TY - JOUR
T1 - Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2
AU - Garami, Attila
AU - Zwartkruis, Fried J.T.
AU - Nobukuni, Takahiro
AU - Joaquin, Manel
AU - Roccio, Marta
AU - Stocker, Hugo
AU - Kozma, Sara C.
AU - Hafen, Ernst
AU - Bos, Johannes L.
AU - Thomas, George
N1 - Funding Information:
We are grateful to D. Kwiatkowski for providing TSC2 +/+ and TSC2 −/− MEFs, J. Sampson for the TSC2 GAP N1643K mutant, F. Nett and S. Gfeller for providing technical advice, P.D. Dennis for his critical reading of the manuscript, and S.-Y. Kim and J. Enserink for their help and discussions. We also thank F. Zilbermann for technical assistance. Finally, we are indebted to S. Oakeley, E. Oakeley, and A. Di Cara for help in preparing figures. A.G. and T.N. are recipients of EMBO Long-Term and Swiss Cancer League Fellowships, respectively. M.R. is supported by the Netherlands Genomics Initiative, and this work was supported in part by a grant to E.H., S.C.K., and G.T. from the Swiss Cancer League. S.C.K. and G.T. are supported by the Novartis Research Foundation.
PY - 2003/6/1
Y1 - 2003/6/1
N2 - Tumor suppressor genes evolved as negative effectors of mitogen and nutrient signaling pathways, such that mutations in these genes can lead to pathological states of growth. Tuberous sclerosis (TSC) is a potentially devastating disease associated with mutations in two tumor suppressor genes, TSC1 and 2, that function as a complex to suppress signaling in the mTOR/S6K/4E-BP pathway. However, the inhibitory target of TSC1/2 and the mechanism by which it acts are unknown. Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin-mediated Rheb activation is PI3K dependent. Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation. Finally, coexpression of a human TSC2 cDNA harboring a disease-associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1.
AB - Tumor suppressor genes evolved as negative effectors of mitogen and nutrient signaling pathways, such that mutations in these genes can lead to pathological states of growth. Tuberous sclerosis (TSC) is a potentially devastating disease associated with mutations in two tumor suppressor genes, TSC1 and 2, that function as a complex to suppress signaling in the mTOR/S6K/4E-BP pathway. However, the inhibitory target of TSC1/2 and the mechanism by which it acts are unknown. Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin-mediated Rheb activation is PI3K dependent. Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation. Finally, coexpression of a human TSC2 cDNA harboring a disease-associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1.
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U2 - 10.1016/S1097-2765(03)00220-X
DO - 10.1016/S1097-2765(03)00220-X
M3 - Article
C2 - 12820960
AN - SCOPUS:0038433304
SN - 1097-2765
VL - 11
SP - 1457
EP - 1466
JO - Molecular Cell
JF - Molecular Cell
IS - 6
ER -
