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The Enzymes, Volume 27 : Part A - Fuyuhiko Tamanoi

The Enzymes, Volume 27

Part A

Hardcover

Published: 25th March 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

Prefacep. xi
TOR Complexes: Composition, Structure, and Phosphorylation
Abstractp. 1
Introductionp. 1
TORC1 and TORC2 Componentsp. 3
Domains of TOR and Its Binding Partnersp. 5
Phosphorylation of TOR and Its Binding Partnersp. 13
Future Directionsp. 14
Acknowledgmentsp. 15
Referencesp. 15
Regulation of TOR Signaling in Mammals
Abstractp. 21
One Enzyme, Two Complexesp. 21
Raptor Defines mTORC1p. 23
Rictor Defines a Rapamycin-Insensitive mTOR Complexp. 25
Additional mTORC1 and mTORC2 Proteinsp. 26
The Regulation of mTOR Signaling by Insulin and PRAS40p. 28
Deptor: A Regulator of mTOR Signaling Found Only in Vertebratesp. 30
The Rag Proteins: Regulation of mTOR Signaling by Amino Acidsp. 31
The Future: Remaining Mysteries of mTOR Signaling and Clinical Significance of mTORp. 33
Acknowledgmentsp. 35
Referencesp. 35
Rheb G-Proteins and the Activation of mTORC1
Abstractp. 39
Rheb Defines a Unique Family Within the Ras Superfamily G-Proteinsp. 39
Activation of mTORC1 by Rhebp. 47
Functions of Rheb that Are Independent of mTORp. 51
Future Prospectsp. 52
Acknowledgmentsp. 52
Referencesp. 53
Regulation of TOR Complex 1 by Amino Acids Through Small GTPases
Abstractp. 57
Amino Acid Regulation of TORC1: Introductionp. 58
Leucine Is the Most Potent Amino Acid Regulator of TORC1p. 59
Rheb Binds and Regulates TORC1p. 59
Cross-competition Among Substrates for Raptor Can Influence TORC1 Signalingp. 63
Phosphatidic Acid Is a Rheb-Directed Regulator of mTORClp. 64
FKBP38 as a Candidate Rheb-Controlled mTORCl Regulatorp. 64
Amino Acids Control the Rheb-mTORC1 Interactionp. 65
Rag GTPases Mediate Amino Acid Regulation of the Rheb-TORC1 Interactionp. 66
Phosphatidyl 3' Phosphate Contributes to Amino Acid Regulation of Mammalian TORC1p. 67
MAP4K3/Glk May Participate in Amino Acid Regulation of mTORC1p. 68
Summaryp. 69
Acknowledgmentsp. 69
Referencesp. 70
Rag GTPases in TORC1 Activation and Nutrient Signaling
Abstractp. 75
mTORC1 Activation by Multiple Signals, Including Amino Acidsp. 76
Rag GTPases and Amino Acid-Induced mTORC1 Activationp. 77
Vam6 as a Rag GEF in Amino Acid-Induced TORC1 Activationp. 81
Raptor Interacts with Both Upstream Regulators and Downstream Substratesp. 82
RalA in Nutrient-Induced mTORC1 Activationp. 83
Referencesp. 85
Amino Acid Regulation of hVps34 and mTORC1 Signaling
Abstractp. 89
Introductionp. 90
AAs as a Signaling Metabolitep. 92
AAs and hVps34p. 95
hVps34 and mTORC1p. 96
Conclusions and Future Perspectivesp. 96
Acknowledgmentsp. 98
Referencesp. 98
AGC Kinases in mTOR Signaling
Abstractp. 101
Introductionp. 102
mTOR, an Atypical Protein Kinasep. 102
AGC Kinase, the "Prototype" of Protein Kinasesp. 104
Phosphorylation of AGC Kinases by mTORp. 105
Phosphorylalion of mTORCs by AGC Kinasesp. 113
Phosphorylation of mTORC Regulators by AGC Kinasesp. 114
mTORC Functions Mediated by AGC Kinasesp. 118
Conclusionp. 121
Acknowledgmentsp. 121
Referencesp. 122
mTORC1 and Cell Cycle Control
Abstractp. 129
Introductionp. 130
TOR Signaling and G0p. 133
Control of G1/S-Phase Progression by (m)TORC1p. 133
Control of Mitotic Entry by TORCsp. 137
A Link Between Mitochondrial Function, mTORC1, and Cell Cycle Progression?p. 139
mTORC1, Ribosome Biogenesis, and Cell Cycle Controlp. 140
Conclusions and Perspectivep. 141
Referencesp. 142
TORC1 Signaling in Budding Yeast
Abstractp. 147
The Discovery of TORp. 147
The Discovery of TOR Complexesp. 148
What is TORC1?p. 150
Where is TORC1?p. 151
What Regulates TORC1?p. 151
What Does TORC1 Regulate?p. 153
Conclusionsp. 169
Acknowledgmentsp. 170
Referencesp. 170
TORC2 and Sphingolipid Biosynthesis and Signaling: Lessons from Budding Yeast
Abstractp. 177
Introductionp. 178
TORC1 Versus TORC2p. 179
Sphingolipid Biosynthesis: A Brief Primerp. 180
Regulation of Sphingolipid Metabolism: Connections to TORp. 184
Implications for Mammalian Cellsp. 191
Conclusions and Perspectivep. 191
Referencesp. 192
TORC1 Signaling in the Budding Yeast Endomembrane System and Control of Cell-Cell Adhesion in Pathogenic Fungi
Abstractp. 199
TORC1 Signaling from the Budding Yeast Endomembrane Systemp. 200
TORC1 Components and Its Major Downstream Effectors Localize to Endomembranesp. 201
Genetic and Functional Interactions Between Tor1 and Protein Trafficking Regulators Provide Insights into TORC1 Activation by Amino Acidsp. 202
Interactions Between Vesicular System Components and TORC1-Controlled Transcriptional Regulators are Required for Balanced Cell Growthp. 206
Tor Signaling in Fungal Pathogensp. 208
Control of Filamentous Differentiation by TORC1 Signaling in Divergent Fungip. 208
The TORC1 Cascade and Cellular Adhesionp. 211
Targeting the Tor Pathway: A Novel Therapeutic Antifungal Approachp. 215
Remarks and Future Directionsp. 220
Acknowledgmentsp. 221
Referencesp. 221
TOR and Sexual Development in Fission Yeast
Abstractp. 229
Introductionp. 230
Cell Cycle Regulation for Sexual Developmentp. 230
Nutritional Signalingp. 231
Mating Pheromone Signalingp. 239
Initiation of Meiosisp. 241
Acknowledgmentsp. 244
Referencesp. 245
Fission Yeast TOR and Rapamycin
Abstractp. 251
Introductionp. 252
TORC1 is a Major Regulator of Cellular Growthp. 253
TORC2 is Required for Responses to Starvation, Survival Under Stress Conditions, Chromatin-Mediated Functions, DNA Damage Response and Maintenance of Telomere Lengthp. 258
The Response to Rapamycin in Fission Yeastp. 262
Conclusion and Future Prospectivep. 265
Acknowledgmentsp. 266
Referencesp. 266
Structure of TOR Complexes in Fission Yeast
Abstractp. 271
S. pombe TOR Kinasesp. 272
S. pombe TORC1p. 275
S. pombe TORC2p. 277
Phosphorylation of TORC Componentsp. 278
Other TOR-Associated Proteinsp. 279
Conclusionp. 280
Referencesp. 281
The TOR Complex and Signaling Pathway in Plants
Abstractp. 285
Introductionp. 286
Plant Homologs of the TOR Complex Proteinsp. 287
Components of the TOR Signaling Pathway in Plantsp. 292
Genetic Analysis of the Plant TOR Signaling Pathway: A Green Growth facTOR?p. 294
Conclusionp. 298
Acknowledgmentsp. 299
Referencesp. 299
Dysregulation of TOR Signaling in Tuberous Sclerosis and Lymphangioleiomyomotosis
Abstractp. 303
TSC and LAM: Clinical Featuresp. 304
Evidence of mTOR Activation in TSC and LAMp. 305
Evidence That Inhibition of TOR Signaling Inhibits Tumor Formation in Mouse Modelsp. 305
Combinational Therapy in Heterozygous Mouse and Subcutaneous Tumor Modelsp. 313
Evidence That Inhibition of TOR Signaling Suppresses the Neurologic Manifestation in Mouse Modelsp. 313
Evidence That Inhibition of TOR Signaling Inhibits Tumor Formation in TSC and LAMp. 316
Evidence of TORC1-Independent Phenotypes in TSCp. 318
Clinical Questions Not Fully Explained by TORC1 Activationp. 320
Clinical Perspectivesp. 320
Acknowledgmentsp. 321
Referencesp. 322
Chemistry and Pharmacology of Rapamycin and Its Derivatives
Abstractp. 329
Introductionp. 330
Primer on the Mechanism of Action of Rapamycinp. 331
Biosynthesis and Medicinal Chemistry of Rapamycin and Its Analogsp. 334
Anticancer Activities of the Rapalogsp. 340
Effects of Rapamycin on Immunity and Longevityp. 350
Conclusions and Future Perspectivesp. 354
Referencesp. 356
Author Indexp. 367
Indexp. 397
Table of Contents provided by Ingram. All Rights Reserved.

ISBN: 9780123815392
ISBN-10: 0123815398
Series: The Enzymes : Book 27
Audience: Professional
Format: Hardcover
Language: English
Number Of Pages: 420
Published: 25th March 2010
Publisher: Elsevier Science Publishing Co Inc
Country of Publication: US
Dimensions (cm): 22.9 x 15.2  x 1.91
Weight (kg): 0.68
Edition Number: 27