IRS2 explained

Insulin receptor substrate 2 is a protein that in humans is encoded by the IRS2 gene.^[1]

Function

This gene encodes the insulin receptor substrate 2, a cytoplasmic signaling molecule that mediates effects of insulin, insulin-like growth factor 1, and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downstream effectors. The product of this gene is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation, as well as by an interleukin 4 receptor-associated kinase in response to IL4 treatment.^[2]

Mice lacking IRS2 have a diabetic phenotype^[3] as well as a 40% reduction in brain mass.^[4]

Interactions

IRS2 has been shown to interact with:

• PLCG1,^[5]
• SOCS1,^[6] and
• PIK3R1,^{[7] [8] [9] [10]}

Further reading

• White MF . The IRS-signalling system: a network of docking proteins that mediate insulin action. . Mol. Cell. Biochem. . 182 . 1–2 . 3–11 . 1999 . 9609109 . 10.1023/A:1006806722619 . 32623861 .
• Jiang H, Harris MB, Rothman P . IL-4/IL-13 signaling beyond JAK/STAT. . J. Allergy Clin. Immunol. . 105 . 6 Pt 1 . 1063–70 . 2000 . 10856136 . 10.1067/mai.2000.107604 . free .
• Sesti G, Federici M, Hribal ML, etal . Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. . FASEB J. . 15 . 12 . 2099–111 . 2001 . 11641236 . 10.1096/fj.01-0009rev . 6429338 . free .
• Gibson SL, Ma Z, Shaw LM . Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis. . Cell Cycle . 6 . 6 . 631–7 . 2007 . 17361103 . 10.4161/cc.6.6.3987. free .
• Dearth RK, Cui X, Kim HJ, etal . Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2. . Cell Cycle . 6 . 6 . 705–13 . 2007 . 17374994 . 10.4161/cc.6.6.4035. free .
• Johnston JA, Wang LM, Hanson EP, etal . Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. . J. Biol. Chem. . 270 . 48 . 28527–30 . 1996 . 7499365 . 10.1074/jbc.270.48.28527 . free .
• Patti ME, Sun XJ, Bruening JC, etal . 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice. . J. Biol. Chem. . 270 . 42 . 24670–3 . 1995 . 7559579 . 10.1074/jbc.270.42.24670 . free .
• Sun XJ, Wang LM, Zhang Y, etal . Role of IRS-2 in insulin and cytokine signalling. . Nature . 377 . 6545 . 173–7 . 1995 . 7675087 . 10.1038/377173a0 . 1995Natur.377..173S . 4336107 .
• Ridderstråle M, Degerman E, Tornqvist H . Growth hormone stimulates the tyrosine phosphorylation of the insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase in primary adipocytes. . J. Biol. Chem. . 270 . 8 . 3471–4 . 1995 . 7876077 . 10.1074/jbc.270.8.3471 . free .
• Platanias LC, Uddin S, Yetter A, etal . The type I interferon receptor mediates tyrosine phosphorylation of insulin receptor substrate 2. . J. Biol. Chem. . 271 . 1 . 278–82 . 1996 . 8550573 . 10.1074/jbc.271.1.278 . free .
• Beitner-Johnson D, Blakesley VA, Shen-Orr Z, etal . The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS. Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling. . J. Biol. Chem. . 271 . 16 . 9287–90 . 1996 . 8621590 . 10.1074/jbc.271.16.9287. free .
• Sawka-Verhelle D, Tartare-Deckert S, White MF, Van Obberghen E . Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786. . J. Biol. Chem. . 271 . 11 . 5980–3 . 1996 . 8626379 . 10.1074/jbc.271.11.5980 . free .
• He W, Craparo A, Zhu Y, etal . Interaction of insulin receptor substrate-2 (IRS-2) with the insulin and insulin-like growth factor I receptors. Evidence for two distinct phosphotyrosine-dependent interaction domains within IRS-2. . J. Biol. Chem. . 271 . 20 . 11641–5 . 1996 . 8662806 . 10.1074/jbc.271.20.11641. free .
• Zhang WR, Li PM, Oswald MA, Goldstein BJ . Modulation of insulin signal transduction by eutopic overexpression of the receptor-type protein-tyrosine phosphatase LAR. . Mol. Endocrinol. . 10 . 5 . 575–84 . 1996 . 10.1210/mend.10.5.8732688 . 8732688 . 42128485 . free .
• Argetsinger LS, Norstedt G, Billestrup N, etal . Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling. . J. Biol. Chem. . 271 . 46 . 29415–21 . 1997 . 8910607 . 10.1074/jbc.271.46.29415 . free .
• Thiselton DL, Hampson RM, Nayudu M, etal . Mapping the RP2 locus for X-linked retinitis pigmentosa on proximal Xp: a genetically defined 5-cM critical region and exclusion of candidate genes by physical mapping. . Genome Res. . 6 . 11 . 1093–102 . 1997 . 8938433 . 10.1101/gr.6.11.1093 . free .
• Izuhara K, Harada N . Interleukin-4 activates two distinct pathways of phosphatidylinositol-3 kinase in the same cells. . Biochem. Biophys. Res. Commun. . 229 . 2 . 624–9 . 1997 . 8954948 . 10.1006/bbrc.1996.1854 .
• Vanhaesebroeck B, Welham MJ, Kotani K, etal . P110delta, a novel phosphoinositide 3-kinase in leukocytes. . Proc. Natl. Acad. Sci. U.S.A. . 94 . 9 . 4330–5 . 1997 . 9113989 . 10.1073/pnas.94.9.4330 . 20722 . 1997PNAS...94.4330V . free .
• Sawka-Verhelle D, Baron V, Mothe I, etal . Tyr624 and Tyr628 in insulin receptor substrate-2 mediate its association with the insulin receptor. . J. Biol. Chem. . 272 . 26 . 16414–20 . 1997 . 9195949 . 10.1074/jbc.272.26.16414 . free .
• Algenstaedt P, Antonetti DA, Yaffe MB, Kahn CR . Insulin receptor substrate proteins create a link between the tyrosine phosphorylation cascade and the Ca2+-ATPases in muscle and heart. . J. Biol. Chem. . 272 . 38 . 23696–702 . 1997 . 9295312 . 10.1074/jbc.272.38.23696 . free .

Notes and References

1. Ogihara T, Isobe T, Ichimura T, Taoka M, Funaki M, Sakoda H, Onishi Y, Inukai K, Anai M, Fukushima Y, Kikuchi M, Yazaki Y, Oka Y, Asano T . 14-3-3 protein binds to insulin receptor substrate-1, one of the binding sites of which is in the phosphotyrosine binding domain . J Biol Chem . 272 . 40 . 25267–74 . Oct 1997 . 9312143 . 10.1074/jbc.272.40.25267 . free .
2. Web site: Entrez Gene: IRS2 insulin receptor substrate 2.
3. Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y, White MF . Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes . J. Clin. Invest. . 114 . 7 . 908–16 . October 2004 . 15467829 . 518668 . 10.1172/JCI22217 .
4. Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL, Farhang-Fallah J, Dikkes P, Warot XM, Rio C, Corfas G, White MF . Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation . J. Neurosci. . 23 . 18 . 7084–92 . August 2003 . 12904469 . 6740672 . 10.1523/JNEUROSCI.23-18-07084.2003.
5. Sozzani P, Hasan L, Séguélas MH, Caput D, Ferrara P, Pipy B, Cambon C . IL-13 induces tyrosine phosphorylation of phospholipase C gamma-1 following IRS-2 association in human monocytes: relationship with the inhibitory effect of IL-13 on ROI production . Biochem. Biophys. Res. Commun. . 244 . 3 . 665–70 . March 1998 . 9535722 . 10.1006/bbrc.1998.8314 .
6. Rui L, Yuan M, Frantz D, Shoelson S, White MF . SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2 . J. Biol. Chem. . 277 . 44 . 42394–8 . November 2002 . 12228220 . 10.1074/jbc.C200444200 . free .
7. Argetsinger LS, Norstedt G, Billestrup N, White MF, Carter-Su C . Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling . J. Biol. Chem. . 271 . 46 . 29415–21 . November 1996 . 8910607 . 10.1074/jbc.271.46.29415 . free .
8. Verdier F, Chrétien S, Billat C, Gisselbrecht S, Lacombe C, Mayeux P . Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2. An alternate pathway for erythropoietin-induced phosphatidylinositol 3-kinase activation . J. Biol. Chem. . 272 . 42 . 26173–8 . October 1997 . 9334184 . 10.1074/jbc.272.42.26173 . free .
9. Kim B, Cheng HL, Margolis B, Feldman EL . Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling . J. Biol. Chem. . 273 . 51 . 34543–50 . December 1998 . 9852124 . 10.1074/jbc.273.51.34543 . free .
10. Hamer I, Foti M, Emkey R, Cordier-Bussat M, Philippe J, De Meyts P, Maeder C, Kahn CR, Carpentier JL . An arginine to cysteine(252) mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events . Diabetologia . 45 . 5 . 657–67 . May 2002 . 12107746 . 10.1007/s00125-002-0798-5 . free .