biochem. J., 385, 255-264 (2005) Motoyama, T.; Ohira, T.; Kadokura, K.; Ichiishi, A.; Fujimura, M.; Yamaguchi, I.; Kudo, T.: An Os-1 family histidine kinase from a filamentous fungus confers fungicide-sensitivity to yeast. Curr. Genet., 47, 298-306 (2005) Qin, L.; Cai, S.; Zhu, Y.; Inouye, M.: Cysteine-scanning analysis of the dimerization domain of EnvZ, an osmosensing histidine kinase. J. Bacteriol., 185, 3429-3435 (2003) Ohta, N.; Newton, A.: The core dimerization domains of histidine kinases contain recognition specificity for the cognate response regulator. J. Bacteriol., 185, 4424-4431 (2003) Brunsing, R.L.; La Clair, C.; Tang, S.; Chiang, C.; Hancock, L.E.; Perego, M.; Hoch, J.A.: Characterization of sporulation histidine kinases of Bacillus anthracis. J. Bacteriol., 187, 6972-6981 (2005) Gilmour, R.; Foster, J.E.; Sheng, Q.; McClain, J.R.; Riley, A.; Sun, P.-M.; Ng, W.-L.; Yan, D.; Nicas, T.I.; Henry, K.; Winkler, M.E.: New class of competitive inhibitor of bacterial histidine kinases. J. Bacteriol., 187, 8196-8200 (2005) Mutsuda, M.; Michel, K.P.; Zhang, X.; Montgomery, B.L.; Golden, S.S.: Biochemical properties of CikA, an unusual phytochrome-like histidine protein kinase that resets the circadian clock in Synechococcus elongatus PCC 7942. J. Biol. Chem., 278, 19102-19110 (2003)

473

Histidine kinase

2.7.13.3

[275] Paithoonrangsarid, K.; Shoumskaya, M.A.; Kanesaki, Y.; Satoh, S.; Tabata, S.; Los, D.A.; Zinchenko, V.V.; Hayashi, H.; Tanticharoen, M.; Suzuki, I.; Murata, N.: Five histidine kinases perceive osmotic stress and regulate distinct sets of genes in Synechocystis. J. Biol. Chem., 279, 53078-53086 (2004) [276] Cai, S.J.; Khorchid, A.; Ikura, M.; Inouye, M.: Probing catalytically essential domain orientation in histidine kinase EnvZ by targeted disulfide crosslinking. J. Mol. Biol., 328, 409-418 (2003) [277] Vakonakis, I.; Klewer, D.A.; Williams, S.B.; Golden, S.S.; LiWang, A.C.: Structure of the N-terminal domain of the circadian clock-associated histidine kinase SasA. J. Mol. Biol., 342, 9-17 (2004) [278] Ning, D.; Xu, X.: alrO117, a two-component histidine kinase gene, is involved in heterocyst development in Anabaena sp. PCC 7120. Microbiology, 150, 447-453 (2004) [279] Kamps, A.; Achebach, S.; Fedtke, I.; Unden, G.; Goetz, F.: Staphylococcal NreB: An O2 -sensing histidine protein kinase with an O2 -labile iron-sulphur cluster of the FNR type. Mol. Microbiol., 52, 713-723 (2004) [280] Rasmussen, A.A.; Porter, S.L.; Armitage, J.P.; Sogaard-Andersen, L.: Coupling of multicellular morphogenesis and cellular differentiation by an unusual hybrid histidine protein kinase in Myxococcus xanthus. Mol. Microbiol., 56, 1358-1372 (2005) [281] Zhang, Z.G.; Zhou, H.L.; Chen, T.; Gong, Y.; Cao, W.H.; Wang, Y.J.; Zhang, J.S.; Chen, S.Y.: Evidence for serine/threonine and histidine kinase activity in the tobacco ethylene receptor protein NTHK2. Plant Physiol., 136, 29712981 (2004) [282] Suzuki, I.; Kanesaki, Y.; Hayashi, H.; Hall, J.J.; Simon, W.J.; Slabas, A.R.; Murata, N.: The histidine kinase Hik34 is involved in thermotolerance by regulating the expression of heat shock genes in Synechocystis. Plant Physiol., 138, 1409-1421 (2005) [283] Karniol, B.; Vierstra, R.D.: The pair of bacteriophytochromes from Agrobacterium tumefaciens are histidine kinases with opposing photobiological properties. Proc. Natl. Acad. Sci. USA, 100, 2807-2812 (2003) [284] Wang, W.; Hall, A.E.; O’Malley, R.; Bleecker, A.B.: Canonical histidine kinase activity of the transmitter domain of the ETR1 ethylene receptor from Arabidopsis is not required for signal transmission. Proc. Natl. Acad. Sci. USA, 100, 352-357 (2003) [285] Marin, K.; Suzuki, I.; Yamaguchi, K.; Ribbeck, K.; Yamamoto, H.; Kanesaki, Y.; Hagemann, M.; Murata, N.: Identification of histidine kinases that act as sensors in the perception of salt stress in Synechocystis sp. PCC 6803. Proc. Natl. Acad. Sci. USA, 100, 9061-9066 (2003) [286] Boyd, J.M.: Localization of the histidine kinase PilS to the poles of Pseudomonas aeruginosa and identification of a localization domain. Mol. Microbiol., 36, 153-162 (2000)

474

Triphosphate-protein phosphotransferase

2.7.99.1

1 Nomenclature EC number 2.7.99.1 Systematic name triphosphate:[microsomal-membrane-protein] phosphotransferase Recommended name triphosphate-protein phosphotransferase Synonyms phosphotransferase, pyrophosphate-protein pyrophosphate-protein phosphotransferase pyrophosphate:protein phosphotransferase CAS registry number 74092-32-3

2 Source Organism Rattus norvegicus (no sequence specified) [1, 2]

3 Reaction and Specificity Catalyzed reaction triphosphate + [microsomal-membrane protein] = diphosphate + phospho[microsomal-membrane protein] Reaction type phospho group transfer Natural substrates and products S diphosphate + microsomal polypeptides (Reversibility: ?) [1] P phosphate + phosphorylated microsomal polypeptides S triphosphate + [microsomal membrane protein] ( reversible phosphorylation in the second phase of membrane protein phosphorylation, competes with ATP-dependent phosphorylation reaction which occurs in the first phase [2]) (Reversibility: ?) [2] P diphosphate + phosphorylated [microsomal membrane protein]

475

Triphosphate-protein phosphotransferase

2.7.99.1

Substrates and products S diphosphate + microsomal polypeptides ( intrinsic membrane polypeptides of rat liver with molecular weights of 145000 Da and 130000 Da [1]) (Reversibility: ?) [1] P phosphate + phosphorylated microsomal polypeptides [1] S tetraphosphate + [microsomal membrane protein] ( reversible phosphorylation, substrates are 145 kD and 130 kD microsomal membrane proteins, higher activity compared to triphosphate as phosphate donor [2]) (Reversibility: ?) [2] P triphosphate + phosphorylated [microsomal membrane protein] S triphosphate + [microsomal membrane protein] ( reversible phosphorylation in the second phase of membrane protein phosphorylation, competes with ATP-dependent phosphorylation reaction which occurs in the first phase [2]; reversible phosphorylation, substrates are 145 kD and 130 kD microsomal membrane proteins [2]) (Reversibility: ?) [2] P diphosphate + phosphorylated [microsomal membrane protein] Inhibitors 5’-adenylimidodiphosphate ( i.e. AMP-PNP, ATP analogue [2]) [2] ADP [2] ATP ( 0.025 mM, weak [1]) [1, 2] Mg2+ ( 1 mM, strong [1]) [1] NaF ( 5 mM, strong [1]) [1] adenosine 5’-(b,g-imino)triphosphate ( i.e. AMP-PNP, ATP analogue [2]) [2] adenosine 5’-(b,g-methylene)triphosphate ( i.e. AMP-PCP or AMPCPP, ATP analogue [2]) [2] adenosine 5’-methylene diphosphate ( i.e. AMP-CP, ATP analogue [2]) [2] Metals, ions Mg2+ ( micromolar levels required [1]) [1] pH-Optimum 6.5-7.5 [1]

5 Isolation/Preparation/Mutation/Application Source/tissue liver [1, 2] Localization membrane [2] microsome ( membrane-bound [1]) [1, 2]

476

2.7.99.1

Triphosphate-protein phosphotransferase

Purification (from liver microsomal membranes by DEAE ion exchange chromatography and gel filtration) [2] (partial) [1]

References [1] Lam, K.S.; Kasper, C.B.: Pyrophosphate:protein phosphotransferase: a membrane-bound enzyme of endoplasmic reticulum. Proc. Natl. Acad. Sci. USA, 77, 1927-1931 (1980) [2] Tsutsui, K.: Tripolyphosphate is an alternative phosphodonor of the selective protein phosphorylation of liver microsomal membrane. J. Biol. Chem., 261, 2645-2653 (1986)

477

Lipoyl synthase

2.8.1.8

1 Nomenclature EC number 2.8.1.8 Systematic name protein N6 -(octanoyl)lysine:sulfur sulfurtransferase Recommended name lipoyl synthase Synonyms LS [8] LipA [3, 6, 8, 10] LipA protein [5] CAS registry number 189398-80-9

2 Source Organism Escherichia coli (no sequence specified) ( ERK2 [5]) [2, 3, 4, 5, 7, 8, 9, 10] Neurospora crassa (no sequence specified) [9] Pisum sativum (no sequence specified) [9] Sulfolobus solfataricus (no sequence specified) [1, 11] Toxoplasma gondii (UNIPROT accession number: Q86650) [6]

3 Reaction and Specificity Catalyzed reaction protein N6 -(octanoyl)lysine + 2 sulfur + 2 S-adenosyl-l-methionine = protein N6 -(lipoyl)lysine + 2 l-methionine + 2 5’-deoxyadenosine ( mechanism: sulfur is first inserted at C6 of octanoyl substrate to form an enzyme bound intermediate. In a subsequent rate determining step, the second sulfur atom is inserted at C8, suggesting an energy profile of the reaction reflecting the relative bond strengths of the primary and secondary C-H bonds to be cleaved at C8 and C6, resp. [11])

478

2.8.1.8

lipoyl synthase

Natural substrates and products S Additional information ( final step in de novo biosynthesis of lipoyl cofactor. The lipoyl cofactor is essential for the function of pyruvate dehydrogenase (E2 domain) [9]) (Reversibility: ?) [9] P ? Substrates and products S protein N6 -(octanoyl)lysine + sulfur + S-adenosyl-l-methionine ( both sulfur atoms in lipoic acid are contributed by the same lipoyl synthase polypeptide [7]) (Reversibility: ?) [7] P protein N6 -(lipoyl)lysine + 2 l-methionine + 2 5’-deoxyadenosyl radicals S protein N6 -(octanoyl)lysine + sulfur + S-adenosyl-l-methionine ( lipoyl-bearing subunit of the glycine cleavage system (H-protein) is a substrate for LipA. 5-deoxyadenosyl radical acts directly on the octanoyl substrate. 2 equivalents of S-adenosyl-l-methionine are cleaved irreversibly in forming 1 equivalent of [lipoyl]H-protein and are consistent with a model in which two LipA proteins are required to synthesize one lipoyl group [3]; tetrapeptide substrate, containing an Ne -octanoyl lysine residue, corresponding in sequence to the lipoyl binding domain of the E2 subunit of pyruvate dehydrogenase [1]) (Reversibility: ir) [1, 3] P protein N6 -(lipoyl)lysine + l-methionine + 5’-deoxyadenosyl radicals S protein N6 -(octanoyl)lysine + sulfur + S-adenosyl-l-methionine ( octanoylated pyruvate dehydrogenase E2 domain [4]) (Reversibility: ?) [4] P protein N6 -(lipoyl)lysine + 2 l-methionine + 5’-deoxyadenosyl radical S Additional information ( final step in de novo biosynthesis of lipoyl cofactor. The lipoyl cofactor is essential for the function of pyruvate dehydrogenase (E2 domain) [9]; insertion of sulfur into octanoyl groups is first at C6 to form an enzyme bound intermediate, and in a subsequent step a second sulfur is inserted at C8 [11]) (Reversibility: ?) [9, 11] P ? Metals, ions iron ( iron-sulfur protein. Presence of [3Fe-4S] and/or [4Fe4S]clusters in both monomeric and dimeric LipA [2]; presence of a (2Fe-2S) center per protein. These clusters are converted to (4Fe-4S) centers during reduction under anaerobic conditions [5]; [Fe-S] protein [6]) [2, 5, 6] Temperature optimum ( C) 60 [1]

4 Enzyme Structure Molecular weight 43300 ( monomer, gel filtration [2]) [2] 84600 ( dimer, gel filtration [2]) [2]

479

lipoyl synthase

2.8.1.8

Subunits ? ( x * 36000, SDS-PAGE [8]) [8] Additional information ( enzyme is isolated as a micture of 70% monomer and 30% dimer [2]) [2]

5 Isolation/Preparation/Mutation/Application Localization apicoplast [6] inclusion body [5] mitochondrion [9] Purification [3, 5] (C-terminally His-tagged protein) [10] (wild-type and hexahistidine-tagged LipA) [2] (recombinant) [1] Cloning [2, 3, 8] (coexpression of lipA with groESL, trxA, or fragments of the isc operon such as iscSUA orhscBAfdx does not improve expression levels of soluble holo-LipA. Coexpression of lipA with iscSUA and hscBAfdx on a multi-cistronic plasmid does improve the expression of soluble LipAH and increases the molar ratios of iron and sulfide per LipAH) [10] (expression in Escherichia coli) [1] [6]

References [1] Bryant, P.; Kriek, M.; Wood, R.J.; Roach, P.L.: The activity of a thermostable lipoyl synthase from Sulfolobus solfataricus with a synthetic octanoyl substrate. Anal. Biochem., 351, 44-49 (2006) [2] Miller, J.R.; Busby, R.W.; Jordan, S.W.; Cheek, J.; Henshaw, T.F.; Ashley, G.W.; Broderick, J.B.; Cronan, J.E., Jr.; Marletta, M.A.: Escherichia coli LipA is a lipoyl synthase: in vitro biosynthesis of lipoylated pyruvate dehydrogenase complex from octanoyl-acyl carrier protein. Biochemistry, 39, 15166-15178 (2000) [3] Cicchillo, R.M.; Iwig, D.F.; Jones, A.D.; Nesbitt, N.M.; Baleanu-Gogonea, C.; Souder, M.G.; Tu, L.; Booker, S.J.: Lipoyl synthase requires two equivalents of S-adenosyl-l-methionine to synthesize one equivalent of lipoic acid. Biochemistry, 43, 6378-6386 (2004) [4] Zhao, X.; Miller, J.R.; Jiang, Y.; Marletta, M.A.; Cronan, J.E.: Assembly of the covalent linkage between lipoic acid and its cognate enzymes. Chem. Biol., 10, 1293-1302 (2003)

480

2.8.1.8

lipoyl synthase

[5] Ollagnier-de Choudens, S.; Fontecave, M.: The lipoate synthase from Escherichia coli is an iron-sulfur protein. FEBS Lett., 453, 25-28 (1999) [6] Thomsen-Zieger, N.; Schachtner, J.; Seeber, F.: Apicomplexan parasites contain a single lipoic acid synthase located in the plastid. FEBS Lett., 547, 8086 (2003) [7] Cicchillo, R.M.; Booker, S.J.: Mechanistic investigations of lipoic acid biosynthesis in Escherichia coli: both sulfur atoms in lipoic acid are contributed by the same lipoyl synthase polypeptide. J. Am. Chem. Soc., 127, 28602861 (2005) [8] vanden Boom, T.J.; Reed, K.E.; Cronan, J.E.: Lipoic acid metabolism in Escherichia coli: isolation of null mutants defective in lipoic acid biosynthesis, molecular cloning and characterization of the E. coli lip locus, and identification of the lipoylated protein of the glycine cleavage system. J. Bacteriol., 173, 6411-6420 (1991) [9] Jordan, S.W.; Cronan, J.E.: A new metabolic link. The acyl carrier protein of lipid synthesis donates lipoic acid to the pyruvate dehydrogenase complex in Escherichia coli. J. Biol. Chem., 272, 17903-17906 (1997) [10] Kriek, M.; Peters, L.; Takahashi, Y.; Roach, P.L.: Effect of iron-sulfur cluster assembly proteins on the expression of Escherichia coli lipoic acid synthase. Protein Expr. Purif., 28, 241-245 (2003) [11] Douglas, P.; Kriek, M.; Bryant, P.; Roach, P.L.: Lipoyl synthase inserts sulfur atoms into an octanoyl substrate in a stepwise manner. Angew. Chem., 45, 5197-5199 (2006)

481

Petromyzonol sulfotransferase

2.8.2.31

1 Nomenclature EC number 2.8.2.31 Systematic name 3’-phosphoadenylyl-sulfate:5a-cholan-3a,7a,12a,24-tetrol sulfotransferase Recommended name petromyzonol sulfotransferase Synonyms PZ-SULT [1] CAS registry number 9032-76-2

2 Source Organism Petromyzon marinus (no sequence specified) [1]

3 Reaction and Specificity Catalyzed reaction 3’-phosphoadenylyl sulfate + 5a-cholan-3a,7a,12a,24-tetrol = adenosine 3’,5’-bisphosphate + 5a-cholan-3a,7a,12a-triol 24-sulfate Substrates and products S 3’-phosphoadenylyl sulfate + 5a-cholan-3a,7a,12a, 24-tetrol (Reversibility: ?) [1] P adenosine 3’,5’-bisphosphate + 5a-cholan-3a,7a,12a-triol 24-sulfate S 3’-phosphoadenylyl sulfate + 7a,12a,24-trihydroxy-5a-cholan-3-one (Reversibility: ?) [1] P adenosine 3’,5’-bisphosphate + 7a,12a-dihydroxy-5a-cholan-3-one 24sulfate Specific activity (U/mg) 2e-006 [1] Km-Value (mM) 0.0025 (3’-phosphoadenosine 5’-phosphosulfate, 22 C, pH 8.0 [1]) [1]

482

2.8.2.31

Petromyzonol sulfotransferase

pH-Optimum 8 [1] pH-Range 5.5-11 ( approx. 25% of maximal activity at pH 6.0 and pH 11.0, respectively [1]) [1] Temperature optimum ( C) 22 [1] Temperature range ( C) 5-60 ( approx. 60% of maximal activity at 10 C, approx. 10% of maximal activity at 40 C [1]) [1]

4 Enzyme Structure Subunits ? ( x * 47000, SDS-PAGE [1]) [1]

5 Isolation/Preparation/Mutation/Application Source/tissue liver ( larval liver [1]) [1] Purification (DEAE column, gel filtration, 3’-phosphoadenosine 5’-phosphate affinity chromatography) [1]

References [1] Venkatachalam, K.V.; Llanos, D.E.; Karami, K.J.; Malinovskii, V.A.: Isolation, partial purification, and characterization of a novel petromyzonol sulfotransferase from Petromyzon marinus (lamprey) larval liver. J. Lipid Res., 45, 486-495 (2004)

483

Scymnol sulfotransferase

2.8.2.32

1 Nomenclature EC number 2.8.2.32 Systematic name 3’-phosphoadenosine 5’-phosphosulfate:5b-scymnol sulfotransferase Recommended name scymnol sulfotransferase CAS registry number 220591-70-4 9032-76-2

2 Source Organism Heterodontus portusjacksoni (no sequence specified) [1, 2, 4] Trygonorrhina fasciata (no sequence specified) [3] Trygonoptera sp. (no sequence specified) [3]

3 Reaction and Specificity Catalyzed reaction 3’-phosphoadenosine 5’-phosphosulfate + 5b-scymnol = adenosine 3’,5’-bisphosphate + 5b-scymnol sulfate Natural substrates and products S 3’-phosphoadenosine 5’-phosphosulfate + (24R)-3a,7a,12a,24,26-pentahydroxy-5b-cholestane-27-ol ( trivial name 5b-scymnol [2, 3]) (Reversibility: ?) [2, 3] P adenosine 3’,5’-diphosphate + (24R)-3a,7a,12a,24,26-pentahydroxy-5bcholestane-27-sulfate ( trivial name 5b-scymnol sulfate [2,3]) S 3’-phosphoadenosine 5’-phosphosulfate + 5b-scymnol (Reversibility: ?) [1, 4] P adenosine 3’,5’-diphosphate + 5b-scymnol sulfate Substrates and products S 3’-phosphoadenosine 5’-phosphosulfate + (24R)-3a,7a,12a,24,26-pentahydroxy-5-b-cholestane-27-yl ( trivial name 5b-scymnol [3]) (Reversibility: ?) [3]

484

2.8.2.32

Scymnol sulfotransferase

P adenosine 3’,5’-diphosphate + (24R)-3a,7a,12a,24,26-pentahydroxy-5bcholestane-27-yl sulfate ( trivial name 5b-scymnol sulfate [3]) S 3’-phosphoadenosine 5’-phosphosulfate + (24R)-3a,7a,12a,24,26-pentahydroxy-5b-cholestane-27-ol ( trivial name 5b-scymnol [1, 2, 3]) (Reversibility: ?) [1, 2, 3] P adenosine 3’,5’-diphosphate + (24R)-3a,7a,12a,24,26-pentahydroxy-5bcholestane-27-sulfate ( trivial name 5b-scymnol sulfate [1,2,3]; trivial name bb-scymnol sulfate [1]; trivial name b-scymnol sulfate [3]) S 3’-phosphoadenosine 5’-phosphosulfate + 5a-cyprinol ( 150% of activity with 5b-scymnol [1]; 174% of activity with 5bscymnol [3]; 250% of activity with 5b-scymnol [3]; 62% of activity with 5b-scymnol [1]) (Reversibility: ?) [1, 2, 3] P adenosine 3’,5’-diphosphate + 5a-cyprinol sulfate S 3’-phosphoadenosine 5’-phosphosulfate + 5b-scymnol ( sulfation occurs at either the C-26 or C-27 position [4]) (Reversibility: ?) [1, 4] P adenosine 3’,5’-diphosphate + 5b-scymnol sulfate S 3’-phosphoadenosine 5’-phosphosulfate + testosterone (Reversibility: ?) [2] P adenosine 3’,5’-diphosphate + testosterone sulfate Inhibitors adenosine 3’,5’-diphosphate ( competitive inhibition [2]; 0.1 mM, 97% inhibition [1]) [1, 2] EDTA ( 50 mM, 89% inhibition [2]) [2] iodoacetate ( 0.1 mM, 99% inhibition [4]) [4] iodoacetic acid ( 0.1 mM, 40% inhibition [3]; 0.1 mM, 93% inhibition [1]; 0.1 mM, 16% inhibition [3]; 0.1 mM, 29% inhibition [2]) [1, 2, 3] NaN3 ( 0.1 mM, 65% inhibition [4]; 0.1 mM, 39% inhibition [2]; 0.1 mM, 24% inhibition [3]; 0.1 mM, 21% inhibition [1]) [1, 2, 3, 4] adenosine-3’,5’-diphosphate ( 0.1 mM, 98% inhibition [4]; 0.1 mM, 95% inhibition [3]; 0.1 mM, 96% inhibition [3]) [3, 4] p-chloromercuribenzoate ( 0.1 mM, 38% inhibition [2]; 0.1 mM, 67% inhibition [4]) [2, 4] Metals, ions Mg2+ ( 0.5 mM, 20% activation [1]; 0.5 mM, 35% activation [3]; 0.5 mM, 63% activation [1]) [1, 3] Specific activity (U/mg) 0.00000002 [2] 0.0000000275 [4] 0.0000000439 [1] 0.0000026 [3] 0.0000035 [3]

485

Scymnol sulfotransferase

2.8.2.32

Km-Value (mM) 0.003 ((24R)-3a,7a,12a,24,26-pentahydroxy-5b-cholestane-27-ol, room temperature, pH 6.5 [2]) [2] 0.0038 ((24R)-3a,7a,12a,24,26-pentahydroxy-5b-cholestane-27-ol, 25 C [1]) [1] 0.004 (3’-phosphoadenosine-5’-phosphosulfate, pH 6.5 [4]) [4] 0.0044 (3’-phosphoadenosine 5’-phosphosulfate, room temperature, pH 6.5 [2]) [2] 0.0059 ((24R)-3a,7a,12a,24,26-pentahydroxy-5b-cholestane-27-ol) [3] 0.013 ((24R)-3a,7a,12a,24,26-pentahydroxy-5b-cholestane-27-ol, 25 C [1]) [1] 0.014 (5b-scymnol, pH 6.5 [4]) [4] 0.018 ((24R)-3a,7a,12a,24,26-pentahydroxy-5-b-cholestane-27-ol) [3] Ki-Value (mM) 0.00037 (adenosine 3’,5’-diphosphate, vs. 3-phosphoadenosine 5phosphosulfate [2]) [2] 0.00054 (adenosine 3’,5’-diphosphate) [1] 0.00084 (adenosine 3’,5’-diphosphate, vs. 5b-scymnol [2]) [2] 0.00098 (adenosine-3’,5’-diphosphate) [3] 0.019 (adenosine-3’,5’-diphosphate) [3] pH-Optimum 6.5 [3] pH-Range 4-7 [1] 5-7 [3] 5.5-7 [1] 5.5-7.5 [3] Temperature optimum ( C) 30 [3] 37 [2] Temperature range ( C) 15-37 [1] 20-45 [1, 2] 22-37 [3] 25-45 [3]

4 Enzyme Structure Molecular weight 40000 ( gel filtration [4]; native PAGE, probably two isoenzymes [4]) [4] 45000 ( native PAGE, probably two isoenzymes [4]) [4]

486

2.8.2.32

Scymnol sulfotransferase

66000 ( gel filtration [3]) [3] 69000 ( gel filtration [3]) [3] 80000 ( gel filtration [1]) [1] Subunits monomer ( 1 * 40000, SDS-PAGE, probably two isoenzymes [4]; 1 * 45000, SDS-PAGE, probably two isoenzymes [4]) [4]

5 Isolation/Preparation/Mutation/Application Source/tissue kidney [1, 3] liver [2, 3, 4] testis [1] Localization cytosol [1, 2, 3, 4] Purification (hydroxyapatite, DEAE-Sephacel, Sephadex G-100, partially purified) [2] (hydroxylapatite, Sephadex G-100) [4] (hydroxylapatite, Sephadex G-100, partially purified) [1] (hydroxylapatite, DEAE-Sephacel) [3] (Sephadex G-100, hydroxylapatite) [3]

6 Stability General stability information , freeze-thawing reduces activity, enzyme has very low stability at 4 C especially during concentration procedures [2] , inactivated by repeated thawing and freezing [1] Storage stability , -80 C, at least 12 months, no loss of activity [2] , -80 C, no loss of activity [1]

References [1] Pettigrew, N.E.; Wright, P.F.A.; Macrides, T.A.: Investigation of 5b-scymnol sulfotransferases from the kidney and testis of Heterodontus portusjacksoni. Comp. Biochem. Physiol. B, 121B, 243-249 (1998) [2] Pettigrew, N.E.; Wright, P.F.A.; Macrides, T.A.: 5b-Scymnol sulfotransferase isolated from the tissues of an Australian shark species. Comp. Biochem. Physiol. B, 121B, 299-307 (1998)

487

Scymnol sulfotransferase

2.8.2.32

[3] Pettigrew, N.E.; Wright, P.F.A.; Macrides, T.A.: 5b-Scymnol sulfotransferases from the liver of two Australian ray species. Comp. Biochem. Physiol. B, 121B, 341-348 (1998) [4] Macrides, T.A.; Faktor, D.A.; Kalafatis, N.; Amiet, R.G.: Enzymic sulfation of bile salts. Partial purification and characterization of an enzyme from the liver of the shark Heterodontus portusjacksoni that catalyses the sulfation of the shark bile steroid 5 b-scymnol. Comp. Biochem. Physiol. B Biochem. Mol. Biol., 107, 461-469 (1994)

488

N-Acetylgalactosamine 4-sulfate 6-O-sulfotransferase

2.8.2.33

1 Nomenclature EC number 2.8.2.33 Systematic name 3’-phosphoadenylyl-sulfate:dermatan 6’-sulfotransferase Recommended name N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase Synonyms GalNAc4S-6ST [5, 7, 8, 9]

2 Source Organism



Mus musculus (no sequence specified) [9] Homo sapiens (no sequence specified) [2, 3, 6, 7] squid (no sequence specified) [4] Homo sapiens (UNIPROT accession number: Q7LFX5) [5] Ommastrephes sloani pacificus (no sequence specified) [1,8]

3 Reaction and Specificity Catalyzed reaction 3’-phosphoadenylyl sulfate + chondroitin = adenosine 3’,5’-bisphosphate + chondroitin 6’-sulfate 3’-phosphoadenylyl sulfate + dermatan = adenosine 3’,5’-bisphosphate + dermatan 6’-sulfate Natural substrates and products S 3’-phosphoadenylyl sulfate + chondroitin ( synthesis of chondroitin sulfate E [7]) (Reversibility: ?) [7] P adenosine 3’,5’-bisphosphate + chondroitin 6’-sulfate S 3’-phosphoadenylyl sulfate + chondroitin A ( synthesis of chondroitin sulfate E [8]; the enzyme helps build up the GlcAb13GalNAc(4,6-bisSO4 ) unit of chondroitin sulfate E [9]) (Reversibility: ?) [8, 9] P adenosine 3’,5’-bisphosphate + chondroitin 6’-sulfate E

489

N-Acetylgalactosamine 4-sulfate 6-O-sulfotransferase

2.8.2.33

S Additional information ( the enzyme is responsible for biosynthesis of chondroitin sulfate E, CS-E plays important roles in numerous biological events, such as neurite outgrowth, overview, in colorectal cancer cells, the enzyme plays a minor role in tumor progression [7]) (Reversibility: ?) [7] P ? Substrates and products S 3’-phosphoadenylyl sulfate + 4-sulfated pentasaccharide ( best substrate, sulfation only with nonreducing terminal GalNAc(4-SO4 ) residues [4,5]) (Reversibility: ?) [4, 5] P adenosine 3’,5’-bisphosphate + 4,6’-sulfated pentasaccharide S 3’-phosphoadenylyl sulfate + 4-sulfated trisaccharide ( 95.2% of activity compared with 4-sulfated pentasaccharide [4,5]) (Reversibility: ?) [4, 5] P adenosine 3’,5’-bisphosphate + 4,6’-sulfated trisaccharide S 3’-phosphoadenylyl sulfate + GalNAc(4SO4 )-d-glucuronic acidGalNAc(4SO4 ) (Reversibility: ?) [6] P adenosine 3’,5’-bisphosphate + GalNAc(4,6SO4 )-d-glucuronic acidGalNAc(4SO4 ) S 3’-phosphoadenylyl sulfate + GalNAc(4SO4 )-d-glucuronic acidGalNAc(6SO4 ) (Reversibility: ?) [6] P adenosine 3’,5’-bisphosphate + GalNAc(4,6SO4 )-d-glucuronic acidGalNAc(6SO4 ) S 3’-phosphoadenylyl sulfate + GalNAc(4SO4 )-Glc(2SO4 )-GalNAc(6SO4 ) ( acceptor is a derivative of chondroitin sulfate A [6]) (Reversibility: ?) [6] P adenosine 3’,5’-bisphosphate + GalNAc(4,6SO4 )-Glc(2SO4 )-GalNAc(6SO4 ) S 3’-phosphoadenylyl sulfate + UDP-GalNAc 4-sulfate (Reversibility: ?) [3] P adenosine 3’,5’-bisphosphate + UDP-GalNAc-4,6-disulfate S 3’-phosphoadenylyl sulfate + chondroitin ( synthesis of chondroitin sulfate E [7]) (Reversibility: ?) [7] P adenosine 3’,5’-bisphosphate + chondroitin 6’-sulfate S 3’-phosphoadenylyl sulfate + chondroitin ( 2.5% of activity compared with 4-sulfated pentasaccharide [5]) (Reversibility: ?) [5] P adenosine 3’,5’-bisphosphate + chondroitin 6’-sulfate S 3’-phosphoadenylyl sulfate + chondroitin 4-sulfate (Reversibility: ?) [3] P adenosine 3’,5’-bisphosphate + chondroitin 4,6’-disulfate ( major terminal sulfotransferase activity plus a minor interior sulfotransferase activity [3]) S 3’-phosphoadenylyl sulfate + chondroitin A ( synthesis of chondroitin sulfate E [7,8,9]; the enzyme helps build up the GlcAb1-3GalNAc(4,6-bisSO4 ) unit of chondroitin sulfate E [9]) (Reversibility: ?) [7, 8, 9] P adenosine 3’,5’-bisphosphate + chondroitin 6’-sulfate E

490

2.8.2.33

N-Acetylgalactosamine 4-sulfate 6-O-sulfotransferase

S 3’-phosphoadenylyl sulfate + chondroitin C ( synthesis of a unique chondroitin sulfate containing E-D hybrid tetrasaccharide structure by the recombinant enzyme [8]) (Reversibility: ?) [8] P adenosine 3’,5’-bisphosphate + chondroitin 6’-sulfate ED S 3’-phosphoadenylyl sulfate + chondroitin sulfate A ( 33.7% of activity compared with 4-sulfated pentasaccharide [5]) (Reversibility: ?) [1, 4, 5, 6] P adenosine 3’,5’-bisphosphate + chondroitin sulfate A 6’-sulfate ( about half of GalNAc(4SO4 ) residues are converted to GalNAc(4,6SO4 ) residues [1]) S 3’-phosphoadenylyl sulfate + chondroitin sulfate C ( 0.5% of activity compared with 4-sulfated pentasaccharide [5]) (Reversibility: ?) [4, 5] P adenosine 3’,5’-bisphosphate + chondroitin sulfate C 6’-sulfate S 3’-phosphoadenylyl sulfate + chondroitin sulfate E ( 0.5% of activity compared with 4-sulfated pentasaccharide [5]) (Reversibility: ?) [5] P adenosine 3’,5’-bisphosphate + chondroitin sulfate E 6’-sulfate S 3’-phosphoadenylyl sulfate + dermatan sulfate ( source pig skin [3]) (Reversibility: ?) [3] P adenosine 3’,5’-bisphosphate + dermatan sulfate 6’-sulfate S 3’-phosphoadenylyl sulfate + dermatan sulfate ( 4.9% of activity compared with 4-sulfated pentasaccharide [5]) (Reversibility: ?) [1, 4, 5] P adenosine 3’,5’-bisphosphate + 6’-sulfated dermatan sulfate S 3’-phosphoadenylyl sulfate + glucuronic acid-GalNAc(SO4 )-glucuronic acid-GalNAc(SO4 ) (Reversibility: ?) [3] P adenosine 3’,5’-bisphosphate + ? S 3’-phosphoadenylyl sulfate + keratan ( 0.3% of activity compared with 4-sulfated pentasaccharide [5]) (Reversibility: ?) [5] P adenosine 3’,5’-bisphosphate + keratan 6’-sulfate S 3’-phosphoadenylyl sulfate + phenyl 2-acetamido-2-deoxy-b-d-galactopyranoside 4-O-sulfate (Reversibility: ?) [2] P adenosine 3’,5’-bisphosphate + phenyl 2-acetamido-2-deoxy-b-d-galactopyranoside 4,6-O-disulfate S Additional information ( sulfatation occurs mainly at position 6 of the internal N-acetylgalactosamine 4-sulfate residue [4]; the enzyme is responsible for biosynthesis of chondroitin sulfate E, CS-E plays important roles in numerous biological events, such as neurite outgrowth, overview, in colorectal cancer cells, the enzyme plays a minor role in tumor progression [7]; the enzyme binds with strong affinity to Midkine, heparin-binding growth factor which plays important regulatory roles in differentiation and morphogenesis during mouse embryonic development [9]) (Reversibility: ?) [4, 7, 9] P ?

491

N-Acetylgalactosamine 4-sulfate 6-O-sulfotransferase

2.8.2.33

Inhibitors phenyl 2-acetamido-2-deoxy-b-d-galactopyranoside 4-O-sulfate ( competitive, 5 mM, 24% residual activity [2]) [2] Activating compounds Ba2+ ( 2.5 to 3.5fold activation [4]) [4] Ca2+ ( 2.5 to 3.5fold activation [4]) [4] CaCl2 ( 5 mM, 2.5 fold stimulation of interior sulfotransferase activity, 1.9 fold stimulation of terminal sulfotransferase activity [3]) [3] Co2+ ( 2.5 to 3.5fold activation [4]) [4] KCl ( 2fold activation [4]) [4] Mg2+ ( 2.5 to 3.5fold activation [4]) [4] Mn2+ ( 2.5 to 3.5fold activation [4]) [4] NaCl ( 2fold activation [4]) [4] protamine ( 2fold activation [4]) [4] Sr2+ ( 2.5 to 3.5fold activation [4]) [4] Metals, ions Ca2+ [8] Specific activity (U/mg) 0.0022 ( substrate UDP-GalNAc 4-sulfate, pH 5.2 [3]) [3] Km-Value (mM) 0.0005 (3’-phosphoadenylyl sulfate, pH 6.8, 25 C [4]) [4] 0.0011 (chondroitin sulfate A, pH 6.8, 25 C [4]) [4] 0.0013 (dermatan sulfate, pH 6.8, 25 C [4]) [4] 0.0038 (UDP-GalNAc 4-sulfate, pH 5.2 [3]) [3] 0.013 (GalNAc(4SO4 )-Glc(2SO4 )-GalNAc(6SO4 ), pH 6.8, 37 C [6]) [6] 0.027 (chondroitin sulfate, pH 6.9 [3]) [3] 0.028 (GalNAc(4SO4 )-d-glucuronic acid-GalNAc(4SO4 ), pH 6.8, 37 C [6]) [6] 0.82 (GalNAc(4SO4 )-d-glucuronic acid-GalNAc(6SO4 ), pH 6.8, 37 C [6]) [6] pH-Optimum 6.2 [4] 6.8 ( assay at [8]) [8] Temperature optimum ( C) 20 ( assay at [8]) [8]

4 Enzyme Structure Molecular weight 66000 ( gel filtration [4]) [4]

492

2.8.2.33

N-Acetylgalactosamine 4-sulfate 6-O-sulfotransferase

Subunits monomer ( 1 * 63000, SDS-PAGE [4]) [4] Posttranslational modification glycoprotein ( contains N-linked oligosaccharides [4]) [4]

5 Isolation/Preparation/Mutation/Application Source/tissue anterior visceral endoderm [9] artery [9] cartilage [1, 4, 8] colon ( mucosa cells, enzyme expression analysis by real-time RTPCR and in situ hybridization in formalin-fixed and paraffin-embedded tissue sections, comparison to cancer tissue [7]) [7] colorectal cancer cell ( samples from 40 patients, enzyme expression analysis by real-time RT-PCR and in situ hybridization in formalin-fixed and paraffin-embedded tissue sections, comparison to healthy tissue [7]) [7] embryo ( enzyme expression pattern during early mouse embryonic development, overview, GalNAc4S-6ST is differentially expressed in the anterior visceral ectoderm at stage E5.5 and later becomes restricted to the embryonic endoderm, especially in the prospective midgut region. During the turning process, expression of GalNAc4S-6ST gene is detected in the forebrain, branchial arches, across the gut tube, i.e. hindgut, midgut and foregut diverticulum, in the vitelline veins and artery and in the splanchnopleure layer [9]) [9] forebrain [9] gut [9] serum [3] Localization Golgi apparatus [9] Purification [4] (recombinant FLAG-tagged GalNAc4S-6ST from COS-7 cells by antiFLAG immunoaffinity chromatography) [8] Cloning (enzyme expression pattern during early mouse embryonic development, overview) [9] (quantitative expression analysis and mRNA preparation using paraffinembedded tissue samples, overview) [7] (expression of FLAG-tagged GalNAc4S-6ST in COS-7 cells) [8]

493

N-Acetylgalactosamine 4-sulfate 6-O-sulfotransferase

2.8.2.33

Application synthesis ( use of enzyme for synthesis of chondroitin sulfate E from chondroitin sulfate A and of oversulfated dermatan sulfate with defined proportions of 4,6-sulfated residues [1]) [1]

References [1] Habuchi, O.; Moroi, R.; Ohtake, S.: Enzymatic synthesis of chondroitin sulfate E by N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase purified from squid cartilage. Anal. Biochem., 310, 129-136 (2002) [2] Sawada, T.; Fujii, S.; Nakano, H.; Ohtake, S.; Kimata, K.; Habuchi, O.: Synthesis of sulfated phenyl 2-acetamido-2-deoxy-d-galactopyranosides. 4-O-Sulfated phenyl 2-acetamido-2-deoxy-b-d-galactopyranoside is a competitive acceptor that decreases sulfation of chondroitin sulfate by N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase. Carbohydr. Res., 340, 1983-1996 (2005) [3] Inoue, H.; Otsu, K.; Suzuki, S.; Nakanishi, Y.: Difference between N-acetylgalactosamine 4-sulfate 6-O-sulfotransferases from human serum and squid cartilage in specificity toward the terminal and interior portion of chondroitin sulfate. J. Biol. Chem., 261, 4470-4475 (1986) [4] Ito, Y.; Habuchi, O.: Purification and characterization of N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase from the squid cartilage. J. Biol. Chem., 275, 34728-34736 (2000) [5] Ohtake, S.; Ito, Y.; Fukuta, M.; Habuchi, O.: Human N-acetylgalactosamine 4sulfate 6-O-sulfotransferase cDNA is related to human B cell recombination activating gene-associated gene. J. Biol. Chem., 276, 43894-43900 (2001) [6] Ohtake, S.; Kimata, K.; Habuchi, O.: A unique nonreducing terminal modification of chondroitin sulfate by N-acetylgalactosamine 4-sulfate 6-o-sulfotransferase. J. Biol. Chem., 278, 38443-38452 (2003) [7] Ito, Y.; Watanabe, M.; Nishizawa, T.; Omachi, T.; Kobayashi, T.; Kasama, S.; Habuchi, O.; Nakayama, J.: The utility of formalin-fixed and paraffin-embedded tissue blocks for quantitative analysis of N-acetylgalactosamine 4sulfate 6-O-sulfotransferase mRNA expressed by colorectal cancer cells. Acta Histochem. Cytochem., 40, 53-59 (2007) [8] Yamaguchi, T.; Ohtake, S.; Kimata, K.; Habuchi, O.: Molecular cloning of squid N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase and synthesis of a unique chondroitin sulfate containing E-D hybrid tetrasaccharide structure by the recombinant enzyme. Glycobiology, 17, 1362-1376 (2007) [9] Salgueiro, A.M.; Filipe, M.; Belo, J.A.: N-acetylgalactosamine 4-sulfate 6-Osulfotransferase expression during early mouse embryonic development. Int. J. Dev. Biol., 50, 705-708 (2006)

494

Glycochenodeoxycholate sulfotransferase

2.8.2.34

1 Nomenclature EC number 2.8.2.34 Systematic name 3’-phosphoadenylyl-sulfate:glycochenodeoxycholate 7-sulfotransferase Recommended name glycochenodeoxycholate sulfotransferase Synonyms BAST [4, 5, 7] BAST I [6, 8] bile acid sulfotransferase [2, 4, 5] bile acid sulfotransferase I [6, 8] bile acid:3’phosphoadenosine-5’phosphosulfate:sulfotransferase [8] bile acid:PAPS:sulfotransferase [7] hydroxysteroid/bile acid sulfotransferase [6] Additional information ( the enzyme is identical with the hydrosteroid sulfotransferase 2 [8]) [8] CAS registry number 72668-90-7 72668-90.7

2 Source Organism Homo sapiens (no sequence specified) [4, 5] Rattus norvegicus (no sequence specified) [1, 2, 3, 6, 8] Mesocricetus auratus (no sequence specified) [7]

3 Reaction and Specificity Catalyzed reaction 3’-phosphoadenylyl sulfate + glycochenodeoxycholate = adenosine 3’,5’-bisphosphate + glycochenodeoxycholate 7-sulfate ( the enzyme is identical with the hydrosteroid sulfotransferase 2 [8])

495

Glycochenodeoxycholate sulfotransferase

2.8.2.34

Natural substrates and products S 3’-phosphoadenylyl 5’-phosphosulfate + dehydroepiandrosterone (Reversibility: ?) [6] P adenosine 3’,5’-bisphosphate + dehydroepiandrosterone 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + glycochenodeoxycholate (Reversibility: ?) [7] P adenosine 3’,5’-bisphosphate + glycochenodeoxycholate 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + lithocholate (Reversibility: ?) [4] P adenosine 3’,5’-bisphosphate + lithocholate 7-sulfate S Additional information ( the enzyme is involved in prevention of toxicity of monohydroxy bile acids [8]; the sulfation reaction may be a protective mechanism against the hepatotoxic effects of some bile acids in facilitating the excretion [5]) (Reversibility: ?) [5, 8] P ? Substrates and products S 3’-phosphoadenylyl 5’-phosphosulfate + 3b-hydroxy-5b-cholanoic acid (Reversibility: ?) [8] P adenosine 3’,5’-bisphosphate + 3b-hydroxy-5b-cholanoic acid 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + 7-hydroxymethyl-12-methylbenz[a]anthracene ( bioactivation to an electrophilic sulfuric acid ester metabolite [6]) (Reversibility: ?) [6] P adenosine 3’,5’-bisphosphate + ? S 3’-phosphoadenylyl 5’-phosphosulfate + chenodeoxycholate ( low activity [8]) (Reversibility: ?) [8] P adenosine 3’,5’-bisphosphate + chenodeoxycholate 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + cotisol ( low activity [8]) (Reversibility: ?) [8] P adenosine 3’,5’-bisphosphate + cortisol 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + dehydroepiandrosterone ( i.e. androst-5-ene-3b-ol-17-one [4,5,6]; i.e. androst-5-ene-3bol-17-one, best substrate [8]) (Reversibility: ?) [4, 5, 6, 8] P adenosine 3’,5’-bisphosphate + dehydroepiandrosterone 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + deoxycholate ( i.e. 3a,12a-dihydroxy-5b-cholan-24-oic acid, low activity [8]) (Reversibility: ?) [8] P adenosine 3’,5’-bisphosphate + deoxycholate 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + estradiol ( low activity [8]) (Reversibility: ?) [1, 8] P adenosine 3’,5’-bisphosphate + ? S 3’-phosphoadenylyl 5’-phosphosulfate + estrone (Reversibility: ?) [5] P adenosine 3’,5’-bisphosphate + estrone 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + glycochenodeoxycholate ( low activity [8]) (Reversibility: ?) [7, 8] P adenosine 3’,5’-bisphosphate + glycochenodeoxycholate 7-sulfate ( product identification [7])

496

2.8.2.34

Glycochenodeoxycholate sulfotransferase

S 3’-phosphoadenylyl 5’-phosphosulfate + glycodeoxycholate (Reversibility: ?) [8] P adenosine 3’,5’-bisphosphate + glycodeoxycholate 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + glycolithocholate ( i.e. N-(3-hydroxy-5b-cholanoyl)glycine [8]) (Reversibility: ?) [8] P adenosine 3’,5’-bisphosphate + glycolithocholate 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + glycolithocholate ( low activity [8]) (Reversibility: ?) [1, 8] P adenosine 3’,5’-bisphosphate + glycolithocholate 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + lithocholate ( low activity [8]) (Reversibility: ?) [4, 5, 8] P adenosine 3’,5’-bisphosphate + lithocholate 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + phenol (Reversibility: ?) [5] P adenosine 3’,5’-bisphosphate + phenyl sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + taurochenodeoxycholate ( low activity [8]) (Reversibility: ?) [8] P adenosine 3’,5’-bisphosphate + taurochenodeoxycholate 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + taurodeoxycholate (Reversibility: ?) [8] P adenosine 3’,5’-bisphosphate + taurodeoxycholate 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + taurolithocholate ( low activity [8]) (Reversibility: ?) [1, 8] P adenosine 3’,5’-bisphosphate + taurolithocholate 7-sulfate S 3’-phosphoadenylyl 5’-phosphosulfate + testosterone ( low activity [8]) (Reversibility: ?) [8] P adenosine 3’,5’-bisphosphate + testosterone 7-sulfate S Additional information ( the enzyme is involved in prevention of toxicity of monohydroxy bile acids [8]; the sulfation reaction may be a protective mechanism against the hepatotoxic effects of some bile acids in facilitating the excretion [5]; poor activity with ursodeoxycholate and chenodeoxycholate, enzyme shows quite strict substrate specificity [5]; substrate specificity of enzyme purified in different ways, overview [4]; substrate specificity, enzyme is most active with bile acids or steroids possessing a 3b-hydroxy group and a 5-6 double bond or a trans A-B ring junction at the steroid nucleus, poor or no activity with cholate and conjugates, ursodeoxycholate, hyodeoxycholate, 3a,6adihydroxy-5b-cholanoate, overview [8]) (Reversibility: ?) [4, 5, 8] P ? Inhibitors 3,6-dioxo-5a-cholanoate [8] 3,6-dioxo-5b-cholanoate [8] 3,7-dioxo-5b-cholanoate [8] 3-oxo-5b-cholanic acid ( 80-90% inhibition at equimolar amounts [8]) [8] 3a,6b-dihydroxy-5b-cholanoate [8]

497

Glycochenodeoxycholate sulfotransferase

2.8.2.34

5a-dihydrotestosterone ( inhibits the hepatic enzyme in sham-operated and castrated male rats, prevents activation by 6-methylene-4-pregnene3,20-dione [3]) [3] 6-oxolithocholate [8] 7-koxolithocholate [8] adenosine 3’,5’-bisphosphate ( potent, competitive inhibition [6]) [6] chenodeoxycholate ( competitive, 50% inhibition at about 0.1 mM [7]) [7, 8] ursodeoxycholate ( competitive, 50% inhibition at about 0.1 mM [7]; mixed inhibition type [5]) [5, 7, 8] glycolithocholate ( competitive, 50% inhibition at 0.04 mM [7]) [7] hyodeoxycholate [8] lithocholate ( substrate inhibition [5]) [5] Additional information ( no inhibition by 3,12-dioxo-5b-cholanoate [8]) [8] Activating compounds 6-methylene-4-pregnene-3,20-dione ( activates the hepatic enzyme in sham-operated and castrated male rats, effect is counteracted by 5a-dihydrotestosterone [3]) [3] Metals, ions Mg2+ ( maximal activity at 5 mM MgCl2 , Mg2+ is not essential for activity [8]; required for activity, best at 2.5 mM [7]) [1, 7, 8] NaCl ( induces aggregation of the purified enzyme at 0.5 M [8]) [8] Additional information ( activity is independent of ionic strength in the range of 25-125 mM [7]) [7] Specific activity (U/mg) 0.0000006 ( male rat liver cytosol, substrate 7-hydroxymethyl-12methylbenz[a]anthracene [6]) [6] 0.000003 ( adrenal gland supernatant fraction [7]) [7] 0.000004 ( proximal intestine supernatant fraction, female hamster [7]) [7] 0.000005 ( proximal intestine supernatant fraction, male hamster [7]) [7] 0.000012 ( castrated male rats with 5a-dihydrotestosterone, hepatic enzyme [3]) [3] 0.000017 ( liver supernatant fraction, male hamster [7]; sham-operated male rats with 5a-dihydrotestosterone, hepatic enzyme [3]) [3, 7] 0.000019 ( sham-operated male rats with 5a-dihydrotestosterone and 6-methylene-4-pregnene-3,20-dione, hepatic enzyme [3]) [3] 0.00002 ( female rat liver cytosol, substrate 7-hydroxymethyl-12methylbenz[a]anthracene [6]) [6] 0.000023 ( sham-operated male rats, hepatic enzyme [3]) [3]

498

2.8.2.34

Glycochenodeoxycholate sulfotransferase

0.000056 ( sham-operated male rats with 6-methylene-4-pregnene3,20-dione, hepatic enzyme [3]) [3] 0.00006 ( castrated male rats, hepatic enzyme [3]) [3] 0.000062 ( liver supernatant fraction, female hamster [7]) [7] 0.000083 ( castrated male rats with 6-methylene-4-pregnene-3,20dione, hepatic enzyme [3]) [3] 0.000094 ( purified enzyme, substrate glycolithocholate [1]) [1] 0.000831 ( purified enzyme, substrate estradiol [1]) [1] 0.018 ( purified enzyme [4]) [4] 0.0187 ( purified enzyme [8]) [8] 0.023 ( purified enzyme from femal rat liver [2]) [2] Km-Value (mM) 0.00023 (glycochenodeoxycholate, male hamster, pH 7.0, 37 C, physiological substrate concentration [7]) [7] 0.00024 (3b-hydroxy-5b-cholanoic acid, pH 6.5, 37 C, 5 mM MgCl2 [8]) [8] 0.00072 (dehydroepiandrosterone, pH 6.5, 37 C, 5 mM MgCl2 [8]) [8] 0.00142 (glycochenodeoxycholate, female hamster, pH 7.0, 37 C, physiological substrate concentration [7]) [7] 0.0016 (lithocholate) [5] 0.079 (glycochenodeoxycholate, female hamster, pH 7.0, 37 C, saturating substrate concentration [7]) [7] 0.317 (glycochenodeoxycholate, male hamster, pH 7.0, 37 C, saturating substrate concentration [7]) [7] Additional information ( hyperbolic kinetics, allosteric effect [8]) [7, 8] Ki-Value (mM) 0.018 (glycolithocholate, pH 7.0, 37 C [7]) [7] 0.071 (chenodeoxycholate, pH 7.0, 37 C [7]) [7] 0.083 (ursodeoxycholate, pH 7.0, 37 C [7]) [7] 0.1 (ursodeoxycholate) [5] 0.26 (3-oxo-5b-cholanic acid, pH 6.5, 37 C, 5 mM MgCl2 [8]) [8] pH-Optimum 6.5 ( assay at [6]; at 5 mM Mg2+ , broad optimum at pH 5.5-7.5 [8]) [6, 8] 7 ( assay at [1]) [1, 7] pH-Range 5-8 [8] 6-8 [7] Temperature optimum ( C) 37 ( assay at [1,6,7,8]) [1, 6, 7, 8]

499

Glycochenodeoxycholate sulfotransferase

2.8.2.34

4 Enzyme Structure Molecular weight 32500 ( gel filtration [1]) [1] Additional information ( enzyme appears in different aggregation forms, overview [2]; the enzyme shows dfferent higher aggregation forms [8]) [2, 8] Subunits ? ( x * 65000, SDS-PAGE [4]; x * 30000, SDS-PAGE [8]; x * 29500, SDS-Page [2]) [2, 4, 8] monomer ( 1 * 32500, SDS-PAGE [1]) [1]

5 Isolation/Preparation/Mutation/Application Source/tissue adrenal gland [7] intestine ( proximal [7]) [7] kidney [2] liver ( foetal [4]) [1, 2, 3, 4, 5, 6, 7, 8] Additional information ( no activity in herat, spleen, skeletal muscle, brain, distal small intestine, and large intestine, activity is higher in femal than in male hamsters [7]) [7] Localization cytosol [1, 4, 6, 8] soluble [2, 7] Purification (from foetal liver cytosol, 760fold, ion exchange chromatography, adenosine 3’,5’-bisphosphate affinity chromatography, and gel filtration, overview) [4] (partially from liver by ion exchange chromatography) [5] (157fold by ultracentrifugation, ion exchange chromatography, and adenosine 3’,5’-bisphosphate affinity chromatpgraphy) [8] (by ultracentrifugation, over 75fold by affinity chromatography on PK1B monoclonal antibody resin, which is especially effective with enzyme from female rat livers, and ammonium sulfate precipitation) [2] (from liver, by gel filtration, affinity chromatography, chromatofocusing, and hydroxyapatite chromatography, to homogeneity) [1] Renaturation (redissolvation after precipitation with 1-6 M urea) [2]

500

2.8.2.34

Glycochenodeoxycholate sulfotransferase

6 Stability General stability information , 20% glycerol stabilizes [1] Storage stability , 4 C, 0.1 mg/ml purified enzyme, 3 weeks, no loss of activity [8] , -20 C, hepatic and intestinal supernatant fractions, completely stable for at least 6 months [7]

References [1] Takikawa, H.; Stolz, A.; Kaplowitz, N.: Purification of a 32.5 kDa monomeric sulfotransferase from rat liver with activity for bile acids and phenolic steroids. FEBS Lett., 207, 193-197 (1986) [2] Collins, R.H.; Lack, L.; Killenberg, P.G.: Rat hepatic bile acid sulfotransferase: enzyme response to androgens and estrogens. Am. J. Physiol., 252, G276G280 (1987) [3] McKinney, S.C.; Collins, R.H.; Killenberg, P.G.; Lack, L.: Effect of 6-methylene-4-pregnene-3,20-dione treatment on hepatic bile acid sulfotransferase activity in male rats. Biochem. Pharmacol., 35, 1050-1052 (1986) [4] Maghsoudloo, M.; Higgins, M.J.P.; Murphy, G.M.: Purification of human fetal hepatic bile acid sulfotransferase (BAST). Biochem. Soc. Trans., 20, 167S (1992) [5] Suckling, R.J.; Murphy, G.M.; Higgins, M.J.P.: Human liver bile acid sulfotransferase: characterization of the partially purified enzyme. Biochem. Soc. Trans., 21, 447S (1993) [6] Falany, C.N.; Wheeler, J.; Coward, L.; Keehan, D.; Falany, J.L.; Barnes, S.: Bioactivation of 7-hydroxymethyl-12-methylbenz[a]anthracene by rat liver bile acid sulfotransferase I. J. Biochem. Toxicol., 7, 241-248 (1992) [7] Barnes, S.; Burhol, P.G.; Zander, R.; Haggstrom, G.; Settine, R.L.; Hirschowitz, B.I.: Enzymic sulfation of glycochenodeoxycholic acid by tissue fractions from adult hamsters. J. Lipid Res., 20, 952-959 (1979) [8] Barnes, S.; Buchina, E.S.; King, R.J.; McBurnett, T.; Taylor, K.B.: Bile acid sulfotransferase I from rat liver sulfates bile acids and 3-hydroxy steroids: purification, N-terminal amino acid sequence, and kinetic properties. J. Lipid Res., 30, 529-540 (1989)

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