Handbook of Cell Signaling : Volume 1.

VOLUME 1 Contributors xlv Preface lxvii CHAPTER 1 Cell Signaling: Yesterday, Today, and Tomorrow 1 Ralph A. Bradshaw and Edward A. Dennis Origins of Cell Signaling Enter Polypeptide Growth Factors Cell Signaling at the Molecular Level Lipid Signaling Cell Signaling Tomorrow References PART I INITIATION: EXTRACELLULAR AND MEMBRANE EVENTS James Wells, Editor Section A: Molecular Recognition Ian Wilson, Editor CHAPTER 2 Structural and Energetic Basis of Molecular Recognition 11 Emil Alexov and Barry Honig Introduction Principles of Binding Nonspecific Association with Membrane Surfaces Protein–Protein Interactions Prospects References CHAPTER 3 Computational Genomics: Prediction of Protein Functional Linkages and Networks 15 Todd O. Yeates and Michael J. Thompson Introduction Approaches to Analyzing Protein Functions on a Genome-Wide Scale Current Issues and Future Prospects for Computing Functional Interactions References CHAPTER 4 Molecular Sociology 21 Irene M. A. Nooren and Janet M. Thornton Transmembrane Signaling Paradigms Structural Basis of Protein–Protein Recognition Conclusion References CHAPTER 5 Free Energy Landscapes in Protein–Protein Interactions 27 Jacob Piehler and Gideon Schreiber Introduction Thermodynamics of Protein–Protein Interactions Interaction Kinetics The Transition State Association of a Protein Complex Dissociation of a Protein Complex Summary References CHAPTER 6 Antibody–Antigen Recognition and Conformational Changes 33 Robyn L. Stanfield and Ian A. Wilson Introduction Antibody Architecture Conformational Changes Conclusion References CHAPTER 7 Binding Energetics in Antigen– Antibody Interfaces 39 Roy A. Mariuzza Introduction Thermodynamic Mapping of Antigen– Antibody Interfaces Conclusions References CHAPTER 8 Immunoglobulin–Fc Receptor Interactions 45 Brian J. Sutton, Rebecca L. Beavil, and Andrew J. Beavil Introduction IgG–Receptor Interactions IgE–Receptor Interactions Summary References CHAPTER 9 Plasticity of Fc Recognition 51 Warren L. DeLano Introduction Structures of the Natural Fc Binding Domains The Consensus Binding Site on Fc Evolution of an Fc Binding Peptide Factors Promoting Plasticity Conserved and Functionally Important Molecular Interactions Conclusion References CHAPTER 10 Ig-Superfold and Its Variable Uses in Molecular Recognition 57 Nathan R. Zaccai and E. Yvonne Jones Introduction The Immunoglobulin Superfamily Ig-Superfold-Mediated Recognition References CHAPTER 11 T-Cell Receptor/pMHC Complexes 63 Markus G. Rudolph and Ian A. Wilson TCR Generation and Architecture Peptide Binding to MHC Class I and II TCR/pMHC Interaction Conclusions and Future Perspectives References CHAPTER 12 Mechanistic Features of Cell-Surface Adhesion Receptors 74 Steven C. Almo, Anne R. Bresnick, and Xuewu Zhang Mechanosensory Mechanisms Cell–Cell Adhesions/Adherens Junctions T-Cell Costimulation Axon Guidance and Neural Development Conclusions References CHAPTER 13 The Immunological Synapse 79 Michael L. Dustin Introduction Migration and the Immunological Synapse The Cytoskeleton and the Immunological Synapse The Role of Self MHCp in T-Cell Sensitivity to Foreign MHCp Integration of Adaptive and Innate Responses Summary References CHAPTER 14 NK Receptors 83 Roland K. Strong Introduction Immunoreceptors Natural Killer Cells Ig-Type NK Receptors: KIR C-Type Lectin-Like NK Receptors: Ly49A C-Type Lectin-Like NK Receptors: NKG2D References CHAPTER 15 Carbohydrate Recognition and Signaling 87 James M. Rini and Hakon Leffler Introduction Biological Roles of Carbohydrate Recognition Carbohydrate Structure and Diversity Lectins and Carbohydrate Recognition Carbohydrate-Mediated Signaling Conclusions References CHAPTER 16 Rhinovirus–Receptor Interactions 95 Elizabeth Hewat References CHAPTER 17 HIV-1 Receptor Interactions 99 Peter D. Kwong Molecular Interactions Atomic Details Recognition in the Context of a Humoral Immune Response References CHAPTER 18 Influenza Virus Neuraminidase Inhibitors 105 Garry L. Taylor Introduction Flu Virus: Role of NA Structure of NA Active Site Inhibitor Development Conclusion References CHAPTER 19 Signal Transduction and Integral Membrane Proteins 115 Geoffrey Chang and Christopher B. Roth Introduction Electrophysiology: Rapid Signal Transduction Mechanosensation: How Do We Feel? Active Transporters: Rapid Response and Energy Management Receptors: Gate Keepers for Cell Signaling References CHAPTER 20 Structural Basis of Signaling Events Involving Fibrinogen and Fibrin 119 Russell F. Doolittle References CHAPTER 21 Structural Basis of Integrin Signaling 123 Robert C. Liddington Introduction Structure Quaternary Changes Tertiary Changes Tail Interactions Concluding Remarks References CHAPTER 22 Structures of Heterotrimeric G Proteins and Their Complexes 127 Stephen R. Sprang Introduction Gα Subunits Ga-Effector Interactions GTP Hydrolysis by Gα and Its Regulation by RGS Proteins Gβγ Dimers GPR/GoLoco Motifs Gα-GPCR Interactions References Section B: Vertical Receptors Henry Bourne, Editor CHAPTER 23 Structure and Function of G-Protein- Coupled Receptors: Lessons from the Crystal Structure of Rhodopsin 139 Thomas P. Sakmar Introduction Introduction to Rhodopsin: a Prototypical G-Protein-Coupled Receptor Molecular Structure of Rhodopsin Molecular Mechanism of Receptor Activation References CHAPTER 24 Human Olfactory Receptors 145 Orna Man, Tsviya Olender, and Doran Lancet References CHAPTER 25 Chemokines and Chemokine Receptors: Structure and Function 149 Carol J. Raport and Patrick W. Gray Introduction Chemokine Structure and Function Chemokine Receptors References CHAPTER 26 The Binding Pocket of G-Protein- Coupled Receptors for Biogenic Amines, Retinal, and Other Ligands 155 Lei Shi and Jonathan A. Javitch Introduction The Binding Pocket of GPCRs A Role of the Second Extracellular Loop in Ligand Binding References CHAPTER 27 Glycoprotein Hormone Receptors: A Unique Paradigm for Ligand Binding and GPCR Activation 161 Gilbert Vassart, Marco Bonomi, Sylvie Claeysen, Cedric Govaerts, Su-Chin Ho, Leonardo Pardo, Guillaume Smits, Virginie Vlaeminck, and Sabine Costagliola Introduction Molecular Pathophysiology Structure Function Relationships of the Glycoprotein Hormone Receptors Conclusions and Perspectives References CHAPTER 28 Protease-Activated Receptors 167 Shaun R. Coughlin Introduction Mechanisms of Activation Protease-Activated Receptor Family Roles of PARs In Vivo References CHAPTER 29 Constitutive and Regulated Signaling in Virus-Encoded 7TM Receptors 173 Thue Schwartz Virus-Encoded Proteins Are Developed through Targeted Evolution In Vivo The Redundant Chemokine System Is an Optimal Target for Viral Exploitation Multiple Virus-Encoded 7TM Receptors Constitutive Signaling through Altered Pathways Viral Receptors Recognize Multiple Ligands with Variable Function Attempts to Identify the Function of Virus-Encoded Receptors In Vivo References CHAPTER 30 Frizzleds as G-Protein-Coupled Receptors for Wnt Ligands 177 Sarah H. Louie, Craig C. Malbon, Randall T. Moon Introduction Wnt Signaling Evidence for Frizzleds as G-Protein- Coupled Receptors Perspective References CHAPTER 31 Agonist-Induced Desensitization and Endocytosis of G-Protein- Coupled Receptors 181 Mark von Zastrow Introduction General Processes of GPCR Regulation Mechanisms of GPCR Desensitization and Endocytosis Functional Consequences of GPCR Endocytosis References CHAPTER 32 Functional Role(s) of Dimeric Complexes Formed from G-Protein- Coupled Receptors 187 Marta Margeta-Mitrovic and Lily Yuh Jan References CHAPTER 33 The Role of Chemokine Receptors in HIV Infection of Host Cells 191 Jacqueline D. Reeves and Robert W. Doms Introduction HIV Entry Coreceptor Use In Vivo Env Domains Involved in Coreceptor Interactions Coreceptor Domains Involved in HIV Infection Receptor Presentation and Processing Role of Signaling in HIV Infection Summary References CHAPTER 34 Chemotaxis Receptor in Bacteria: Transmembrane Signaling, Sensitivity, Adaptation, and Receptor Clustering 197 Weiru Wang and Sung-Hou Kim Signaling at Periplasmic Ligand Binding Domain Signaling at the Cytoplasmic Domain Adaptation Clustering of the Chemoreceptor and Sensitivity Future Studies References CHAPTER 35 Overview: Function and Three- Dimensional Structures of Ion Channels 203 Daniel L. Minor, Jr. Introduction Studies of Full-Length Ion Channels General Pore Features Revealed by Bacterial Channels viii Contents Pore Helices: Electrostatic Aids to Permeation Open Channels Eukaryotic Ion Channels at High Resolution: Divide and Conquer Ion Channel Accessory Subunits: Soluble and Transmembrane The Future: Ion Channels as Electrosomes References CHAPTER 36 How Do Voltage-Gated Channels Sense the Membrane Potential? 209 Chris S. Gandhi and Ehud Y. Isacoff Introduction The Voltage-Sensing Gating Particle S4 Is the Primary Voltage Sensor Physical Models of Activation: Turning a Screw through a Bolt Coupling Gating to S4 Voltage-Sensing Motions References CHAPTER 37 Ion Permeation: Mechanisms of Ion Selectivity and Block 215 Bertil Hille Aqueous Pore Ion Selectivity Block References CHAPTER 38 Agonist Binding Domains of Glutamate Receptors: Structure and Function 219 Mark L. Mayer References CHAPTER 39 Nicotinic Acetylcholine Receptors 223 Arthur Karlin Function Structure References CHAPTER 40 Small Conductance Ca2+-Activated K+ Channels: Mechanism of Ca2+ Gating 227 John P. Adelman Introduction Clones Encoding SK Channels Biophysical and Pharmacological Profiles Mechanisms of Ca2+-gating Pantophobiac After All References CHAPTER 41 Regulation of Ion Channels by Direct Binding of Cyclic Nucleotides 233 Edgar C. Young and Steven A. Siegelbaum Introduction The Cyclic Nucleotide-Gated Channels Other Channels Directly Regulated by Cyclic Nucleotides References Section C: Horizontal Receptors Robert Stroud, Editor CHAPTER 42 Overview of Cytokine Receptors 239 Robert M. Stroud CHAPTER 43 Growth Hormone and IL-4 Families of Hormones and Receptors: The Structural Basis for Receptor Activation and Regulation 241 Anthony A. Kossiakoff Introduction The Growth Hormone Family of Hormones and Receptors Structural Basis for Receptor Homodimerization Hormone Specificity and Cross-Reactivity Determine Physiological Roles Hormone-Receptor Binding Sites Receptor–Receptor Interactions Hormone–Receptor Binding Energetics Biological Implications of Transient Receptor Dimerization A High-Affinity Variant of hGH (hGHv) Reveals an Altered Mode for Receptor Homodimerization Site1 and Site2 Are Structurally and Functionally Coupled IL-4 Hormone-Induced Receptor Activation IL-4–α-Chain Receptor Interface Binding of the γ-Chain Receptor Comparisons of IL-4 with GH(PRL) Concluding Remarks References CHAPTER 44 Erythropoietin Receptor as a Paradigm for Cytokine Signaling 251 Deborah J. Stauber, Minmin Yu, and Ian A. Wilson Introduction Biochemical Studies Supporting Preformed Dimers Contents ix Other Cytokine Receptor Superfamily Members Conclusions References CHAPTER 45 A New Paradigm of Cytokine Action Revealed by Viral IL-6 Complexed to gp130: Implications for GCSF Interaction with GCSFR 259 Dar-chone Chow, Lena Brevnova, Xiao-lin He, and K. Christopher Garcia Introduction Receptor/Ligand Interactions The gp130 System Viral Interleukin-6 GCSF and GCSFR Structure of the Viral IL-6–gp130 Complex Site 1 The Site 2 Interface The Site 3 Interface Implications of the vIL-6–gp130 Tetramer Structure for the Active GCSF–GCSFR Extracellular Signaling Complex References CHAPTER 46 The Fibroblast Growth Factor (FGF) Signaling Complex 265 Fen Wang and Wallace L. McKeehan Introduction FGF Polypeptides FGFR Tyrosine Kinases Heparan Sulfate Oligomeric FGF–FGFR–HS Signaling Complex Intracellular Signal Transduction by the FGFR Complex References CHAPTER 47 Structure of IFN-γ and Its Receptors 271 Mark R. Walter References CHAPTER 48 Structure and Function of Tumor Necrosis Factor at the Cell Surface 275 Stephen R. Sprang Introduction Structure of Tumor Necrosis Factor TNF Receptors Extracellular (Ligand Binding) Domains of TNF Family Receptors Ligand–Receptor Complexes Consequences of Ligand–Receptor Complex Formation Receptor Preassociation Conclusion References CHAPTER 49 The Mechanism of NGF Suggested by the NGF–TrkA-D5 Complex 281 Abraham M. de Vos and Christian Wiesmann Introduction Neurotrophins Trks NGF–TrkA-D5 Complex p75NTR References CHAPTER 50 The Mechanism of VEGFR Activation Suggested by the Complex of VEGF–flt1-D2 285 Christian Wiesmann and Abraham M. de Vos Introduction Heparin-Binding Domain of VEGF Receptor-Binding Domain VEGF VEGF Receptors VEGF–flt1-D2 Complex References CHAPTER 51 Receptor–Ligand Recognition in the TGFβ Family as Suggested by the Crystal Structures of BMP-2–BR-IAec and TGFβ3–TR-IIec 289 Matthias K. Dreyer Introduction Ligand and Receptor Structures Receptor–Ligand Complexes BMP-2–BR-IAec Complex Complex Formation with TGFβ Is Different than for BMP-2 References CHAPTER 52 Insulin Receptor Complex and Signaling by Insulin 293 Lindsay G. Sparrow and S. Lance Macaulay Introduction Insulin Receptor Domain Structure Binding Determinants of the IR Insulin Signaling to Glucose Transport References x Contents CHAPTER 53 Structure and Mechanism of the Insulin Receptor Tyrosine Kinase 299 Steven R. Hubbard Introduction Structural/Mechanistic Studies Prospects References CHAPTER 54 What Does the Structure of Apo2L/ TRAIL Bound to DR5 Tell Us About Death Receptors? 305 Sarah G. Hymowitz and Abraham M. de Vos Introduction Novel Features in the Structure of Apo2L/TRAIL Apo2L/TRAIL:DR5 Structures Ligand-Independent Receptor Assembly Intracellular Consequences of Ligand Binding Conclusion References Section D: Membrane Proximal Events Tom Alber, Editor CHAPTER 55 TNF Receptor Associated Factors 311 Jee Y. Chung, Young Chul Park, Hong Ye, and Hao Wu References CHAPTER 56 Assembly of Signaling Complexes for TNF Receptor Family Molecules 315 Gail A. Bishop and Bruce S. Hostager Introduction Receptor Aggregation Raft Recruitment Ubiquitination Receptor Interactions Conclusions References CHAPTER 57 Mechanisms of CD40 Signaling in the Immune System 319 Aymen Al-Shamkhani, Martin J. Glennie, and Mark S. Cragg Introduction Signaling Pathways Triggered by CD40 Engagement CD40 Signaling Is Mediated by TRAF-Dependent and TRAF-Independent Pathways References CHAPTER 58 Role of Lipid Domains in EGF Receptor Signaling 323 Linda J. Pike Introduction Localization of the EGF Receptor to Lipid Rafts Rafts and EGF-Receptor-Mediated Signaling The EGF Receptor and Caveolin Summary References CHAPTER 59 Structure and Function of B-Cell Antigen Receptor Complexes 327 Michael Reth and Michael Huber Introduction The Structure of the B Cell Antigen Receptor Initiation of BCR Signaling Is Controlled by Redox Regulation References CHAPTER 60 Lipid-Mediated Localization of Signaling Proteins 331 Maurine E. Linder Introduction Protein Lipidation Summary References CHAPTER 61 G-Protein Organization and Signaling 335 Maria R. Mazzoni and Heidi E. Hamm Introduction G-Protein Molecular Organization Structural Features of G Protein Activation Structural Determinants of Receptor– G-Protein Specificity Gα Interactions with Effector Molecules Gβγ Interactions with Effector Molecules Conclusions References CHAPTER 62 JAK–STAT Signaling 343 Rashna Bhandari and John Kuriyan Introduction Cytokine Signaling Proteins JAK Structure and Localization Contents xi STAT Structure and Function Inhibition of Cytokine Signaling Summary References CHAPTER 63 Organization of Photoreceptor Signaling Complexes 349 Susan Tsunoda INAD Organizes Signaling Complexes INAD-Signaling Complexes in Phototransduction Assembly, Targeting, and Anchoring of Signaling Complexes Signaling Complexes in Vertebrate Photoreceptors References CHAPTER 64 Protein Localization in Negative Signaling 355 Jackson G. Egen and James P. Allison Introduction The Role of CD28 and CTLA-4 in T-Cell Activation Expression and Localization of CTLA-4 and CD28: Consequences for Receptor Function Mechanisms of CTLA-4-Mediated Negative Signaling Conclusions References CHAPTER 65 Transmembrane Receptor Oligomerization 361 Darren Tyson and Ralph A. Bradshaw Introduction Tyrosine Kinase-Containing Receptors Cytokine Receptors Guanylyl Cyclase-Containing Receptors Serine/Threonine Kinase-Containing Receptors Tumor Necrosis Factor Receptors Heptahelical Receptors (G-Protein-Coupled Receptors) Concluding Remarks References PART II TRANSMISSION: EFFECTORS AND CYTOSOLIC EVENTS Tony Hunter, Editor PART II Introduction 369 Tony Hunter, Editor Section A: Protein Phosphorylation Tony Pawson CHAPTER 66 Eukaryotic Kinomes: Genomic Cataloguing of Protein Kinases and Their Evolution 373 Tony Hunter and Gerard Manning Introduction The Yeasts: Saccharomyces cerevisiae and Schizosaccharomyces pombe Nematodes: Caenorhabditis elegans Insects: Drosophila melanogaster Vertebrates: Homo sapiens Comparative Kinomics Coda References CHAPTER 67 Modular Protein Interaction Domains in Cellular Communication 379 Tony Pawson and Piers Nash Introduction Phosphotyrosine-Dependent Protein– Protein Interactions Interaction Domains: A Common Theme in Signaling Adaptors, Pathways, and Networks Evolution of a Phospho-Dependent Docking Protein Multisite Phosphorylation, Ubiquitination, and Switch-Like Responses Summary References CHAPTER 68 Structures of Serine/Threonine and Tyrosine Kinases 387 Matthew A. Young and John Kuriyan Introduction Structures of Protein Kinases Structures of Inactive Protein Kinases Summary References CHAPTER 69 Protein Tyrosine Kinase Receptor Signaling Overview 391 Carl-Henrik Heldin Introduction PTK Subfamilies Mechanism of Activation Control of PTK Receptor Activity Cross-Talk Between Signaling Pathways xii Contents PTK Receptors and Disease References CHAPTER 70 Signaling by the Platelet-Derived Growth Factor Receptor Family 397 M. V. Kovalenko and Andrius Kazlauskas Introduction Platelet-Derived Growth Factors, Their Receptors, and Assembly of the PDGF Receptor Signaling Complex Some Aspects of Regulation of the PDGF Receptor-Initiated Signaling References CHAPTER 71 EGF Receptor Family 405 Mina D. Marmor and Yosef Yarden Introduction Domain Structure of ErbBs Subcellular Localization of ErbB Proteins ErbB-Induced Signaling Pathways Negative Regulatory Pathways Specificity of Signaling Through the ErbB Network ErbB Proteins and Pathological Conditions References CHAPTER 72 IRS-Protein Scaffolds and Insulin/IGF Action 409 Morris F. White IRS-Proteins: The Beginnings IRS-Proteins and Insulin Signaling IRS-Protein Structure and Function IRS-Protein Signaling in Growth, Nutrition, and Longevity Interleukin-4 and IRS2 Signaling Heterologous Regulation of IRS-Protein Signals IRS2 and Pancreatic β-Cells Summary References CHAPTER 73 Eph Receptors 421 Rüdiger Klein Introduction Ephs and Ephrins Eph Receptor Signaling Via Cytoplasmic Protein Tyrosine Kinases Eph Receptor Signaling Via Rho Family GTPases Effects on Cell Proliferation Eph Receptor Signaling through PDZ-Domain- Containing Proteins Eph Receptors and Cell Adhesion Ephrin Reverse Signaling EphrinB Reverse Signaling Via Phosphotyrosine EphrinB Reverse Signaling Via PDZ Domain Interactions Summary References CHAPTER 74 Cytokine Receptor Superfamily Signaling 427 James N. Ihle Cytokine Receptor Superfamily Signaling References CHAPTER 75 Negative Regulation of the JAK/STAT Signaling Pathway 431 Joanne L. Eyles and Douglas J. Hilton Introduction The Phosphatases STAT Phosphatases PIAS (Protein Inhibitors of Activated STATS) SOCS (Suppressors of Cytokine Signaling) Family Concluding Comments References CHAPTER 76 Activation of Oncogenic Protein Kinases 441 G. Steven Martin Introduction Physiological Regulation of Protein Kinases Activation of Protein Kinases by Retroviruses Activation of Protein Kinases in Human Cancer Oncogenic Protein Kinases as Targets for Therapy References CHAPTER 77 Protein Kinase Inhibitors 451 Alexander Levitzki Signal Transduction Therapy Protein Tyrosine Kinase Inhibitors SER/THR Kinase Inhibitors References CHAPTER 78 Integrin Signaling: Cell Migration, Proliferation, and Survival 463 J. Thomas Parsons, Jill K. Slack-Davis, and Karen H. Martin Introduction Integrins Nucleate the Formation of Multi- Protein Complexes Contents xiii Cell Migration: A Paradigm for Studying Integrin Signaling Integrin Regulation of Cell Proliferation and Survival: Links to Cancer Concluding Remarks References CHAPTER 79 Downstream Signaling Pathways: Modular Interactions 471 Bruce J. Mayer Introduction General Properties of Interaction Modules Roles in Signaling Prospects References CHAPTER 80 Non-Receptor Protein Tyrosine Kinases in T-Cell Antigen Receptor Function 475 Kiminori Hasegawa, Shin W. Kang, Chris Chiu and Andrew C. Chan Introduction T-Cell Antigen Receptor Structure Src PTKs Csk (c-Src PTK) ZAP-70/Syk PTKs Tec PTKs Summary References CHAPTER 81 Cbl: A Physiological PTK Regulator 483 Wallace Y. Langdon Introduction Domains of Cbl Proteins Sli-1: A Negative Regulator of RPTKs PTK Downregulation by Polyubiquitylation Cbl-Deficient Mice Future Directions References CHAPTER 82 TGFβ Signal Transduction 487 Jeffrey L. Wrana Introduction The Smad Pathway Smads and the Ubiquitin–Proteasome System Smad-Independent Signaling Pathways Other Receptor Interaction Proteins References CHAPTER 83 MAP Kinases 493 James R. Woodgett Introduction The ERK Module Stress-Activated MAPKs, Part 1: SAPK/JNKs Stress-Activated MAPKs, Part 2: p38 MAPKs MAPKKs MAPKKKs MAPKKKKs Summary References CHAPTER 84 Cytoskeletal Regulation: Small G-Protein–Kinase Interactions 499 Ed Manser Introduction P21-Activated Kinases Myotonic Dystrophy Kinase-Related Cdc42- Binding Kinase Rho-Associated Kinase (ROK) References CHAPTER 85 Recognition of Phospho- Serine/Threonine Phosphorylated Proteins 505 Stephen J. Smerdon and Michael B. Yaffe Introduction 14-3-3 Proteins FHA Domains WW Domains Leucine-Rich Repeats and WD40 Domains Concluding Remarks References CHAPTER 86 Role of PDK1 in Activating AGC Protein Kinase 513 Dario R. Alessi Introduction Mechanisms of Activation of PKB PKB Is Activated by PDK1 Activation of Other Kinases by PDK1 Phenotype of PDK1 PKB- and S6K-Deficient Mice and Model Organisms Hydrophobic Motif of AGC Kinases Mechanisms of Regulation of PDK1 Activity Structure of the PDK1 Catalytic Domain Concluding Remarks References xiv Contents CHAPTER 87 Regulation of Cell Growth and Proliferation in Metazoans by mTOR and the p70 S6 Kinase 523 Joseph Avruch Introduction Functions of TOR Signaling from TOR Regulation of mTOR Activity References CHAPTER 88 AMP-Activated Protein Kinase 535 D. Grahame Hardie Introduction Structure of the AMPK Complex Regulation of the AMPK Complex Regulation in Intact Cells and Physiological Targets Medical Implications of the AMPK System References CHAPTER 89 Principles of Kinase Regulation 539 Bostjan Kobe and Bruce E. Kemp Introduction Protein Kinase Structure General Principles of Control Regulatory Sites in Protein Kinase Domains Conclusions References CHAPTER 90 Calcium/Calmodulin-Dependent Protein Kinase II 543 Mary B. Kennedy Introduction Structure of CaMKII Regulation by Autophosphorylation Regulatory Roles of CaMKII in Neurons References CHAPTER 91 Glycogen Synthase Kinase 3 547 Philip Cohen and Sheelagh Frame Introduction The Substrate Specificity of GSK3 The Regulation of GSK3 Activity by Insulin and Growth Factors GSK3 as a Drug Target The Role of GSK3 in Embryonic Development GSK3 and Cancer References CHAPTER 92 Protein Kinase C: Relaying Signals from Lipid Hydrolysis to Protein Phosphorylation 551 Alexandra C. Newton Introduction Protein Kinase C Family Regulation of Protein Kinase C Function of Protein Kinase C Summary References CHAPTER 93 The PIKK Family of Protein Kinases 557 Graeme C. M. Smith and Stephen P. Jackson Introduction Overview of PIKK Family Members Overall Architecture of PIKK Family Proteins MTOR: A Key Regulator of Cell Growth DNA-Pkes: At the Heart of the DNA Nonhomologous End-Joining Machinery ATM and ATR: Signalers of Genome Damage SMG-1: A Regulator of Nonsense-Mediated mRNA Decay TRRAP: A Crucial Transcriptional Co-Activator PIKK Family Members as Guardians of Nucleic Acid Structure, Function, and Integrity? References CHAPTER 94 Histidine Kinases 563 Fabiola Janiak-Spens and Ann H. West References CHAPTER 95 Atypical Protein Kinases: The EF2/MHCK/ChaK Kinase Family 567 Angus C. Nairn Introduction Identification of an Atypical Family of Protein Kinases: EF2 Kinase, Myosin Heavy Chain Kinase and ChaK The Structure of the Atypical Kinase Domain Reveals Similarity to Classical Protein Kinases and to Metabolic Enzymes with ATP-Grasp Domains Substrate Specificity of Atypical Kinases Regulation of Atypical Kinases Functions of the Atypical Family of Protein Kinases References Contents xv xvi Contents CHAPTER 96 Casein Kinase I and Regulation of the Circadian Clock 575 Saul Kivimäe, Michael W. Young, and Lino Saez Introduction double-time: A Casein Kinase I Homolog in Drosophila Casein Kinase I in the Mammalian Clock Casein Kinase I in the Neurospora Clock Similarities and Differences of CKI Function in Different Clock Systems References CHAPTER 97 The Leucine-Rich Repeat Receptor Protein Kinases of Arabidopsis thaliana: A Paradigm for Plant LRR Receptors 579 John C. Walker and Kevin A. Lease Introduction LRR Receptor Protein Kinases: The Genomic Point of View LRR Receptor Protein Kinases: The Functional View Summary References CHAPTER 98 Engineering Protein Kinases with Specificity for Unnatural Nucleotides and Inhibitors 583 Chao Zhang and Kevan M. Shokat References Section B: Protein Dephosphorylation Jack E. Dixon, Editor CHAPTER 99 Overview of Protein Dephosphorylation 591 Jack E. Dixon CHAPTER 100 Protein Serine/Threonine Phosphatases and the PPP Family 593 Patricia T. W. Cohen Current Classification of Protein Serine/Threonine Phosphatases Background Evolution and Conserved Features of the PPP Family Catalytic Activities of the PPP Family Members Eukaryotic PPP Subfamilies Domain and Subunit Structure of PPP Family Members Medical Importance of the PPP Family References CHAPTER 101 The Structure and Topology of Protein Serine/Threonine Phosphatases 601 David Barford Introduction Protein Serine/Threonine Phosphatases of the PPP Family Protein Serine/Threonine Phosphatases of the PPM Family Conclusions References CHAPTER 102 Naturally Occurring Inhibitors of Protein Serine/Threonine Phosphatases 607 Carol MacKintosh and Julie Diplexcito Introduction Effects of Inhibitors in Cell-Based Experiments The Toxins Bind to the Active Sites of Protein Phosphatases Chemical Synthesis of Protein Phosphatase Inhibitors Microcystin Affinity Chromatography and Affinity Tagging Avoiding the Menace of Toxins in the Real World Outside the Laboratory References CHAPTER 103 Protein Phosphatase 1 Binding Proteins 613 Anna A. Depaoli-Roach Introduction Protein Phosphatase 1 (PP1) PP1 Regulatory or Targeting Subunits Conclusions References CHAPTER 104 Role of PP2A in Cancer and Signal Transduction 621 Gernot Walter Introduction Structure of PP2A Subunit Interaction Association of PP2A with Cellular Proteins Alteration or Inhibition of PP2A Is Essential in Human Cancer Development Mutation of Aα and Aβ Isoforms in Human Cancer Differences between Aα and Aβ Subunits PP2A and Wnt Signaling PP2A and MAP Kinase Pathway Summary References Contents xvii CHAPTER 105 Serine/Threonine Phosphatase Inhibitor Proteins 627 Shirish Shenolikar Introduction Protein Phosphatase 1 (PP1) Inhibitors I-1, DARPP-32, and Other Phosphorylation- Dependent Phosphatase Inhibitors Latent Phosphatase Complexes Activated by Inhibitor Phosphorylation Inhibitors of Type-2 Serine/Threonine Phosphatases Conclusions References CHAPTER 106 Calcineurin 631 Claude B. Klee and Seun-Ah Yang Introduction Enzymatic Properties Structure Regulation Distribution and Isoforms Functions Muscle Differentiation Conclusion References CHAPTER 107 Protein Serine/Threonine-Phosphatase 2C (PP2C) 637 Hisashi Tatabe and Kazuhiro Shiozaki Introduction Regulation of the Stress-Activated MAP Kinase Cascades Control of the CFTR Chloride Channel by PP2C Plant Hormone Abscisic Acid Signaling Fem-2: A Sex-Determining PP2C in Nematode Stress-Responsive PP2Cs in Bacillus subtilis References CHAPTER 108 Overview of Protein Tyrosine Phosphatases 641 Nicholas K. Tonks Background Structural Diversity within the PTP Family The Classical PTPs The Dual Specificity Phosphates (DSPs) Regulation of PTP Function Oxidation of PTPs in Tyrosine Phosphorylation- Dependent Signaling Substrate Specificity of PTPs PTPs and Human Disease Perspectives References CHAPTER 109 Protein Tyrosine Phosphatase Structure and Mechanisms 653 Youngjoo Kim and John M. Denu Introduction Introduction to the Protein Tyrosine Phosphatase Family Structure Mechanism Regulation References CHAPTER 110 Bioinformatics: Protein Tyrosine Phosphatases 659 Niels Peter H. Møller, Peter Gildsig Jansen, Lars F. Iversen, and Jannik N. Andersen Introduction to Bioinformatics Amino Acid Homology Among PTP Domains and Structure-Function Studies Identification of the Genomic Complement of PTPs Functional Aspects of PTPs in Health and Disease: Bioinformatics References CHAPTER 111 PTP Substrate Trapping 671 Andrew J. Flint Introduction Original C→S and D→A Substrate-Trapping Mutants Second-Generation Trapping Mutants Accessory or Noncatalytic Site Contributions to Substrate Recognition New Twists on Trapping Other Applications of Substrate Trapping Mutants References CHAPTER 112 Inhibitors of Protein Tyrosine Phosphatases 677 Zhong-Yin Zhang Introduction Covalent PTP Modifiers Oxyanions as PTP Inhibitors PTyr Surrogates as PTP Inhibitors Bidentate PTP Inhibitors Other PTP Inhibitors Concluding Remarks References CHAPTER 113 Regulating Receptor PTP Activity 685 Erica Dutil Sonnenburg, Tony Hunter, and Joseph P. Noel Introduction Regulation by Dimerization Regulation by Phosphorylation Regulation by D2 Domain References CHAPTER 114 CD45 689 Zheng Xu, Michelle L. Hermiston, and Arthur Weiss Introduction Structure Function Regulation References CHAPTER 115 Properties of the Cdc25 Family of Cell-Cycle Regulatory Phosphatases 693 William G. Dunphy Introduction Physiological Functions of Cdc25 Regulation of Cdc25 Concluding Remarks References CHAPTER 116 Cell-Cycle Functions and Regulation of Cdc14 Phosphatases 697 Harry Charbonneau Introduction The Cdc14 Phosphatase Subgroup of PTPs Budding Yeast Cdc14 is Essential for Exit from Mitosis Fission Yeast Cdc14 Coordinates Cytokinesis with Mitosis Potential Cell-Cycle Functions of Human Cdc14A and B References CHAPTER 117 MAP Kinase Phosphatases 703 Marco Muda and Steve Arkinstall Introduction MAPK Phosphatases in Yeast A MAPK Phosphatase in C. elegans MAPK Phosphatases in Drosophila melanogaster MAPK Phosphatases in Mammals Summary References CHAPTER 118 SH2-Domain-Containing Protein– Tyrosine Phosphatases 707 Benjamin G. Neel, Haihua Gu, and Lily Pao History and Nomenclature Structure, Expression, and Regulation Biological Functions of Shps Shp Signaling and Substrates Determinants of Shp Specificity Shps and Human Disease Summary and Future Disease References CHAPTER 119 Insulin Receptor PTP: PTP1B 729 Alan Cheng and Michel L. Tremblay Introduction PTP1B as a Bona Fide IR Phosphatase PTP1B Gene Polymorphisms and In