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.