Sancak, Y. et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903-915

Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA.
Molecular Cell (Impact Factor: 14.02). 04/2007; 25(6):903-15. DOI: 10.1016/j.molcel.2007.03.003
Source: PubMed


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.

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    • "Indeed, the removal of all Akt phosphorylation sites from TSC-1 and TSC-2 does not lead to an increase in TORC1 activity, as judged by an absence of a growth increase in vivo (Dong and Pan 2004; Schleich and Teleman 2009); this result indicates that, under physiological conditions, Akt function does not contribute to TORC1 activation. More recently, the protein PRAS40 ( proline-rich Akt substrate 40) was proposed to link IIS to TORC1 in cultured cells (Sancak et al. 2007; Vander Haar et al. 2007). PRAS40 binds to TORC1 and prevents it from interacting with its substrates. "
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    • "At the same time, Akt phosphorylates also Pras40. Pras40 is a direct TORC1 inhibitor, which functions through scaffolding of the essential TORC1 component Raptor (Sancak et al., 2007; Vander Haar et al., 2007). On the other hand, if a cell is in a low energy state TSC-mediated inhibition of TORC1 prevails. "
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    • "In Vitro mTOR Kinase Assay The mTOR kinase activity was assessed by in vitro kinase assay as described (Sancak et al., 2007). Briefly, pCDNA3-Flag-mTOR variants were transfected into HEK293T cells by calcium phosphate transfection. "
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