Insulin Receptor Signaling Pathway
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 (Bad, FoxO transcription factors, GSK-3, and MST1). Akt phosphorylates and directly inhibits FoxO transcription factors, which also regulate metabolism and autophagy. Inversely, AMPK is known to directly regulate FoxO3 and activate transcriptional activity. 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. The insulin signaling pathway inhibits autophagy via the ULK1 kinase, which is inhibited by Akt and mTORC1, and activated by AMPK. 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. In addition, insulin signaling inhibits gluconeogenesis in the liver, through disruption of CREB/CBP/mTORC2 binding. Insulin signaling induces fatty acid and cholesterol synthesis via the regulation of SREBP transcription factors. Insulin signaling also promotes fatty acid synthesis through activation of USF1 and LXR. A negative feedback signal emanating from Akt/PKB, PKCζ, p70 S6K, and the MAPK cascades results in serine phosphorylation and inactivation of IRS signaling.
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We would like to thank Ashley Webb and Prof. Anne Brunet Stanford University, Sanford, CA for reviewing this diagram.
created June 2003
revised June 2014