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

Front Cover 1
The Enzymes 4
Copyright Page 5
Contents 6
Preface 12
Chapter 1: TOR Complexes: Composition, Structure, and Phosphorylation 14
II. Introduction 14
III. TORC1 and TORC2 Components 16
IV. Domains of TOR and Its Binding Partners 18
V. Phosphorylation of TOR and Its Binding Partners 26
VI. Future Directions 27
Acknowledgments 28
References 28
Chapter 2: Regulation of TOR Signaling in Mammals 34
II. One Enzyme, Two Complexes 34
III. Raptor Defines mTORC1 36
IV. Rictor Defines a Rapamycin-Insensitive mTOR Complex 38
V. Additional mTORC1 and mTORC2 Proteins 39
VI. The Regulation of mTOR Signaling by Insulin and PRAS40 41
VII. DEPTOR: A Regulator of mTOR Signaling Found Only in Vertebrates 43
VIII. The Rag Proteins: Regulation of mTOR Signaling by Amino Acids 44
IX. The Future: Remaining Mysteries of mTOR Signaling and Clinical Significance of mTOR 46
Acknowledgments 48
References 48
Chapter 3: Rheb G-Proteins and the Activation of mTORC1 52
II. Rheb Defines a Unique Family Within the Ras Superfamily G-Proteins 52
III. Activation of mTORC1 by Rheb 60
IV. Functions of Rheb that Are Independent of mTOR 64
V. Future Prospects 65
Acknowledgments 65
References 66
Chapter 4: Regulation of TOR Complex 1 by Amino Acids Through Small GTPases 70
II. Amino Acid Regulation of TORC1: Introduction 71
III. Leucine Is the Most Potent Amino Acid Regulator of TORC1 72
IV. Rheb Binds and Regulates TORC1 72
V. Cross-competition Among Substrates for Raptor Can Influence TORC1 Signaling 76
VI. Phosphatidic Acid Is a Rheb-Directed Regulator of mTORC1 77
VII. FKBP38 as a Candidate Rheb-Controlled mTORC1 Regulator 77
VIII. Amino Acids Control the Rheb-mTORC1 Interaction 78
IX. Rag GTPases Mediate Amino Acid Regulation of the Rheb-TORC1 Interaction 79
X. Phosphatidyl 3' Phosphate Contributes to Amino Acid Regulation of Mammalian TORC1 80
XI. MAP4K3/Glk May Participate in Amino Acid Regulation of mTORC1 81
XII. Summary 82
Acknowledgments 82
References 83
Chapter 5: Rag GTPases in TORC1 Activation and Nutrient Signaling 88
II. mTORC1 Activation by Multiple Signals, Including Amino Acids 89
III. Rag GTPases and Amino Acid-Induced mTORC1 Activation 90
IV. Vam6 as a Rag GEF in Amino Acid-Induced TORC1 Activation 94
V. Raptor Interacts with Both Upstream Regulators and Downstream Substrates 95
VI. RalA in Nutrient-Induced mTORC1 Activation 96
References 98
Chapter 6: Amino Acid Regulation of hVps34 and mTORC1 Signaling 102
II. Introduction 103
III. AAs as a Signaling Metabolite 105
IV. AAs and hVps34 108
V. hVps34 and mTORC1 109
VI. Conclusions and Future Perspectives 109
Acknowledgments 111
References 111
Chapter 7: AGC Kinases in mTOR Signaling 114
II. Introduction 115
III. mTOR, an Atypical Protein Kinase 115
IV. AGC Kinase, the "Prototype" of Protein Kinases 117
V. Phosphorylation of AGC Kinases by mTOR 118
VI. Phosphorylation of mTORCs by AGC Kinases 126
VII. Phosphorylation of mTORC Regulators by AGC Kinases 127
VIII. mTORC Functions Mediated by AGC Kinases 131
IX. Conclusion 134
Acknowledgments 134
References 135
Chapter 8: mTORC1 and Cell Cycle Control 142
II. Introduction 143
III. TOR Signaling and G0 146
IV. Control of G1/S-Phase Progression by (m)TORC1 146
V. Control of Mitotic Entry by TORCs 150
VI. A Link Between Mitochondrial Function, mTORC1, and Cell Cycle Progression? 152
VII. mTORC1, Ribosome Biogenesis, and Cell Cycle Control 153
VIII. Conclusions and Perspective 154
References 155
Chapter 9: TORC1 Signaling in Budding Yeast 160
II. The Discovery of TOR 160
III. The Discovery of TOR Complexes 161
IV. What is TORC1? 163
V. Where is TORC1? 164
VI. What Regulates TORC1? 164
VII. What Does TORC1 Regulate? 166
VIII. Conclusions 182
Acknowledgments 183
References 183
Chapter 10: TORC2 and Sphingolipid Biosynthesis and Signaling: Lessons from Budding Yeast 190
II. Introduction 191
III. TORC1 Versus TORC2 192
IV. Sphingolipid Biosynthesis: A Brief Primer 193
V. Regulation of Sphingolipid Metabolism: Connections to TOR 197
VI. Implications for Mammalian Cells 204
VII. Conclusions and Perspective 204
References 205
Chapter 11: TORC1 Signaling in the Budding Yeast Endomembrane System and Control of Cell-Cell Adhesion in Pathogenic Fungi 212
II. TORC1 Signaling from the Budding Yeast Endomembrane System 213
III. TORC1 Components and Its Major Downstream Effectors Localize to Endomembranes 214
IV. Genetic and Functional Interactions Between Tor1 and Protein Trafficking Regulators Provide Insights into TORC1 Activation by AminoAcids 215
V. Interactions Between Vesicular System Components and TORC1-Controlled Transcriptional Regulators are Required for Balanced Cell Growth 219
VI. Tor Signaling in Fungal Pathogens 221
VII. Control of Filamentous Differentiation by TORC1 Signaling in Divergent Fungi 221
VIII. The TORC1 Cascade and Cellular Adhesion 224
IX. Targeting the Tor Pathway: A Novel Therapeutic Antifungal Approach 228
X. Remarks and Future Directions 233
Acknowledgments 234
References 234
Chapter 12: TOR and Sexual Development in Fission Yeast 242
II. Introduction 243
III. Cell Cycle Regulation for Sexual Development 243
IV. Nutritional Signaling 244
V. Mating Pheromone Signaling 252
VI. Initiation of Meiosis 254
Acknowledgments 257
References 258
Chapter 13: Fission Yeast TOR and Rapamycin 264
II. Introduction 265
III. TORC1 is a Major Regulator of Cellular Growth 266
IV. TORC2 is Required for Responses to Starvation, Survival Under Stress Conditions, Chromatin-Mediated Functions, DNA Damage Response and Maintenance of Telomere Length 271
V. The Response to Rapamycin in Fission Yeast 275
VI. Conclusion and Future Prospective 278
Acknowledgments 279
References 279
Chapter 14: Structure of TOR Complexes in Fission Yeast 284
II. S. pombe TOR Kinases 285
III. S. pombe TORC1 288
IV. S. pombe TORC2 290
V. Phosphorylation of TORC Components 291
VI. Other TOR-Associated Proteins 292
VII. Conclusion 293
References 294
Chapter 15: The TOR Complex and Signaling Pathway in Plants 298
II. Introduction 299
III. Plant Homologs of the TOR Complex Proteins 300
IV. Components of the TOR Signaling Pathway in Plants 305
V. Genetic Analysis of the Plant TOR Signaling Pathway: A Green Growth facTOR? 307
VI. Conclusion 311
Acknowledgments 312
References 312
Chapter 16: Dysregulation of TOR Signaling in Tuberous Sclerosis and Lymphangioleiomyomotosis 316
II. TSC and LAM: Clinical Features 317
III. Evidence of mTOR Activation in TSC and LAM 318
IV. Evidence That Inhibition of TOR Signaling Inhibits Tumor Formation in Mouse Models 318
V. Combinational Therapy in Heterozygous Mouse and Subcutaneous Tumor Models 326
VI. Evidence That Inhibition of TOR Signaling Suppresses the Neurologic Manifestation in Mouse Models 326
VII. Evidence That Inhibition of TOR Signaling Inhibits Tumor Formation in TSC and LAM 329
VIII. Evidence of TORC1-Independent Phenotypes in TSC 331
IX. Clinical Questions Not Fully Explained by TORC1 Activation 333
X. Clinical Perspectives 333
Acknowledgments 334
References 335
Chapter 17: Chemistry and Pharmacology of Rapamycin and Its Derivatives 342
II. Introduction 343
III. Primer on the Mechanism of Action of Rapamycin 344
IV. Biosynthesis and Medicinal Chemistry of Rapamycin and Its Analogs 347
V. Anticancer Activities of the Rapalogs 353
VI. Effects of Rapamycin on Immunity and Longevity 363
VII. Conclusions and Future Perspectives 367
References 369
Author Index 380
Index 410
Color Plates 418