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Mol Cell DOI:10.1016/j.molcel.2007.03.003

PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase.

Publication TypeJournal Article
Year of Publication2007
AuthorsSancak, Y, Thoreen, CC, Peterson, TR, Lindquist, RA, Kang, SA, Spooner, E, Carr, SA, Sabatini, DM
JournalMol Cell
Date Published2007 Mar 23
KeywordsAdaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Line, Enzyme Inhibitors, Humans, Insulin, Kinetics, Mice, Multiprotein Complexes, Phosphoproteins, Phosphorylation, Protein Kinase Inhibitors, Proteins, TOR Serine-Threonine Kinases, Transcription Factors

The heterotrimeric mTORC1 protein kinase nucleates a signaling network that promotes cell growth in response to insulin and becomes constitutively active in cells missing the TSC1 or TSC2 tumor suppressors. Insulin stimulates the phosphorylation of S6K1, an mTORC1 substrate, but it is not known how mTORC1 kinase activity is regulated. We identify PRAS40 as a raptor-interacting protein that binds to mTORC1 in insulin-deprived cells and whose in vitro interaction with mTORC1 is disrupted by high salt concentrations. PRAS40 inhibits cell growth, S6K1 phosphorylation, and rheb-induced activation of the mTORC1 pathway, and in vitro it prevents the great increase in mTORC1 kinase activity induced by rheb1-GTP. Insulin stimulates Akt/PKB-mediated phosphorylation of PRAS40, which prevents its inhibition of mTORC1 in cells and in vitro. We propose that the relative strengths of the rheb- and PRAS40-mediated inputs to mTORC1 set overall pathway activity and that insulin activates mTORC1 through the coordinated regulation of both.


Alternate JournalMol. Cell
PubMed ID17386266
Grant ListR01 CA129105 / CA / NCI NIH HHS / United States
R01 CA129105-02 / CA / NCI NIH HHS / United States
R01 AI47389 / AI / NIAID NIH HHS / United States
R01 CA103866 / CA / NCI NIH HHS / United States