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Gene Review

Irs2  -  insulin receptor substrate 2

Mus musculus

Synonyms: 4PS, IRS-2, Insulin receptor substrate 2, Irs-2
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Disease relevance of Irs2


High impact information on Irs2


Chemical compound and disease context of Irs2

  • In conclusion, our findings suggest that the association of homozygosity for the Asp1057 allele in IRS-2 with type 2 diabetes in Pima Indians may be mediated by interaction of the polymorphism with obesity on several diabetes-related traits [7].
  • In addition, we characterized the effect of an insulin sensitizer, pioglitazone, on the atherogenesis in IRS2(+/-) ApoE(-/-) mice [8].

Biological context of Irs2


Anatomical context of Irs2


Associations of Irs2 with chemical compounds

  • Insulin signals are mediated by tyrosine phosphorylation of the insulin receptor and its downstream targets, such as Irs1 and Irs2 [13].
  • Screening for transcripts of genes involved in fatty acid and triglyceride synthesis to investigate the mechanism of the hypertrophic change in the adipocytes showed that expression of DGAT2 mRNA was up-regulated in the white adipose tissue (WAT) of Irs2-/- mice, whereas that of DGAT1 was down-regulated [14].
  • Insulin signaling studies revealed a total loss of IRS-2-associated phosphatidylinositol (PI) 3-kinase activity and a reduction in phosphotyrosine-associated PI 3-kinase by 30% (p < 0.05) in the KO cells [15].
  • It was also concentration dependent (EC50 approximately 50 nM) and not inhibited by cycloheximide, suggesting a direct effect on the IRS-2 promoter [16].
  • Additionally, IRS-2(-)(/-) mice also showed marked insulin resistance in adipose tissue as reflected by reduced suppression of plasma free fatty acid concentrations and glycerol turnover during the hyperinsulinemic-euglycemic clamp [17].
  • Insulin failed to activate the Akt--> FoxO cascade in Irs2(-/-) MEFs because Irs1 expression was reduced in these cells, and p110alpha-PI 3-kinase was inefficiently activated during recruitment by Irs1 [18].

Physical interactions of Irs2


Enzymatic interactions of Irs2

  • The residual insulin/IGF-1 action correlated with the appearance of a new tyrosine-phosphorylated protein (IRS-2) which binds to PI(3)K, but is slightly larger than and immunologically distinct from IRS-1 [23].

Regulatory relationships of Irs2

  • The partial differentialPHPTB IRS-2 protein is dependent for its effect on an activated IGF-IR, is cytoplasmic, binds to the beta-subunit of the IGF-IR, and requires for its action the presence of phosphatidylinositol 3-kinase binding sequences [20].
  • These results provide evidence for a critical role of IRS-2 as a mediator of insulin-stimulated Glut4 translocation and glucose uptake in adipocytes [15].
  • The lack of IRS-2 did not result in enhanced IRS-1 tyrosine phosphorylation or IRS-1-associated phosphatidylinositol (PI) 3-kinase activity on insulin stimulation [24].
  • Socs1 deficiency increases IRS-2 expression and enhances hepatic insulin sensitivity in vivo indicating that inhibition of SOCS1 may be a logical strategy in type 2 diabetes [25].
  • The IGFBP-3-induced dephosphorylation of IRS-2 is prevented by cotreatment of cells with insulin, (Q3A4Y15L16) IGF-I, or TbetaR-V/LRP-1 antagonists [26].
  • Suppression of Glut1 expression inhibits Irs-2-dependent invasion, which links glycolysis to mammary tumor progression [27].

Other interactions of Irs2


Analytical, diagnostic and therapeutic context of Irs2


  1. Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. Lin, X., Taguchi, A., Park, S., Kushner, J.A., Li, F., Li, Y., White, M.F. J. Clin. Invest. (2004) [Pubmed]
  2. Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) mouse liver. Tobe, K., Suzuki, R., Aoyama, M., Yamauchi, T., Kamon, J., Kubota, N., Terauchi, Y., Matsui, J., Akanuma, Y., Kimura, S., Tanaka, J., Abe, M., Ohsumi, J., Nagai, R., Kadowaki, T. J. Biol. Chem. (2001) [Pubmed]
  3. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Shimomura, I., Matsuda, M., Hammer, R.E., Bashmakov, Y., Brown, M.S., Goldstein, J.L. Mol. Cell (2000) [Pubmed]
  4. Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus. Kubota, N., Terauchi, Y., Tobe, K., Yano, W., Suzuki, R., Ueki, K., Takamoto, I., Satoh, H., Maki, T., Kubota, T., Moroi, M., Okada-Iwabu, M., Ezaki, O., Nagai, R., Ueta, Y., Kadowaki, T., Noda, T. J. Clin. Invest. (2004) [Pubmed]
  5. Both insulin signaling defects in the liver and obesity contribute to insulin resistance and cause diabetes in Irs2(-/-) mice. Suzuki, R., Tobe, K., Aoyama, M., Inoue, A., Sakamoto, K., Yamauchi, T., Kamon, J., Kubota, N., Terauchi, Y., Yoshimatsu, H., Matsuhisa, M., Nagasaka, S., Ogata, H., Tokuyama, K., Nagai, R., Kadowaki, T. J. Biol. Chem. (2004) [Pubmed]
  6. Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Withers, D.J., Burks, D.J., Towery, H.H., Altamuro, S.L., Flint, C.L., White, M.F. Nat. Genet. (1999) [Pubmed]
  7. Metabolic effects of the Gly1057Asp polymorphism in IRS-2 and interactions with obesity. Stefan, N., Kovacs, P., Stumvoll, M., Hanson, R.L., Lehn-Stefan, A., Permana, P.A., Baier, L.J., Tataranni, P.A., Silver, K., Bogardus, C. Diabetes (2003) [Pubmed]
  8. Attenuation of accumulation of neointimal lipid by pioglitazone in mice genetically deficient in insulin receptor substrate-2 and apolipoprotein E. Clough, M.H., Schneider, D.J., Sobel, B.E., White, M.F., Wadsworth, M.P., Taatjes, D.J. J. Histochem. Cytochem. (2005) [Pubmed]
  9. Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. Dong, X., Park, S., Lin, X., Copps, K., Yi, X., White, M.F. J. Clin. Invest. (2006) [Pubmed]
  10. Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. Park, S., Dong, X., Fisher, T.L., Dunn, S., Omer, A.K., Weir, G., White, M.F. J. Biol. Chem. (2006) [Pubmed]
  11. Differential contribution of insulin receptor substrates 1 versus 2 to insulin signaling and glucose uptake in l6 myotubes. Huang, C., Thirone, A.C., Huang, X., Klip, A. J. Biol. Chem. (2005) [Pubmed]
  12. Pdx1 restores beta cell function in Irs2 knockout mice. Kushner, J.A., Ye, J., Schubert, M., Burks, D.J., Dow, M.A., Flint, C.L., Dutta, S., Wright, C.V., Montminy, M.R., White, M.F. J. Clin. Invest. (2002) [Pubmed]
  13. Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. Kushner, J.A., Haj, F.G., Klaman, L.D., Dow, M.A., Kahn, B.B., Neel, B.G., White, M.F. Diabetes (2004) [Pubmed]
  14. Expression of DGAT2 in white adipose tissue is regulated by central leptin action. Suzuki, R., Tobe, K., Aoyama, M., Sakamoto, K., Ohsugi, M., Kamei, N., Nemoto, S., Inoue, A., Ito, Y., Uchida, S., Hara, K., Yamauchi, T., Kubota, N., Terauchi, Y., Kadowaki, T. J. Biol. Chem. (2005) [Pubmed]
  15. Essential role of insulin receptor substrate-2 in insulin stimulation of Glut4 translocation and glucose uptake in brown adipocytes. Fasshauer, M., Klein, J., Ueki, K., Kriauciunas, K.M., Benito, M., White, M.F., Kahn, C.R. J. Biol. Chem. (2000) [Pubmed]
  16. Thiazolidinediones (PPARgamma agonists) but not PPARalpha agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes. Smith, U., Gogg, S., Johansson, A., Olausson, T., Rotter, V., Svalstedt, B. FASEB J. (2001) [Pubmed]
  17. Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. Previs, S.F., Withers, D.J., Ren, J.M., White, M.F., Shulman, G.I. J. Biol. Chem. (2000) [Pubmed]
  18. The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling. Guo, S., Dunn, S.L., White, M.F. Mol. Endocrinol. (2006) [Pubmed]
  19. Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Kellerer, M., Koch, M., Metzinger, E., Mushack, J., Capp, E., Häring, H.U. Diabetologia (1997) [Pubmed]
  20. Deletion of the pleckstrin and phosphotyrosine binding domains of insulin receptor substrate-2 does not impair its ability to regulate cell proliferation in myeloid cells. Sun, H., Baserga, R. Endocrinology (2004) [Pubmed]
  21. Release of insulin receptor substrate proteins from an intracellular complex coincides with the development of insulin resistance. Clark, S.F., Molero, J.C., James, D.E. J. Biol. Chem. (2000) [Pubmed]
  22. Mutation of tyrosine 960 within the insulin receptor juxtamembrane domain impairs glucose transport but does not inhibit ligand-mediated phosphorylation of insulin receptor substrate-2 in 3T3-L1 adipocytes. Chaika, O.V., Chaika, N., Volle, D.J., Hayashi, H., Ebina, Y., Wang, L.M., Pierce, J.H., Lewis, R.E. J. Biol. Chem. (1999) [Pubmed]
  23. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Araki, E., Lipes, M.A., Patti, M.E., Brüning, J.C., Haag, B., Johnson, R.S., Kahn, C.R. Nature (1994) [Pubmed]
  24. Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes. Valverde, A.M., Burks, D.J., Fabregat, I., Fisher, T.L., Carretero, J., White, M.F., Benito, M. Diabetes (2003) [Pubmed]
  25. Socs1 deficiency enhances hepatic insulin signaling. Jamieson, E., Chong, M.M., Steinberg, G.R., Jovanovska, V., Fam, B.C., Bullen, D.V., Chen, Y., Kemp, B.E., Proietto, J., Kay, T.W., Andrikopoulos, S. J. Biol. Chem. (2005) [Pubmed]
  26. Identification of insulin receptor substrate proteins as key molecules for the TbetaR-V/LRP-1-mediated growth inhibitory signaling cascade in epithelial and myeloid cells. Huang, S.S., Leal, S.M., Chen, C.L., Liu, I.H., Huang, J.S. FASEB J. (2004) [Pubmed]
  27. Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1. Pankratz, S.L., Tan, E.Y., Fine, Y., Mercurio, A.M., Shaw, L.M. J. Biol. Chem. (2009) [Pubmed]
  28. Pdx1 expression in Irs2-deficient mouse beta-cells is regulated in a strain-dependent manner. Suzuki, R., Tobe, K., Terauchi, Y., Komeda, K., Kubota, N., Eto, K., Yamauchi, T., Azuma, K., Kaneto, H., Taguchi, T., Koga, T., German, M.S., Watada, H., Kawamori, R., Wright, C.V., Kajimoto, Y., Kimura, S., Nagai, R., Kadowaki, T. J. Biol. Chem. (2003) [Pubmed]
  29. The role of insulin receptor substrate 2 in hypothalamic and beta cell function. Choudhury, A.I., Heffron, H., Smith, M.A., Al-Qassab, H., Xu, A.W., Selman, C., Simmgen, M., Clements, M., Claret, M., Maccoll, G., Bedford, D.C., Hisadome, K., Diakonov, I., Moosajee, V., Bell, J.D., Speakman, J.R., Batterham, R.L., Barsh, G.S., Ashford, M.L., Withers, D.J. J. Clin. Invest. (2005) [Pubmed]
  30. Castration rapidly decreases local insulin-like growth factor-1 levels and inhibits its effects in the ventral prostate in mice. Ohlson, N., Bergh, A., Persson, M.L., Wikstr??m, P. Prostate (2006) [Pubmed]
  31. Liver-specific deletion of insulin receptor substrate 2 does not impair hepatic glucose and lipid metabolism in mice. Simmgen, M., Knauf, C., Lopez, M., Choudhury, A.I., Charalambous, M., Cantley, J., Bedford, D.C., Claret, M., Iglesias, M.A., Heffron, H., Cani, P.D., Vidal-Puig, A., Burcelin, R., Withers, D.J. Diabetologia (2006) [Pubmed]
  32. Essential role of Stat6 in IL-4 signalling. Takeda, K., Tanaka, T., Shi, W., Matsumoto, M., Minami, M., Kashiwamura, S., Nakanishi, K., Yoshida, N., Kishimoto, T., Akira, S. Nature (1996) [Pubmed]
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