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Gene Review

Irs1  -  insulin receptor substrate 1

Rattus norvegicus

Synonyms: IRS-1, Insulin receptor substrate 1, Irs-1, pp185
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Disease relevance of Irs1


High impact information on Irs1


Chemical compound and disease context of Irs1


Biological context of Irs1


Anatomical context of Irs1


Associations of Irs1 with chemical compounds


Physical interactions of Irs1

  • Simultaneous treatment with both hormones led to marked increases in the associations of IRS-1 and -2 with growth factor receptor-binding protein 2 and in the dual phosphorylation of ERK1/2 compared with the administration of AngII or insulin alone [25].
  • IRS-1 binds several proteins containing Src homology 2 domains through its multiple tyrosine phosphorylation sites [26].
  • Co-immunoprecipitation with anti-insulin receptor antibody, anti-JAK2 antibody, and anti-IRS-1 antibody showed that JAK2 interacts with the insulin receptor and IRS-1 to form stable complexes following stimulation by insulin [27].
  • No effects were observed on IRS-1 content in liver or on insulin binding or protein expression of p85 or SHP2 in both tissues [28].
  • The interaction was modulated by Ca2+, and calmodulin binding to IRS-1 was enhanced by increasing intracellular Ca2+ with A23187 [29].

Enzymatic interactions of Irs1

  • Insulin receptor substrate-1 (IRS-1) is tyrosine-phosphorylated in response to insulin resulting in association with and activation of phosphatidylinositol 3-kinase (PI 3-kinase), thereby initiating some of the effects of insulin [20].
  • Calmodulin-dependent tyrosine phosphatase activity of calcineurin was observed in vitro using both immunoprecipitated and recombinant tyrosine-phosphorylated IRS-1 as substrates [30].
  • These data demonstrate that phosphorylation of IRS-1 plays an essential role in IGF-I and insulin signaling in oocyte maturation and that this effect occurs through interactions of the phosphorylated YMXM/YXXM motifs of IRS-1 with SH2 domains of PtdIns 3-kinase or some related molecules [31].
  • Additionally, protein tyrosine phosphatase (PTPase) activities towards immobilized phosphorylated insulin receptor or phosphorylated IRS-1 of membrane (MF) and cytosolic fractions (CF) of these tissues were measured [28].
  • However, insulin receptor substrate-1/2 protein expressions were enhanced in DZ-ZDF (p<0.02) and DZ-ZL (p<0.03) rats corresponding to increased phosphorylated protein kinase B levels in both strains (p<0.03) [32].

Co-localisations of Irs1


Regulatory relationships of Irs1


Other interactions of Irs1


Analytical, diagnostic and therapeutic context of Irs1


  1. Short-term in vivo inhibition of insulin receptor substrate-1 expression leads to insulin resistance, hyperinsulinemia, and increased adiposity. Araújo, E.P., De Souza, C.T., Gasparetti, A.L., Ueno, M., Boschero, A.C., Saad, M.J., Velloso, L.A. Endocrinology (2005) [Pubmed]
  2. Acidosis impairs insulin receptor substrate-1-associated phosphoinositide 3-kinase signaling in muscle cells: consequences on proteolysis. Franch, H.A., Raissi, S., Wang, X., Zheng, B., Bailey, J.L., Price, S.R. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  3. Mechanisms of hemorrhage-induced hepatic insulin resistance: role of tumor necrosis factor-alpha. Ma, Y., Toth, B., Keeton, A.B., Holland, L.T., Chaudry, I.H., Messina, J.L. Endocrinology (2004) [Pubmed]
  4. Phosphorylation of insulin receptor substrate-1 serine 307 correlates with JNK activity in atrophic skeletal muscle. Hilder, T.L., Tou, J.C., Grindeland, R.E., Wade, C.E., Graves, L.M. FEBS Lett. (2003) [Pubmed]
  5. Aspirin inhibits serine phosphorylation of IRS-1 in muscle and adipose tissue of septic rats. Barreiro, G.C., Prattali, R.R., Caliseo, C.T., Fugiwara, F.Y., Ueno, M., Prada, P.O., Velloso, L.A., Saad, M.J., Carvalheira, J.B. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  6. An IL-4 receptor region containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cell growth. Keegan, A.D., Nelms, K., White, M., Wang, L.M., Pierce, J.H., Paul, W.E. Cell (1994) [Pubmed]
  7. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Sun, X.J., Rothenberg, P., Kahn, C.R., Backer, J.M., Araki, E., Wilden, P.A., Cahill, D.A., Goldstein, B.J., White, M.F. Nature (1991) [Pubmed]
  8. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Hotamisligil, G.S., Peraldi, P., Budavari, A., Ellis, R., White, M.F., Spiegelman, B.M. Science (1996) [Pubmed]
  9. Prevention of fat-induced insulin resistance by salicylate. Kim, J.K., Kim, Y.J., Fillmore, J.J., Chen, Y., Moore, I., Lee, J., Yuan, M., Li, Z.W., Karin, M., Perret, P., Shoelson, S.E., Shulman, G.I. J. Clin. Invest. (2001) [Pubmed]
  10. 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]
  11. Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. Saad, M.J., Folli, F., Kahn, C.R. Endocrinology (1995) [Pubmed]
  12. A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration. Ruiz-Alcaraz, A.J., Liu, H.K., Cuthbertson, D.J., McManus, E.J., Akhtar, S., Lipina, C., Morris, A.D., Petrie, J.R., Hundal, H.S., Sutherland, C. Biochem. J. (2005) [Pubmed]
  13. Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. Jiang, G., Dallas-Yang, Q., Biswas, S., Li, Z., Zhang, B.B. Biochem. J. (2004) [Pubmed]
  14. Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. Giorgino, F., Almahfouz, A., Goodyear, L.J., Smith, R.J. J. Clin. Invest. (1993) [Pubmed]
  15. Insulin signaling through insulin receptor substrate 1 and 2 in normal liver development. Khamzina, L., Gruppuso, P.A., Wands, J.R. Gastroenterology (2003) [Pubmed]
  16. beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1. Usui, I., Imamura, T., Huang, J., Satoh, H., Shenoy, S.K., Lefkowitz, R.J., Hupfeld, C.J., Olefsky, J.M. Mol. Cell. Biol. (2004) [Pubmed]
  17. 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]
  18. Specific increase in p85alpha expression in response to dexamethasone is associated with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells. Giorgino, F., Pedrini, M.T., Matera, L., Smith, R.J. J. Biol. Chem. (1997) [Pubmed]
  19. Insulin receptor substrate (IRS)-2 is dephosphorylated more rapidly than IRS-1 via its association with phosphatidylinositol 3-kinase in skeletal muscle cells. Ogihara, T., Shin, B.C., Anai, M., Katagiri, H., Inukai, K., Funaki, M., Fukushima, Y., Ishihara, H., Takata, K., Kikuchi, M., Yazaki, Y., Oka, Y., Asano, T. J. Biol. Chem. (1997) [Pubmed]
  20. Growth hormone stimulates the tyrosine phosphorylation of the insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase in primary adipocytes. Ridderstråle, M., Degerman, E., Tornqvist, H. J. Biol. Chem. (1995) [Pubmed]
  21. Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of insulin-like growth factor-I signaling in vascular smooth muscle cells. Hayashi, K., Shibata, K., Morita, T., Iwasaki, K., Watanabe, M., Sobue, K. J. Biol. Chem. (2004) [Pubmed]
  22. Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Ueno, M., Carvalheira, J.B., Tambascia, R.C., Bezerra, R.M., Amaral, M.E., Carneiro, E.M., Folli, F., Franchini, K.G., Saad, M.J. Diabetologia (2005) [Pubmed]
  23. Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Tzatsos, A., Kandror, K.V. Mol. Cell. Biol. (2006) [Pubmed]
  24. In vivo phosphorylation of insulin receptor substrate 1 at serine 789 by a novel serine kinase in insulin-resistant rodents. Qiao, L.Y., Zhande, R., Jetton, T.L., Zhou, G., Sun, X.J. J. Biol. Chem. (2002) [Pubmed]
  25. The cross-talk between angiotensin and insulin differentially affects phosphatidylinositol 3-kinase- and mitogen-activated protein kinase-mediated signaling in rat heart: implications for insulin resistance. Carvalheira, J.B., Calegari, V.C., Zecchin, H.G., Nadruz, W., Guimarães, R.B., Ribeiro, E.B., Franchini, K.G., Velloso, L.A., Saad, M.J. Endocrinology (2003) [Pubmed]
  26. Gastrin stimulates tyrosine phosphorylation of insulin receptor substrate 1 and its association with Grb2 and the phosphatidylinositol 3-kinase. Kowalski-Chauvel, A., Pradayrol, L., Vaysse, N., Seva, C. J. Biol. Chem. (1996) [Pubmed]
  27. Insulin induces tyrosine phosphorylation of JAK2 in insulin-sensitive tissues of the intact rat. Saad, M.J., Carvalho, C.R., Thirone, A.C., Velloso, L.A. J. Biol. Chem. (1996) [Pubmed]
  28. Ramipril increases the protein level of skeletal muscle IRS-1 and alters protein tyrosine phosphatase activity in spontaneously hypertensive rats. Krützfeldt, J., Raasch, W., Klein, H.H. Naunyn Schmiedebergs Arch. Pharmacol. (2000) [Pubmed]
  29. Ca2+ regulates calmodulin binding to IQ motifs in IRS-1. Munshi, H.G., Burks, D.J., Joyal, J.L., White, M.F., Sacks, D.B. Biochemistry (1996) [Pubmed]
  30. Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) by oxidant stress in cerebellar granule neurons: modulation by N-methyl-D-aspartate through calcineurin activity. Hallak, H., Ramadan, B., Rubin, R. J. Neurochem. (2001) [Pubmed]
  31. Insulin-stimulated oocyte maturation requires insulin receptor substrate 1 and interaction with the SH2 domains of phosphatidylinositol 3-kinase. Chuang, L.M., Myers, M.G., Backer, J.M., Shoelson, S.E., White, M.F., Birnbaum, M.J., Kahn, C.R. Mol. Cell. Biol. (1993) [Pubmed]
  32. Diazoxide attenuates insulin secretion and hepatic lipogenesis in zucker diabetic fatty rats. Alemzadeh, R., Tushaus, K. Med. Sci. Monit. (2005) [Pubmed]
  33. Insulin receptor substrate-1 (IRS-1) expression in rat brain. Baskin, D.G., Schwartz, M.W., Sipols, A.J., D'Alessio, D.A., Goldstein, B.J., White, M.F. Endocrinology (1994) [Pubmed]
  34. Sennidin stimulates glucose incorporation in rat adipocytes. Abe, D., Saito, T., Sekiya, K. Life Sci. (2006) [Pubmed]
  35. Active Rho kinase (ROK-alpha ) associates with insulin receptor substrate-1 and inhibits insulin signaling in vascular smooth muscle cells. Begum, N., Sandu, O.A., Ito, M., Lohmann, S.M., Smolenski, A. J. Biol. Chem. (2002) [Pubmed]
  36. Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. Lima, M.H., Ueno, M., Thirone, A.C., Rocha, E.M., Carvalho, C.R., Saad, M.J. Endocrine (2002) [Pubmed]
  37. Shc is the predominant signaling molecule coupling insulin receptors to activation of guanine nucleotide releasing factor and p21ras-GTP formation. Sasaoka, T., Draznin, B., Leitner, J.W., Langlois, W.J., Olefsky, J.M. J. Biol. Chem. (1994) [Pubmed]
  38. Insulin receptor substrate-1 is present in hepatocyte nuclei from intact rats. Boylan, J.M., Gruppuso, P.A. Endocrinology (2002) [Pubmed]
  39. 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]
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