Structure, Function and Regulation of TOR complexes from Yeasts to Mammals: Part A

Contents......Page 5
Preface......Page 11
Introduction......Page 13
TORC1......Page 15
TORC2......Page 16
TOR Domains......Page 17
Domains of TORC2-Specific Components......Page 22
TORC1 and TORC2 are Multimers......Page 23
Activating Mutations in TOR......Page 24
Phosphorylation of TOR and Its Binding Partners......Page 25
Future Directions......Page 26
References......Page 27
One Enzyme, Two Complexes......Page 33
Raptor Defines mTORC1......Page 35
Genetic and Functional Interactions Between Tor1 and Protein Trafficking Regulators Provide Insights into TORC1 Activation by Amino Acids
......Page 37
Additional mTORC1 and mTORC2 Proteins......Page 38
Conclusions and Future Perspectives......Page 40
DEPTOR: A Regulator of mTOR Signaling Found Only in Vertebrates......Page 42
The Rag Proteins: Regulation of mTOR Signaling by Amino Acids......Page 43
Ste20......Page 289
References......Page 47
The Ras Superfamily G-Proteins......Page 51
Rheb Binds and Regulates TORC1......Page 71
Rheb Protein Structure......Page 53
Farnesylation and Localization of Rheb......Page 55
Biochemical Activity and Regulators......Page 56
Rheb Mutants......Page 57
The Plant TORC2 Complex......Page 59
Rheb Enhances Recruitment of the Substrate Protein to mTORC1......Page 61
FKBP38 Appears not to Play a Major Role in the Activation of mTORC1 by Rheb......Page 62
Functions of Rheb that Are Independent of mTOR......Page 63
Acknowledgments......Page 64
References......Page 65
Regulation of TOR Complex 1 by Amino Acids Through Small GTPases......Page 69
Amino Acid Regulation of TORC1: Introduction......Page 70
Identification of Plant Homologs of Proteins Belonging to the TOR Complexes......Page 75
FKBP38 as a Candidate Rheb-Controlled mTORC1 Regulator......Page 76
Amino Acids Control the Rheb-mTORC1 Interaction......Page 77
Rag GTPases Mediate Amino Acid Regulation of the Rheb-TORC1 Interaction......Page 78
Remarks and Future Directions......Page 79
MAP4K3/Glk May Participate in Amino Acid Regulation of mTORC1......Page 80
Acknowledgments......Page 81
References......Page 82
Rag GTPases in TORC1 Activation and Nutrient Signaling......Page 87
mTORC1 Activation by Multiple Signals, Including Amino Acids......Page 88
Structure of S. pombe TOR Kinases......Page 284
Vam6 as a Rag GEF in Amino  Acid-Induced TORC1 Activation......Page 93
Raptor Interacts with Both Upstream Regulators and Downstream Substrates......Page 94
RalA in Nutrient-Induced mTORC1 Activation......Page 95
References......Page 97
Amino Acid Regulation of hVps34 and mTORC1 Signaling......Page 101
Introduction......Page 102
AAs as a Signaling Metabolite......Page 104
AAs and hVps34......Page 107
hVps34 and mTORC1......Page 108
References......Page 110
AGC Kinases in mTOR Signaling......Page 113
mTOR, an Atypical Protein Kinase......Page 114
AGC Kinase, the ``Prototype´´ of Protein Kinases......Page 116
Phosphorylation of AGC Kinases by mTOR......Page 117
S6K......Page 118
Akt/PKB......Page 121
PKC......Page 122
SGK......Page 124
Phosphorylation of mTORCs by AGC Kinases......Page 125
Phosphorylation of mTORC Regulators by AGC Kinases......Page 126
mTORC Functions Mediated by AGC Kinases......Page 130
Transcription/Cell Survival......Page 131
Cell Cycle/Cell Proliferation......Page 132
Acknowledgments......Page 133
References......Page 134
mTORC1 and Cell Cycle Control......Page 141
mTORC1 Controls the Cell Cycle......Page 142
CSG2 as an Early Inroad to Sphingolipid Regulation......Page 196
Control of G1/S-Phase Progression by (m)TORC1......Page 145
Control of Mitotic Entry by TORCs......Page 149
A Link Between Mitochondrial Function, mTORC1, and Cell Cycle Progression?......Page 151
mTORC1, Ribosome Biogenesis, and Cell Cycle Control......Page 152
Conclusions and Perspective......Page 153
References......Page 154
TORC1 Signaling in the Budding Yeast Endomembrane System and Control of Cell-Cell Adhesion in Pathogenic Fungi......Page 159
TORC1 Signaling from the Budding Yeast Endomembrane System......Page 160
TORC1 Components and Its Major Downstream Effectors Localize to Endomembranes......Page 161
Genetic and Functional Interactions Between Tor1 and Protein Trafficking Regulators Provide Insights into TORC1 Activation by Amino Acids
......Page 162
Interactions Between Vesicular System Components and TORC1-Controlled Transcriptional Regulators are Required for Balanced Cell Growth
......Page 218
Control of Filamentous Differentiation by TORC1 Signaling in Divergent Fungi......Page 168
The TORC1 Cascade and Cellular Adhesion......Page 171
Targeting the Tor Pathway: A Novel Therapeutic Antifungal Approach......Page 175
References......Page 181
TORC2 and Sphingolipid Biosynthesis and Signaling: Lessons from Budding Yeast
......Page 189
Introduction......Page 190
TORC1 Versus TORC2......Page 191
Sphingolipid Biosynthesis: A Brief Primer......Page 192
Tsc2+/- Heterozygous Mice......Page 197
Calcineurin: Another Level of Control for TORC2/SLM1/2 and Sphingolipids......Page 199
TORC2, YPK1/2, and the Ceramide/LCBP Rheostat......Page 200
Conclusions and Perspective......Page 203
References......Page 204
TORC1 Signaling in the Budding Yeast Endomembrane System and Control of Cell-Cell Adhesion in Pathogenic Fungi......Page 211
TORC1 Signaling from the Budding Yeast Endomembrane System......Page 212
TORC1 Components and Its Major Downstream Effectors Localize to Endomembranes......Page 213
Control of Filamentous Differentiation by TORC1 Signaling in Divergent Fungi......Page 220
Role of mTORC2 in Cancer......Page 355
Remarks and Future Directions......Page 232
References......Page 233
TOR and Sexual Development in Fission Yeast......Page 241
Cell Cycle Regulation for Sexual Development......Page 242
The cAMP-PKA Pathway......Page 243
Regulation of Nitrogen Starvation Responses and Amino Acid Uptake by the TSC-Rhb1-TORC1 Module......Page 267
Tor2 and Nitrogen Sensing......Page 244
Homologs of Sch9 Kinase......Page 247
Stress-Activated MAP Kinase Cascade......Page 248
The Tor1 Pathway......Page 250
S. pombe TORC2......Page 251
Mei2, the Master Regulator of Meiosis......Page 253
Acknowledgments......Page 256
References......Page 257
Fission Yeast TOR and Rapamycin......Page 263
Introduction......Page 264
TORC1 is a Major Regulator of Cellular Growth......Page 265
Biosynthesis and Medicinal Chemistry of Rapamycin and Its Analogs......Page 346
Rapamycin Reduces Amino Acid Uptake in Wild-Type Fission Yeast Cells......Page 269
Tor1 and Tor2 Oppositely Regulate Responses to Nitrogen Starvation......Page 270
Determinants of mTOR Inhibitor Responsiveness in Cancer......Page 272
The Effects of Rapamycin on Sexual Development......Page 274
Mutations that Render the Growth of Fission Yeast Sensitive to Rapamycin......Page 275
Conclusion and Future Prospective......Page 277
References......Page 278
Structure of TOR Complexes in Fission Yeast......Page 283
Functions of S. pombe TOR Kinases......Page 286
TOR Kinase in TORC1......Page 287
Wat1/Pop3......Page 288
Phosphorylation of TORC Components......Page 290
Other TOR-Associated Proteins......Page 291
Conclusion......Page 292
References......Page 293
The TOR Complex and Signaling Pathway in Plants......Page 297
Introduction......Page 298
Evidence That Inhibition of TOR Signaling Inhibits Tumor Formation in Mouse Models......Page 299
TOR......Page 300
RAPTOR......Page 301
The Plant TORC1 Complex......Page 303
S6K/TAP42......Page 304
Mei2-Like Proteins......Page 305
Genetic Analysis of the Plant TOR Signaling Pathway: A Green Growth facTOR?......Page 306
TOR......Page 307
Conclusion......Page 310
References......Page 311
Dysregulation of TOR Signaling in Tuberous Sclerosis and Lymphangioleiomyomotosis......Page 315
TSC and LAM: Clinical Features......Page 316
Evidence of mTOR Activation in TSC and LAM......Page 317
Tsc2Ek/+ Eker Rat......Page 321
Tsc1+/- Heterozygous Mice......Page 322
Subcutaneous Tumor Models......Page 324
Evidence That Inhibition of TOR Signaling Suppresses the Neurologic Manifestation in Mouse Models......Page 325
Evidence That Inhibition of TOR Signaling Inhibits Tumor Formation in TSC and LAM......Page 328
Evidence of TORC1-Independent Phenotypes in TSC......Page 330
Clinical Perspectives......Page 332
Acknowledgments......Page 333
References......Page 334
Chemistry and Pharmacology of Rapamycin and Its Derivatives......Page 341
Introduction......Page 342
Primer on the Mechanism of Action of Rapamycin......Page 343
Anticancer Activities of the Rapalogs......Page 352
The mTOR Pathway and Carcinogenesis......Page 353
Translational Regulation of Oncogenic Proteins by mTORC1......Page 354
Clinical Development of Rapalogs as Anticancer Agents......Page 357
High-Dose Effects of Rapalogs and Development of Second-Generation MKIs......Page 360
Effects of Rapamycin on Immunity and Longevity......Page 362
Conclusions and Future Perspectives......Page 366
References......Page 368
Author Index......Page 379
Index......Page 409