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 (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.

Selected Reviews:

• Altarejos JY, Montminy M (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat. Rev. Mol. Cell Biol. 12(3), 141–51.
• Cheng Z, Tseng Y, White MF (2010) Insulin signaling meets mitochondria in metabolism. Trends Endocrinol. Metab. 21(10), 589–98.
• 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.
• Guo S (2014) Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J. Endocrinol. 220(2), T1–T23.
• Rowland AF, Fazakerley DJ, James DE (2011) Mapping insulin/GLUT4 circuitry. Traffic 12(6), 672–81.
• Siddle K (2011) Signalling by insulin and IGF receptors: supporting acts and new players. J. Mol. Endocrinol. 47(1), R1–10.
• Shao W, Espenshade PJ (2012) Expanding roles for SREBP in metabolism. Cell Metab. 16(4), 414–9.
• Wong RH, Sul HS (2010) Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective. Curr Opin Pharmacol 10(6), 684–91.

We would like to thank Ashley Webb and Prof. Anne Brunet Stanford University, Sanford, CA for reviewing this diagram.