Tamanoi Structure, Function and Regulation of TOR complexes from Yeasts to Mammals

Part A
1. Auflage 2010
ISBN: 978-0-12-381540-8
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 420 Seiten

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

Autoren/Hrsg.

Tamanoi, Fuyuhiko

Inhaltsverzeichnis

1;Front Cover;1
2;The Enzymes;4
3;Copyright Page;5
4;Contents;6
5;Preface;12
6;Chapter 1: TOR Complexes: Composition, Structure, and Phosphorylation;14
6.1;II. Introduction;14
6.2;III. TORC1 and TORC2 Components;16
6.3;IV. Domains of TOR and Its Binding Partners;18
6.4;V. Phosphorylation of TOR and Its Binding Partners;26
6.5;VI. Future Directions;27
6.6;Acknowledgments;28
6.7;References;28
7;Chapter 2: Regulation of TOR Signaling in Mammals;34
7.1;II. One Enzyme, Two Complexes;34
7.2;III. Raptor Defines mTORC1;36
7.3;IV. Rictor Defines a Rapamycin-Insensitive mTOR Complex;38
7.4;V. Additional mTORC1 and mTORC2 Proteins;39
7.5;VI. The Regulation of mTOR Signaling by Insulin and PRAS40;41
7.6;VII. DEPTOR: A Regulator of mTOR Signaling Found Only in Vertebrates;43
7.7;VIII. The Rag Proteins: Regulation of mTOR Signaling by Amino Acids ;44
7.8;IX. The Future: Remaining Mysteries of mTOR Signaling and Clinical Significance of mTOR;46
7.9;Acknowledgments;48
7.10;References;48
8;Chapter 3: Rheb G-Proteins and the Activation of mTORC1;52
8.1;II. Rheb Defines a Unique Family Within the Ras Superfamily G-Proteins;52
8.2;III. Activation of mTORC1 by Rheb;60
8.3;IV. Functions of Rheb that Are Independent of mTOR;64
8.4;V. Future Prospects;65
8.5;Acknowledgments;65
8.6;References;66
9;Chapter 4: Regulation of TOR Complex 1 by Amino Acids Through Small GTPases;70
9.1;II. Amino Acid Regulation of TORC1: Introduction;71
9.2;III. Leucine Is the Most Potent Amino Acid Regulator of TORC1;72
9.3;IV. Rheb Binds and Regulates TORC1;72
9.4;V. Cross-competition Among Substrates for Raptor Can Influence TORC1 Signaling;76
9.5;VI. Phosphatidic Acid Is a Rheb-Directed Regulator of mTORC1;77
9.6;VII. FKBP38 as a Candidate Rheb-Controlled mTORC1 Regulator;77
9.7;VIII. Amino Acids Control the Rheb-mTORC1 Interaction;78
9.8;IX. Rag GTPases Mediate Amino Acid Regulation of the Rheb-TORC1 Interaction;79
9.9;X. Phosphatidyl 3' Phosphate Contributes to Amino Acid Regulation of Mammalian TORC1;80
9.10;XI. MAP4K3/Glk May Participate in Amino Acid Regulation of mTORC1;81
9.11;XII. Summary;82
9.12;Acknowledgments;82
9.13;References;83
10;Chapter 5: Rag GTPases in TORC1 Activation and Nutrient Signaling;88
10.1;II. mTORC1 Activation by Multiple Signals, Including Amino Acids ;89
10.2;III. Rag GTPases and Amino Acid-Induced mTORC1 Activation;90
10.3;IV. Vam6 as a Rag GEF in Amino Acid-Induced TORC1 Activation;94
10.4;V. Raptor Interacts with Both Upstream Regulators and Downstream Substrates;95
10.5;VI. RalA in Nutrient-Induced mTORC1 Activation;96
10.6;References;98
11;Chapter 6: Amino Acid Regulation of hVps34 and mTORC1 Signaling;102
11.1;II. Introduction;103
11.2;III. AAs as a Signaling Metabolite;105
11.3;IV. AAs and hVps34;108
11.4;V. hVps34 and mTORC1;109
11.5;VI. Conclusions and Future Perspectives;109
11.6;Acknowledgments;111
11.7;References;111
12;Chapter 7: AGC Kinases in mTOR Signaling;114
12.1;II. Introduction;115
12.2;III. mTOR, an Atypical Protein Kinase;115
12.3;IV. AGC Kinase, the "Prototype" of Protein Kinases;117
12.4;V. Phosphorylation of AGC Kinases by mTOR;118
12.5;VI. Phosphorylation of mTORCs by AGC Kinases;126
12.6;VII. Phosphorylation of mTORC Regulators by AGC Kinases;127
12.7;VIII. mTORC Functions Mediated by AGC Kinases;131
12.8;IX. Conclusion;134
12.9;Acknowledgments;134
12.10;References;135
13;Chapter 8: mTORC1 and Cell Cycle Control;142
13.1;II. Introduction;143
13.2;III. TOR Signaling and G0;146
13.3;IV. Control of G1/S-Phase Progression by (m)TORC1;146
13.4;V. Control of Mitotic Entry by TORCs;150
13.5;VI. A Link Between Mitochondrial Function, mTORC1, and Cell Cycle Progression?;152
13.6;VII. mTORC1, Ribosome Biogenesis, and Cell Cycle Control;153
13.7;VIII. Conclusions and Perspective;154
13.8;References;155
14;Chapter 9: TORC1 Signaling in Budding Yeast;160
14.1;II. The Discovery of TOR;160
14.2;III. The Discovery of TOR Complexes;161
14.3;IV. What is TORC1?;163
14.4;V. Where is TORC1?;164
14.5;VI. What Regulates TORC1?;164
14.6;VII. What Does TORC1 Regulate?;166
14.7;VIII. Conclusions;182
14.8;Acknowledgments;183
14.9;References;183
15;Chapter 10: TORC2 and Sphingolipid Biosynthesis and Signaling: Lessons from Budding Yeast ;190
15.1;II. Introduction;191
15.2;III. TORC1 Versus TORC2;192
15.3;IV. Sphingolipid Biosynthesis: A Brief Primer;193
15.4;V. Regulation of Sphingolipid Metabolism: Connections to TOR;197
15.5;VI. Implications for Mammalian Cells;204
15.6;VII. Conclusions and Perspective;204
15.7;References;205
16;Chapter 11: TORC1 Signaling in the Budding Yeast Endomembrane System and Control of Cell-Cell Adhesion in Pathogenic Fungi;212
16.1;II. TORC1 Signaling from the Budding Yeast Endomembrane System;213
16.2;III. TORC1 Components and Its Major Downstream Effectors Localize to Endomembranes;214
16.3;IV. Genetic and Functional Interactions Between Tor1 and Protein Trafficking Regulators Provide Insights into TORC1 Activation by AminoAcids;215
16.4;V. Interactions Between Vesicular System Components and TORC1-Controlled Transcriptional Regulators are Required for Balanced Cell Growth;219
16.5;VI. Tor Signaling in Fungal Pathogens;221
16.6;VII. Control of Filamentous Differentiation by TORC1 Signaling in Divergent Fungi;221
16.7;VIII. The TORC1 Cascade and Cellular Adhesion;224
16.8;IX. Targeting the Tor Pathway: A Novel Therapeutic Antifungal Approach;228
16.9;X. Remarks and Future Directions;233
16.10;Acknowledgments;234
16.11;References;234
17;Chapter 12: TOR and Sexual Development in Fission Yeast;242
17.1;II. Introduction;243
17.2;III. Cell Cycle Regulation for Sexual Development;243
17.3;IV. Nutritional Signaling;244
17.4;V. Mating Pheromone Signaling;252
17.5;VI. Initiation of Meiosis;254
17.6;Acknowledgments;257
17.7;References;258
18;Chapter 13: Fission Yeast TOR and Rapamycin;264
18.1;II. Introduction;265
18.2;III. TORC1 is a Major Regulator of Cellular Growth;266
18.3;IV. TORC2 is Required for Responses to Starvation, Survival Under Stress Conditions, Chromatin-Mediated Functions, DNA Damage Response and Maintenance of Telomere Length;271
18.4;V. The Response to Rapamycin in Fission Yeast;275
18.5;VI. Conclusion and Future Prospective;278
18.6;Acknowledgments;279
18.7;References;279
19;Chapter 14: Structure of TOR Complexes in Fission Yeast;284
19.1;II. S. pombe TOR Kinases;285
19.2;III. S. pombe TORC1;288
19.3;IV. S. pombe TORC2;290
19.4;V. Phosphorylation of TORC Components;291
19.5;VI. Other TOR-Associated Proteins;292
19.6;VII. Conclusion;293
19.7;References;294
20;Chapter 15: The TOR Complex and Signaling Pathway in Plants;298
20.1;II. Introduction;299
20.2;III. Plant Homologs of the TOR Complex Proteins;300
20.3;IV. Components of the TOR Signaling Pathway in Plants;305
20.4;V. Genetic Analysis of the Plant TOR Signaling Pathway: A Green Growth facTOR?;307
20.5;VI. Conclusion;311
20.6;Acknowledgments;312
20.7;References;312
21;Chapter 16: Dysregulation of TOR Signaling in Tuberous Sclerosis and Lymphangioleiomyomotosis;316
21.1;II. TSC and LAM: Clinical Features;317
21.2;III. Evidence of mTOR Activation in TSC and LAM;318
21.3;IV. Evidence That Inhibition of TOR Signaling Inhibits Tumor Formation in Mouse Models;318
21.4;V. Combinational Therapy in Heterozygous Mouse and Subcutaneous Tumor Models;326
21.5;VI. Evidence That Inhibition of TOR Signaling Suppresses the Neurologic Manifestation in Mouse Models;326
21.6;VII. Evidence That Inhibition of TOR Signaling Inhibits Tumor Formation in TSC and LAM;329
21.7;VIII. Evidence of TORC1-Independent Phenotypes in TSC;331
21.8;IX. Clinical Questions Not Fully Explained by TORC1 Activation;333
21.9;X. Clinical Perspectives;333
21.10;Acknowledgments;334
21.11;References;335
22;Chapter 17: Chemistry and Pharmacology of Rapamycin and Its Derivatives;342
22.1;II. Introduction;343
22.2;III. Primer on the Mechanism of Action of Rapamycin;344
22.3;IV. Biosynthesis and Medicinal Chemistry of Rapamycin and Its Analogs;347
22.4;V. Anticancer Activities of the Rapalogs;353
22.5;VI. Effects of Rapamycin on Immunity and Longevity;363
22.6;VII. Conclusions and Future Perspectives;367
22.7;References;369
23;Author Index;380
24;Index;410
25;Color Plates;418