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Joaquín Ariño • Denis R. Alexander (Eds.)
ProteinPhosphatases
With 43 Figures, 16 of Them in Color; and 15 Tables
123
Joaquín Ariño, Ph. D.Dept. Bioquímica y BiologíaMolecularFacultat de VeterinàriaUniversitat Autònoma de Barcelona08193 Bellaterra, BarcelonaSpain
ISSN 1610-2096ISBN 3-540-20560-8 Springer-Verlag Berlin Heidelberg New York
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Bibliographic information published by Die Deutsche BibliothekDie Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailedbibliographic data is available in the Internet at <http:/dnb.ddb.de>
This work is subject to copyright. All rights reserved, whether the whole or part of the material isconcerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broad-casting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of thispublication or parts thereof is permitted only under the provisions of the German Copyright Law ofSeptember 9, 1965, in its current version, and permission for use must always be obtained fromSpringer-Verlag. Violations are liable for prosecution under the German Copyright Law.
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© Springer-Verlag Berlin Heidelberg 2004Printed in Germany
The use of general descriptive names, registered names, trademarks, etc. in this publication does notimply, even in the absence of a specific statement, that such names are exempt from the relevant pro-tective laws and regulations and therefore free for general use.
Typesetting: Camera ready by editorsData-conversion: PTP-Berlin, Stefan Sossna e.K.Cover Design: Design & Production, Heidelberg39/3150 - 5 4 3 2 1 0 - Printed on acid-free paper
The cover illustration depicts pseudohyphal filaments of the ascomycete Saccharomyces cerevisiaethat enable this organism to forage for nutrients. Pseudohyphal filaments were induced here in a wild-type haploid MATa Σ1278b strain by an unknown readily diffusible factor provided by growth in con-frontation with an isogenic petite yeast strain in a sealed petri dish for two weeks and photographedat 100X magnification (provided by Xuewen Pan and Joseph Heitman).
Dr. Denis R. AlexanderChairman, Molecular ImmunologyProgrammeThe Babraham InstituteBabraham, Cambridge CB2 4ATUnited Kingdom
List of contributors
Alexander, Denis R. Laboratory of Lymphocyte Signalling and Development, Molecular Immunol-ogy Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK [email protected]
Alonso, Andres
Program of Signal Transduction, Cancer Research Center, The Burnham Insti-tute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Andersen, Jannik N.
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
Bechmann, Gunther
Institut für Pharmazeutische & Medizinische Chemie, Westfälische Wilhelms-Universität, Hittorfstr. 58-62, 48149 Münster, Germany
Bourdeau , Annie
McGill Cancer Center, McGill University, McIntyre Medical Science Building Room 701, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 1Y6
Brunet, Daniel V.
McGill Cancer Center, McGill University, McIntyre Medical Science Building Room 701, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 1Y6 Department of Biochemistry, McGill University, Montreal, Quebec, Canada, H3G 1Y6
Chinkers, Michael
Department of Pharmacology, University of South Alabama, Mobile, Alabama 36688, USA [email protected]
Cohen, Patricia T.W.
Medical Research Council Protein Phosphorylation Unit, School of Life Sci-ences, University of Dundee, Dundee DD15EH, Scotland, UK [email protected]
XIV
Collas, Philippe Institute of Medical Biochemistry, University of Oslo, PO Box 1112 Blindern, Oslo 0317, Norway [email protected]
Cunningham, Kyle W.
Department of Biology, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA [email protected]
den Hertog, Jeroen
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Upp-salalaan 8, 3584 CT Utrecht, The Netherlands [email protected]
Dombrádi, Viktor
Department of Medical Chemistry, Medical and Health Science Center, Fac-ulty of Medicine, University of Debrecen, Bem tér 18/B, Debrecen, Hungary, H-4026 [email protected]
Farkas, Ilona
Department of Medical Chemistry, Medical and Health Science Center, Fac-ulty of Medicine, University of Debrecen, Bem tér 18/B, Debrecen, Hungary, H-4026
Feng, Gen-Sheng
Program in Signal Transduction Research, The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA [email protected]
Godzik, Adam
Program of Bioinformatics, Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Haystead, Timothy A. J.
Department of Pharmacology and Cancer Biology, Center for Chemical Biol-ogy, Duke University Medical Center, Durham, NC 27710, USA [email protected]
Heinonen, Krista M.
McGill Cancer Center, McGill University, McIntyre Medical Science Building Room 701, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 1Y6 Division of Experimental Medicine McGill University, Montreal, Quebec, Canada, H3G 1Y6
List of contributors XV
Hilioti, Zoe Department of Biology, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA
Klumpp, Susanne
Institut für Pharmazeutische & Medizinische Chemie, Westfälische Wilhelms-Universität, Hittorfstr. 58-62, 48149 Münster, Germany [email protected]
Kobayashi, Takayasu
Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan
Kókai, Endre
Department of Medical Chemistry, Medical and Health Science Center, Fac-ulty of Medicine, University of Debrecen, Bem tér 18/B, Debrecen, Hungary, H-4026
Komaki, Ken-ichiro
Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan
Krieglstein, Josef
Institut für Pharmakologie & Toxikologie, Philipps-Universität, Ketzerbach 63, 35032 Marburg, Germany
Küntziger, Thomas
Institute of Medical Biochemistry, University of Oslo, PO Box 1112 Blindern, Oslo 0317, Norway
Kwiek, Nicole A.
Department of Pharmacology and Cancer Biology, Center for Chemical Biol-ogy, Duke University Medical Center, Durham, NC 27710, USA
Lai, Lisa A.
Program in Signal Transduction Research, The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA
Landsverk, Helga B.
Institute of Medical Biochemistry, University of Oslo, PO Box 1112 Blindern, Oslo 0317, Norway
Lapp, Wayne S.
Department of Physiology, McGill University, Montreal, Quebec, Canada, H3G 1Y6
XVI
Li, Ming Guang Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan
McCain, Daniel F.
Departments of Biochemistry, Albert Einstein College of Medicine, 1300 Mor-ris Park Avenue, Bronx, New York 10461, USA [email protected]
Matthews, Reginald James
Section of Infection and Immunity, University of Wales College of medicine, Heath Park, CARDIFF CF14 4XX, Wales, UK. [email protected]
Mäurer, Anette
Institut für Pharmazeutische & Medizinische Chemie, Westfälische Wilhelms-Universität, Hittorfstr. 58-62, 48149 Münster
Mumby, Marc C.
Department of Pharmacology, University of Texas Southwestern Medical Cen-ter, 5323 Harry Hines Boulevard, Dallas, TX 75390-9041, USA [email protected]
Mustelin, Tomas
Program of Signal Transduction, Cancer Research Center, The Burnham Insti-tute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA [email protected]
Rojas, Ana
Program of Bioinformatics, Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Sasaki, Masato
Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan
Sathish, Jean Gerard
Section of Infection and Immunity, University of Wales College of medicine, Heath Park, CARDIFF CF14 4XX, Wales, UK.
Tailor, Pankaj
McGill Cancer Center, McGill University, McIntyre Medical Science Building Room 701, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 1Y6
List of contributors XVII
Tamura, Shinri Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan [email protected]
Tonks, Nicholas K.
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA [email protected]
Tremblay, Michel L.
McGill Cancer Center, McGill University, McIntyre Medical Science Building Room 701, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 1Y6 Department of Biochemistry, McGill University, Montreal, Quebec, Canada, H3G 1Y6 [email protected]
Zhao, Chunmei
Program in Signal Transduction Research, The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA
Zhang, Eric E.
Program in Signal Transduction Research, The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA
Zhang, Zhong-Yin
Departments of Biochemistry and Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA [email protected]
Table of contents
1 Overview of protein serine/threonine phosphatases........................................1 Patricia T.W. Cohen...........................................................................................1
Abstract .........................................................................................................1 1.1 Protein serine/threonine phosphatases and their classification................1 1.2 The PPP family........................................................................................2
1.2.1 Phylogenetic and structural relationships in the PPP family............2 1.2.2 Functional genomic analyses of the PPP family ..............................5
1.3 The PPM family ....................................................................................12 1.3.1 Phylogenetic and structural relationships in the PPM family ........12 1.3.2 Functional genomic analyses of the PPM family...........................13
1.4 The FCP family .....................................................................................14 Acknowledgements .....................................................................................15 References ...................................................................................................15
2 Protein phosphatase 1 ......................................................................................21 Viktor Dombrádi, Endre Kókai and Ilona Farkas ............................................21
Abstract .......................................................................................................21 2.1 Biochemical characterization of protein phosphatase 1 .......................21 2.2 Cloning of the catalytic subunit of protein phosphatase 1.....................22 2.3 The structure of the protein phosphatase 1 catalytic subunit.................24 2.4 Non-catalytic (regulatory) subunits and interacting proteins of protein phosphatase 1 ..................................................................................26 2.5 Functions of Protein Phosphatase 1.......................................................29
2.5.1 Cell cycle regulation ......................................................................29 2.5.2 Glycogen metabolism ....................................................................31 2.5.3 Contractility ...................................................................................32 2.5.4 Morphogenesis...............................................................................34 2.5.5 Spermatogenesis ............................................................................35 2.5.6 Memory and learning.....................................................................35
2.6 Conclusions ...........................................................................................35 Acknowledgements .....................................................................................36 References ...................................................................................................36 List of abbreviations:...................................................................................43
3 Protein phosphatase 2A: A multifunctional regulator of cell signaling.......45 Marc C. Mumby...............................................................................................45
Abstract .......................................................................................................45 3.1 Introduction ...........................................................................................45 3.2 The PP2A core dimer ............................................................................46 3.2.1 The catalytic subunit ..........................................................................46
3.2.2 The scaffold subunit.......................................................................49
VI Table of contents
3.3 PP2A regulatory subunits ................................................................. 51 3.3.1 PP2A holoenzyme formation......................................................... 52 3.3.2 The R2 family ................................................................................ 54 3.3.3 The R3 family ................................................................................ 58 3.3.4 The R4 family ................................................................................ 59 3.3.5 The R5 family ................................................................................ 60
3.4 PP2A interacting proteins...................................................................... 62 References................................................................................................... 63
4 Calcineurin: Roles of the Ca2+/calmodulin-dependent protein phosphatase in diverse eukaryotes........................................................................................... 73
Zoe Hilioti and Kyle W. Cunningham............................................................. 73 Abstract ....................................................................................................... 73 4.1 Overview of calcineurin structure and function .................................... 73 4.2 Phylogenetic distribution of calcineurin in nature................................. 75 4.3 Calcineurin-sensitive processes............................................................. 77
4.3.1 Roles of calcineurin in Metazoa, a brief overview ........................ 77 4.3.2 Roles of calcineurin in Fungi......................................................... 78 4.3.3 Roles of calcineurin in Mycetozoa ................................................ 82 4.3.4 Absence of calcineurin in plants and alga...................................... 83 4.3.5 Roles of calcineurin in other eukaryotes........................................ 84
4.4 Summary and future prospects .............................................................. 84 References................................................................................................... 85
5 Roles of mammalian protein phosphatase 2C family members in the regulation of cellular functions .......................................................................... 91
Shinri Tamura, Ming Guang Li, Ken-ichiro Komaki, Masato Sasaki and Takayasu Kobayashi........................................................................................ 91
Abstract ....................................................................................................... 91 5.1 Introduction........................................................................................... 91 5.2 Structure of the PP2C catalytic site ....................................................... 92 5.3 Regulation of stress-activated protein kinase signaling pathways......... 94
5.3.1 PP2Cα............................................................................................ 94 5.3.2 PP2Cβ ............................................................................................ 95 5.3.3 Wip1 .............................................................................................. 95 5.3.4 PP2Cε ............................................................................................ 96
5.4 Cell cycle regulation.............................................................................. 96 5.4.1 PP2Cα and PP2Cβ......................................................................... 96 5.4.2 PP2Cδ ............................................................................................ 97
5.5 Regulation of actin cytoskeleton organization ...................................... 97 5.5.1 PP2Cα............................................................................................ 97 5.5.2 POPXs ........................................................................................... 97
5.6 Regulation of Wnt signaling pathways ................................................. 98 5.6.1 PP2Cα............................................................................................ 98 5.6.2 ILKAP (PP2Cδ)............................................................................. 99
Table of contents VII
5.7 Regulation of the cystic fibrosis transmembrane conductance regulator ......................................................................................................99
5.7.1 PP2Cα............................................................................................99 5.8 Regulation of pre-mRNA splicing.......................................................100
5.8.1 PP2Cγ...........................................................................................100 5.9 Conclusions and Perspectives..............................................................101 References .................................................................................................102
6 PP5: the TPR phosphatase ............................................................................107 Michael Chinkers...........................................................................................107
Abstract .....................................................................................................107 6.1 Introduction .........................................................................................107 6.2 PP5: a TPR protein ..............................................................................108 6.3 Expression and localization.................................................................109 6.4 Regulation of PP5 activity...................................................................111 6.5 Inhibitors of PP5..................................................................................112 6.6 PP5 binding proteins ...........................................................................113
6.6.1 ANP receptor ...............................................................................113 6.6.2 Heat shock protein 90 (hsp90) .....................................................114 6.6.3 ASK1 ...........................................................................................117 6.6.4 Gα12 and Gα13 ..............................................................................117 6.6.5 Copines ........................................................................................118 6.6.6 PP2A............................................................................................118 6.6.7 Anaphase-promoting complex .....................................................120 6.6.8 CRY2 ...........................................................................................120 6.6.9 Other PP5-interacting proteins.....................................................121
6.7 Genetics of PP5 ...................................................................................121 6.7.1 S. cerevisiae .................................................................................121 6.7.2 C. elegans ....................................................................................122 6.7.3 D. melanogaster...........................................................................122 6.7.4 Antisense studies..........................................................................123
6.8 Conclusions .........................................................................................124 References .................................................................................................125
7 Protein histidine phosphatases in signal transduction and metabolism ....131 Susanne Klumpp, Gunther Bechmann, Anette Mäurer, Josef Krieglstein .....131
Abstract .....................................................................................................131 7.1 Introduction .........................................................................................131 7.2 Protein histidine kinases at a glance....................................................133 7.3 Histidine phosphatases in vertebrates..................................................133
7.3.1 Proteins as a substrate ..................................................................134 7.3.2 Phosphopeptides as a substrate ....................................................135 7.3.3 Phosphohistidine as a substrate....................................................136
7.4 Histidine and aspartate phosphatases in bacteria.................................137 7.4.1 Aspartate phosphatases ................................................................138 7.4.2 Histidine phosphatases.................................................................139
VIII Table of contents
7.5 Nucleoside diphosphate kinases.......................................................... 140 7.6 Concluding remarks ............................................................................ 141 Acknowledgements ................................................................................... 141 References................................................................................................. 141
8 Anchoring of protein kinase and phosphatase signaling units ................... 145 Philippe Collas, Thomas Küntziger, and Helga B. Landsverk ...................... 145
Abstract ..................................................................................................... 145 8.1 Introduction......................................................................................... 145 8.2 Intracellular targeting of cAMP signaling by A-kinase anchoring proteins...................................................................................................... 146 8.3 A signaling complex formed by AKAP79, PP2B/calcineurin, PKA, PKC, and MAGUK ................................................................................... 147 8.4 AKAP220 anchors PKA, PP1, and GSK-3β in a quaternary complex..................................................................................................... 148 8.5 Yotiao anchors PKA and PP1 at the NMDA receptor......................... 150 8.6 Kinase/phosphatase adaptors at the centrosome/microtubule system . 150
8.6.1 Microtubule association............................................................... 150 8.6.2 Centrosome association ............................................................... 152
8.7 Integration of cAMP and Ca2+ signaling at the cardiomyocyte nuclear envelope by mAKAP.................................................................... 154 8.8 Targeting of PP1 to the nuclear envelope by AKAP149: implications on cell cycle progression ...................................................... 155
8.8.1 Targeting of PP1 to the nuclear envelope by AKAP149 is essential for reentry into interphase ...................................................... 156 8.8.2 AKAP149 is a B-type lamin specifier ......................................... 157 8.8.3 AKAP149-PP1 association in G1: control of nuclear integrity ... 157
8.9 Anchoring of AMY-1 to S-AKAP84/AKAP149................................. 158 8.10 Perspectives....................................................................................... 158 Acknowledgments..................................................................................... 159 References................................................................................................. 159 List of abbreviations.................................................................................. 164
9 Functional proteomics in phosphatase research.......................................... 167 Nicole C. Kwiek, Timothy A. J. Haystead .................................................... 167
Abstract ..................................................................................................... 167 9.1 Introduction to functional proteomics ................................................. 167
9.1.1 Protein phosphatase-1 research: Identification of novel regulatory subunits ............................................................................... 168 9.1.2 Yeast two-hybrid systems and arrays .......................................... 169 9.1.3 Microcystin affinity chromatography .......................................... 170
9.2 PP1 research: Defining the regulation of regulatory subunits ............. 174 9.2.1 Phosphorylation site analysis....................................................... 175 9.2.2 Identification of the endogenous smooth muscle myosin phosphatase-associated kinase.............................................................. 176
Table of contents IX
9.3 PP1 Research: Identifying substrates of a PP1/regulatory subunit complex .....................................................................................................177
9.3.1 Reg1p targets PP1 to dephosphorylate hexokinase II in Saccharomyces cerevisiae ....................................................................177
9.4 Conclusions .........................................................................................180 Acknowledgments.....................................................................................180 References .................................................................................................180
10 Structure and function of the T-cell protein tyrosine phosphatase..........185 Annie Bourdeau, Krista M. Heinonen, Daniel V. Brunet, Pankaj Tailor, Wayne S. Lapp, Michel L. Tremblay.........................................................................185
Abstract .....................................................................................................185 10.1 Cloning and characterization of T-cell protein tyrosine phosphatase (TC-PTP) ..............................................................................185
10.1.1 The gene.....................................................................................185 10.1.2 The promoter..............................................................................186 10.1.3 The protein.................................................................................186
10.2 Expression and localization of TC-PTP ............................................188 10.2.1 TC-PTP tissue expression ..........................................................188 10.2.2 Intracellular localization of TC-PTP..........................................188
10.3 Analysis of TC-PTP function in vitro................................................190 10.3.1 Identification of downstream substrates.....................................190 10.3.2 Cell cycle regulation and TC-PTP .............................................192
10.4 Analysis of TC-PTP function in vivo ................................................193 10.4.1 TC-PTP knockout mice..............................................................193 10.4.2 TC-PTP and hematopoiesis........................................................193 10.4.3 TC-PTP and immune function ...................................................194 10.4.4 p53 and TC-PTP ........................................................................195
10.5 Conclusion.........................................................................................196 Acknowledgments.....................................................................................197 References .................................................................................................197
11 Protein tyrosine phosphatase-based therapeutics: lessons from PTP1B.................................................................................................................201
Jannik N. Andersen and Nicholas K. Tonks ..................................................201 Abstract .....................................................................................................201 11.1 Introduction .......................................................................................201 11.2 PTP1B structure and mechanism.......................................................202 11.3 Substrate-trapping mutant PTPs ........................................................203 11.4 The biological function of PTP1B.....................................................205 11.5 Insights from the structure of PTP1B-substrate complexes...............207 11.6 The development of PTP1B as a therapeutic target...........................210 11.7 Structure-based design of PTP1B inhibitors......................................211 11.8 Conclusions and perspectives............................................................219 Acknowledgments.....................................................................................223 References .................................................................................................223
X Table of contents
12 The CD45 phosphotyrosine phosphatase ................................................... 231 Denis R. Alexander........................................................................................ 231
Abstract ..................................................................................................... 231 12.1 Introduction....................................................................................... 231 12.2 CD45 regulates lymphocyte development......................................... 232 12.3 CD45 regulates the Src family tyrosine kinases................................ 234
12.3.1 In T cell antigen receptor signalling .......................................... 234 12.3.2 In B cell antigen receptor signalling .......................................... 236 12.3.3 In integrin receptor signalling.................................................... 237 12.3.4 In chemokine receptor signalling............................................... 237
12.4. The subcellular localisation of CD45 in relation to its substrates .... 238 12.4.1 CD45 and lipid rafts................................................................... 238 12.4.2 CD45 and the immune synapse.................................................. 239
12.5 How are the actions of CD45 regulated?........................................... 240 12.6 The role of CD45 isoforms................................................................ 241
12.6.1 The exogenous ligand model ..................................................... 243 12.6.2 The size exclusion model........................................................... 243 12.6.3 The cis-cis interaction model ..................................................... 244 12.6.4 The homodimerisation model .................................................... 245
12.7 Concluding remarks .......................................................................... 246 Acknowledgements ................................................................................... 247 References................................................................................................. 247
13 Receptor protein tyrosine phosphatases..................................................... 253 Jeroen den Hertog.......................................................................................... 253
Abstract ..................................................................................................... 253 13.1 Introduction....................................................................................... 253 13.2 The function of RPTPs in vivo.......................................................... 254
13.2.1 DRPTPs in fly axonogenesis ..................................................... 255 13.2.2. RPTP function in the mouse ..................................................... 256 13.2.3 RPTPs and zebrafish.................................................................. 259
13.3 RPTP signalling ................................................................................ 260 13.3.1 RPTP substrates ......................................................................... 260 13.3.2 Ligand binding to RPTPs........................................................... 263 13.3.3 Regulation of RPTPs by dimerization ....................................... 264 13.3.4 Regulation of RPTPs by redox signalling.................................. 266
References................................................................................................. 267
14 The Shp-2 tyrosine phosphatase.................................................................. 275 Lisa A. Lai, Chunmei Zhao, Eric E. Zhang, and Gen-Sheng Feng................ 275
Abstract ..................................................................................................... 275 14.1 Introduction....................................................................................... 275 14.2 Shp-2 function in development ......................................................... 276 14.3 Shp-2 and human diseases................................................................. 277 14.4 Shp-2 in cell proliferation and differentiation ................................... 280 14.5 Shp-2 and cell motility ...................................................................... 281
Table of contents XI
14.6 Shp-2 and cell apoptosis....................................................................282 14.7 Shp-2 and cytoplasmic signaling.......................................................283
14.7.1 Shp-2 plays a positive role in the Ras/MAPK pathway .............284 14.7.2 Shp-2 is involved in the regulation of the JAK/STAT pathway.................................................................................................285 14.7.3 Shp-2 functions in other signaling pathways .............................286
14.8 Interaction of Shp-2 with scaffold proteins .......................................286 14.8.1 Interaction with GAB proteins...................................................286 14.8.2 Interaction with FRS proteins ....................................................288 14.8.3 Interaction with SHPS-1 ............................................................289
14.9 Concluding remarks ..........................................................................290 Acknowledgements ...................................................................................290 References .................................................................................................290
15 SHP-1 twelve years on: structure, ligands, substrates and biological roles ...................................................................................................301
Jean Gerard Sathish, Reginald James Matthews............................................301 Abstract .....................................................................................................301 15.1 Introduction .......................................................................................301 15.2 Expression .........................................................................................302 15.3 Structure ............................................................................................303
15.3.1 SH2 domains and their ligands ..................................................303 15.3.2 PTP domain and substrate(s) .....................................................309 15.3.3 Carboxy-terminus and potential adaptor role.............................312
15.4 Function.............................................................................................313 15.4.1 T lymphocytes............................................................................313 15.4.2 B lymphocytes ...........................................................................315 15.4.3 Natural killer cells......................................................................316 15.4.4 Myeloid lineage cells .................................................................317
15.5 Summary ...........................................................................................319 Acknowledgements ...................................................................................319 References .................................................................................................319
16 The dual-specific protein tyrosine phosphatase family .............................333 Andres Alonso, Ana Rojas, Adam Godzik, Tomas Mustelin ........................333
Abstract .....................................................................................................333 16.1 Introduction .......................................................................................333 16.2 Phylogeny and classification .............................................................338 16.3. Structural features of the DSP family...............................................339
16.3.1 The catalytic domain..................................................................339 16.3.2 The rhodanese domain ...............................................................344
16.4 Interaction of DSPs with their substrates ..........................................346 16.4.1 Interaction of classical DSPs with MAPKs ...............................346 16.4.2 Interaction of atypical DSPs with their substrates .....................348
16.5 Regulation of DSPs ...........................................................................348 16.5.1 Transcriptional regulation of classical DSPs .............................348
XII Table of contents
16.5.2 Catalytic activation of classical DSPs by substrate binding ...... 349 16.5.3 Regulation of DSPs by phosphorylation.................................... 350
16.6 Physiological roles ............................................................................ 350 16.7 Conclusions and future perspectives ................................................. 352 Acknowledgements ................................................................................... 353 References................................................................................................. 353
17 Tyrosine phosphatases in cancer: Targets for therapeutic intervention........................................................................................................ 359
Daniel F. McCain and Zhong-Yin Zhang ...................................................... 359 Abstract ..................................................................................................... 359 17.1 Introduction....................................................................................... 359 17.2 PTPases that activate SRC ................................................................ 360 17.3 PTPases involved in growth factor or cytokine signaling ................. 362 17.4 FAP-1: A PTPase that suppresses apoptosis ..................................... 363 17.5. The cell cycle ................................................................................... 363
17.5.1 CDC25....................................................................................... 364 17.5.2 KAP ........................................................................................... 365 17.5.3 CDC14....................................................................................... 366 17.5.4 PRL............................................................................................ 367
17.6 Conclusions ....................................................................................... 368 Acknowledgements ................................................................................... 368 References................................................................................................. 368
Index................................................................................................................... 375