TSC2 integrates Wnt and energy signals through coordinated AMPK and GSK3 phosphorylation.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Cell |
| Year | 2006 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.cell.2006.06.055 · PMID 16959574 |
Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.
| Intervention | Biochemical/genetic (AMPK, GSK3, TSC2) |
| Target | TSC2 / AMPK / GSK3 / mTOR |
| Model | Mammalian cells |
| Effect | AMPK and GSK3 coordinately phosphorylate TSC2 to integrate Wnt and energy signals controlling growth |