Phosphoinositide 3-kinase in Health and Disease (eBook)

Contents 6
Contributors 8
Introduction 12
1 Establishing Order Within the Cell 12
2 Phosphatidylinositol and Phosphoinositides as Ideal Substrates 13
3 Nucleating a Protein Complex at a Target Location 14
4 Coupling PI3K Activity to Extracellular Cues 14
5 Disease Implications 16
References 17
PDK1: The Major Transducer of PI 3-Kinase Actions 19
1 Introduction 20
2 Mechanism of Activation of the AGC Kinases 20
2.1 PDK1, the Common T-Loop Kinase 21
2.2 mTORC1 and mTORC2, the Hydrophobic Motif Kinases 22
2.3 Two Mechanisms of Regulation by PDK1 24
3 Structure of PDK1 26
4 Genetic Models and Disease 27
4.1 PDK1 and Diabetes 27
4.2 PDK1 and T-Cell Development 29
4.3 PDK1, Growth and Cancer 29
5 PDK1 as a Druggable Target 30
6 Concluding Remarks 32
References 33
Protein Kinase B (PKB/Akt), a Key Mediator of the PI3K Signaling Pathway 40
1 Classification, Structure, and Substrates of PKB 41
2 Regulation of PKB Activity 42
2.1 Regulation of PKB Activity by Phosphorylation Events 42
2.2 Regulation of PKB Activity by Binding Partners 44
2.2.1 PKB Activators 45
2.2.2 PKB Inhibitors 47
2.2.3 PKB-Interacting Proteins with Undefined Functions 47
2.3 Regulation of PKB by CTMP 48
3 The Role of PKB in Physiological and Pathological Conditions 49
3.1 Effects of Knocking-Out Individual PKB Isoforms in Mice 50
3.2 PKB in Embryonic Development 50
3.3 PKB in Thymocyte Development 51
3.4 PKB in Adipocyte Differentiation 52
3.5 PKB in Glucose Homeostasis 53
3.6 PKB in Tumor Formation 55
4 Conclusion 56
References 57
PI3Ks in Lymphocyte Signaling and Development 66
1 Introduction 68
2 PI3K in B Cells 71
2.1 B-Cell Development 71
2.2 BcR Signaling, Antigen Presentation, and Metabolism 72
2.3 Immunoglobulin Gene Rearrangement and Isotype Switching 74
2.4 B-Cell Chemotaxis and Trafficking 76
3 PI3K in T Cells 76
3.1 T-Cell Development and Differentiation 76
3.1.1 A Surprising Redundancy Between p110delta and p110gamma During T-Cell Development 76
3.2 TcR Signaling and Costimulation 77
3.2.1 PI3K Regulates Some, But Not All, TcR-Dependent Signaling Pathways 79
3.3 T-Helper Cell Differentiation 80
3.4 Survival and Glucose Homeostasis in Mature T cells 81
3.5 PI3K Controls the Development and Suppressive Function of Regulatory T Cells 81
3.6 T-Cell Chemotaxis and Migration in Lymph Nodes: Not All About PI3K 83
3.7 T-Cell Trafficking 84
3.8 Nonessential Role for PI3K in Cytotoxic Responses 85
4 Prospects for PI3K Inhibitors in Inflammation and Autoimmunity 85
References 86
The Regulation of Class IA PI 3-Kinases by Inter-Subunit Interactions 95
1 Structural Organization of p85a/p110a 96
2 p85a Inhibits and Stabilizes p110 98
3 Activation of p85a/p110a Dimers by Phosphopeptides 100
4 A Mechanism for Phosphopeptide Activation 101
5 Activation of p85/p110 by GTPases 104
6 Activation by Binding to p85 SH3 and Proline-Rich Domains 107
7 Regulation by Autophosphorylation 107
8 Oncogenic Mutation of p85a and p110 108
8.1 Helical Domain Mutants: Disruption of the nSH2-Helical Domain Interface 109
8.2 The Kinase Domain Mutant H1047R 110
8.3 p110a Mutations Disrupting the C2-iSH2 Domain Interface 110
8.4 p85a Mutations Disrupting the C2-iSH2 Domain Interface 111
9 Regulation of p85/p110 In vivo: Activation Versus Translocation 112
10 Unanswered Mechanistic Questions on p85-p110 Interactions 113
References 115
Phosphoinositide Signalling Pathways in Metabolic Regulation 123
1 Introduction 124
2 Role of Insulin Signalling Network Molecules in Metabolic Regulation as Revealed by Global Gene Inactivation in Mice 125
3 Role of INSR/PI3K Pathway Components in the Development and Function of Insulin Sensitive Tissues 131
3.1 Insulin Sensitive Peripheral Tissues 131
3.2 Pancreatic Islets 134
3.3 Central Nervous System 137
4 Role of the INSR/PI3K Pathway in the Integration of Nutrient Availability and Growth Factor/Hormonal Signals 139
5 Molecular Basis of Insulin Resistance Development: Signal Termination Feedback Loops 140
6 Discussion 141
References 142
Role of RAS in the Regulation of PI 3-Kinase 150
1 RAS Proteins 151
2 RAS Effectors 153
3 RAS-PI3K Interaction 157
4 RAS-PI3K in Normal Signalling 158
5 RAS-PI3K in Oncogenesis 160
6 RAS-PI3K-RAF Pathway Interconnections 164
7 Inhibitors 167
8 Conclusions 168
References 169
More Than Just Kinases: The Scaffolding Function of PI3K 177
1 The Double Identity of PI3Kgamma 178
1.1 Cardiomyocytes 179
1.2 Circulating Endothelial Progenitor Cells 179
1.3 Platelets 180
2 The Double Identity of PI3Kbeta 180
2.1 Cell Growth 180
2.2 Metabolism 182
2.3 Oncogenesis 183
3 The Double Identity of Adaptor Subunits 183
4 Conclusions 184
References 185
PI3K Signaling in Neutrophils 188
1 Neutrophil Biology 189
2 Regulation of PI3Ks 192
3 Regulation of PtdIns(3,4,5)P3 195
4 Effectors of PI3K Signaling Pathways 195
5 Class I PI3K Regulation of Rho Family GTPases in the Context of Cell Spreading and Movement 196
6 Class I and Class III PI3K Regulation of the NADPH Oxidase 198
7 PI3Ks in Neutrophils as Therapeutic Targets 201
8 Conclusions 202
References 202
PI 3-Kinase p110beta Regulation of Platelet Integrin aIIbbeta3 208
1 Introduction 209
2 Basic Principles of Platelet Adhesion and Activation 210
3 Integrin aIIbbeta3: The Key Receptor Mediating Stable Platelet Aggregation and Thrombus Development 211
3.1 Gq 211
3.2 G12/13 213
3.3 Gi 213
3.4 PI 3-Kinase Signaling Downstream of Gq-Coupled Receptors? 213
4 Signaling Cross Talk Between Adhesion- and Gi-Coupled Receptors Amplifies PI 3-Kinase Activation 215
5 Functional Role of Type I PI 3-Kinases in Platelets 215
5.1 Roles of p110beta and p110gamma in Gi-Signaling 217
5.2 Contribution of PI 3-Kinase Isoforms to Adhesion Receptor Signaling 217
5.3 PI 3-Kinase Modulation of Integrin aIIbbeta3 Affinity 219
5.4 Potential Role for PI 3-Kinases in Regulating Integrin aIIbbeta3 Avidity 220
5.5 PI 3-Kinase and Shear-Resistant Platelet Adhesion 221
6 PI 3-Kinase Inhibitors as Potential Antithrombotic Agents 221
7 Conclusions 222
References 222
Regulatory Subunits of Class IA PI3K 230
1 Introduction 230
2 Structure and PI3K Enzyme Regulation 231
2.1 Modular Domains 231
2.2 Regulation of the Catalytic Subunit 233
3 Expression and Localization 235
4 Function in Health and Disease 236
4.1 Biochemical Mechanisms of Class IA PI3K Activation 236
4.2 Adaptor Functions 237
4.3 Gene-Targeting Studies 237
4.3.1 Defects in Mouse Development 238
4.3.2 Defects in Glucose Homeostasis 239
4.3.3 Defects in Immune Function 241
4.3.4 Role in Cancer 242
5 Conclusions 243
References 243
The Neurodevelopmental Implications of PI3K Signaling 250
1 PI3Ks: The Basics 251
2 Isoform Specific Functions of Class I PI3K in the Nervous System 252
3 Upstream and Downstream of PI3K Signaling 253
4 PI3K Signaling, Neuronal Migration and Cortical Development 255
5 PI3K Signaling and Neuronal Morphogenesis 256
6 PI3K Signaling in the Control of Dendrite and Spine Development 258
7 PI3K Signaling in Neurodevelopmental Disorders 259
7.1 PI3K Signaling and Schizophrenia 259
7.2 PI3K Signaling and Autism Spectrum Disorder 261
8 Conclusions 262
References 263
PI3 Kinase Regulation of Skeletal Muscle Hypertrophy and Atrophy 271
1 Protein Synthesis Pathways Downstream of PI3K 272
2 Hypertrophy Mediators Downstream of PI3K and Akt: The Akt/TORC1/p70S6K and Akt/GSK3 Pathways 273
3 A Second Hypertrophy Mediator Downstream of PI3K and Akt: GSK3beta 274
4 Skeletal Muscle Atrophy Occurs via Induction of Distinct E3 Ubiquitin Ligases, Whose Expression Can Be Inhibited by the PI3K/Akt Pathway 275
5 IGF-1/PI3K/Akt Inhibition of FOXO Transcription Factors Blocks Upregulation of MuRF1 and MAFbx 276
6 Akt Regulation of Myostatin 277
7 Conclusion 278
References 279
Taking PI3Kdelta and PI3Kgamma One Step Ahead: Dual Active PI3Kdelta/gamma Inhibitors for the Treatment of Immune-Mediated Inflammatory Diseases 283
1 p110delta and p110gamma Function in Neutrophils 284
2 p110delta and p110gamma Function in Mast Cells 285
3 p110delta and p110gamma Function in NK Cells 287
4 p110delta and p110gamma Function in Lymphocytes 287
5 p110delta and p110gamma Function in Inflammatory Leukocyte Recruitment 289
6 p110delta and p110gamma in Inflammatory Arthritis 290
7 p110delta and p110gamma in Allergic and Inflammatory Lung Disease 291
8 p110delta and p110gamma (p110delta/gamma) Deficient Mice 294
9 Conclusions 294
References 299
Index 304
Contents of Volume II 310