Handbook ofCell Signaling

Volume 1

Ralph A. Bradshaw

Edward A. Dennis

VOLUME 1 ProspectsReferences

Contributors

xlv

CHAPTER3Preface

lxvii

Computational Genomics: Prediction

CHAPTER Z

of Protein Functional Linkagesand Networks

15Cell Signaling : Yesterday, Today, and Todd O . Yeates and Michael J. Thompso nTomorrow

1Ralph A. Bradshaw and Edward A . Dennis

IntroductionApproaches to Analyzing Protein Functions on a

Origins of Cell Signaling

Genome-Wide ScaleEnter Polypeptide Growth Factors

Current Issues and Future Prospects for Computin gCell Signaling at the Molecular Level

Functional Interaction sLipid Signaling

ReferencesCell Signaling TomorrowReferences

CHAPTER4Molecular Sociology

21PARTI

Irene M . A . Nooren and Janet M . Thornton

INITIATION : EXTRACELLULAR

Transmembrane Signaling Paradigm s

AND MEMBRANE EVENTS

Structural Basis of Protein-Protein Recognition

James Wells, Editor

Conclusio nReference s

Section A: Molecular Recognition

CHAPTER$Ian Wilson, Editor

-Free Energy Landscapes in

CHAPTER 2

Protein-Protein Interactions

27Jacob Piehler and Gideon Schreiber

Structural and Energetic Basis o fMolecular Recognition

11 Introduction

Emil Alexov and Barry Honig

Thermodynamics of Protein-Protein InteractionsInteraction Kinetic s

Introduction

The Transition StatePrinciples of Binding

Association of a Protein Comple xNonspecific Association with Membrane

Dissociation of a Protein ComplexSurfaces

SummaryProtein-Protein Interactions

References

CHAPTER6

CHAPTER 1 1Antibody-Antigen Recognition and

T-Cell Receptor/pMHC Complexes

63Conformational Changes

33 Markus G . Rudolph and Ian A . Wilson

Robyn L. Stanfield and Ian A . Wilson

TCR Generation and Architecture

Introduction

Peptide Binding to MHC Class I and II

Antibody Architecture

TCR/pMHC Interactio n

Conformational Changes

Conclusions and Future Perspective s

Conclusion

References

ReferencesCHAPTER 12

CHAPTER 7

Mechanistic Features of Cell-Surfac eBinding Energetics in Antigen-

Adhesion Receptors

74Antibody Interfaces

39

Steven C . Almo, Anne R. Bresnick, and Xuewu Zhan g

Roy A . Mariuzza

Mechanosensory Mechanism s

Introduction

Cell-Cell Adhesions/Adherens Junction s

Thermodynamic Mapping of Antigen-

T Cell Costimulatio n

Antibody Interfaces

Axon Guidance and Neural Development

Conclusions

Conclusion s

References

Reference s

CHAPTER8

CHAPTER 13

Immunoglobulin-Fc Receptor

The Immunological Synapse

79

Interactions

45

Michael L . Dusti n

Brian J . Sutton, Rebecca L. Beavil, and

IntroductionAndrew J . Beavil

Migration and the Immunological Synapse

Introduction

The Cytoskeleton and the Immunological Synaps e

IgG-Receptor Interactions

The Role of Self MHCp in T-Cell Sensitivity t o

IgE-Receptor Interactions

Foreign MHCp

Summary

Integration of Adaptive and Innate Responses

References

SummaryReference s

CHAPTER9

CHAPTER 14Plasticity of Fc Recognition

51 NK Receptors

83Warren L . DeLano

Roland K. Strong

Introduction

IntroductionStructures of the Natural Fc Binding Domains

ImmunoreceptorsThe Consensus Binding Site on Fc

Natural Killer CellsEvolution of an Fc Binding Peptide

Ig-Type NK Receptors : KIRFactors Promoting Plasticity

C-Type Lectin-Like NK Receptors : Ly49AConserved and Functionally Important

C-Type Lectin-Like NK Receptors : NKG2 DMolecular Interactions

ReferencesConclusionReferences

CHAPTER 15

CHAPTER 10

Carbohydrate Recognition and Signaling 87James M. Rini and Hakon Leffler

Ig-Superfold and Its Variable Uses i nMolecular Recognition

57 Introductio n

Nathan R . Zaccai and E . Yvonne Jones

Biological Roles of Carbohydrate RecognitionCarbohydrate Structure and Diversit y

Introduction

Lectins and Carbohydrate RecognitionThe Immunoglobulin Superfamily

Carbohydrate-Mediated Signalin gIg-Superfold-Mediated Recognition

Conclusion sReferences

References

CHAPTER 16

Concluding Remarks

Rhinovirus-Receptor Interactions

95 Reference s

Elizabeth Hewat

CHAPTER 22References

Structures of Heterotrimeric G Proteins

CHAPTER 17

and Their Complexes

127Stephen R . Sprang

HIV-1 Receptor Interactions

99Peter D. Kwong

IntroductionGa Subunits

Molecular Interactions

Ga-Effector Interaction sAtomic Details

GTP Hydrolysis by Ga and Its Regulation byRecognition in the Context of a Humoral

RGS Protein sImmune Response

G(3y DimersReferences

GPRIGoLoco MotifsGa-GPCR Interaction s

CHAPTER 18

ReferencesInfluenza Virus Neuraminidas eInhibitors

105

Section B: Vertical ReceptorsGarry L. Taylor Henry Bourne, Editor

IntroductionFlu Virus : Role of NA

CHAPTER 23Structure of NA

Structure and Function of G-Protein-Active SiteInhibitor Development

Coupled Receptors : Lessons from th eConclusion

Crystal Structure of Rhodopsin

139References

Thomas P. Sakmar

IntroductionCHAPTER 19 Introduction to Rhodopsin : a Prototypica lSignal Transduction and Integral

G-Protein-Coupled Recepto rMembrane Proteins

115 Molecular Structure of RhodopsinGeoffrey Chang and Christopher B . Roth

Molecular Mechanism of Receptor Activatio n

Introduction

Reference s

Electrophysiology : Rapid Signal Transduction

CHAPTER 24Mechanosensation: How Do We Feel?

Human Olfactory Receptors

145Active Transporters : Rapid Response and

Oma Man, Tsviya Olender, and Doran Lance tEnergy Management

Receptors : Gate Keepers for Cell Signaling

ReferencesReferences

CHAPTER 25CHAPTER 20

Chemokines and Chemokine Receptors :Structural Basis of Signaling Events

Structure and Function

149Involving Fibrinogen and Fibrin

119

Carol J . Raport and Patrick W. Gray

Russell F. Doolittle

Introduction

References

Chemokine Structure and Functio nChemokine Receptors

CHAPTER 21

Reference s

Structural Basis of Integrin Signaling

123 CHAPTER 26Robert C . Liddington

The Binding Pocket of G-Protein -Introduction

Coupled Receptors for BiogenicStructureQuaternary Changes

Amines, Retinal, and Other Ligands

155Tertiary Changes

Lei Shi and Jonathan A . Javitc h

Tail Interactions

Introduction

The Binding Pocket of GPCRs

CHAPTER 31A Role of the Second Extracellular Loop i n

Ligand Binding

Agonist-Induced Desensitization

References

and Endocytosis of G-Protein -Coupled Receptors

181CHAPTER 27

Mark von Zastrow

Glycoprotein Hormone Receptors : A

IntroductionUnique Paradigm for Ligand Binding

General Processes of GPCR Regulation

and GPCR Activation

161 Mechanisms of GPCR Desensitizatio n

Gilbert Vassart, Marco Bonomi, Sylvie Claeysen, Cedric

and Endocytosi sGovaerts, Su-Chin Ho, Leonardo Pardo, Guillaume Smits,

Functional Consequences of GPCR Endocytosi sVirginie Vlaeminck, and Sabine Costagliola

References

Introduction

CHAPTER 32Molecular Pathophysiolog yStructure Function Relationships of the Glycoprotein

Functional Role(s) of Dimeri cHormone Receptors

Complexes Formed from G-Protein-Conclusions and Perspectives

Coupled Receptors

187References

Marta Margeta-Mitrovic and Lily Yuh Ja n

CHAPTER 28

References

Protease-Activated Receptors

167 CHAPTER 33Shaun R . Coughlin

The Role of Chemokine Receptors i nIntroduction

HIV Infection of Host Cells

191Mechanisms of Activation

Jacqueline D . Reeves and Robert W. Dom sProtease-Activated Receptor FamilyRoles of PARs In Vivo

Introduction

References

HIV EntryCoreceptor Use In Vivo

CHAPTER 29

Env Domains Involved in Coreceptor Interaction s

Constitutive and Regulated Signaling in

Coreceptor Domains Involved in HIV Infectio n

Virus-Encoded 7TM Receptors

173 Receptor Presentation and Processing

Thue Schwartz

Role of Signaling in H1V InfectionSummary

Virus-Encoded Proteins Are Developed through

Reference sTargeted Evolution In Vivo

The Redundant Chemokine System Is an Optimal

CHAPTER 34Target for Viral Exploitation

Chemotaxis Receptor in Bacteria :Multiple Virus-Encoded 7TM Receptors

Transmembrane Signaling, Sensitivity,Constitutive signaling through Altered Pathways

Adaptation, and Receptor Clustering

197Viral Receptors Recognize Multiple Ligands wit h

Variable Function

Weiru Wang and Sung-Hou Ki m

Attempts to Identify the Function of Virus-Encoded

Signaling at Periplasmic Ligand Binding Domai nReceptors In Vivo

Signaling at the Cytoplasmic DomainReferences

Adaptatio nClustering of the Chemoreceptor and Sensitivit y

CHAPTER 30

Future Studie s

Frizzleds as G-Protein-Coupled Receptors

Reference s

for Wnt Ligands

177CHAPTER 35Sarah H . Louie, Craig C . Malbon, Randall T. MoonOverview: Function and Three -

Introduction

Dimensional Structures of Ion Channels 203Wnt SignalingEvidence for Frizzleds as G-Protein- Coupled

Daniel L . Minor, Jr.

Receptors

Introductio nPerspective

Studies of Full-Length Ion ChannelsReferences

General Pore Features Revealed by Bacterial Channels

Pore Helices : Electrostatic Aids to Permeation

CHAPTER 4 1Open Channels

Regulation of Ion Channels by Direc tEukaryotic Ion Channels at High Resolution :

Divide and Conquer

Binding of Cyclic Nucleotides

233Ion Channel Accessory Subunits : Soluble

Edgar C . Young and Steven A . Siegelbaum

and Transmembrane

Introductio nThe Future : Ion Channels as Electrosomes

The Cyclic Nucleotide-Gated Channel sReferences

Other Channels Directly Regulated b y

36

Cyclic Nucleotide sCHAPTER Reference sHow Do Voltage-Gated Channels Sensethe Membrane Potential?

209Chris S . Gandhi and Ehud Y. Isacoff

Section C: Horizontal ReceptorsRobert Stroud, Editor

Introductio nThe Voltage-Sensing Gating Particl eS4 Is the Primary Voltage Sensor

CHAPTER 42Physical Models of Activation : Turning a Screw

Overview of Cytokine Receptors

239through a Bolt

Robert M. StroudCoupling Gating to S4 Voltage-Sensing MotionsReferences

CHAPTER 43CHAPTER 37

Growth Hormone and IL-4 Familie sIon Permeation : Mechanisms of Ion

of Hormones and Receptors: TheSelectivity and Block

215 Structural Basis for Receptor ActivationBertil Hille

and Regulation

241Aqueous Pore

Anthony A . Kossiakoff

Ion Selectivity

IntroductionBlock

The Growth Hormone Family of Hormone sReferences

and Receptors

CHAPTER 38

Structural Basis for Receptor Homodimerizatio nHormone Specificity and Cross-Reactivity Determine

Agonist Binding Domains of Glutamate

Physiological Role sReceptors : Structure and Function

219 Hormone-Receptor Binding SitesMark L . Mayer

Receptor-Receptor Interactions

References

Hormone-Receptor Binding EnergeticsBiological Implications of Transient

CHAPTER 39

Receptor DimerizationA High-Affinity Variant of hGH (hGH,) Reveals an

Nicotinic Acetylcholine Receptors

223

Altered Mode for Receptor Homodimerizatio nArthur Karlin

Sitel and Site2 Are Structurally and

Function

Functionally Couple d

Structure

IL-4 Hormone-Induced Receptor Activatio n

References

IL-4-a-Chain Receptor InterfaceBinding of the y-Chain Recepto r

CHAPTER 40

Comparisons of IL-4 with GH(PRL )

Small Conductance Ca t+-Activated K+

Concluding Remarks

Channels : Mechanism of Cat+ Gating

227 References

John P. Adelman

CHAPTER 44Introduction

Erythropoietin Receptor as a Paradig mClones Encoding SK Channels

for Cytokine Signaling

251Biophysical and Pharmacological ProfilesMechanisms of Cat+ gating

Deborah J . Stauber, Minmin Yu, and Ian A . Wilson

Pantophobiac After All

IntroductionReferences

Biochemical Studies Supporting Preformed Dimers

Other Cytokine Receptor Superfamily Members

Ligand-Receptor Complexe sConclusions

Consequences of Ligand-ReceptorReferences

Complex FormationReceptor Preassociation

CHAPTER 45

Conclusion

A New Paradigm of Cytokine Action

References

Revealed by Viral IL-6 Complexed

CHAPTER 49to gpl3O: Implications for GCS FInteraction with GCSFR

259 The Mechanism of NGF Suggeste d

Dar-chone Chow, Lena Brevnova, Xiao-lin He, and

by the NGF-TrkA-D5 Complex

28 1K. Christopher Garcia

Abraham M. de Vos and Christian Wiesman n

Introduction

Introduction

Receptor/Ligand Interactions

Neurotrophin s

The gp130 System

Trks

Viral Interleukin-6p7F-

rkA DS Comple x5NT R

GCSF and GCSFRStructure of the Viral IL-6-gp 130 Complex

References

Site 1The Site 2 Interface

CHAPTER 50The Site 3 Interface

The Mechanism of VEGFR Activatio nImplications of the vIL-6-gp130 Tetramer

Suggested by the Complex ofStructure for the Active GCSF-GCSFR

VEGF-fltl-D2

285Extracellular Signaling Complex

Christian Wiesmann and Abraham M. de Vo sReferences

Introductio n

CHAPTER 46

Heparin-Binding Domain of VEGF

The Fibroblast Growth Factor (FGF)

Receptor Binding Domain VEGFVEGF Receptors

Signaling Complex

265 VEGF-ßtl-D2 ComplexFen Wang and Wallace L. McKeehan

Reference s

IntroductionFGF Polypeptides

CHAPTER 5 1FGFR Tyrosine Kinases

Receptor-Ligand Recognition in theHeparan Sulfate

TGFß Family as Suggested by theOligomeric FGF-FGFR-HS Signaling Complex

Crystal Structures of BMP-2-BR-IAeCIntracellular Signal Transduction by the

and TGFß3-TR-II ec

289FGFR ComplexReferences

Matthias K . Dreyer

IntroductionCHAPTER 47

Ligand and Receptor Structure s

Structure of IFN-y and Its Receptors

271 Receptor-Ligand Complexes

Mark R. Walter

BMP-2-BR-IA ec ComplexComplex Formation with TGFß Is Different

References

than for BMP- 2Reference s

CHAPTER 48Structure and Function of

CHAPTER 52Tumor Necrosis Factor at the

Insulin Receptor Complex and Signalin gCell Surface

275 by Insulin

293Stephen R . Sprang

Lindsay G. Sparrow and S . Lance Macaulay

Introduction

IntroductionStructure of Tumor Necrosis Factor

Insulin Receptor Domain StructureTNF Receptors

Binding Determinants of the IRExtracellular (Ligand Binding) Domains of TNF

Insulin Signaling to Glucose TransportFamily Receptors

References

CHAPTER 53

CD40 Signaling Is Mediated by TRAF-Dependen t

Structure and Mechanism of the

and TRAF Independent Pathways

Insulin Receptor Tyrosine Kinase

299Reference s

Steven R . Hubbard

CHAPTER 58Introduction

Role of Lipid Domains in EGFStructural/Mechanistic Studies

Receptor Signaling

323Prospects

Linda J . PikeReferences

Introductio n

CHAPTER 54

Localization of the EGF Receptor to Lipid Raft sRafts and EGF-Receptor-Mediated Signaling

What Does the Structure of Apo2L/

The EGF Receptor and Caveoli nTRAIL Bound to DR5 Tell Us About

SummaryDeath Receptors?

305 Reference sSarah G. Hymowitz and Abraham M . de Vos

Introduction

CHAPTER 59

Novel Features in the Structure of Apo2L/TRAIL

Structure and Function of B-Cel lApo2L/TRAIL :DR5 Structures

Antigen Receptor Complexes

327Ligand-Independent Receptor Assembly

Michael Reth and Michael Huber

Intracellular Consequences of Ligand Binding

Introductio nConclusion

The Structure of the B Cell Antigen ReceptorReferences

Initiation of BCR Signaling Is Controlled b yRedox Regulation

Reference sSection D: Membrane Proximal Events

Tom Alber, Editor

CHAPTER 60Lipid-Mediated Localization of

CHAPTER 55

Signaling Proteins

331

TNF Receptor Associated Factors

311 Maurine E . Linder

Jee Y. Chung, Young Chul Park, Hong Ye, and Hao Wu

Introduction

References

Protein LipidationSummary

CHAPTER 56

Reference s

Assembly of Signaling Complexes for

CHAPTER 61TNF Receptor Family Molecules

315 G-Protein Organization and Signaling

335Gail A . Bishop and Bruce S . Hostager

Maria R. Mazzoni and Heidi E. Hamm

Introduction

IntroductionReceptor Aggregation

G-Protein Molecular Organizatio nRaft Recruitment

Structural Features of G Protein ActivationUbiquitination

Structural Determinants of Receptor-Receptor Interactions

G-Protein SpecificityConclusions

Ga Interactions with Effector MoleculesReferences

G(3y Interactions with Effector Molecule sConclusion s

CHAPTER 57

References

Mechanisms of CD40 Signaling in th eImmune System

319 CHAPTER 62Aymen Al-Shamkhani, Martin J . Glennie, and

JAK-STAT Signaling

343Mark S . Cragg

Rashna Bhandari and John Kuriya n

Introduction

IntroductionSignaling Pathways Triggered by CD40

Cytokine Signaling Protein sEngagement

JAK Structure and Localization

STAT Structure and Function

Section A: Protein Phosphorylatio nInhibition of Cytokine Signaling

Tony PawsonSummaryReferences CHAPTER 66CHAPTER 63

Eukaryotic Kinomes: GenomicOrganization of Photoreceptor

Cataloguing of Protein Kinases and

Signaling Complexes

349 Their Evolution

373Susan Tsunoda

Tony Hunter and Gerard Mannin g

INAD Organizes Signaling Complexes

Introduction

INAD-Signaling Complexes in Phototransduction

The Yeasts : Saccharomyces cerevisiae and

Assembly, Targeting, and Anchoring of Signaling

Schizosaccharomyces pombe

Complexes

Nematodes : Caenorhabditis elegans

Signaling Complexes in Vertebrate Photoreceptors

Insects : Drosophila melanogaste r

References

Vertebrates : Homo sapien sComparative Kinomic s

CHAPTER 64

Coda

Protein Localization in

Reference s

Negative Signaling

355 CHAPTER 67Jackson G. Egen and James P. Allison

Modular Protein Interaction Domain sIntroduction

in Cellular Communication

379The Role of CD28 and CTLA-4 in T-Cell Activation

Tony Pawson and Piers Nas h

Expression and Localization of CTLA-4 and CD28 :

IntroductionConsequences for Receptor Function

Phosphotyrosine-Dependent Protein -Mechanisms of CTLA-4-Mediated Negative Signaling

Protein Interaction sConclusions Interaction Domains : A Common ThemeReferences in Signaling

Adaptors, Pathways, and NetworksCHAPTER 65

Evolution of a Phospho-Dependent Docking Protei n

Transmembrane Receptor

Multisite Phosphorylation, Ubiquitination, an d

Oligomerization

361

Switch-Like Response s

Darren Tyson and Ralph A . Bradshaw

SummaryRe

Introduction

ferences

Tyrosine Kinase-Containing Receptors

CHAPTER68Cytokine Receptors Structures of Serine/Threonine andGuanylyl Cyclase-Containing ReceptorsSerine/Threonine Kinase-Containing Receptors

Tyrosine Kinases

387Tumor Necrosis Factor Receptors

Matthew A . Young and John Kuriya n

Heptahelical Receptors

Introduction(G-Protein-Coupled Receptors)

Structures of Protein Kinase sConcluding Remarks

Structures of Inactive Protein Kinase sReferences

Summary

Reference s

PART II

CHAPTER69

TRANSMISSION: EFFECTORS AND Protein Tyrosine Kinase Receptor

CYTOSOLIC EVENTS

Signaling Overview

39 1Carl-Henrik Heldin

Tony Hunter, EditorIntroductionPTK Subfamilies

PART II Mechanism of ActivationIntroduction

369

Control of PTK Receptor ActivityTony Hunter, Editor

Cross-Talk Between Signaling Pathways

PTK Receptors and Disease

Eph Receptors and Cell Adhesio nReferences

Ephrin Reverse Signalin gEphrinB Reverse Signaling Via Phosphotyrosin e

CHAPTER70

EphrinB Reverse Signaling Via PD Z

Signaling by the Platelet-Derived

Domain Interactions

Growth Factor Receptor Family

397SummaryReference s

M . V. Kovalenko and Andrius Kazlauska s

Introduction

CHAPTER 74Platelet-Derived Growth Factors, Their

Cytokine Receptor Superfamil yReceptors, and Assembly of the PDGF

Signaling

427Receptor Signaling Complex

James N . IhleSome Aspects of Regulation of the PDGF

Receptor-Initiated Signaling

Cytokine Receptor Superfamily Signaling

References

References

CHAPTER 71

CHAPTER 75

EGF Receptor Family

405 Negative Regulation of the JAK/STATMina D . Marmor and Yosef Yarden

Signaling Pathway

431Joanne L . Eyles and Douglas J . Hilton

IntroductionDomain Structure of ErbBs

Introductio n

Subcellular Localization of ErbB Proteins

The Phosphatase s

ErbB-Induced Signaling Pathways

STAT Phosphatases

Negative Regulatory Pathways

PIAS (Protein Inhibitors of Activated STATS )Specificity of Signaling Through the ErbB Network

SOCS (Suppressors of Cytokine Signaling) FamilyErbB Proteins and Pathological Conditions

Concluding Comments

References

Reference s

CHAPTER 72

CHAPTER76

IRS-Protein Scaffolds and Insulin/IGF

Activation of Oncogenic Protein Kinases 441Action

409

G. Steven Marti n

Morris F. White

Introduction

IRS Proteins : The Beginnings

Physiological Regulation of Protein Kinases

IRS Proteins and Insulin Signaling

Activation of Protein Kinases by Retroviruse s

IRS Protein Structure and Function

Activation of Protein Kinases in Human Cance rOncogenic Protein Kinases as Targets for Therapy

IRS-Protein Signaling in Growth, Nutrition,

Referencesand Longevity

Interleukin-4 and IRS2 Signaling

CHAPTER 77Heterologous Regulation of IRS-Protein Signal sIRS2 and Pancreatic ß Cells

Protein Kinase Inhibitors

451Summary

Alexander Levitzk i

References

Signal Transduction Therap yProtein Tyrosine Kinase Inhibitor s

CHAPTER 73

SERITHR Kinase Inhibitors

Eph Receptors

421 Reference s

Rüdiger KleinCHAPTER 78

Introduction

Integrin Signaling : Cell Migration ,Ephs and Ephrin sEph Receptor Signaling Via Cytoplasmic Protein

Proliferation, and Survival

463Tyrosine Kinases

J . Thomas Parsons, Jill K. Slack-Davis, an d

Eph Receptor Signaling Via Rho Family GTPases

Karen H. Marti n

Effects on Cell Proliferation

IntroductionEph Receptor Signaling through PDZ-Domain-

Integrins Nucleate the Formation of Multi -Containing Proteins

Protein Complexes

Cell Migration : A Paradigm for Studying

CHAPTER 83Integrin Signaling

MAP Kinases

493Integrin Regulation of Cell Proliferation and Survival :

James R . WoodgettLinks to Cance r

Concluding Remarks

Introductio n

References

The ERK ModuleStress-Activated MAPKs, Part 1 : SAPKIJNK s

CHAPTER 79

Stress-Activated MAPKs, Part 2 : p38 MAPK s

Downstream Signaling Pathways :

MAPKK s

Modular Interactions

471MAPKKKs

Bruce J . Mayer

MAPKKKKsSummary

Introduction

References

General Properties of Interaction ModulesRoles in Signaling

CHAPTER 84Prospects

Cytoskeletal Regulation: Smal lReferences

G-Protein-Kinase Interactions

499

CHAPTER80

Ed Manser

Non-Receptor Protein Tyrosine

Introduction

Kinases in T-Cell Antigen

P21-Activated Kinases

Receptor Function

475

Myotonic Dystrophy Kinase-Related Cdc42 -

Kiminori Hasegawa, Shin W. Kang, Chris Chiu and

Binding Kinase

Andrew C. Chan

Rho-Associated Kinase (ROK )References

IntroductionT-Cell Antigen Receptor Structure

CHAPTER85Src PTKsCsk (c-Src PTK)

Recognition of Phospho -ZAP-70/Syk PTKs

Serine/ThreonineTec PTKs

Phosphorylated Proteins

505Summary

Stephen J . Smerdon and Michael B . YaffeReferences

Introduction

CHAPTER 81

14-3-3 ProteinsFHA Domain s

Cbl : A Physiological PTK

WW Domain sRegulator

483 Leucine-Rich Repeats and WD40 Domain sWallace Y. Langdon

Concluding Remarks

Introduction

References

Domains of Cbl ProteinsSli-1 : A Negative Regulator of RPTKs

CHAPTER86PTK Downregulation by Polyubiquitylation

Role of PDK1 in Activating AGCCbl-Deficient Mice

Protein Kinase

513Future Directions Dario R . Aless iReferences

Introduction

CHAPTER 82

Mechanisms of Activation of PKB

TGFß Signal Transduction

487 PKB Is Activated by PDK 1

Jeffrey L . Wrana

Activation of Other Kinases by PDK 1Phenotype of PDK1 PKB- and S6K-Deficien t

Introduction

Mice and Model Organisms

The Smad Pathway

Hydrophobic Motif of AGC Kinases

Smads and the Ubiquitin-Proteasome System

Mechanisms of Regulation of PDK1 Activity

Smad-Independent Signaling Pathways

Structure of the PDKI Catalytic Domai n

Other Receptor Interaction Proteins

Concluding Remarks

References

References

CHAPTER 87

CHAPTER 92Regulation of Cell Growth and

Protein Kinase C : Relaying SignalsProliferation in Metazoans by mTOR

from Lipid Hydrolysis to Proteinand the p70 S6 Kinase

523 Phosphorylation

551Joseph Avruch

Alexandra C . Newto n

Introduction

IntroductionFunctions of TOR

Protein Kinase C FamilySignaling from TOR

Regulation of Protein Kinase CRegulation of mTOR Activity

Function of Protein Kinase CReferences

SummaryReferences

CHAPTER 88AMP-Activated Protein Kinase

535 CHAPTER 93D. Grahame Hardie

The PIKK Family of Protein Kinases

557Introduction

Graeme C . M. Smith and Stephen P. Jackson

Structure of the AMPK Complex

Introductio nRegulation of the AMPK Complex

Overview of PIKK Family Member sRegulation in Intact Cells and Physiological Targets

Overall Architecture of PIKK Family Protein sMedical Implications of the AMPK System

MTOR: A Key Regulator of Cell GrowthReferences

DNA-Pkes : At the Heart of the DNA

CHAPTER89

Nonhomologous End-Joining MachineryATM and ATR: Signalers of Genome Damage

Principles of Kinase Regulation

539 SMG-1 : A Regulator of Nonsense-Mediate dBostjan Kobe and Bruce E . Kemp

mRNA Decay

Introduction

TRRAP: A Crucial Transcriptional

Protein Kinase Structure

Co Activato r

General Principles of Control

PIKK Family Members as Guardians ofNucleic Acid Structure, Function ,

Regulatory Sites in Protein Kinase Domain sConclusions

and Integrity ?

ReferencesReference s

CHAPTER 90

CHAPTER 94

Calcium/Calmodulin-Dependent

Histidine Kinases

563Protein Kinase II

543

Fabiola Janiak-Spens and Ann H . Wes t

Mary B . Kennedy

References

Introductio nStructure of CaMKII

CHAPTER 95Regulation by Autophosphorylation

Atypical Protein Kinases : TheRegulatory Roles of CaMKII in Neurons

EF2/MHCK/ChaK Kinase Family

567References

Angus C . Nairn

CHAPTER 91

Introductio n

Glycogen Synthase Kinase 3

547

Identification of an Atypical Family of Protei n

Philip Cohen and Sheelagh Frame

Kinases : EF2 Kinase, Myosin Heavy ChainKinase and ChaK

Introduction

The Structure of the Atypical Kinase Domai nThe Substrate Specificity of GSK3

Reveals Similarity to Classical Protei nThe Regulation of GSK3 Activity by Insulin and

Kinases and to Metabolic Enzymes withGrowth Factors

ATP-Grasp DomainsGSK3 as a Drug Target

Substrate Specificity of Atypical Kinase sThe Role of GSK3 in Embryonic Development

Regulation of Atypical Kinase sGSK3 and Cancer

Functions of the Atypical Family of Protein Kinase sReferences

References

CHAPTER 96

CHAPTER 101Casein Kinase I and Regulation of the

The Structure and Topology of ProteinCircadian Clock

575 Serine/Threonine Phosphatases

601Saul Kivimäe, Michael W. Young, and Lino Saez

David Barfor d

Introduction

Introductiondouble-time : A Casein Kinase I Homolog

Protein Serine/Threonine Phosphatases of thein Drosophila

PPP FamilyCasein Kinase I in the Mammalian Clock

Protein Serine/Threonine Phosphatases of theCasein Kinase I in the Neurospora Clock

PPM Famil ySimilarities and Differences of CKI Function in

Conclusion sDifferent Clock Systems

Reference sReference s

CHAPTER 97

CHAPTER 102

The Leucine-Rich Repeat Receptor Protein

Naturally Occurring Inhibitors of Protein

Kinases of Arabidopsis thaliana : A Paradigm

Serine/Threonine Phosphatases

607

for Plant LRR Receptors

579

Carol MacKintosh and Julie Diplexcito

John C . Walker and Kevin A . Lease

IntroductionEffects of Inhibitors in Cell-Based Experiment s

Introduction The Toxins Bind to the Active Sites of ProteinLRR Receptor Protein Kinases : The Genomic Phosphatase s

Point of View

Chemical Synthesis of Protein Phosphatase Inhibitor sLRR Receptor Protein Kinases : The Functional View

Microcystin Affinity Chromatography andSummary

Affinity Taggin gReferences

Avoiding the Menace of Toxins in the Real World

CHAPTER98

Outside the Laboratory

Engineering Protein Kinases with

Reference s

Specificity for Unnatural Nucleotides

CHAPTER 103and Inhibitors

583Chao Zhang and Kevan M . Shokat

Protein Phosphatase 1 Binding Proteins 613Anna A. Depaoli-Roach

ReferencesIntroductionProtein Phosphatase 1 (PP1 )

Section B: Protein Dephosphorylation

PP1 Regulatory or Targeting Subunit sJack E . Dixon, Editor

ConclusionsReferences

CHAPTER 99Overview of Protein Dephosphorylation 591 CHAPTER 104Jack E. Dixon

Role of PP2A in Cancer andSignal Transduction

621CHAPTER 100

Gernot Walter

Protein Serine/Threonine Phosphatases

Introductionand the PPP Family

593 Structure of PP2APatricia T. W. Cohen

Subunit InteractionCurrent Classification of Protein Serine/Threonine

Association of PP2A with Cellular Protein sPhosphatases

Alteration or Inhibition of PP2A Is Essential

Background

in Human Cancer DevelopmentEvolution and Conserved Features of the PPP Family

Mutation of Act and A(3 Isoforms in Human CancerCatalytic Activities of the PPP Family Members

Differences between Aot and A(3 Subunit sEukaryotic PPP Subfamilies

PP2A and Wnt SignalingDomain and Subunit Structure of PPP Family Members

PP2A and MAP Kinase PathwayMedical Importance of the PPP Family

SummaryReferences

References

CHAPTER 105

PTPs and Human Diseas e

Serine/Threonine Phosphatase

Perspective s

Inhibitor Proteins

627Reference s

Shirish Shenolikar

CHAPTER109Introduction

Protein Tyrosine Phosphatase StructureProtein Phosphatase 1 (PP1) Inhibitors

and Mechanisms

653I-1, DARPP-32, and Other Phosphorylation -

Youngjoo Kim and John M. DenuDependent Phosphatase Inhibitor s

Latent Phosphatase Complexes Activated by

IntroductionInhibitor Phosphorylation

Introduction to the Protein TyrosineInhibitors of Type-2 Serine/Threonine Phosphatases

Phosphatase FamilyConclusions

StructureReferences

Mechanis mRegulation

CHAPTER 106

Reference s

Calcineurin

631Claude B . Klee and Seun-Ah Yang

CHAPTER 110

Introduction

Bioinformatics: Protein Tyrosin e

Enzymatic Properties

Phosphatases

659Structure

Niels Peter H . Moller, Peter Gildsig Jansen ,

Regulation

Lars F. Iversen, and Jannik N. Andersen

Distribution and Isoforms

Introduction to BioinformaticsFunctions

Amino Acid Homology Among PTP Domains andMuscle Differentiation

Structure-Function StudiesConclusion

Identification of the Genomic Complement of PTP sReferences

Functional Aspects of PTPs in Health and Disease :Bioinformatic s

CHAPTER 107

References

Protein Serine/Threonine-Phosphatase2C (PP2C)

637 CHAPTER 111Hisashi Tatabe and Kazuhiro Shiozaki

PTP Substrate Trapping

671Introduction

Andrew J . Flint

Regulation of the Stress-Activated MAP

Introductio nKinase Cascades

Original C-S and D-*A Substrate-Trapping Mutant sControl of the CFTR Chloride Channel by PP2C

Second-Generation Trapping Mutant sPlant Hormone Abscisic Acid Signaling

Accessory or Noncatalytic Site Contributions toFem-2: A Sex-Determining PP2C in

Substrate Recognitio nNematode

New Twists on Trappin gStress-Responsive PP2Cs in Bacillus subtilis

Other Applications of Substrate Trapping Mutant sReferences

Reference s

CHAPTER 108

CHAPTER 112Overview of Protein Tyrosine

Inhibitors of Protein Tyrosin ePhosphatases

641 Phosphatases

677Nicholas K . Tonks

Zhong-Yin Zhang

Background

IntroductionStructural Diversity within the PTP Family

Covalent PTP ModifiersThe Classical PTPs

Oxyanions as PTP Inhibitor sThe Dual Specificity Phosphates (DSPs)

PTyr Surrogates as PTP InhibitorsRegulation of PTP Function

Bidentate PTP Inhibitor sOxidation of PTPs in Tyrosine Phosphorylation-

Other PTP InhibitorsDependent Signaling

Concluding Remark sSubstrate Specificity of PTPs

References