Insulin Receptor Signaling

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Pathway Description:

Insulin is the major hormone controlling critical energy functions such as glucose and lipid metabolism. Insulin activates the insulin receptor tyrosine kinase IR, which phosphorylates and recruits different substrate adaptors including the IRS family of proteins. Tyrosine phosphorylated IRS then displays binding sites for numerous signaling partners. Among them, PI3K has a major role in insulin function mainly via the activation of the Akt/PKB and the PKCz cascades. Activated Akt induces glycogen synthesis through inhibition of GSK-3, protein synthesis via mTOR and downstream elements, and cell survival through inhibition of several pro-apoptotic agents (Bad, Forkhead family transcription factors, GSK-3). Insulin stimulates glucose uptake in muscle and adipocytes via translocation of GLUT4 vesicles to the plasma membrane. GLUT4 translocation involves the PI3K/Akt pathway and IR mediated phosphorylation of CAP and formation of the CAP:Cbl:CrkII complex. Insulin signaling also has growth and mitogenic effects that are mostly mediated by the Akt cascade as well as by activation of the Ras/MAPK pathway. A negative feedback signal emanating from Akt/PKB, PKCz, p70 S6K and the MAPK cascades results in serine phosphorylation and inactivation of IRS signaling.

Selected Reviews:

• Bertrand L, Horman S, Beauloye C, Vanoverschelde JL (2008) Insulin signalling in the heart. Cardiovasc. Res. 79(2), 238–48.
• Brozinick JT, Berkemeier BA, Elmendorf JS (2007) "Actin"g on GLUT4: membrane & cytoskeletal components of insulin action. Curr Diabetes Rev 3(2), 111–22.
• Fritsche L, Weigert C, Häring HU, Lehmann R (2008) How insulin receptor substrate proteins regulate the metabolic capacity of the liver--implications for health and disease. Curr. Med. Chem. 15(13), 1316–29.
• Tremblay ML, Giguère V (2008) Phosphatases at the heart of FoxO metabolic control. Cell Metab. 7(2), 101–3.
• Zaid H, Antonescu CN, Randhawa VK, Klip A (2008) Insulin action on glucose transporters through molecular switches, tracks and tethers. Biochem. J. 413(2), 201–15.

CST would like to thank Prof. Andre Marette, Centre Hospitalier de l’Université Laval, Ste-Foy, Québec, and Prof. Xiao Jian Sun, Department of Medicine, University of Chicago, Chicago, Illinois, for reviewing this IRS diagram.