Transduction Mechanisms in Cellular Signaling (eBook)

Front Cover 1
Transduction Mechanisms in Cellular Signaling 4
Copyright Page 5
Editorial Advisory Board 6
Contents 8
Preface 12
Contributors 14
Section A: Overview 18
Chapter 1: Intracellular Signaling 20
Origins of Cell Signaling Research 20
Intracellular Signaling Mechanisms 21
Focus and Scope of this Volume 23
References 24
Section B: Phosphorylation/Dephosphorylation 26
Part 1: Kinases 28
Chapter 2: Eukaryotic Kinomes: Genomics and Evolution of Protein Kinases 30
Introduction 30
The Human Kinome 30
Comparative Kinomics 32
Saccharomyces cerevisiae 32
Caenorhabditis elegans 33
Drosophila melanogaster 33
Emergence and Diversity of Vertebrate Kinomes 33
Coda 33
References 34
Chapter 3: Modular Protein Interaction Domains in Cellular Communication 36
Introduction 36
Phosphotyrosine-Dependent Protein – Protein Interactions 36
Interaction Domains: a Common Theme in Signaling 40
Interaction Domains in the Evolution of Signaling Pathways 43
Emergent Properties of Modular Protein Interaction Domain-Driven Signaling Networks 44
Acknowledgements 45
References 45
Chapter 4: Recognition of Phospho-Serine/Threonine Phosphorylated Proteins by Phospho-Serine/Threonine-Binding Domains 50
Introduction 50
14-3-3 Proteins 50
FHA Domains 51
WW Domains 53
Polo-Box Domains 54
Tandem Brct-Repeat Domains 55
Tandem Brct-Repeat Domains 56
Concluding Remarks 56
Acknowledgements 57
References 57
Chapter 5:Protein Kinase Inhibitors 62
Signal Transduction Therapy and Protein Kinase Inhibitors 62
Protein Tyrosine Kinase Inhibitors 62
Ser/Thr Kinase Inhibitors 66
References 69
Chapter 6: Principles of Kinase Regulation 72
Introduction 72
Protein Kinase Structure 72
General Principles of Control 72
Regulatory Sites in Protein Kinase Domains 74
Conclusions 75
References 75
Chapter 7: Mammalian MAP Kinases 78
Introduction 78
The ERK Group of MAP Kinases 78
The P38 Group of MAP Kinases 81
The JNK Group of MAP Kinases 82
MAP Kinase Docking Interactions 82
Scaffold Proteins 83
KSR 83
MP-1 84
MORG1 84
JIP 84
POSH 85
OSM 86
References 86
Chapter 8: The Negative Regulation ofJAK/STAT Signaling 92
Introduction 92
Modulation of JAK Kinase Activity by Extrinsic Kinases 95
Protein Inhibitors of Activated Stats (PIAS) 95
Suppressors of Cytokine Signaling 97
Future Outlook 99
Acknowledgements 100
References 100
Chapter 9: Protein Proximity Interactions 106
Advances in the Analysis of Protein – Protein Interactions 106
Subcellular Structures and Multiprotein Complexes that Contribute to Cell Signaling 106
Kinase and Phosphatase Targeting 106
Chapter 10: Global Analysis of PhosphoregulatoryNetworks 108
Introduction 108
Global Mapping of Phosphorylation 108
Global Mapping of Phosphorylationglobal Identification of Kinase – Substrate Pairs 113
Conclusion 116
References 116
Part 2: Phosphatases 120
Chapter 11: Phosphatase Families DephosphorylatingSerine and Threonine Residues in Proteins 122
Current Classification of Protein Serine/Threonine Phosphatases 122
Background 122
Evolution and Conserved Features of the PPP Family 124
Holoenzyme Structures of PPP Family Members 126
Catalytic Activities of the PPP Family Members 129
Functions of PPP Family Members 130
Medical Importance of the PPP Family 131
The PPM Family 132
The FCP Family 132
Concluding Remarks 132
Acknowledgements 137
References 137
Chapter 12: The Structure and Topology of ProteinSerine/Threonine Phosphatases 140
Introduction 140
Protein Serine/Threonine Phosphatases of the PPP Family 140
Protein Serine/Threonine Phosphatases of the PPM Family 143
Conclusions 143
References 144
Chapter 13: SH2 Domain-Containing Protein-TyrosinePhosphatases 146
History and Nomenclature 146
Structure, Expression, and Regulation 146
Biological Functions of Shps 151
Shp Signaling and Substrates 154
Determinants of Shp Specificity 167
Shps and Human Disease 167
Summary and Future Directions 169
Acknowledgements 170
References 170
Chapter 14: Calcineurin 186
Introduction 186
Enzymatic Properties 186
Structure 187
Regulation 187
Distribution and Isoforms 188
Functions 188
Conclusion 190
References 190
Chapter 15: Protein Serine/Threonine-Phosphatase2C (PP2C) 192
Introduction 192
PP2C Functions Conserved in Both Lower and Higher Eukaryotes 192
PP2C Functions Specific in Higher Eukaryotes 193
References 195
Chapter 16 Inhibitors of Protein TyrosinePhosphatases 198
Introduction 198
Covalent PTP Modifiers 198
Oxyanions as PTP Inhibitors 200
Non-Hydrolyzable pTyr Surrogates as PTP Inhibitors 200
Bidentate PTP Inhibitors 202
Other PTP Inhibitors 203
Concluding Remarks 203
Acknowledgement 204
References 204
Chapter 17: MAP Kinase Phosphatases 208
Introduction 208
Ser/Thr Protein Phosphatases and the Regulation of MAPK Activity 208
MAPK Regulation by Classical Protein Tyrosine Phosphatases (PTPS) 210
Mapk Regulation by Dual-Specificity Protein Phosphatases 212
Mammalian Dual-Specificity MAPK Phosphatases 213
Summary 217
Acknowledgements 218
References 218
Chapter 18: Protein Phosphatase 2A 224
Introduction 224
PP2A Regulatory Subunits Mediate Proximity Interactions 224
PP2A-Interacting Proteins 233
References 233
Section C: Lipid Signaling 238
Chapter 19: Lipid-Mediated Localization ofSignaling proteins 240
Introduction 240
Lipid Modifications on the Cytoplasmic Face of Membranes 240
Lipid Modifications in the Lumen of the Secretory Pathway 242
Localization of Lipid-Modified Proteins 243
Summary 245
Acknowledgements 245
References 245
Structural Principles of Lipid Second Messenger Recognition 248
Introduction 248
Phospholipid Second Messenger Recognition by Active Sites of Enzymes 248
Phosphoinositide-Binding Domains 252
Non-Phosphoinositide Lipid Messenger Recognition 254
Future Directions 254
Acknowledgements 254
References 254
Chapter 21: Pleckstrin Homology (PH) Domains 256
Identification and Definition of PH Domains 256
The Structure of PH Domains 256
PH Domains as Phosphoinositidebinding Modules 256
Highly Specific Recognition of Phosphoinositides (and Inositol Phosphates) by PH Domains 257
Binding of PH Domains to Nonphosphoinositide Ligands 260
Possible Roles of Nonphosphoinositide PH Ligands 260
Conclusions 261
References 261
Chapter 22: PX Domains 266
History and Overview of PX Domains 266
Lipid-Binding Specificity and Structure of PX Domains 266
Physiological Function of PX Domains 269
References 270
Chapter 23: FYVE Domains in Membrane Traffickingand Cell Signaling 274
Introduction 274
Role For PI(3)P in Membrane Trafficking and Identification of the FYVE Domain 274
Structural Basis for PI(3)P Recognition by the FYVE Domain 275
Conservation of the FYVE Domain and Localization of PI(3)P 276
FYVE Domain-Containing Proteins in Membrane Trafficking 276
FYVE Domain-Containing Proteins Involved in PI(3)P Metabolism 279
FYVE Domain-Containing Proteins in Signaling 280
FYVE-Like Domains 281
Conclusions 281
Acknowledgements 281
References 281
Chapter 24: Type I Phosphatidylinositol 4-Phosphate5-Kinases (PI4P 5-kinases) 286
Introduction 286
Basic Properties 286
Regulation 288
Function 289
Acknowledgements 289
References 289
Chapter 25: Phosphoinositide 3-Kinases 292
Introduction 292
The Enzymes 292
The Products 293
Phosphatases 294
Lipid Binding Domains 294
Effectors and Responses 296
Genetics 297
Pharmacology 299
Synopsis 299
References 300
Chapter 26: Inositol Pentakisphosphate: A SignalTransduction Hub 304
Introduction 304
Synthesis of Ins(1,3,4,5,6)P5 304
Functions of Ins(1,3,4,5,6)P 5 as a Precursor Pool 305
Dephosphorylation of Ins(1,3,4,5,6)P 5 To Ins(3,4,5,6)P4 305
Phosphorylation of Ins(1,3,4,5,6)P5 To PP-Insp4 306
Phosphorylation of Ins(1,3,4,5,6)P5 to Insp6 306
Other Functions for Ins(1,3,4,5,6)P 5 : Regulation of Pten 307
An Expanding List of Further Proposed Functions for Ins(1,3,4,5,6)P5 307
Concluding Statement 307
References 308
Chapter 27: IP3 Receptors 312
Introduction 312
Diversity of IP 3 RS 312
Structure of IP 3 R 313
Regulation of IP 3 Rs by IP3 and Ca2+ 314
Modulation of IP 3R 314
Protein Interactions with IP3 R 314
References 315
Chapter 28: PTEN 318
Introduction 318
PTEN Discovery and Function 318
PTEN and Cancer 318
Mouse Models for PTEN Function 320
PTEN Structure 320
The PTEN Signaling Pathway 320
Haploinsufficiency and Senescence in Cancer 321
PTEN in Cancer Therapy 322
References 322
Chapter 29: PTEN/MTM PhosphatidylinositolPhosphatases 324
PTEN 324
Myotubularin: A Novel Family of Phosphatidylinositol Phosphatases 326
References 327
Chapter 30: Diacylglycerol Kinases 328
Abbreviations 328
Introduction 328
The DGK Family 328
Regulation of DGKS 329
Paradigms of DGK Function 330
Conclusions 331
References 331
Chapter 31: Phospholipase C 334
Introduction 334
PLC Anatomy 334
PLC Activation Mechanisms 334
PLC- ß 334
PLC- . 335
PLC- d 336
PLC- e 336
PLC Physiology 336
References 337
Chapter 32: Phospholipase D 340
Introduction 340
THe PLD Gene Family 341
Vesicle Trafficking 343
Endocytosis 343
Exocytosis 343
Signal Transduction 344
PLD, A Potential Drug Target 345
Acknowledgements 346
References 346
Chapter 33: Role of Phospholipase A2 Forms inArachidonic Acid Mobilization and Eicosanoid Generation 350
Introduction 350
PLA2 Groups 350
Cellular Function in AA Release 351
Cross-Talk Between Cpla2aa and Spla2 352
References 353
Chapter 34: Prostaglandin Mediators 356
Introduction 356
The Cyclooxygenase Pathway 356
Prostanoid Receptors 357
Thromboxane A2 (TXA2) 357
Prostacyclin (PGI2) 358
Prostaglandin D2 (PGD2) 359
DP Deletion 359
Prostaglandin E2 (PGE2) 359
EP Deletion 360
Prostaglandin F2a(PGF2a) 360
Concluding Remarks 361
References 361
Chapter 35: Leukotriene Mediators 366
Introduction 366
5-Lipoxygenase 366
Acknowledgements 370
References 370
Chapter 36: Sphingosine-1-Phosphate Receptors:An Update 372
Introduction 372
Transactivation of S1PRS 372
S1PRS and the Immune System 373
S1PRS and the Cardiovascular System 374
Concluding Remarks 375
Acknowledgements 375
References 375
Section D: Lipid Signaling 380
Chapter 37: Adenylyl Cyclases 382
Introduction 382
Classification/Structure/Function 382
Endogenous and Exogenous Regulation 385
Roles in Physiology and Diseases 387
Summary 388
References 388
Chapter 38: Phosphodiesterase Families 392
Introduction 392
The Gene Families 393
Implications of Multiple Gene Families/Splice Variants 394
Altered PDE Expression in Pathological States 395
PDE Inhibitors as Therapeutic Agents 395
Where do we go from here? 396
Acknowledgements 396
References 396
Chapter 39: cAMP-Dependent Protein Kinase 398
Introduction 398
Catalytic Subunit 398
Structure of the Catalytic Subunit 399
Protein Kinase Inhibitor 402
Regulatory Subunits 402
Holoenzyme Complexes 403
Acknowledgements 404
References 404
Chapter 40: Cyclic GMP-Dependent Protein Kinase:Targeting and Control of Expression 408
Introduction 408
Cyclic GMP-Dependent Protein Kinase: Structure and Function 408
Targeting of PKG-I in VSMC 409
Role of PKG-I in the Regulation of VSMC Proliferation and Phenotype 410
Regulation of PKG-I Expression 411
Regulation of PFG-I Mrna Levels 411
Final Thoughts 412
References 412
Chapter 41: Substrates of Cyclic Nucleotide-Dependent Protein Kinases 416
Introduction 416
Classification and Nomenclature 416
Substrates of PKA and PKG 416
Structural and Sequence Features Relevant to Peptide Specificity 417
Conclusions 422
References 422
Chapter 42: Physiological Substrates ofPKA and PKG 424
Introduction 424
Abundance of PKA and PKG Phosphorylation Sites in the Human Proteome 424
Physiological Substrates 425
Concluding Remarks 438
References 438
Chapter 43: Inhibitors of Cyclic AMP- and CyclicGMP-Dependent Protein Kinases 442
Introduction 442
Cyclic Nucleotide Binding Site-Targeted Inhibitors 443
ATP Binding Site-Targeted Inhibitors 443
Peptide Binding Site-Targeted Inhibitors 446
Conclusions 447
Acknowledgements 447
References 447
Chapter 44: AKAP Transduction Units: Contextdependent Assembly of SignalingComplexes 452
Introduction 452
G-Protein Signaling Through AKAP Signaling Complexes 452
Kinase/Phosphatase Signaling Complexes 454
Camp Signaling Units 454
Conclusions and Perspectives 455
Acknowledgements 455
References 456
Chapter 45: Cyclic Nucleotide Specificity and Cross-Activation of Cyclic Nucleotide Receptors 458
Molecular Basis for CAMP/CGMP Selectivity of PKA and PKG 458
Confounding Factors in Crossactivation Studies 459
Camp Cross-Activation of PKG 459
cGMP Cross-Activation of PKA 460
References 461
Section E: G-Proteins 464
Chapter 46: Signal Transduction by G Proteins: BasicPrinciples, Molecular Diversity, and Structural Basis of Their Actions 466
Introduction 466
Ras, the Prototypic Regulatory Gtpase 467
Heterotrimeric G Proteins 469
Mechanism of G-Protein Activation by Receptors 474
Modulation of Activity by Shortening or Extension of the Active State 479
Future Direction 481
In Memoriam 481
Acknowledgements 481
References 481
Chapter 47: G-Protein-Coupled Receptors, SignalFidelity, and Cell Transformation 484
Introduction 484
GPCRS and Oncogenesis 485
A Mapk Signaling Network Links Gpcrs to Biological Outcomes 486
ERK Cascade 487
G Protein-Independent Signaling 489
GPCR Effectors are Organized by Scaffolding Molecules 490
AKAPs 492
Conclusion: GPCR Biology Requires Both Signal Integration and Fidelity 493
Acknowledgements 493
References 493
Chapter 48: Regulation of G Proteins by CovalentModification 498
Introduction 498
N-Terminal Acylation of Ga Subunits 498
C-Terminal Modification of G. 499
Structural and Functional Consequences of Lipid Modifications 499
Lipidation Influences G-Protein Trafficking and Localization 500
Conclusions 501
References 501
Chapter 49: Signaling Through Gz 504
Introduction 504
General Properties 504
Regulators of GZ Signaling: RGS Proteins 505
Receptors that Couple to GZ 505
Effectors of GZ Signaling 506
Phenotype of GaZ Knockout Mice 506
Concluding Remarks 507
References 507
Chapter 50: Mono-ADP-Ribosylation ofHeterotrimeric G Proteins 510
Introduction 510
The Mono-ADP-Ribosylation Reaction 510
Bacterial-Toxin-Induced ADP-Ribosylation 511
Endogenous Mono-Adpribosylation 513
Acknowledgements 514
References 514
Chapter 51: Specificity of G-Protein ß. Dimer Signaling 518
Introduction 518
Diversity of . 518
Application of Genetic Systems for Analysis of . Specificity 519
Conclusions 525
Acknowledgements 525
References 525
Chapter 52: Reversible Palmitoylation in G ProteinSignaling 528
Introduction 528
Sites of Palmitoylation in Ga and RGS Proteins 528
Activation-Regulated Palmitoylation of Ga 529
Mechanisms of Reversible Palmitoylation 530
Functions of Reversible Palmitoylation 531
Conclusions 532
References 533
Chapter 53: The Influence of Intracellular Location onFunction of Ras Proteins 536
Introduction 536
Does Location Actually Influence Ras Signaling? 536
Modifications by Endomembrane Enzymes – New Opportunities to Abort Ras Trafficking? 537
Ras Proteins begin their March toward the Cell Surface 537
Ras Activation on ER and Golgi Membranes 538
Destination Cell Surface: Ras Proteins Distribute among Several Plasma Membrane Domains 539
New Destinations – Mitochondria 540
Old Destinations – Endosomes 541
A Reality check – the first Structures of Lipid-Modified Ras on Lipid Membranes 541
References 541
Chapter 54: Role of R-Ras in Cell Growth 544
Introduction 544
General Properties of R-RAS Proteins: Variations On RAS 544
R-RAS 548
TC21/R-RAS-2 549
M-RAS/R-RAS-3 550
Conclusions 551
Acknowledgements 551
References 551
Chapter 55: The Ran GTPase: Cellular Roles andRegulation 554
Introduction 554
Structural Analysis of Ran Pathway Components 554
Ran’s Role in Nuclear Transport 556
Ran’s Function in Spindle Assembly 557
Ran’s Function in Cell Cycle Progression 558
Ran’s Role in Nuclear Envelope Dynamics 559
Biological Regulation of Core Ran Pathway Components 559
Conclusions 560
References 560
Chapter 56: Cdc42 and Its Cellular Functions 564
Introduction 564
Cdc42 Regulates a Variety of Cellular Functions 564
Spatial and Temporal Control of Cdc42 Activity 567
Cooperation Between Cdc42 and other Small Gtpases in Cellular Functions 569
Conclusions 571
References 571
Chapter 57: Structure of Rho Family Targets 574
Rho Subfamily Protein Structures and Conformational Switch 574
CRIB Proteins 574
Non-CRIB Rac Effectors 579
Rho Effectors 582
ROCK 585
Concluding Remarks 586
References 587
Index 590