Structure, Function and Regulation of Tor Complexes from Yeasts to Mammals

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ISBN: 9780123815392 | 0123815398
Cover: Hardcover
Copyright: 3/25/2010

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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

Preface	p. xi
TOR Complexes: Composition, Structure, and Phosphorylation
Abstract	p. 1
Introduction	p. 1
TORC1 and TORC2 Components	p. 3
Domains of TOR and Its Binding Partners	p. 5
Phosphorylation of TOR and Its Binding Partners	p. 13
Future Directions	p. 14
Acknowledgments	p. 15
References	p. 15
Regulation of TOR Signaling in Mammals
Abstract	p. 21
One Enzyme, Two Complexes	p. 21
Raptor Defines mTORC1	p. 23
Rictor Defines a Rapamycin-Insensitive mTOR Complex	p. 25
Additional mTORC1 and mTORC2 Proteins	p. 26
The Regulation of mTOR Signaling by Insulin and PRAS40	p. 28
Deptor: A Regulator of mTOR Signaling Found Only in Vertebrates	p. 30
The Rag Proteins: Regulation of mTOR Signaling by Amino Acids	p. 31
The Future: Remaining Mysteries of mTOR Signaling and Clinical Significance of mTOR	p. 33
Acknowledgments	p. 35
References	p. 35
Rheb G-Proteins and the Activation of mTORC1
Abstract	p. 39
Rheb Defines a Unique Family Within the Ras Superfamily G-Proteins	p. 39
Activation of mTORC1 by Rheb	p. 47
Functions of Rheb that Are Independent of mTOR	p. 51
Future Prospects	p. 52
Acknowledgments	p. 52
References	p. 53
Regulation of TOR Complex 1 by Amino Acids Through Small GTPases
Abstract	p. 57
Amino Acid Regulation of TORC1: Introduction	p. 58
Leucine Is the Most Potent Amino Acid Regulator of TORC1	p. 59
Rheb Binds and Regulates TORC1	p. 59
Cross-competition Among Substrates for Raptor Can Influence TORC1 Signaling	p. 63
Phosphatidic Acid Is a Rheb-Directed Regulator of mTORCl	p. 64
FKBP38 as a Candidate Rheb-Controlled mTORCl Regulator	p. 64
Amino Acids Control the Rheb-mTORC1 Interaction	p. 65
Rag GTPases Mediate Amino Acid Regulation of the Rheb-TORC1 Interaction	p. 66
Phosphatidyl 3' Phosphate Contributes to Amino Acid Regulation of Mammalian TORC1	p. 67
MAP4K3/Glk May Participate in Amino Acid Regulation of mTORC1	p. 68
Summary	p. 69
Acknowledgments	p. 69
References	p. 70
Rag GTPases in TORC1 Activation and Nutrient Signaling
Abstract	p. 75
mTORC1 Activation by Multiple Signals, Including Amino Acids	p. 76
Rag GTPases and Amino Acid-Induced mTORC1 Activation	p. 77
Vam6 as a Rag GEF in Amino Acid-Induced TORC1 Activation	p. 81
Raptor Interacts with Both Upstream Regulators and Downstream Substrates	p. 82
RalA in Nutrient-Induced mTORC1 Activation	p. 83
References	p. 85
Amino Acid Regulation of hVps34 and mTORC1 Signaling
Abstract	p. 89
Introduction	p. 90
AAs as a Signaling Metabolite	p. 92
AAs and hVps34	p. 95
hVps34 and mTORC1	p. 96
Conclusions and Future Perspectives	p. 96
Acknowledgments	p. 98
References	p. 98
AGC Kinases in mTOR Signaling
Abstract	p. 101
Introduction	p. 102
mTOR, an Atypical Protein Kinase	p. 102
AGC Kinase, the "Prototype" of Protein Kinases	p. 104
Phosphorylation of AGC Kinases by mTOR	p. 105
Phosphorylalion of mTORCs by AGC Kinases	p. 113
Phosphorylation of mTORC Regulators by AGC Kinases	p. 114
mTORC Functions Mediated by AGC Kinases	p. 118
Conclusion	p. 121
Acknowledgments	p. 121
References	p. 122
mTORC1 and Cell Cycle Control
Abstract	p. 129
Introduction	p. 130
TOR Signaling and G₀	p. 133
Control of G1/S-Phase Progression by (m)TORC1	p. 133
Control of Mitotic Entry by TORCs	p. 137
A Link Between Mitochondrial Function, mTORC1, and Cell Cycle Progression?	p. 139
mTORC1, Ribosome Biogenesis, and Cell Cycle Control	p. 140
Conclusions and Perspective	p. 141
References	p. 142
TORC1 Signaling in Budding Yeast
Abstract	p. 147
The Discovery of TOR	p. 147
The Discovery of TOR Complexes	p. 148
What is TORC1?	p. 150
Where is TORC1?	p. 151
What Regulates TORC1?	p. 151
What Does TORC1 Regulate?	p. 153
Conclusions	p. 169
Acknowledgments	p. 170
References	p. 170
TORC2 and Sphingolipid Biosynthesis and Signaling: Lessons from Budding Yeast
Abstract	p. 177
Introduction	p. 178
TORC1 Versus TORC2	p. 179
Sphingolipid Biosynthesis: A Brief Primer	p. 180
Regulation of Sphingolipid Metabolism: Connections to TOR	p. 184
Implications for Mammalian Cells	p. 191
Conclusions and Perspective	p. 191
References	p. 192
TORC1 Signaling in the Budding Yeast Endomembrane System and Control of Cell-Cell Adhesion in Pathogenic Fungi
Abstract	p. 199
TORC1 Signaling from the Budding Yeast Endomembrane System	p. 200
TORC1 Components and Its Major Downstream Effectors Localize to Endomembranes	p. 201
Genetic and Functional Interactions Between Tor1 and Protein Trafficking Regulators Provide Insights into TORC1 Activation by Amino Acids	p. 202
Interactions Between Vesicular System Components and TORC1-Controlled Transcriptional Regulators are Required for Balanced Cell Growth	p. 206
Tor Signaling in Fungal Pathogens	p. 208
Control of Filamentous Differentiation by TORC1 Signaling in Divergent Fungi	p. 208
The TORC1 Cascade and Cellular Adhesion	p. 211
Targeting the Tor Pathway: A Novel Therapeutic Antifungal Approach	p. 215
Remarks and Future Directions	p. 220
Acknowledgments	p. 221
References	p. 221
TOR and Sexual Development in Fission Yeast
Abstract	p. 229
Introduction	p. 230
Cell Cycle Regulation for Sexual Development	p. 230
Nutritional Signaling	p. 231
Mating Pheromone Signaling	p. 239
Initiation of Meiosis	p. 241
Acknowledgments	p. 244
References	p. 245
Fission Yeast TOR and Rapamycin
Abstract	p. 251
Introduction	p. 252
TORC1 is a Major Regulator of Cellular Growth	p. 253
TORC2 is Required for Responses to Starvation, Survival Under Stress Conditions, Chromatin-Mediated Functions, DNA Damage Response and Maintenance of Telomere Length	p. 258
The Response to Rapamycin in Fission Yeast	p. 262
Conclusion and Future Prospective	p. 265
Acknowledgments	p. 266
References	p. 266
Structure of TOR Complexes in Fission Yeast
Abstract	p. 271
S. pombe TOR Kinases	p. 272
S. pombe TORC1	p. 275
S. pombe TORC2	p. 277
Phosphorylation of TORC Components	p. 278
Other TOR-Associated Proteins	p. 279
Conclusion	p. 280
References	p. 281
The TOR Complex and Signaling Pathway in Plants
Abstract	p. 285
Introduction	p. 286
Plant Homologs of the TOR Complex Proteins	p. 287
Components of the TOR Signaling Pathway in Plants	p. 292
Genetic Analysis of the Plant TOR Signaling Pathway: A Green Growth facTOR?	p. 294
Conclusion	p. 298
Acknowledgments	p. 299
References	p. 299
Dysregulation of TOR Signaling in Tuberous Sclerosis and Lymphangioleiomyomotosis
Abstract	p. 303
TSC and LAM: Clinical Features	p. 304
Evidence of mTOR Activation in TSC and LAM	p. 305
Evidence That Inhibition of TOR Signaling Inhibits Tumor Formation in Mouse Models	p. 305
Combinational Therapy in Heterozygous Mouse and Subcutaneous Tumor Models	p. 313
Evidence That Inhibition of TOR Signaling Suppresses the Neurologic Manifestation in Mouse Models	p. 313
Evidence That Inhibition of TOR Signaling Inhibits Tumor Formation in TSC and LAM	p. 316
Evidence of TORC1-Independent Phenotypes in TSC	p. 318
Clinical Questions Not Fully Explained by TORC1 Activation	p. 320
Clinical Perspectives	p. 320
Acknowledgments	p. 321
References	p. 322
Chemistry and Pharmacology of Rapamycin and Its Derivatives
Abstract	p. 329
Introduction	p. 330
Primer on the Mechanism of Action of Rapamycin	p. 331
Biosynthesis and Medicinal Chemistry of Rapamycin and Its Analogs	p. 334
Anticancer Activities of the Rapalogs	p. 340
Effects of Rapamycin on Immunity and Longevity	p. 350
Conclusions and Future Perspectives	p. 354
References	p. 356
Author Index	p. 367
Index	p. 397
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