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Gene Review

Irs2  -  insulin receptor substrate 2

Rattus norvegicus

Synonyms: 4PS, IRS-2
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Disease relevance of Irs2


High impact information on Irs2


Biological context of Irs2


Anatomical context of Irs2


Associations of Irs2 with chemical compounds

  • In contrast, insulin-dependent IRS-1 and IRS-2 tyrosine phosphorylation was severely reduced in cells preincubated with HGA for 24 h [14].
  • Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002 [18].
  • Exposure to leptin + insulin additively reduced glucose production and PEPCK activity (approximately 50%; P < 0.001 vs. control) and doubled IRS-2 pY (P < 0.01 vs. insulin) [11].
  • Estrogen and exercise may enhance beta-cell function and mass via insulin receptor substrate 2 induction in ovariectomized diabetic rats [19].
  • IRS-2- and phosphotyrosine-associated PI3K activity were increased 3.5- and 4.8-fold, respectively, by insulin in glycerol-infused rats but only 1.6- and 2.3-fold in lipid-infused rats [20].

Physical interactions of Irs2

  • We have previously shown that IRS-1 and IRS-2 interact with the juxtamembrane (JM) but not with the carboxyl-terminal (CT) region of the insulin receptor (IR) in vitro [21].
  • Both IRS-1 and IRS-2 co-immunoprecipitate with calmodulin from insulin target tissues in rats [22].

Regulatory relationships of Irs2


Other interactions of Irs2


Analytical, diagnostic and therapeutic context of Irs2

  • Finally, by immunoprecipitation, the detection of insulin-stimulated IRS-2 phosphorylation followed the same pattern as that for IRS-1 in both liver of 2- and 20-month-old rats [29].
  • Semiquantitative RT-PCR analysis showed that insulin (10(4) microU/ml) alone or in combination with glucose (15 mm) markedly suppressed IRS-2 gene expression, whereas IRS-1 mRNA was unaffected by the culture conditions [30].
  • Impairment of glucose uptake capacity after treatment with high glucose and insulin was most pronounced after 3 h, whereas IRS-1 and IRS-2 protein levels were unaffected up to 6 h but were reduced after 16 h [30].
  • Moreover, denervation reduced insulin-induced association between IRS1/IRS2 and p85/phosphatidylinositol (PI) 3-kinase [31].
  • Western blot analysis revealed no significant differences in the amount of insulin receptor (IR), insulin receptor substrates-1 and -2 (IRS-1, IRS-2), and the p85 subunit of phosphatidylinositol (PI) 3-kinase [32].


  1. Exercise enhances insulin and leptin signaling in the cerebral cortex and hypothalamus during dexamethasone-induced stress in diabetic rats. Park, S., Jang, J.S., Jun, D.W., Hong, S.M. Neuroendocrinology (2005) [Pubmed]
  2. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. Schubert, M., Brazil, D.P., Burks, D.J., Kushner, J.A., Ye, J., Flint, C.L., Farhang-Fallah, J., Dikkes, P., Warot, X.M., Rio, C., Corfas, G., White, M.F. J. Neurosci. (2003) [Pubmed]
  3. A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. Paz, K., Hemi, R., LeRoith, D., Karasik, A., Elhanany, E., Kanety, H., Zick, Y. J. Biol. Chem. (1997) [Pubmed]
  4. Hepatic insulin resistance precedes the development of diabetes in a model of intrauterine growth retardation. Vuguin, P., Raab, E., Liu, B., Barzilai, N., Simmons, R. Diabetes (2004) [Pubmed]
  5. Insulin in UW solution exacerbates hepatic ischemia / reperfusion injury by energy depletion through the IRS-2 / SREBP-1c pathway. Li, X.L., Man, K., Ng, K.T., Lee, T.K., Lo, C.M., Fan, S.T. Liver Transpl. (2004) [Pubmed]
  6. Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Leibiger, I.B., Leibiger, B., Moede, T., Berggren, P.O. Mol. Cell (1998) [Pubmed]
  7. SREBPs suppress IRS-2-mediated insulin signalling in the liver. Ide, T., Shimano, H., Yahagi, N., Matsuzaka, T., Nakakuki, M., Yamamoto, T., Nakagawa, Y., Takahashi, A., Suzuki, H., Sone, H., Toyoshima, H., Fukamizu, A., Yamada, N. Nat. Cell Biol. (2004) [Pubmed]
  8. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. Jiang, Z.Y., Lin, Y.W., Clemont, A., Feener, E.P., Hein, K.D., Igarashi, M., Yamauchi, T., White, M.F., King, G.L. J. Clin. Invest. (1999) [Pubmed]
  9. Insulin receptor substrate-4 signaling in quiescent rat hepatocytes and in regenerating rat liver. Escribano, O., Fernández-Moreno, M.D., Zueco, J.A., Menor, C., Fueyo, J., Ropero, R.M., Diaz-Laviada, I., Román, I.D., Guijarro, L.G. Hepatology (2003) [Pubmed]
  10. Insulin signaling through insulin receptor substrate 1 and 2 in normal liver development. Khamzina, L., Gruppuso, P.A., Wands, J.R. Gastroenterology (2003) [Pubmed]
  11. Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2. Anderwald, C., Müller, G., Koca, G., Fürnsinn, C., Waldhäusl, W., Roden, M. Mol. Endocrinol. (2002) [Pubmed]
  12. IRS-3 inhibits IRS-2-mediated signaling in pancreatic beta-cells. Lingohr, M.K., Dickson, L.M., Wrede, C.E., McCuaig, J.F., Myers, M.G., Rhodes, C.J. Mol. Cell. Endocrinol. (2003) [Pubmed]
  13. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. Samuel, V.T., Liu, Z.X., Qu, X., Elder, B.D., Bilz, S., Befroy, D., Romanelli, A.J., Shulman, G.I. J. Biol. Chem. (2004) [Pubmed]
  14. Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism. Miele, C., Riboulet, A., Maitan, M.A., Oriente, F., Romano, C., Formisano, P., Giudicelli, J., Beguinot, F., Van Obberghen, E. J. Biol. Chem. (2003) [Pubmed]
  15. Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: differential effects on insulin-receptor substrates 1 and 2. Chibalin, A.V., Yu, M., Ryder, J.W., Song, X.M., Galuska, D., Krook, A., Wallberg-Henriksson, H., Zierath, J.R. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  16. Different subcellular distribution and regulation of expression of insulin receptor substrate (IRS)-3 from those of IRS-1 and IRS-2. Anai, M., Ono, H., Funaki, M., Fukushima, Y., Inukai, K., Ogihara, T., Sakoda, H., Onishi, Y., Yazaki, Y., Kikuchi, M., Oka, Y., Asano, T. J. Biol. Chem. (1998) [Pubmed]
  17. Specific regulation of IRS-2 expression by glucose in rat primary pancreatic islet beta-cells. Lingohr, M.K., Briaud, I., Dickson, L.M., McCuaig, J.F., Alárcon, C., Wicksteed, B.L., Rhodes, C.J. J. Biol. Chem. (2006) [Pubmed]
  18. Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. Pirola, L., Bonnafous, S., Johnston, A.M., Chaussade, C., Portis, F., Van Obberghen, E. J. Biol. Chem. (2003) [Pubmed]
  19. Estrogen and exercise may enhance beta-cell function and mass via insulin receptor substrate 2 induction in ovariectomized diabetic rats. Choi, S.B., Jang, J.S., Park, S. Endocrinology (2005) [Pubmed]
  20. Fatty acid infusion selectively impairs insulin action on Akt1 and protein kinase C lambda /zeta but not on glycogen synthase kinase-3. Kim, Y.B., Shulman, G.I., Kahn, B.B. J. Biol. Chem. (2002) [Pubmed]
  21. The juxtamembrane but not the carboxyl-terminal domain of the insulin receptor mediates insulin's metabolic functions in primary adipocytes and cultured hepatoma cells. Paz, K., Boura-Halfon, S., Wyatt, L.S., LeRoith, D., Zick, Y. J. Mol. Endocrinol. (2000) [Pubmed]
  22. Binding of IRS proteins to calmodulin is enhanced in insulin resistance. Li, Z., Joyal, J.L., Sacks, D.B. Biochemistry (2000) [Pubmed]
  23. Angiotensin II subtype 2 receptor activation inhibits insulin-induced phosphoinositide 3-kinase and Akt and induces apoptosis in PC12W cells. Cui, T.X., Nakagami, H., Nahmias, C., Shiuchi, T., Takeda-Matsubara, Y., Li, J.M., Wu, L., Iwai, M., Horiuchi, M. Mol. Endocrinol. (2002) [Pubmed]
  24. Signalling pathways of insulin-like growth factor-I that are augmented by cAMP in FRTL-5 cells. Ariga, M., Nedachi, T., Akahori, M., Sakamoto, H., Ito, Y., Hakuno, F., Takahashi, S. Biochem. J. (2000) [Pubmed]
  25. Rosiglitazone ameliorates abnormal expression and activity of protein tyrosine phosphatase 1B in the skeletal muscle of fat-fed, streptozotocin-treated diabetic rats. Wu, Y., Ouyang, J.P., Wu, K., Wang, S.S., Wen, C.Y., Xia, Z.Y. Br. J. Pharmacol. (2005) [Pubmed]
  26. Prolactin-signal transduction in neonatal rat pancreatic islets and interaction with the insulin-signaling pathway. Amaral, M.E., Ueno, M., Carvalheira, J.B., Carneiro, E.M., Velloso, L.A., Saad, M.J., Boschero, A.C. Horm. Metab. Res. (2003) [Pubmed]
  27. Differential role of insulin receptor substrate (IRS)-1 and IRS-2 in L6 skeletal muscle cells expressing the Arg1152 --> Gln insulin receptor. Miele, C., Caruso, M., Calleja, V., Auricchio, R., Oriente, F., Formisano, P., Condorelli, G., Cafieri, A., Sawka-Verhelle, D., Van Obberghen, E., Beguinot, F. J. Biol. Chem. (1999) [Pubmed]
  28. Insulin receptor substrate (IRS)-1 and IRS-2 are tyrosine-phosphorylated and associated with phosphatidylinositol 3-kinase in response to brain-derived neurotrophic factor in cultured cerebral cortical neurons. Yamada, M., Ohnishi, H., Sano, S., Nakatani, A., Ikeuchi, T., Hatanaka, H. J. Biol. Chem. (1997) [Pubmed]
  29. Effect of aging on insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of rats. Carvalho, C.R., Brenelli, S.L., Silva, A.C., Nunes, A.L., Velloso, L.A., Saad, M.J. Endocrinology (1996) [Pubmed]
  30. Insulin receptor substrates-1 and -2 are both depleted but via different mechanisms after down-regulation of glucose transport in rat adipocytes. Renström, F., Burén, J., Eriksson, J.W. Endocrinology (2005) [Pubmed]
  31. Reversal of denervation-induced insulin resistance by SHIP2 protein synthesis blockade. Bertelli, D.F., Ueno, M., Amaral, M.E., Toyama, M.H., Carneiro, E.M., Marangoni, S., Carvalho, C.R., Saad, M.J., Velloso, L.A., Boschero, A.C. Am. J. Physiol. Endocrinol. Metab. (2003) [Pubmed]
  32. Elevated basal PI 3-kinase activity and reduced insulin signaling in sucrose-induced hepatic insulin resistance. Pagliassotti, M.J., Kang, J., Thresher, J.S., Sung, C.K., Bizeau, M.E. Am. J. Physiol. Endocrinol. Metab. (2002) [Pubmed]
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