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RESEARCH COMMUNICATION
1 Department of Biological Chemistry , 2 Institute of Gerontology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA , 3 Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06536, USA
Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2. The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1. These functions of TSC1/TSC2 are likely mediated by mTOR. Here we report that TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase. Rheb stimulates phosphorylation of S6K and 4EBP1. This function of Rheb is blocked by rapamycin and dominant-negative mTOR. Rheb stimulates the phosphorylation of mTOR and plays an essential role in regulation of S6K and 4EBP1 in response to nutrients and cellular energy status. Our data demonstrate that Rheb acts downstream of TSC1/TSC2 and upstream of mTOR to regulate cell growth.
[Keywords: TSC2; Rheb; mTOR; S6K; GAP; tuberous sclerosis complex]
Received May 6, 2003; revised version accepted June 2, 2003.
Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1110003.
4 These authors contributed equally to this work.
5 E-MAIL kunliang{at}umich.edu; FAX (734) 763-4581.
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