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• _5 value "Insulin Stimulated phosphorylation cascade This pathway involves the tyrosine phosphorylation of IRS proteins and/or Shc, which in turn interact with the adapter protein Grb2, recruiting the Son-of-sevenless (SOS) exchange protein to the plasma membrane for activation of Ras. The activation of Ras also requires stimulation of the tyrosine phosphatase SHP2, through its interaction with receptor substrates such as Gab-1 or IRS1/2. Activated ERK can translocate into the nucleus, where it catalyses the phosphorylation of transcription factors such as p62TCF, Blockade of the pathway with dominant negative mutants or pharmacological inhibitors prevents the stimulation of cell growth by insulin, but has no effect on the metabolic actions of the hormone54. Insulin increases synthesis and blocks the degradation of proteins through activation of mTOR. The stimulation of this protein kinase involves PI(3)K activation, although another signal may also be required56. mTOR can control the mammalian translation machinery by direct phosphorylation and activation of p70 ribosomal S6 kinase (p70rsk)57, as well as phosphorylation of the initiation factor 4E for eukaryotic translation (eIF-4E) inhibitor, PHAS1 or 4E-binding protein 1 (ref. 58). P70rsk activates ribosome biosynthesis by phosphorylating the ribosomal S6 protein, producing increased translation of mRNAs with a 58-terminal oligopyrimidine tract. P70rsk also requires a second PtdIns(3,4,5)P3-dependent phosphorylation, presumably catalysed by PDK1. Phosphorylation of PHAS-1 by mTOR results in its dissociation from eIF-2, allowing capdependent translation of mRNAs with a highly structured 58-untranslated region. Although the mechanism of activation of mTOR remains unclear, it seems to require the presence of amino acids in the media for full activation by growth factors, and thus may also represent a nutrient sensor55. Glucose and lipid regulation Regulation of glycogen synthesis Insulin stimulates glycogen accumulation through a coordinated increase in glucose transport and glycogen synthesis. The hormone activates glycogen synthase by promoting its dephosphorylation, through the inhibition of kinases such as PKA or GSK-3 (ref. 59), and activation of protein phosphatase 1 (PP1)60." provenance.
• _5 wasQuotedFrom 11742412 provenance.