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Gene Review

IRS1  -  insulin receptor substrate 1

Homo sapiens

Synonyms: HIRS-1, IRS-1, Insulin receptor substrate 1
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Disease relevance of IRS1


High impact information on IRS1

  • Overall, ligand binding by IRS-1 and Shc PTB domains is similar, but residues critical for phosphotyrosine recognition are not conserved [6].
  • The PTB domains of IRS-1 and Shc share a common fold with pleckstrin homology domains [6].
  • SUMMARY: Crystal structures of the insulin receptor substrate-1 (IRS-1) phosphotyrosine-binding (PTB) domain, alone and complexed with the juxtamembrane region of the insulin receptor, show how this domain recognizes phosphorylated "NPXY" sequence motifs [6].
  • Mutation of Y497 to F yielded receptors that caused little or no IRS-1 phosphorylation in response to huIL-4 when expressed in 32D-IRS-1 cells [7].
  • Furthermore, a glutathione-S-transferase fusion protein containing the I4R motif-bound IRS-1, tyrosine kinase(s), and other unidentified phosphoproteins with molecular sizes of 140, 80, and 55 kd [7].

Chemical compound and disease context of IRS1


Biological context of IRS1


Anatomical context of IRS1

  • Although expression of IRS1 resulted in a biphasic increase of insulin signaling in parental CHO cells, coexpression of IRS1 with the insulin receptor resulted in inhibition of signaling [13].
  • IRS1 is preferentially depleted from the high-speed pellet fraction in TSC1/2-deficient mouse embryo fibroblasts or in HEK293/293T cells overexpressing Rheb [12].
  • Moreover, SH2-B directly enhanced autophosphorylation of insulin receptor and tyrosine phosphorylation of IRS1 and IRS2 in an SH2 domain-dependent manner in cultured cells [15].
  • The association of variants in IRS1 with type 2 diabetes and type 2 diabetes-related phenotypes and the differential expression of IRS1 in adipocytes and skeletal muscle suggest a role of this gene in the pathogenesis of type 2 diabetes in Pima Indians [16].
  • Finally, small interfering RNA (siRNA)-specific gene silencing targeted specifically against p47(phox) (p47siRNA), in both L6 and primary myotubes, reduced the cognate protein expression, decreased NADPH oxidase activity, restored Ang II-impaired IRS1 and Akt activation as well as GLUT4 translocation by insulin [17].

Associations of IRS1 with chemical compounds

  • In contrast, m-HT did not modulate IRS1, phosphoinositide 3-kinase, or PKB activity [18].
  • Based on these expression differences and the known physiologic role of IRS1, this gene was investigated as a candidate gene for susceptibility to type 2 diabetes in Pima Indians, a population with an extremely high incidence and prevalence of type 2 diabetes [16].
  • Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha on both Akt and IRS1 [14].
  • RESULTS: Concomitant with reductions in mitochondrial membrane potential (DeltaPsim) and ATP synthesis, production of IRS1 and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) were reduced [19].
  • Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess [20].
  • These results suggest that a feed-forward mechanism may exist whereby insulin activation of Akt leads to phosphorylation of IRS-1 at Ser(629), resulting in decreased phosphorylation of IRS-1 at Ser(636) and enhanced downstream signaling [21].

Physical interactions of IRS1

  • Notably, a fraction of the cytosolic ER-alpha colocalized and coprecipitated with IRS-1 and IRS-2, indicating a possible common destination for these proteins [10].
  • The activated receptors of IL-4 and IGF-I both docked to IRS-1 and IRS-2 and invoked IRS complex formation with phosphatidylinositol (PI) 3-kinase, as assessed by immunoprecipitation and detection of the precipitated compounds by immunoblot analysis [22].
  • There was also a tendency for a decrease in Grb2 binding to IRS-1 and insulin-stimulated mitogen-activated protein kinase activity, however, these were not statistically significant [23].
  • Furthermore, these results are consistent with the notion that SH-PTP2 may bind to IRS-1 through its SH2 domains in response to insulin and dephosphorylate the phosphotyrosine residue to which it binds, thereby regulating its association with IRS-1 [24].
  • Recently, IRS-1 was found to interact with alphav beta3 integrins upon insulin stimulation [25].

Enzymatic interactions of IRS1


Regulatory relationships of IRS1


Other interactions of IRS1


Analytical, diagnostic and therapeutic context of IRS1


  1. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Kawaguchi, T., Yoshida, T., Harada, M., Hisamoto, T., Nagao, Y., Ide, T., Taniguchi, E., Kumemura, H., Hanada, S., Maeyama, M., Baba, S., Koga, H., Kumashiro, R., Ueno, T., Ogata, H., Yoshimura, A., Sata, M. Am. J. Pathol. (2004) [Pubmed]
  2. Transactivation of the cytomegalovirus ICP36 gene promoter requires the alpha gene product TRS1 in addition to IE1 and IE2. Stasiak, P.C., Mocarski, E.S. J. Virol. (1992) [Pubmed]
  3. The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer. Wagner, K., Hemminki, K., Grzybowska, E., Klaes, R., Butkiewicz, D., Pamula, J., Pekala, W., Zientek, H., Mielzynska, D., Siwinska, E., Försti, A. Carcinogenesis (2004) [Pubmed]
  4. Aspirin, NSAIDs, and colorectal cancer: possible involvement in an insulin-related pathway. Slattery, M.L., Samowitz, W., Hoffman, M., Ma, K.N., Levin, T.R., Neuhausen, S. Cancer Epidemiol. Biomarkers Prev. (2004) [Pubmed]
  5. Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer. Slattery, M.L., Samowitz, W., Curtin, K., Ma, K.N., Hoffman, M., Caan, B., Neuhausen, S. Cancer Epidemiol. Biomarkers Prev. (2004) [Pubmed]
  6. Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor. Eck, M.J., Dhe-Paganon, S., Trüb, T., Nolte, R.T., Shoelson, S.E. Cell (1996) [Pubmed]
  7. 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]
  8. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Gual, P., Le Marchand-Brustel, Y., Tanti, J.F. Biochimie (2005) [Pubmed]
  9. RNAi-mediated silencing of insulin receptor substrate 1 (IRS-1) enhances tamoxifen-induced cell death in MCF-7 breast cancer cells. Cesarone, G., Garofalo, C., Abrams, M.T., Igoucheva, O., Alexeev, V., Yoon, K., Surmacz, E., Wickstrom, E. J. Cell. Biochem. (2006) [Pubmed]
  10. Estrogen receptor-alpha regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells. Morelli, C., Garofalo, C., Bartucci, M., Surmacz, E. Oncogene (2003) [Pubmed]
  11. Oxygen tension regulates the stability of insulin receptor substrate-1 (IRS-1) through caspase-mediated cleavage. Kang, S.G., Brown, A.L., Chung, J.H. J. Biol. Chem. (2007) [Pubmed]
  12. Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis. Shah, O.J., Hunter, T. Mol. Cell. Biol. (2006) [Pubmed]
  13. Enhancement or inhibition of insulin signaling by insulin receptor substrate 1 is cell context dependent. Yamauchi, K., Pessin, J.E. Mol. Cell. Biol. (1994) [Pubmed]
  14. Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. Jiang, G., Dallas-Yang, Q., Liu, F., Moller, D.E., Zhang, B.B. J. Biol. Chem. (2003) [Pubmed]
  15. Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. Duan, C., Yang, H., White, M.F., Rui, L. Mol. Cell. Biol. (2004) [Pubmed]
  16. The role of insulin receptor substrate-1 gene (IRS1) in type 2 diabetes in Pima Indians. Kovacs, P., Hanson, R.L., Lee, Y.H., Yang, X., Kobes, S., Permana, P.A., Bogardus, C., Baier, L.J. Diabetes (2003) [Pubmed]
  17. Angiotensin II-induced NADPH Oxidase Activation Impairs Insulin Signaling in Skeletal Muscle Cells. Wei, Y., Sowers, J.R., Nistala, R., Gong, H., Uptergrove, G.M., Clark, S.E., Morris, E.M., Szary, N., Manrique, C., Stump, C.S. J. Biol. Chem. (2006) [Pubmed]
  18. Serotonin (5-Hydroxytryptamine), a novel regulator of glucose transport in rat skeletal muscle. Hajduch, E., Rencurel, F., Balendran, A., Batty, I.H., Downes, C.P., Hundal, H.S. J. Biol. Chem. (1999) [Pubmed]
  19. Mitochondrial dysfunction induces aberrant insulin signalling and glucose utilisation in murine C2C12 myotube cells. Lim, J.H., Lee, J.I., Suh, Y.H., Kim, W., Song, J.H., Jung, M.H. Diabetologia (2006) [Pubmed]
  20. Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess. Witchel, S.F., Kahsar-Miller, M., Aston, C.E., White, C., Azziz, R. Fertil. Steril. (2005) [Pubmed]
  21. Phosphorylation of human insulin receptor substrate-1 at Serine 629 plays a positive role in insulin signaling. Luo, M., Langlais, P., Yi, Z., Lefort, N., De Filippis, E.A., Hwang, H., Christ-Roberts, C.Y., Mandarino, L.J. Endocrinology (2007) [Pubmed]
  22. Mono- or dual-phosphorylation of akt kinase is regulated by distinct receptors that involve the common insulin receptor substrate. Schnyder, B., Lahm, H., Pittet, M., Schnyder-Candrian, S. J. Recept. Signal Transduct. Res. (2002) [Pubmed]
  23. A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. Almind, K., Inoue, G., Pedersen, O., Kahn, C.R. J. Clin. Invest. (1996) [Pubmed]
  24. Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Noguchi, T., Matozaki, T., Horita, K., Fujioka, Y., Kasuga, M. Mol. Cell. Biol. (1994) [Pubmed]
  25. Insulin receptor substrate-1 as a signaling molecule for focal adhesion kinase pp125(FAK) and pp60(src). Lebrun, P., Mothe-Satney, I., Delahaye, L., Van Obberghen, E., Baron, V. J. Biol. Chem. (1998) [Pubmed]
  26. Insulin receptor substrate proteins create a link between the tyrosine phosphorylation cascade and the Ca2+-ATPases in muscle and heart. Algenstaedt, P., Antonetti, D.A., Yaffe, M.B., Kahn, C.R. J. Biol. Chem. (1997) [Pubmed]
  27. Phosphatidylinositol 3'-kinase associates with an insulin receptor substrate-1 serine kinase distinct from its intrinsic serine kinase. Cengel, K.A., Kason, R.E., Freund, G.G. Biochem. J. (1998) [Pubmed]
  28. Further evidence for the involvement of insulin receptor substrates in epidermal growth factor-induced activation of phosphatidylinositol 3-kinase. Fujioka, T., Kim, J.H., Adachi, H., Saito, K., Tsujimoto, M., Yokoyama, S., Ui, M. Eur. J. Biochem. (2001) [Pubmed]
  29. Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 PTB domain. Zhou, M.M., Huang, B., Olejniczak, E.T., Meadows, R.P., Shuker, S.B., Miyazaki, M., Trüb, T., Shoelson, S.E., Fesik, S.W. Nat. Struct. Biol. (1996) [Pubmed]
  30. Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein. Goldstein, B.J., Bittner-Kowalczyk, A., White, M.F., Harbeck, M. J. Biol. Chem. (2000) [Pubmed]
  31. Insulin resistance induced by high glucose and high insulin precedes insulin receptor substrate 1 protein depletion in human adipocytes. Renström, F., Burén, J., Svensson, M., Eriksson, J.W. Metab. Clin. Exp. (2007) [Pubmed]
  32. Interleukin-1{beta}-Induced Insulin Resistance in Adipocytes through Down-Regulation of Insulin Receptor Substrate-1 Expression. Jager, J., Gr??meaux, T., Cormont, M., Le Marchand-Brustel, Y., Tanti, J.F. Endocrinology (2007) [Pubmed]
  33. Multiple signaling pathways mediate interleukin-4-induced 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 1 gene expression in human breast cancer cells. Gingras, S., Côté, S., Simard, J. Mol. Endocrinol. (2000) [Pubmed]
  34. Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. Shi, B., Sepp-Lorenzino, L., Prisco, M., Linsley, P., deAngelis, T., Baserga, R. J. Biol. Chem. (2007) [Pubmed]
  35. IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. Uchida, T., Myers, M.G., White, M.F. Mol. Cell. Biol. (2000) [Pubmed]
  36. Janus kinase-dependent activation of insulin receptor substrate 1 in response to interleukin-4, oncostatin M, and the interferons. Burfoot, M.S., Rogers, N.C., Watling, D., Smith, J.M., Pons, S., Paonessaw, G., Pellegrini, S., White, M.F., Kerr, I.M. J. Biol. Chem. (1997) [Pubmed]
  37. Insulin receptor substrate-1 (IRS1) and Shc compete for a limited pool of Grb2 in mediating insulin downstream signaling. Yamauchi, K., Pessin, J.E. J. Biol. Chem. (1994) [Pubmed]
  38. 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]
  39. Insulin resistance in human adipocytes occurs downstream of IRS1 after surgical cell isolation but at the level of phosphorylation of IRS1 in type 2 diabetes. Danielsson, A., Ost, A., Lystedt, E., Kjolhede, P., Gustavsson, J., Nystrom, F.H., Strålfors, P. FEBS J. (2005) [Pubmed]
  40. Developmental expression of insulin receptor substrate-2 during dimethylsulfoxide-induced differentiation of human HL-60 cells. Schacher, D.H., VanHoy, R.W., Liu, Q., Arkins, S., Dantzer, R., Freund, G.G., Kelley, K.W. J. Immunol. (2000) [Pubmed]
  41. Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes. Florez, J.C., Sjögren, M., Burtt, N., Orho-Melander, M., Schayer, S., Sun, M., Almgren, P., Lindblad, U., Tuomi, T., Gaudet, D., Hudson, T.J., Daly, M.J., Ardlie, K.G., Hirschhorn, J.N., Altshuler, D., Groop, L. Diabetes (2004) [Pubmed]
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