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Science 318 (5852): 977-980

Copyright © 2007 by the American Association for the Advancement of Science

Rheb Activates mTOR by Antagonizing Its Endogenous Inhibitor, FKBP38

Xiaochun Bai,1,3 Dongzhu Ma,1 Anling Liu,1 Xiaoyun Shen,1 Qiming J. Wang,1 Yongjian Liu,2 Yu Jiang1*

Abstract: The mammalian target of rapamycin, mTOR, is a central regulator of cell growth. Its activity is regulated by Rheb, a Ras-like small guanosine triphosphatase (GTPase), in response to growth factor stimulation and nutrient availability. We show that Rheb regulates mTOR through FKBP38, a member of the FK506-binding protein (FKBP) family that is structurally related to FKBP12. FKBP38 binds to mTOR and inhibits its activity in a manner similar to that of the FKBP12-rapamycin complex. Rheb interacts directly with FKBP38 and prevents its association with mTOR in a guanosine 5'-triphosphate (GTP)–dependent manner. Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability.

1 Department of Pharmacology, University of Pittsburgh School of Medicine, E1357 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
2 Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
3 Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.

* To whom correspondence should be addressed. E-mail: jiang{at}server.pharm.pitt.edu


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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 283, 28897-28908
   Abstract »    Full Text »    PDF »
Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1.
M. Rosner and M. Hengstschlager (2008)
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   Abstract »    Full Text »    PDF »
The Switch I Region of Rheb Is Critical for Its Interaction with FKBP38.
D. Ma, X. Bai, S. Guo, and Y. Jiang (2008)
J. Biol. Chem. 283, 25963-25970
   Abstract »    Full Text »    PDF »
Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events.
C. Nardella, Z. Chen, L. Salmena, A. Carracedo, A. Alimonti, A. Egia, B. Carver, W. Gerald, C. Cordon-Cardo, and P. P. Pandolfi (2008)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »

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