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Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2.

Abstract：

: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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Garami A,Zwartkruis FJ,Nobukuni T,Joaquin M,Roccio M,Stocker H,Kozma SC,Hafen E,Bos JL,Thomas G

doi

10.1016/s1097-2765(03)00220-x

subject

Has Abstract

pub_date

2003-06-01 00:00:00

pages

1457-66

issue

6

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(03)00220-X

journal_volume

11

pub_type

杂志文章

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