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Science 9 November 2007:
Vol. 318. no. 5852, pp. 977 - 980
DOI: 10.1126/science.1147379
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Reports

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*

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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Science. ISSN 0036-8075 (print), 1095-9203 (online)