Table Of Content279
Current Topics
in Microbiology
and Immunology
Editors
R.W. Compans, Atlanta/Georgia
M.D.Cooper,Birmingham/Alabama
H.Koprowski, Philadelphia/Pennsylvania
F.Melchers, Basel •M.B.A.Oldstone,LaJolla/California
S.Olsnes, Oslo-M.Potter, Bethesda/Maryland
P.K.Vogt,LaIolla/Calitornia- H.Wagner, Munich
Springer-Verlag Berlin Heidelberg GmbH
G. Thomas D.M. Sabatini
M.N. Hall (Eds.)
TOR
Target of Rapamycin
With 49 Figures and 7 Tables
Springer
George Thomas
Friedrich-Miescher-Institute, Maulbeerstrasse 66, 4058 Basel, Switzerland
e-mail: [email protected]
David M. Sabatini, MD, PhD
Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02142, USA
e-mail: [email protected]
Michael N. Han
Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel,
Switzerland
e-mail: [email protected]
Cover Illustration by Sonja Dames:
Structure of the ternary complex consisting of FKBP12 (blue ribbon), rapamycin (red
space filling representation), and the FRB domain of human TOR (yeliow ribbon).
The figure is based on the crystal structure published by J. Choi, J. Chen, S.L. Schrei
ber, and J. Clardy (1996, Science 273: 239-242, 'Structure of the FKBP12-Rapamycin
Complex Interacting with the Binding Domain of Human FRAP'; PDB file: lFAP).
ISBN 978-3-642-62360-8 ISBN 978-3-642-18930-2 (eBook)
DOI 10.1007/978-3-642-18930-2
Library of Congress Catalog Card Number 72-152360
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Originally published by Springer-Verlag Berlin Heidelberg New York in 2004
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Preface
Asthe role ofTORcontinues to unfold, it isclear that this atypical protein
kinase occupies a central role in eukaryotic biology as an energy and nu
trient effector. It is also clear that with the advent of metazoans, the an
cient signal transduction pathway in which TORresides has been integra
ted with those that arose later to control metabolism and growth through
out amulticellularorganism. TORwasfirst identifiedin Saccharomyces ce
revisiae in agenetic selection for mutants resistant to the cytostatic effects
ofrapamycin.Rapamycin isanaturalmetaboliteproducedbysoilbacteria,
Streptomyces hygroscopicus, isolated from a soil sample collected on Easter
Island, which the natives refer to as Rapa Nui. Later, it was shown that
rapamycin forms a complex with the immunophilin FKBP12, and this
complex then binds and inhibits TOR. Initially, rapamycin was brought
into the laboratoryas a fungicide, but was rapidlyset aside when found to
have immunosuppressive activity.With the advent oftransplantation ther
apy, however, it was eventually "rediscovered" and approved for clinical
use as an immunosuppressant. Recent attention has focused on rapamycin
and its analogues in the treatment of solid tumors, rheumatoid arthritis,
and restenosis.
Here we have attempted to gather the leaders in the field of TOR rese
arch to review the latest findings from their specific areas of expertise,
from nutrient sensing in single cellorganisms to the role ofTORin patho
genic states. However,since the writing ofthe chapters herein,and reflect
ing the rapid pace of the TORfield, important new players have emerged
in the TORsignal transduction pathway.The new players include the pro
ducts ofthe twotumorsuppressorgenes TSCI and TSC2,the small GTPase
Rheb, and AMPdependent protein kinase. Alsonew is the suggestion that
TORmay link nutrients and ageing.These newadvances and insights con
tinue to add to the excitementsurrounding the TORfield.
Finally, we wish to thank the authors, who took time from very busy
schedules, to describe their research. We also thank our colleagues at
Springer-Verlag, in particular Anne Clauss and Angelique Gcouta, who
producedthe book.
August 2003 G.Thomas, D.Sabatini,M.N.Hall
List of Contents
TOR:The FirstTenYears
A.Lorberg and M.N.Hall .
The RoleofPhosphatases in TORSignalingin Yeast
K.Duveland J.R.Broach 19
YeastTORSignaling:AMechanism for Metabolic Regulation
T.Powers, I. Dilova,C.-Y. Chen, and K.Wedaman 39
Nutrient SignalingThroughTORKinases Controls Gene Expression
and CellularDifferentiationin Fungi
J.R.Rohde and M.E.Cardenas ................................ 53
Autophagyin Yeast: ATOR-MediatedResponse to NutrientStarvation
Y.Kamada, T.Sekito, and Y.Ohsumi ........................... 73
The FissionYeastTORProteins andthe Rapamycin Response:
an UnexpectedTale
R.Weisman 85
Plant Growth andthe TORPathway
B.Menand, C.Meyer,and C.Robaglia .......................... 97
TORActionin Mammalian Cellsand in Caenorhabditis elegans
X.Long,F.Muller,and J.Avruch 115
Genetic Analysis ofTORSignaling in Drosophila
Th.P.Neufeld .............................................. 139
InterplayBetweenGrowth FactorandNutrient Signaling:
Lessons from Drosophila TOR
E.Hafen .................................................. 153
mTORSignalingto Translation
A.-C.Gingras, B.Raught, and N.Sonenberg ..................... 169
VIII ListofContents
Modulation ofthe Protein Kinase ActivityofmTOR
J.e. Lawrence,[r.,T.-A.Lin,L.P.McMahon,and K.M.Choi ......... 199
RoleofmTORSignalingin the Control ofTranslation Initiation
and Elongation by Nutrients
C.G.Proud. ............................................... 215
NovelRegulatoryMechanisms ofmTORSignaling
J.Chen 245
Raptor and mTOR:Subunitsofa Nutrient-Sensitive Complex
D.H.Kim and D.M.Sabatini .................................. 259
Kinase Activities Associatedwith mTOR
K.Yonezawa,K.-I.Yoshino,e. Tokunaga,and K.Hara 271
mTOR:AMediatorofIntracellularHomeostasis
A.[aeschke,P.B.Dennis,and G.Thomas ........................ 283
mTORas a Positive Regulator ofTumorCellResponses to Hypoxia
R.T.Abraham. ............................................. 299
RetroviralOncogenes and TOR
M.Aokiand P.K.Vogt ................................... .... 321
mTORas aTarget for CancerTherapy
P.J.Houghton and S. Huang 339
Subject Index 361
List of Contributors
(Theiraddresses can be found at the beginningoftheir respectivechapters.)
Abraham, R.T. 299 Karnada, Y. 73
Aoki, M. 321 Kim, D.-H. 259
Avruch, J. 115 Lawrence, J.e. 199
Broach,J.R. 19 Lin, T.-A. 199
Cardenas, M.E. 53 Long, X. 115
Chen, Cr-Y, 39 Lorberg, A. 1
Chen, J. 245 McMahon, L.P. 199
Choi, K.M. 199 Menand, B. 97
Dennis, P.B. 283 Meyer, e. 97
Dilova.L 39 Muller, F. 115
Diivel, K. 19 Neufeld, T.P. 139
Gingras, A.-C. 169 Ohsumi,Y. 73
Hafen,E. 153 Powers, T. 39
Hall, M.N. Proud, e.G. 215
Hara, K. 271 Raught, B. 169
Houghton, P.J. 339 Robaglia, C. 97
Huang, S. 339 Rohde, J.R. 53
Iaeschke,A. 283 Sabatini,D.M. 259
x
List ofContributors
Sekito,T. 73 Wedaman, K. 39
Sonenberg,N. 169 Weisman,R. 85
Thomas, G. 283 Yonezawa,K. 271
Tokunaga,C. 271 Yoshino, K.-I. 271
Vogt,P.K. 321
TOR: The First 10 Years
A.Lorberg' M.N.Hall
DivisionofBiochemistry, Biozentrum,University ofBasel,Klingelbergstr.70,
4056,Basel,Switzerland
E-mail: [email protected]
Introduction . . . . . . . .
2 The DiscoveryofTOR... 2
3 TORControls CellGrowth inResponse toNutrients . 7
3.1 Temporal Control ofCellGrowth . . . . . . . . 9
3.1.1TranslationInitiation. . . . . . . . . . . . . . . . . . . 10
3.1.2ProteinTrafficand Degradation. . . . . . . . . . . . . . . . . . . . . 10
3.1.3Nuclear Localization ofNutrient-ResponsiveTranscriptionFactors . . .. 11
3.2 Spatial Control ofCellGrowth. . . . . . 12
3.2.1Polarizationofthe ActinCytoskeleton. 12
4 TwoTORComplexes . . .. 13
5 Conclusion 14
References. . . . 14
Abstract TORwas discovered and christened 10years ago. Onthe occa
sion of this anniversary, we revisit the discovery of TOR and chronicle
subsequent breakthroughs in S.cerevisiae that contributed to an under
standing of TOR function in yeast and higher eukaryotes. In particular,
wediscuss findings that led to the realization that the function ofTORis
to control cellgrowth in response to nutrients.
1
Introduction
TORwas discovered and christened 10years ago (Heitman et al. 1991a;
Kunz et al. 1993).On the occasion ofthis anniversary, werevisit the dis
covery of TORand chronicle subsequent breakthroughs in S.cerevisiae
that contributed to an understanding ofTORfunction inyeast and high
er eukaryotes. In particular, we discuss findings that led to the realiza-
