Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-658
Garami, A; Zwartkruis, F J T; Nobukuni, T; Joaquin, M; Roccio, M; Stocker, H; Kozma, S C; Hafen, E; Bos, J L; Thomas, G (2003). Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Molecular Cell, 11(6):1457-1466.
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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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|Item Type:||Journal Article, refereed|
|Communities & Collections:||07 Faculty of Science > Institute of Zoology (former)|
|Dewey Decimal Classification:||570 Life sciences; biology
590 Animals (Zoology)
|Date:||1 June 2003|
|Deposited On:||11 Feb 2008 12:17|
|Last Modified:||27 Nov 2013 22:19|
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