The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

IRS2  -  insulin receptor substrate 2

Homo sapiens

Synonyms: IRS-2, Insulin receptor substrate 2
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of IRS2


High impact information on IRS2

  • Although IRS1 was originally isolated as a specific insulin receptor substrate, both IRS1 and IRS2 appear to play a broader role, functioning also as proximal substrates in growth hormone and cytokine receptor signalling [6].
  • The study also provides strong evidence that insulin receptor substrate 2 (Irs2), which is known to have major effects on beta cell growth and survival, is a key downstream mediator of the effects of glucose found in this study [7].
  • Insulin also inhibited transcription of a reporter gene driven by the human IRS-2 promoter that was transfected into freshly isolated rat hepatocytes [8].
  • We examined the expression and function of IRS-1 and IRS-2 in adipocytes from healthy and diabetic individuals [9].
  • Mammary Tumorigenesis and Metastasis Caused by Overexpression of Insulin Receptor Substrate 1 (IRS-1) or IRS-2 [10].

Chemical compound and disease context of IRS2


Biological context of IRS2


Anatomical context of IRS2

  • We have investigated the expression of IRS-1 and IRS-2 in several cell lines with erythroid and/or megakaryocytic features, and we observed that IRS-2 was expressed in all cell lines tested [16].
  • Thus, IRS-2, not IRS-1, signals insulin activation of GS in the L6hIR skeletal muscle cells [17].
  • Here, we demonstrate that induction of granulocytic differentiation of human promyeloid HL-60 cells leads to an increase in the amount of IRS-2 that is phosphorylated in response to insulin-like growth factor (IGF)-I [18].
  • These IRS-2-positive cells could not differentiate into more mature myeloid cells in serum-free medium unless IGF-I was added [18].
  • In MDA-MB-231 cells cultured under serum-free conditions, IRS-1 and IRS-2 were degraded through the 26S proteasome and calpain pathways [19].

Associations of IRS2 with chemical compounds


Physical interactions of IRS2

  • In this study we utilize the yeast two-hybrid system and assays of in vitro interaction to demonstrate that IRS-2 interacts directly with the IR and the insulin-like growth factor I receptor [23].
  • In addition to the pleckstrin homology domain and the phosphotyrosine binding domain in insulin receptor substrate (IRS)-1 and IRS-2, a region between amino acids 591 and 786 in IRS-2 (IRS-2-(591-786)) binds to the insulin receptor [24].

Enzymatic interactions of IRS2


Regulatory relationships of IRS2


Other interactions of IRS2

  • The 180- and 70-kD proteins have been previously shown to be IRS2 and the Epo receptor [29].
  • In this report, we show that the 116-kD protein is the IRS2-related molecular adapter, GAB1 [29].
  • Analysis of genes encoding proteins that may activate the pathway upstream of Pi3k revealed variable fractions of tumors with EGFR amplification (31%), PDGFRA amplification (8%), and IRS2 amplification (2%) [30].
  • The signaling molecules insulin receptor substrate (IRS)-1 and the newly described IRS-2 (4PS) molecule are major insulin and interleukin 4 (IL-4)-dependent phosphoproteins [31].
  • IRS1, IRS2 and SHC1 are the key mediators for the downstream pathway processes [15].

Analytical, diagnostic and therapeutic context of IRS2


  1. Energy balance, insulin-related genes and risk of colon and rectal cancer. Slattery, M.L., Murtaugh, M., Caan, B., Ma, K.N., Neuhausen, S., Samowitz, W. Int. J. Cancer (2005) [Pubmed]
  2. Complex haplotypes of IRS2 gene are associated with severe obesity and reveal heterogeneity in the effect of Gly1057Asp mutation. Lautier, C., El Mkadem, S.A., Renard, E., Brun, J.F., Gris, J.C., Bringer, J., Grigorescu, F. Hum. Genet. (2003) [Pubmed]
  3. Prostate cancer risk and IRS1, IRS2, IGF1, and INS polymorphisms: strong association of IRS1 G972R variant and cancer risk. Neuhausen, S.L., Slattery, M.L., Garner, C.P., Ding, Y.C., Hoffman, M., Brothman, A.R. Prostate (2005) [Pubmed]
  4. Epidermal growth factor induces insulin receptor substrate-2 in breast cancer cells via c-Jun NH(2)-terminal kinase/activator protein-1 signaling to regulate cell migration. Cui, X., Kim, H.J., Kuiatse, I., Kim, H., Brown, P.H., Lee, A.V. Cancer Res. (2006) [Pubmed]
  5. Common polymorphisms in the genes regulating the early insulin signalling pathway: effects on weight change and the conversion from impaired glucose tolerance to Type 2 diabetes. The Finnish Diabetes Prevention Study. Laukkanen, O., Pihlajamäki, J., Lindström, J., Eriksson, J., Valle, T.T., Hämäläinen, H., Ilanne-Parikka, P., Keinänen-Kiukaanniemi, S., Tuomilehto, J., Uusitupa, M., Laakso, M. Diabetologia (2004) [Pubmed]
  6. Insulin receptor substrate 1 and 2 (IRS1 and IRS2): what a tangled web we weave. Waters, S.B., Pessin, J.E. Trends Cell Biol. (1996) [Pubmed]
  7. A dominant role for glucose in beta cell compensation of insulin resistance. Weir, G.C., Bonner-Weir, S. J. Clin. Invest. (2007) [Pubmed]
  8. Insulin inhibits transcription of IRS-2 gene in rat liver through an insulin response element (IRE) that resembles IREs of other insulin-repressed genes. Zhang, J., Ou, J., Bashmakov, Y., Horton, J.D., Brown, M.S., Goldstein, J.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  9. Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. Rondinone, C.M., Wang, L.M., Lonnroth, P., Wesslau, C., Pierce, J.H., Smith, U. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  10. Mammary Tumorigenesis and Metastasis Caused by Overexpression of Insulin Receptor Substrate 1 (IRS-1) or IRS-2. Dearth, R.K., Cui, X., Kim, H.J., Kuiatse, I., Lawrence, N.A., Zhang, X., Divisova, J., Britton, O.L., Mohsin, S., Allred, D.C., Hadsell, D.L., Lee, A.V. Mol. Cell. Biol. (2006) [Pubmed]
  11. Progesterone crosstalks with insulin-like growth factor signaling in breast cancer cells via induction of insulin receptor substrate-2. Cui, X., Lazard, Z., Zhang, P., Hopp, T.A., Lee, A.V. Oncogene (2003) [Pubmed]
  12. Differential regulation of insulin receptor substrate-2 and mitogen-activated protein kinase tyrosine phosphorylation by phosphatidylinositol 3-kinase inhibitors in SH-SY5Y human neuroblastoma cells. Kim, B., Leventhal, P.S., White, M.F., Feldman, E.L. Endocrinology (1998) [Pubmed]
  13. Inhibition of insulin-like growth factor-1 receptor and IRS-2 signaling by ethanol in SH-SY5Y neuroblastoma cells. Seiler, A.E., Ross, B.N., Rubin, R. J. Neurochem. (2001) [Pubmed]
  14. Identification of a single nucleotide polymorphism showing no insulin-mediated suppression of the promoter activity in the human insulin receptor substrate 2 gene. Iwamoto, K., Mori, H., Okazawa, H., Hashiramoto, M., Kasuga, M. Diabetologia (2002) [Pubmed]
  15. 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]
  16. Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2. An alternate pathway for erythropoietin-induced phosphatidylinositol 3-kinase activation. Verdier, F., Chrétien, S., Billat, C., Gisselbrecht, S., Lacombe, C., Mayeux, P. J. Biol. Chem. (1997) [Pubmed]
  17. Insulin receptor substrate-2 phosphorylation is necessary for protein kinase C zeta activation by insulin in L6hIR cells. Oriente, F., Formisano, P., Miele, C., Fiory, F., Maitan, M.A., Vigliotta, G., Trencia, A., Santopietro, S., Caruso, M., Van Obberghen, E., Beguinot, F. J. Biol. Chem. (2001) [Pubmed]
  18. 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]
  19. 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]
  20. Structural and functional characterization of insulin receptor substrate proteins and the molecular mechanisms of their interaction with insulin superfamily tyrosine kinase receptors and effector proteins. Shpakov, A.O., Pertseva, M.N. Membrane & cell biology. (2000) [Pubmed]
  21. Metformin modulates insulin post-receptor signaling transduction in chronically insulin-treated Hep G2 cells. Yuan, L., Ziegler, R., Hamann, A. Acta Pharmacol. Sin. (2003) [Pubmed]
  22. Human insulin receptor substrate-2: gene organization and promoter characterization. Vassen, L., Wegrzyn, W., Klein-Hitpass, L. Diabetes (1999) [Pubmed]
  23. 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. He, W., Craparo, A., Zhu, Y., O'Neill, T.J., Wang, L.M., Pierce, J.H., Gustafson, T.A. J. Biol. Chem. (1996) [Pubmed]
  24. Tyr624 and Tyr628 in insulin receptor substrate-2 mediate its association with the insulin receptor. Sawka-Verhelle, D., Baron, V., Mothe, I., Filloux, C., White, M.F., Van Obberghen, E. J. Biol. Chem. (1997) [Pubmed]
  25. Immunoreceptor tyrosine-based inhibitory motif of the IL-4 receptor associates with SH2-containing phosphatases and regulates IL-4-induced proliferation. Kashiwada, M., Giallourakis, C.C., Pan, P.Y., Rothman, P.B. J. Immunol. (2001) [Pubmed]
  26. 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]
  27. Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells. Neid, M., Datta, K., Stephan, S., Khanna, I., Pal, S., Shaw, L., White, M., Mukhopadhyay, D. J. Biol. Chem. (2004) [Pubmed]
  28. Resistin overexpression impaired glucose tolerance in hepatocytes. Zhou, L., Li, Y., Xia, T., Feng, S., Chen, X., Yang, Z. Eur. Cytokine Netw. (2006) [Pubmed]
  29. Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase. Lecoq-Lafon, C., Verdier, F., Fichelson, S., Chrétien, S., Gisselbrecht, S., Lacombe, C., Mayeux, P. Blood (1999) [Pubmed]
  30. Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Knobbe, C.B., Reifenberger, G. Brain Pathol. (2003) [Pubmed]
  31. Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. Johnston, J.A., Wang, L.M., Hanson, E.P., Sun, X.J., White, M.F., Oakes, S.A., Pierce, J.H., O'Shea, J.J. J. Biol. Chem. (1995) [Pubmed]
  32. 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]
  33. Identification of insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the alpha6beta4 integrin-dependent activation of phosphoinositide 3-OH kinase and promotion of invasion. Shaw, L.M. Mol. Cell. Biol. (2001) [Pubmed]
  34. Relationship of insulin receptor substrate-1 and -2 genotypes to phenotypic features of polycystic ovary syndrome. Ehrmann, D.A., Tang, X., Yoshiuchi, I., Cox, N.J., Bell, G.I. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
WikiGenes - Universities