The signalling function of mTOR complex 1 is activated by Rheb-GTP, which controls the catalytic competence of the mTOR (mammalian target of rapamycin) kinase domain by an incompletely understood mechanism. Rheb can bind directly to the mTOR kinase domain, and association with inactive nucleotide-deficient Rheb mutants traps mTOR in a catalytically inactive state. Nevertheless, Rheb-GTP targets other than mTOR, such as FKBP38 (FK506-binding protein 38) and/or PLD1 (phospholipase D1), may also contribute to mTOR activation. Once activated, the mTOR catalytic domain phosphorylates substrates only when they are bound to raptor (regulatory associated protein of mTOR), a separate polypeptide within the complex. The mechanism of insulin/nutrient stimulation of mTOR complex 1 signalling, in addition to Rheb-GTP activation of the mTOR catalytic function, also involves a stable modification of the configuration of mTORC1 (mTOR complex 1) that increases access of substrates to their binding site on the raptor polypeptide. The mechanism underlying this second step in the activation of mTORC1 is unknown.
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February 2009
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Conference Article|
January 20 2009
Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor1
Joseph Avruch;
Joseph Avruch
2
*Diabetes Research Laboratory, Department of Molecular Biology, Diabetes Unit, Medical Services, Massachusetts General Hospital, Simches Research Building, 6408, 185 Cambridge Street, Boston, MA 02114, U.S.A.
2To whom correspondence should be addressed (email avruch@molbio.mgh.harvard.edu).
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Xiaomeng Long;
Xiaomeng Long
*Diabetes Research Laboratory, Department of Molecular Biology, Diabetes Unit, Medical Services, Massachusetts General Hospital, Simches Research Building, 6408, 185 Cambridge Street, Boston, MA 02114, U.S.A.
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Yenshou Lin;
Yenshou Lin
*Diabetes Research Laboratory, Department of Molecular Biology, Diabetes Unit, Medical Services, Massachusetts General Hospital, Simches Research Building, 6408, 185 Cambridge Street, Boston, MA 02114, U.S.A.
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Sara Ortiz-Vega;
Sara Ortiz-Vega
*Diabetes Research Laboratory, Department of Molecular Biology, Diabetes Unit, Medical Services, Massachusetts General Hospital, Simches Research Building, 6408, 185 Cambridge Street, Boston, MA 02114, U.S.A.
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Joseph Rapley;
Joseph Rapley
*Diabetes Research Laboratory, Department of Molecular Biology, Diabetes Unit, Medical Services, Massachusetts General Hospital, Simches Research Building, 6408, 185 Cambridge Street, Boston, MA 02114, U.S.A.
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Angela Papageorgiou;
Angela Papageorgiou
*Diabetes Research Laboratory, Department of Molecular Biology, Diabetes Unit, Medical Services, Massachusetts General Hospital, Simches Research Building, 6408, 185 Cambridge Street, Boston, MA 02114, U.S.A.
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Noriko Oshiro;
Noriko Oshiro
*Diabetes Research Laboratory, Department of Molecular Biology, Diabetes Unit, Medical Services, Massachusetts General Hospital, Simches Research Building, 6408, 185 Cambridge Street, Boston, MA 02114, U.S.A.
†Biosignal Research Center, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
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Ushio Kikkawa
Ushio Kikkawa
†Biosignal Research Center, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
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Publisher: Portland Press Ltd
Received:
November 16 2008
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem Soc Trans (2009) 37 (1): 223–226.
Article history
Received:
November 16 2008
Citation
Joseph Avruch, Xiaomeng Long, Yenshou Lin, Sara Ortiz-Vega, Joseph Rapley, Angela Papageorgiou, Noriko Oshiro, Ushio Kikkawa; Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor1. Biochem Soc Trans 1 February 2009; 37 (1): 223–226. doi: https://doi.org/10.1042/BST0370223
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