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

Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA.
Molecular Cell (Impact Factor: 14.46). 04/2007; 25(6):903-15. DOI: 10.1016/j.molcel.2007.03.003
Source: PubMed

ABSTRACT 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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Available from: Seong A Kang, Aug 19, 2015
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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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    • "Insulin-sensitive protein , PRAS40 (proline-rich Akt substrate of 40 kDa), is shown to be bound to Raptor and an inhibitor of mTORC1 kinase activity (Sancak et al., 2007; Vander Haar et al., 2007), and muscle activity increases insulin sensitivity (Vander Haar et al., 2007). Upon stimulation with insulin, Akt-induced phosphorylation of PRAS40 resulted in the dissociation from mTORC1 and an increase in mTORC1 signaling (Sancak et al., 2007; Vander Haar et al., 2007). Alternatively, the GbL, mSin1, and Rictor associate to form the mTORC2 complex. "
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    • "TSC1/2 complex (a direct upstream regulator of Rheb) is not implicated in the effect of amino acids on mTORC1 (Roccio et al. 2006). Moreover, PKB/Akt can directly phosphorylate PRAS40, and relieve the inhibition of PRAS40 (a negative regulator) to mTORC1 (Sancak et al. 2007; Vander Haar et al. 2007). Interestingly, there are some similar aspects of Rheb and Rag-dependent modulation of mTORC1. "
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