Structure, Function and Regulation of TOR complexes from Yeasts to Mammals (eBook)

Front Cover 1
The Enzymes: Structure, Function and Regulation of TOR complexes from Yeasts to Mammals Part B 4
Copyright Page 5
Contents 6
Preface 12
Chapter 1: mTORC1-Mediated Control of Protein Translation 14
II. Introduction 14
III. mTORC1 Targets and Control of Translation 18
IV. Conclusion 28
References 28
Chapter 2: The TSC1-TSC2 Complex: A Key Signal-Integrating Node Upstream of TOR 34
II. Introduction 35
III. Downstream Functions: Regulation of the TOR Complexes by the TSC1-TSC2 Complex 39
IV. Upstream Regulation: The TSC1-TSC2 Complex Integrates Diverse Signals to Regulate mTORC1 43
V. Aberrant Inhibition of the TSC1-TSC2 Complex Leading to Activation of mTORC1 in the Majority of Human Tumors 51
VI. Important Outstanding Questions Concerning the TSC1-TSC2 Complex 53
References 54
Chapter 3: AMPK Control of mTOR Signaling and Growth 62
II. AMPK is an Energy Sensing Kinase 63
III. mTOR is a Central Conserved Regulator of Growth and Metabolism 65
IV. AMPK Inhibits mTORC1 Through Phosphorylation of TSC2 and Raptor 67
V. AMPK and mTOR Have Opposing Roles in Specialized Metabolic Tissues in Mammals 70
VI. AMPK and TOR Function in Model Organisms to Control Growth, Metabolism, Autophagy, and Aging 73
VII. Therapeutic Implications 75
VIII. Future Perspectives 79
Acknowledgments 80
References 81
Chapter 4: mTOR Signaling by Amino Acid Nutrients: Involvement of MAP4K3 90
II. Nutrient Signaling to mTOR: Introduction 91
III. The Sensing of Amino Acid Nutrients 92
IV. Amino Acid Transporters and mTOR Signaling 95
V. Evidence That Intracellular Signaling Molecules Relay the Presence of Amino Acid Sufficiency to mTORC1 98
VI. MAP4K3 Participates in Amino Acid Signaling and Maintenance of Cell Size 100
VII. MAP4K3 Promotes Apoptosis via Regulation of the BH3-Only Proteins 103
Acknowledgments 105
References 105
Chapter 5: mTORC2: The Other Facet of mTOR 112
II. Structure of mTOR Complex 2 (mTORC2) 113
III. Role of mTORC2 115
IV. Regulation of mTORC2 120
V. Potential of mTOR Inhibitors in Cancer Treatment 127
References 129
Chapter 6: TORC2 and Chemotaxis in Dictyostelium discoideum 138
II. Introduction 139
III. The Life Cycle of D. discoideum 140
IV. The Components of TORC2-PDK-PKB Pathway in D. discoideum 141
V. The Signal Transduction Pathway for Chemotaxis 146
VI. Conclusion 152
Acknowledgments 153
References 153
Chapter 7: The TOR-Mediated Regulation of Autophagy in the Yeast Saccharomyces cerevisiae 156
II. Autophagy and ATG Genes in Yeast 157
III. Induction of Autophagy by Nutrient Limitation 157
IV. Induction of Autophagy by TOR Inactivation 161
V. Regulation of Atg1 Kinase Complex by TOR Complex1 162
VI. Phosphorylation of Atg13 by TORC1 to Regulate Autophagy 168
VII. ULK Complex: Mammalian Counterpart of Yeast Atg1 Complex 170
VIII. Concluding Remarks 171
Acknowledgments 173
References 173
Chapter 8: Conservation of the Tsc/Rheb/TORC1/S6K/S6 Signaling in Fission Yeast 180
II. Introduction 181
III. Overview of the TSC/Rheb/TORC1 Signaling in Fission Yeast 182
IV. PAS Assay and Detection of S6 in Fission Yeast 186
V. S6 Kinase in Fission Yeast 190
VI. Regulation of the TORC1 Signaling 191
VII. Effect of Rapamycin on the TORC1 Signaling 192
VIII. Future Prospects 195
Acknowledgments 195
References 195
Chapter 9: The Systemic Control of Growth, Physiology, and Behavior by TOR Signaling in Drosophila 202
II. Introduction 202
III. Growth Rate 204
IV. Developmental Timing 208
V. Feeding Behavior 210
VI. Fertility 211
VII. Control of Lifespan 213
References 214
Chapter 10: Cell-Intrinsic Functions and Regulation of TOR Signaling in Drosophila 218
II. Introduction 219
III. Genetic Screens: Identification of Network Components and Their Relationships 219
IV. Identification and Analysis of TOR-Dependent Cellular Functions in Drosophila 223
References 227
Chapter 11: TOR Signaling and Cell Death 230
II. Introduction: Overview of the TOR Signaling Pathway 231
III. Anti-Cell Death Functions of TOR 233
IV. Cell Death Associated with the Upregulation of TOR 239
V. Autophagy Protects Cells from Neurodegenerative Diseases 244
VI. Conclusions and Prospectives 251
References 252
Chapter 12: Elucidating TOR Signaling in Chlamydomonas reinhardtii 258
II. Introduction 259
III. Inhibition of TOR Signaling by Rapamycin in Chlamydomonas 260
IV. TOR Complexes 262
V. Control of Autophagy by TOR 267
VI. Perspectives 270
Acknowledgments 270
References 271
Chapter 13: mTORC1 and mTORC2 in Energy Homeostasis 276
II. Introduction 276
III. mTORC1 in the Hypothalamus 277
IV. mTORC1 in Pancreatic beta-Cells 280
V. mTORC1 and mTORC2 in Adipose Tissue 281
VI. mTORC1 and mTORC2 in Muscle 283
VII. mTORC1 in the Liver 284
VIII. Conclusion 286
Acknowledgments 286
References 286
Chapter 14: TOR Signaling and Aging 292
II. Introduction 293
III. TOR and Aging in S. cerevisiae 293
IV. TOR and Aging in C. elegans 298
V. TOR and Aging in Drosophila 302
VI. TOR and Aging in Mammals 304
VII. Conclusion and Future Perspectives 306
Acknowledgments 307
References 307
Chapter 15: mTOR Signaling and Human Cancer 314
II. Introduction 315
III. Frequent Activation of the mTOR Signaling in Human Cancer 316
IV. Identification of mTOR Mutations in Human Cancer 319
V. Inhibitors of the mTOR Signaling 322
VI. Future Prospects 326
Acknowledgment 327
References 327
Chapter 16: Systems Biology and TOR: Past, Present, and Future 330
II. Introduction 331
III. Genome-Wide Approach to Defining the TOR Network 333
IV. Integration of Data 346
V. Computational Modeling and Prediction 349
VI. Future: TOR and Cancer 352
References 355
Author Index 362
Index 394