Intercellular Signaling in Development and Disease (eBook)

Front Cover 1
Intercellular Signaling in Development and Disease 4
Copyright Page 5
Editorial Advisory Board 6
Contents 8
Preface 12
Contributors 14
Section A: Overview 18
Chapter 1: Signaling in Development and Disease 20
Origins of Cell Signaling Research 20
Receptors and Intracellular Signaling 21
Intercellular Signaling 23
Focus and Scope of this Volume 24
References 24
Section B: Cell-Cell Signaling 26
Chapter 2: Overview of Cell – Cell and Cell – Matrix Interactions 28
References 29
Chapter 3: Integrin Signaling: Cell Migration, Proliferation, and Survival 30
Introduction 30
Integrins Nucleate the Formation of Dynamic Multi-Protein Complexes 30
Cell Migration: A Paradigm for Studying Integrin Signaling 32
Lamellipodia Extension, and Adhesion Formation and Stabilization at the Leading Edge 32
Maturation, Detachment, and Release of Adhesions 33
Growth Factor Receptor and Integrin Signaling-Synergistic Regulation of Cell Proliferation and Survival 33
Integrin Signals and Links to Cancer 34
Concluding Remarks 35
Acknowledgements 35
References 35
Chapter 4: The Focal Adhesion: A Network of Molecular Interactions 40
Introduction 40
Integrin Activation 40
Adhesion Strengthening 40
Intracellular Signaling and Molecular Scaffolds 41
Focal Adhesion Turnover 42
Focal Adhesions and Gene Expression 43
The Future 43
Acknowledgements 43
References 43
Chapter 5: Cadherin Regulation of Adhesive Interactions 46
Introduction 46
The Cadherin Family 46
Cadherin Structure – Function Relationships 49
Multiple Modes for Regulating Cadherin Adhesive Activity 51
Conclusions and Perspectives 54
Acknowledgements 54
References 55
Chapter 6: In vivo Functions of Heterotrimeric G Proteins 60
Introduction 60
Development 60
Central Nervous System 60
Immune System 63
Heart 63
Sensory Systems 63
Hemostasis 63
Conclusions 64
References 64
Chapter 7: G-Protein Signaling in Chemotaxis 68
Introduction 68
Chemotaxis: Membrane Extensions, Directional Sensing, and Polarization 68
Chemoattractant Signaling Regulates Multiple Downstream Pathways 68
Front and Back Signaling 69
Mechanisms of Directional Sensing 71
Polarization 72
Conclusion 73
Acknowledgements 73
References 73
Chapter 8: Interactive Signaling Pathways in the Vasculature 76
Introduction 76
Interactive Networks as Models of Cell Signaling 76
Cross-Talk Between FGF and Notch Signaling 76
Novel Modulators of TGFß Signaling 78
Notch, FGF, and Smad Signaling Interactions 79
Feedback Inhibitory Mechanisms in Vascular Cell Signaling 79
Implications in Vascular Remodeling 80
References 80
Chapter 9: Signaling Pathways Involved in Cardiogenesis 84
Introduction 84
Origin of Cardiomyocyte Precursors 84
Cardiomyocyte and Heart Tube Formation 86
Complex Regulation of Cardiac Morphogenesis 87
Molecular Regulation of Septal Formation 89
Microrna Regulation of Cardiomyocyte Differentiation 89
Summary 90
Acknowledgements 90
References 90
Chapter 10: Calcium Signaling in Cardiac Muscle 94
Introduction 94
Calcium-Induced Calcium Release 94
How is SR Calcium Content Controlled? 95
Which Factors Control the Amplitude of the Systolic Calcium Transient? 95
Calcium Signaling in Heart Failure 96
References 96
Chapter 11: Calcium Signaling in Smooth Muscle 98
Introduction 98
The Role of Calcium Signaling in Smooth Muscle 98
Overview of Types of Calcium Signals in Smooth Muscle 99
Calcium Entry Mechanisms 100
Calcium Efflux Mechanisms 101
SR and Calcium Signaling 101
Mitochondrial and Other Organellar Contribution to Calcium Signaling 105
Global Calcium Transients 105
Local Calcium Signals 105
Calcium Oscillations and Waves 106
Caveolae, Microdomains, and Calcium Signals 107
References 108
Chapter 12: Trophic Effects of Gut Hormones in the Gastrointestinal Tract 116
Introduction 116
Trophic Effects of Gut Peptides in the Stomach, Small Bowel, and Colon 116
GI Hormone Receptors and Signal Transduction Pathways 118
Signaling Pathways Mediating the Effects of Intestinal Peptides 119
Conclusions 121
Acknowledgements 121
References 121
Chapter 13: Cell – Cell and Cell – Matrix Interactions in Bone 126
Introduction to Bone and Bone Disease 126
Diseases of Bone 126
Bone Cells and their Functions 127
Mechanical Strain 128
Hormones Responsible for Bone Development, Growth and Maintenance 129
Growth, Signaling, and Transcription Factors Responsible for Bone Development and Growth 131
Bone Extracellular Matrix (ECM) 135
Conclusion anSummary 136
References 136
Chapter 14: Cell – Cell Signaling in the Testis and Ovary 142
Introduction 142
Cell – Cell Signaling in the Testis 142
Cell – Cell Signaling in the Ovary 146
Summary 150
References 150
Chapter 15: Kidney 158
Overview of Kidney Function and Cell-to-Cell Interactions 158
Vascular Smooth Muscle Cells 160
Vascular Endothelial Cells 161
Vasoactive Paracrine/Autocrine Agents – Actions in the Renal Vasculature 164
Endothelial Cell Connections: Connexins and Gap Junctions 168
Paracrine Signaling in Renal-Tubule Epithelial Cells 172
Interstitial Cell – Tubule Communication 177
Conclusions 178
Acknowledgements 179
References 179
Chapter16: Cytokines and Cytokine Receptors Regulating Cell Survival, Proliferation, and Differentiation in Hematopoiesis 184
General Aspects of Hematopoiesis 184
Hematopoietic Cytokines 184
Signaling through Cytokine Receptors 186
Concluding Statements 193
References 193
Chapter 17: CD45 194
Introduction 194
Structure 194
Function 195
Regulation 196
Synopsis 197
Acknowledgements 197
References 198
Chapter 18: Signal Transduction in T Lymphocytes 200
Introduction 200
Signaling Receptors in T Cells form Dynamic Macromolecular Signaling Complexes 207
Co-receptor and Co-stimulatory Proteins Modulate T Cell Signaling Pathways 203
Intracellular Signaling Pathways Induced by Antigen Stimulation of T Cells 206
Conclusions 207
References 207
Chapter 19: Signal Transduction via the B Cell Antigen Receptor: A Crucial Regulator of B Cell Biology 210
Introduction 210
Initiation of Signal Transduction through the BCR 210
Propagation of Signal Transduction Via the BCR 211
Conclusion 216
References 216
Chapter 20: Signaling Pathways Regulating Growth and Differentiation of Adult Stem Cells 220
Introduction 220
Stem Cell Properties 220
Signaling Intermediates and Pathways in CD133 Stem Cells 221
Conclusions 226
References 226
Section C: Signaling in Development 230
Chapter 21: Wnt Signaling in Development 232
Introduction 232
Canonical Wnt Signaling 232
Wnt Signaling in Invertebrate Development 232
Wnt Signaling in Vertebrate Development 233
Wnt/Planar Cell Polarity 234
Acknowledgements 235
References 235
Chapter 22: Interactions between Wnt/ß -Catenin/Fgf and Chemokine Signaling in Lateral Line Morphogenesis 238
Introduction 238
FGF Signaling Controls Sensory Organ Formation in the Migrating Primordium 239
Wnt/ß -Catenin Signaling Restricts Neurogenesis to Trailing Cells and Maintains the Progenitor Zone 240
The FGF Pathway Restricts Wnt/ß - Catenin Signaling to the Leading Edge Ensuring Normal Migration 240
Chemokine Signaling Guides the Migrating Primordium 241
A Feedback Loop Between FGF and Wnt/ß -Catenin Signaling Controls Migration by Localizing Chemokine Receptor Expression 242
Cell Migration and Rosettogenesis are Independently Regulated 242
Summary 242
References 242
Chapter 23: Integration of BMP, RTK, and Wnt Signaling Through Smad1 Phosphorylations 244
Introduction 244
Neural Induction: Linking RTKs and Anti-BMP Signals 244
MAPK Activation Explains Heterologous Neural Inducers 245
Epidermal Differentiation: Integration of Wnt and BMP Signals 245
Smad1 as a Platform for MAPK Integration 246
Smad1 as a Platform for Wnt Signals 246
A Conserved Mechanism of Signal Integration 247
Concluding Remarks 247
References 247
Chapter 24: Hedgehog Signaling in Development and Disease 250
The Hedgehog Proteins: Generation and Distribution 250
Transmitting the HH Signal 250
HH in Development and Disease 251
Acknowledgements 253
References 253
Chapter 25: Regulation of Vertebrate Left-Right Axis Development by Calcium 256
Introduction 256
Conserved Molecular Pathways Regulating LR Asymmetry 256
Initiating a Break in Symmetry 257
Conserved Role of Calcium in Left – Right Asymmetry Determination 258
Conclusions 259
Acknowledgements 260
References 260
Chapter 26: LIN-12/Notch Signaling: Induction, Lateral Specification, and Interaction with the EGF/Ras Pathway 262
The LIN-12/Notch Pathway 262
Inductive Signaling Versus Lateral Specification 262
Cellular outcome of the Activation of the LIN-12/Notch Pathway 265
Acknowledgement 265
References 266
Chapter 27: Proteolytic Activation of Notch Signaling: Roles for Ligand Endocytosis and Mechanotransduction 268
Introduction 268
DSL Ligand Endocytosis is Required for Activation of Notch Signaling 269
Ubiquitin and Epsin-Dependent Recycling to Produce an Active DSL Ligand 269
Notch Signaling Requires Proteolysis and Nuclear Translocation 270
DSL Ligand Endocytosis to Produce a Force for Notch Proteolytic Activation 270
Converting DSL Ligand Endocytosis into a Force-Generating Process 271
Conclusions and Future Directions 272
References 272
Chapter 28:Vascular Endothelial Growth Factors and Receptors: Signaling in Vascular Development 276
Introduction to Vegfs and VEGF Receptors 276
Developmental Processes Vasculogenesis and Angiogenesis
VEGFR2 and its Ligands in Vascular Development 277
VEGFR1 and its Ligands in Vascular Development and Inflammatory Responses 281
VEGFR3 and its Ligands in Lymphatic Development 281
VEGF and its Coreceptors in Modulation of Signal Transduction 282
Conclusions 283
Acknowledgements 283
References 283
Chapter 29:BMPs in Development 288
Introduction 288
BMP Signal Transduction 288
Extracellular and Intracellular BMP Antagonists and the Establishment of Morphogen Gradients 290
Bmps in Vertebrate Embryo Patterning 291
Bmps and Bone Development 291
Perspectives 292
References 292
Chapter 30: Signaling from Fibroblast Growth Factor Receptors in Development and Disease 296
Introduction 296
FGFR Expression and Role During Development 296
Signaling Pathways Mediated by FGFRs 297
FGFRs and Developmental Disorders 297
Role of FGFRs in Human Cancer 298
References 300
Chapter 31: Regulation of Synaptic Fusion by Heterotrimeric G Proteins 306
Introduction 306
The Vesicle Fusion Machinery 306
Modes of Synaptic Vesicle Fusion 307
G-Protein-Coupled Receptor Mediated Modulation at the Presynaptic Terminal 307
Possible Mechanisms of Presynaptic Inhibition by G Proteins 307
GaQ Signaling Ca2+ Stores, Dag and Modulation of Neurotransmitter Release 310
G Proteins and Phosphorylation 310
References 310
Chapter 32: The Role of Receptor Protein Tyrosine Phosphatases in Axonal Pathfinding 314
Introduction 314
RPTPS and the Visual System 314
Neuromuscular System 316
Further Axon Growth and Guidance Roles 316
Axonal Signaling by RPTPS. 316
References 318
Chapter: 33 Neurotrophin Signaling in Development 320
Introduction 320
The Neurotrophin Ligands 320
Neurotrophin Receptors 321
Signaling Specificity During Development 321
Interacting Proteins 322
Retrograde Axonal Transport 323
Neurotrophin Signaling in the Adult Nervous System 323
References 323
Chapter: 34 Attractive and Repulsive Signaling in Nerve Growth Cone Navigation 326
Introduction 326
Netrin Signaling 326
Semaphorin Signaling 327
Slit Signaling 328
Ephrin Signaling 328
Nogo and Myelin-Associated Glycoprotein Signaling 328
Critical Roles of Modulatory Signals 328
Concluding Remarks 329
References 329
Chapter 35: Semaphorins and their Receptors in Vertebrates and Invertebrates 332
The Semaphorin Family 332
Receptors for Semaphorins 332
Intracellular Signaling Pathways 333
CRMP 333
Summary and Future Directions 334
Acknowledgements 335
References 335
Chapter 36: Signaling Pathways that Regulate Cell Fate in the Embryonic Spinal Cord 338
Introduction 338
Patterning Along the Dorsoventral Axis 338
Dorsal Spinal Cord Development 338
Ventral Spinal Cord Development 342
Rostrocaudal Specification 343
References 344
Section D: Signaling in Disease 346
Chapter 37: Ras and Cancer 348
Introduction: Ras Activation in Cancer 348
Pathways Downstream of Ras 348
Mouse Models of Cancer 349
Prospects for Cancer Therapy Based on Ras 350
References 350
Chapter 38: Targeting Ras for Anticancer Drug Discovery 352
Introduction 352
Ras Proteins Function as Signaling Nodes 352
Ras Activation in Human Cancers: Validation and Druggability 353
Targeting Ras Membrane Association 354
Targeting Ras Effector Signaling 360
Inhibitors of PI3K-AKT-MTOR Signaling 363
Inhibitors of Other Ras Effector Pathways 366
Conclusions and Future Directions 367
Acknowledgements 367
References 367
Chapter 39: The Roles of Ras Family Small GTPases in Breast Cancer 374
Introduction 374
Ras in Breast Cancer 376
Rheb 377
ARHI/DI-Ras3/NOEY2 378
Rerg 379
Therapeutic Re-Expression of ARHI or Rerg in Breast Cancer 379
Other Ras Family Proteins in Breast Cancer 380
References 380
Chapter 40: Signaling Pathways in the Normal and Neoplastic Breast 384
Introduction 384
The Epidermal Growth Factor Family 385
Other Growth Factor Families 387
The PI 3-Kinase – AKT and PTEN Axis 387
Conclusions 388
Acknowledgements 389
Dedication 389
References 389
Chapter 41: Aberrant Signaling Pathways in Pancreatic Cancer: Opportunities for Targeted Therapeutics 392
Introduction 392
Oncogenic Activation in PDAC 393
Loss of Tumor Suppressor Function in PDAC 395
Contributions of Pancreatic Stroma and Stromal Components in PDAC 396
Differentiation 397
Apoptotic Pathways and Apoptotic Resistance 398
Clinical Aspects of PDAC 398
Conclusions 400
Acknowledgement 400
References 400
Chapter 42: Regulatory Signaling in Pancreatic Organogenesis: Implications for Aberrant Signaling in Pancreatic Cancer 408
Introduction 408
Notch Signaling Pathway 408
Hedgehog Signaling Pathway 409
Transforming Growth Factor-Beta Signaling Pathway 410
Wnt Signaling Pathway 412
Fibroblast Growth Factors Signaling Pathway 412
Conclusion 414
Acknowledgements 414
References 414
Chapter 43: Angiogenesis Signaling Pathways as Targets in Cancer Therapy 418
Introduction 418
Overview of Angiogenesis and its Role in Tumor Development 418
Tumor Vessel Structure 418
Tumor Stroma and the Extracellular Matrix 419
The Role of Hypoxia in Regulating Tumor Angiogenesis 419
Overview of Critical Pathways Involved in Stimulating Angiogenesis 420
The Role of Cytokines in Angiogenesis 421
The Angiopoietins and the Angiogenic Shift 422
Angiogenesis Inhibitors 422
Anti-Angiogenesis Approaches and Treatments 423
Implications of Targeting Angiogenesis – Advantages And Disadvantages 424
Conclusions 424
Acknowledgement 424
References 424
Chapter 44: Clinical Applications of Kinase Inhibitors in Solid Tumors 430
Introduction 430
Rationale for Kinase Inhibition in the Treatment of Solid Tumors 430
Kinase Inhibition in Gastrointestinal Stromal Tumors 432
Kinase Inhibitors in Non-Small Cell Lung Cancer 434
EGFR Mutations in Lung Cancer 436
Kinase Inhibitors in Renal Cell Carcinoma 438
Kinase Inhibitors in Other Solid Tumors 440
Lessons Learned? 440
Glossary 441
Acknowledgements 441
References 441
Chapter 45: Adipokine Signaling: Implications for Obesity 448
Adipose Tissue and its Relation to Obesity 448
Leptin 448
Adiponectin 452
Proinflammatory Cytokines 453
Other Adipokines Related to Obesity 454
Concluding Remarks 454
Acknowledgement 454
References 454
Chapter 46: CXC Chemokine Signaling in Interstitial Lung Diseases 458
Introduction 458
Chemokine Regulation of Angiogenesis in Pulmonary Fibrosis: Reciprocal Roles of CXCR2 and CXCR3 458
Mesenchymal Progenitors in Pulmonary Fibrosis: Role of CXCR4 459
Potential Therapeutic Applications of Chemokine Signaling 460
Conclusions 460
Acknowledgement 460
References 460
Chapter 47: ER and Oxidative Stress: Implications in Disease 464
Introduction 464
UPR Signaling 464
IRE1 Signaling 465
PERK Signaling 466
ATF6 Signaling 466
ER Stress Induced Apoptosis 467
ER – Mitochondrial Interactions 468
Oxidative Protein Folding in the ER 468
ER Stress and Oxidative Stress: Implications in Human Disease 468
UPR and Oxidative Stress in Metabolic Disease 469
Neurodegenerative Diseases 469
Future Directions 470
Acknowledgements 470
References 470
Chapter 48: Protein Serine/Threonine Phosphatase Inhibitors and Human Disease 474
Introduction 474
Environmental Toxins as Phosphatase Inhibitors 474
New Insights in Cellular Phosphatase Inhibitors 475
Cellular Phosphatase Inhibitors and Human Disease 476
Concluding Remarks 477
References 478
Chapter 49: Signal Transduction in Rheumatoid Arthritis and Systemic Lupus Erythematosus 480
Introduction 480
STAT4 RS7574865 Allele and the Risk of RA 481
TNFR1 and C5 (RS376147 and RS2900180) and the Risk of RA 481
Challenges to the Application of Findings from Genetic Mapping Studies to Clinical Consequences 482
PTPN22 483
CTLA4 484
IL4R Variants I50V and Q551R and RA 484
TLR Signaling and Arthritis and Autoimmunity 484
NF.B Signaling in Arthritis and Inflammation 485
B Cell Signaling in Autoimmunity 485
CD22 488
PD-1 489
SHP-1 489
Ship 490
Summary 490
References 490
Chapter 50: Translational Concepts in Vasculitis 494
Introduction 494
Mechanisms in the Pathogenesis of Vasculitis 494
Translational Approaches to Therapeutics in Vasculitis 499
Classification Of Vasculitic Syndromes 500
Conclusions 501
References 502
Chapter 51: Translational Implications of Proteomics 506
Introduction 506
Profiling of Tissues to Identify Potential Circulating Markers 506
Proteomic Profiling of Proximal Biological Fluids 507
Profiling of Tumor Cell Populations 507
Profiling the Plasma Proteome for Cancer Biomarker Identification 507
Posttranslational Modifications as A Source of Cancer Biomarkers 509
Microarray Based Approaches for Biomarker Identification 510
Validation Strategies for Discovered Protein Biomarkers 510
References 510
Chapter 52: Translational Implications of MicroRNAs in Clinical Diagnostics and Therapeutics 512
Biogenesis and Functions of Animal Micrornas 512
Micrornas in Physiological and Metabolic Processes 514
Micrornas in Human Disease 516
Micrornas in Human Cancer 516
Micrornas and Viral Life Cycles 520
Future Microrna Based Therapeutic Strategies 520
Conclusions 524
Acknowledgements 524
References 524
Index 530