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Rheb Activates mTOR by Antagonizing Its Endogenous Inhibitor, FKBP38
Xiaochun Bai,1,3Dongzhu Ma,1Anling Liu,1Xiaoyun Shen,1Qiming J. Wang,1Yongjian Liu,2Yu Jiang1*
The mammalian target of rapamycin, mTOR, is a central regulatorof cell growth. Its activity is regulated by Rheb, a Ras-likesmall guanosine triphosphatase (GTPase), in response to growthfactor stimulation and nutrient availability. We show that Rhebregulates mTOR through FKBP38, a member of the FK506-bindingprotein (FKBP) family that is structurally related to FKBP12.FKBP38 binds to mTOR and inhibits its activity in a manner similarto that of the FKBP12-rapamycin complex. Rheb interacts directlywith FKBP38 and prevents its association with mTOR in a guanosine5'-triphosphate (GTP)–dependent manner. Our findings suggestthat FKBP38 is an endogenous inhibitor of mTOR, whose inhibitoryactivity is antagonized by Rheb in response to growth factorstimulation 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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