TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006 Sep 08;126(5):955-68
Date
09/09/2006Pubmed ID
16959574DOI
10.1016/j.cell.2006.06.055Scopus ID
2-s2.0-33748153690 (requires institutional sign-in at Scopus site) 1180 CitationsAbstract
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.
Author List
Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KLMESH terms used to index this publication - Major topics in bold
AMP-Activated Protein KinasesAnimals
Antibiotics, Antineoplastic
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic
Glycogen Synthase Kinase 3
Humans
Mammary Neoplasms, Experimental
Mice
Multienzyme Complexes
Mutation
Phosphorylation
Protein Kinases
Signal Transduction
Sirolimus
TOR Serine-Threonine Kinases
Transfection
Tumor Suppressor Proteins
Wnt Proteins
