[Mechanism of insulin action].
Insulin is a key hormone regulating glucose homeostasis. Its major target tissues are the liver, the skeletal muscle and the adipose tissue. At the cellular level, insulin activates glucose and amino acids transport, lipid and glycogen metabolism, protein synthesis, and transcription of specific genes. Insulin-induced biological responses are mediated by a specific cell-surface receptor with tyrosine kinase activity. This receptor is a heterotetrameric protein consisting of two extracellular alpha subunits containing the ligand binding site, and two transmembrane beta subunits containing the hormone-sensitive enzymatic activity. The first step following insulin binding consists in receptor autophosphorylation on multiple specific sites and phosphorylation of cellular substrates. We will review the receptor structure, its mechanism of activation, and the autophosphorylation process. Two of the insulin receptor substrates have been identified as IRS-1 and Shc. IRS-1 is phosphorylated at several sites by the insulin receptor, and acts as a docking protein by associating several SH2-containing proteins. One of these proteins is the p85 subunit of P13-kinase which is rapidly stimulated by insulin in adipocytes and skeletal muscle. The phosphorylated IRS-1 also associates Grb2, as does the phosphorylated Shc. This allows recruitment of the preformed complex Grb2-Sos to the plasma membrane. Sos is then capable of stimulating the Ras protein, which in turn activates Raf, the first element of the MAP-kinase cascade. The role of these proteins in insulin signalling will be discussed.
Baron
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V
INSERM U 145, Faculté de Médecine, Nice, France.
Van Obberghen
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E
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000493:pharmacokinetics; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism
D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011972:Receptor, Insulin; D017871:Calcium-Calmodulin-Dependent Protein Kinases
Mécanisme d'action de l'insuline.