期刊
CELL
卷 121, 期 2, 页码 179-193出版社
CELL PRESS
DOI: 10.1016/j.cell.2005.02.031
关键词
-
资金
- NCI NIH HHS [P30 CA08748, U01 CA-84292] Funding Source: Medline
Tuberous sclerosis (TSC) is a tumor syndrome caused by mutation in TSC1 or TSC2genes. TSC tumorigenesis is not always accompanied by loss of heterozygosity (LOH). Recently, extracellular signal-regulated kinase (Erk) has been found activated in TSC lesions lacking TSC1 or TSC2 LOH. Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. Importantly, expression of an Erk nonphosphorylatable TSC2 mutant in TSC2(+/-) tumor cells where Erk is constitutively activated blocks tumori-genecity in vivo, while wild-type TSC2 is ineffective. Our findings position the Ras/MAPK pathway upstream of the TSC complex and suggest that Erk may modulate mTOR signaling and contribute to disease progression through phosphorylation and inactivation of TSC2.
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