Structure, Function and Regulation of TOR complexes from Yeasts to Mammals: Part A (Volume 27) (The Enzymes, Volume 27)

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 Cell growth is highly regulated and is controlled by the TOR signaling network. Dysfunction of signaling pathways controlling cell growth results in cells of altered sizes and in turn causes developmental errors and a wide range of pathological conditions. An understanding of the TOR signaling network may lead to novel drugs for the treatment of, for example, cancer, diabetes, inflammation, muscle atrophy, learning disabilities, depression, obesity and aging.

There has been an explosion of knowledge in this area in recent years and this volume provides an in-depth review of our current knowledge of TOR complexes by the leaders in the field.

* Contributions from leading authorities
* Informs and updates on all the latest developments in the field