Insulin Receptor Signaling
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 such as 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 PKCζ 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, including Bad, Forkhead family transcription factors and 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, which 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, PKCζ, p70 S6K and the MAPK cascades results in serine phosphorylation and inactivation of IRS signaling.
Selected Reviews:
- Burks DJ, White MF (2001) IRS proteins and beta-cell function. Diabetes 50 Suppl 1, S140–5.
- Johnston AM, Pirola L, Van Obberghen E (2003) Molecular mechanisms of insulin receptor substrate protein-mediated modulation of insulin signalling. FEBS Lett. 546(1), 32–6.
- Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414(6865), 799–806.
- Saltiel AR, Pessin JE (2002) Insulin signaling pathways in time and space. Trends Cell Biol. 12(2), 65–71.
- Surmacz E (2003) Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor I receptor. Oncogene 22(42), 6589–97.
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 diagram.
created June 2003 • revised December 2006
