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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    • "Growth factors such as insulin promote the phosphorylation of the kinase Akt. Once activated, Akt phosphorylates and inhibits the tuberous sclerosis complex 2 (TSC2) which suppresses the conversion of Rheb-GDP to Rheb-GTP, a small GTPase which resides at the lysosomal surface and functions as a potent stimulator of the mTORC1 kinase activity (Sancak et al., 2007). The recruitment of TORC1 to this lysosomal surface represents an essential step in its activation by Rheb and is mainly driven by amino acids. "
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    ABSTRACT: Supplementation of fish diets with crystalline methionine is needed to overcome the low methionine content of plant based diet and to ensure good growth performances of the farmed fish. The study aimed to investigate the consequences of methionine imbalance on the expression of genes related to hepatic intermediary metabolism in rainbow trout. For this purpose, juvenile trout were fed during 6 weeks diets containing either deficient, adequate or excess levels of methionine. The results indicate that the methionine deficiency increased the expression of the activating transcription factor 4 (ATF4) target genes asparagine synthetase (ASNS), system A amino acid transporter 2 (SNAT2) and cationic amino acid transporter 1 (CAT1) as a result of the activation of the GCN2/eIF2α pathway. In contrast, dietary methionine supplied in excess produced broader changes on hepatic gene expression by increasing the levels of transcripts related to fatty acid synthesis (fatty acid synthesis, FAS) and oxidation (hydroxyacyl-CoA dehydrogenase, HOAD), gluconeogenesis (glucose-6-phosphatase 2, G6Pase2 and phosphoénolpyruvate carboxykinase, PEPCK) and amino acid catabolism (glutamate dehydrogenase 1 and 2, GDH 1 and 2). Methionine excess also led to a post-prandial down-regulation of G6Pase2 and PEPCK gene expression not occurring in fish fed the methionine deficient or adequate diet. This study shows that a dietary methionine imbalance in juvenile trout strongly affects hepatic gene expression and that the response highly depends on the nature of the imbalance: deficiency or excess. Statement of relevance: Precise amino acid supplementation of fish diet.
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    • " insulin receptor substrate (IRS) and indirectly via activation of IGF-1 signaling [reviewed in (Lamming 2014)]. mTORC2 activity promotes mTORC1 activity via the activation of Akt. Akt activates mTORC1 signaling through two different mechanisms. First, Akt phosphorylates PRAS40, a protein which, when unphosphorylated, binds to and inhibits mTORC1 (Sancak et al . 2007). Secondly, Akt phosphorylates TSC2, a member of the tuberous sclerosis complex which is composed of TSC1 (hamartin) and TSC2 (tuberin) (Tee et al . 2003). The TSC complex acts as a GTPase-activating protein (GAP) upon Rheb, a GTPase that stimulates mTORC1 activity (Inoki et al . 2003). However, the TSC complex is also responsive to man"
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    • "Since it is mTORC1 that conveys signals to S6Ks and rpS6, it will be mentioned in the remainder of this review, rather than mTOR, when transduction of signals is discussed. Akt can also activate mTORC1 independently of TSC1eTSC2 by phosphorylating PRAS40, thereby relieving the PRAS40-mediated inhibition of mTORC1 (Sancak et al., 2007; Vander Haar et al., 2007). Active mTORC1 phosphorylates two translational regulators, S6Ks and eukaryotic initiation factor 4E (eIF-4E)-binding protein (4E-BP1, 2, and 3) (Hay and Sonenberg, 2004). "
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    ABSTRACT: The phosphorylation of ribosomal protein S6 (rpS6) has been described for the first time about four decades ago. Since then, numerous studies have shown that this modification occurs in response to a wide variety of stimuli on five evolutionarily conserved serine residues. However, despite a large body of information on the respective kinases and the signal transduction pathways, the physiological role of rpS6 phosphorylation remained obscure until genetic manipulations were applied in both yeast and mammals in an attempt to block this modification. Thus, studies based on both mice and cultured cells subjected to disruption of the genes encoding rpS6 and the respective kinases, as well as the substitution of the phosphorylatable serine residues in rpS6, have laid the ground for the elucidation of the multiple roles of this protein and its posttranslational modification. This review focuses primarily on newly identified kinases that phosphorylate rpS6, pathways that transduce various signals into rpS6 phosphorylation, and the recently established physiological functions of this modification. It should be noted, however, that despite the significant progress made in the last decade, the molecular mechanism(s) underlying the diverse effects of rpS6 phosphorylation on cellular and organismal physiology are still poorly understood.
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