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.
View at publisher
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.
126 downloads since deposited on 11 Feb 2008
28 downloads since 12 months
|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|
Users (please log in): suggest update or correction for this item
Repository Staff Only: item control page