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Gene Review

Irs1  -  insulin receptor substrate 1

Mus musculus

Synonyms: G972R, IRS-1, Insulin receptor substrate 1, Irs-1
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Disease relevance of Irs1


High impact information on Irs1

  • We intercrossed mice heterozygous for two null alleles (Irs1+/- and Irs2+/-) and investigated growth and glucose metabolism in mice with viable genotypes [5].
  • Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles [6].
  • Mice double heterozygous for null alleles in the insulin receptor and insulin receptor substrate-1 genes exhibit the expected approximately 50% reduction in expression of these two proteins, but a synergism at a level of insulin resistance with 5- to 50-fold elevated plasma insulin levels and comparable levels of beta cell hyperplasia [6].
  • Conversely, Erk activation by insulin was suppressed in LGKO liver, leading to defective IRS-1 Ser612 phosphorylation [7].
  • To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation [8].

Chemical compound and disease context of Irs1


Biological context of Irs1


Anatomical context of Irs1


Associations of Irs1 with chemical compounds

  • Insulin signals are mediated by tyrosine phosphorylation of the insulin receptor and its downstream targets, such as Irs1 and Irs2 [18].
  • The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex [19].
  • Since hormonal activation of IRS-1 is epithelial, estrogen-specific, and initiated before maximal DNA synthesis occurs following treatment with hormone, this protein, as part of the IGF-1R pathway, may be important in mediating estrogen-stimulated proliferation in the uterus [17].
  • The nonestrogenic steroid hormones examined did not stimulate the P-Tyr content of IGF-1R or IRS-1 [17].
  • Furthermore, 2-DOG uptake was affected by amino acid availability even when the degradation of IRS-1 was inhibited by lactacystin [20].

Physical interactions of Irs1


Enzymatic interactions of Irs1

  • However, the precise molecular mechanism by which the IKK complex phosphorylates IRS-1 is unknown [25].
  • Both the insulin receptor and IRS-1 are tyrosine-phosphorylated to the same extent in response to acute insulin stimulation following cellular TNF-alpha exposure [26].
  • As a result, the affinity constants of IRS-1 to phosphorylated and unphosphorylated IGF-1R were (8.06+/-5.18)x10(9) M(-1) and (9.81+/-4.61)x10(8) M(-1), respectively [24].
  • One consequence of obesity is that JNK phosphorylates the adapter protein insulin receptor substrate 1 (IRS-1) on Ser 307 and inhibits signaling by the insulin receptor [27].

Regulatory relationships of Irs1

  • NEMO expression also enhanced TNF-alpha-induced Ser307-IRS-1 phosphorylation and inhibited glucose uptake [25].
  • Nuclear translocation of IRS-1 occurs also in MEF stimulated with IGF-I or in MEF expressing the oncogene v-src [4].
  • We therefore conclude that IRS-1 deficiency impairs bone healing at least partly by inhibiting chondrocyte proliferation through the phosphatidylinositol 3-kinase/Akt pathway, and we propose that IRS-1 can be a target molecule for bone regenerative medicine [28].
  • Only the A isoform of the insulin receptor (IR) can induce IRS-1 nuclear translocation, which is significant when the receptor is over-expressed [29].
  • In contrast, dominant inhibitory Myo1c cargo domain expression diminished this interaction and inhibited IRS-1 phosphorylation [25].
  • These data suggest that LR-enriched IRS-1 contributes substantially to GH-induced ERK activation in LR in 3T3-F442A fibroblasts [30].

Other interactions of Irs1


Analytical, diagnostic and therapeutic context of Irs1


  1. 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]
  2. Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. Ogata, N., Chikazu, D., Kubota, N., Terauchi, Y., Tobe, K., Azuma, Y., Ohta, T., Kadowaki, T., Nakamura, K., Kawaguchi, H. J. Clin. Invest. (2000) [Pubmed]
  3. Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis. Ma, Z., Gibson, S.L., Byrne, M.A., Zhang, J., White, M.F., Shaw, L.M. Mol. Cell. Biol. (2006) [Pubmed]
  4. Nuclear translocation of insulin receptor substrate-1 by oncogenes and Igf-I. Effect on ribosomal RNA synthesis. Tu, X., Batta, P., Innocent, N., Prisco, M., Casaburi, I., Belletti, B., Baserga, R. J. Biol. Chem. (2002) [Pubmed]
  5. 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]
  6. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Brüning, J.C., Winnay, J., Bonner-Weir, S., Taylor, S.I., Accili, D., Kahn, C.R. Cell (1997) [Pubmed]
  7. Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action. Bard-Chapeau, E.A., Hevener, A.L., Long, S., Zhang, E.E., Olefsky, J.M., Feng, G.S. Nat. Med. (2005) [Pubmed]
  8. 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]
  9. IRS1 degradation and increased serine phosphorylation cannot predict the degree of metabolic insulin resistance induced by oxidative stress. Potashnik, R., Bloch-Damti, A., Bashan, N., Rudich, A. Diabetologia (2003) [Pubmed]
  10. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Shintani, Y., Fujie, H., Miyoshi, H., Tsutsumi, T., Tsukamoto, K., Kimura, S., Moriya, K., Koike, K. Gastroenterology (2004) [Pubmed]
  11. Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction. Sakoda, H., Ogihara, T., Anai, M., Funaki, M., Inukai, K., Katagiri, H., Fukushima, Y., Onishi, Y., Ono, H., Fujishiro, M., Kikuchi, M., Oka, Y., Asano, T. Diabetes (2000) [Pubmed]
  12. Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes. Shirakami, A., Toyonaga, T., Tsuruzoe, K., Shirotani, T., Matsumoto, K., Yoshizato, K., Kawashima, J., Hirashima, Y., Miyamura, N., Kahn, C.R., Araki, E. J. Endocrinol. (2002) [Pubmed]
  13. Lipoatrophic diabetes in Irs1(-/-)/Irs3(-/-) double knockout mice. Laustsen, P.G., Michael, M.D., Crute, B.E., Cohen, S.E., Ueki, K., Kulkarni, R.N., Keller, S.R., Lienhard, G.E., Kahn, C.R. Genes Dev. (2002) [Pubmed]
  14. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Tamemoto, H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., Hayakawa, T., Terauchi, Y., Ueki, K., Kaburagi, Y., Satoh, S. Nature (1994) [Pubmed]
  15. Caspase-mediated Cleavage of Insulin Receptor Substrate. Green, K.A., Naylor, M.J., Lowe, E.T., Wang, P., Marshman, E., Streuli, C.H. J. Biol. Chem. (2004) [Pubmed]
  16. Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. Hennige, A.M., Stefan, N., Kapp, K., Lehmann, R., Weigert, C., Beck, A., Moeschel, K., Mushack, J., Schleicher, E., Häring, H.U. FASEB J. (2006) [Pubmed]
  17. Estradiol stimulates tyrosine phosphorylation of the insulin-like growth factor-1 receptor and insulin receptor substrate-1 in the uterus. Richards, R.G., DiAugustine, R.P., Petrusz, P., Clark, G.C., Sebastian, J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  18. 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]
  19. The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. Luo, J., Field, S.J., Lee, J.Y., Engelman, J.A., Cantley, L.C. J. Cell Biol. (2005) [Pubmed]
  20. Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin. Takano, A., Usui, I., Haruta, T., Kawahara, J., Uno, T., Iwata, M., Kobayashi, M. Mol. Cell. Biol. (2001) [Pubmed]
  21. Regulation of upstream binding factor 1 activity by insulin-like growth factor I receptor signaling. Wu, A., Tu, X., Prisco, M., Baserga, R. J. Biol. Chem. (2005) [Pubmed]
  22. Increased insulin sensitivity in IGF-I receptor--deficient brown adipocytes. Mur, C., Valverde, A.M., Kahn, C.R., Benito, M. Diabetes (2002) [Pubmed]
  23. Insulin receptor substrate 1 regulation of sarco-endoplasmic reticulum calcium ATPase 3 in insulin-secreting beta-cells. Borge, P.D., Wolf, B.A. J. Biol. Chem. (2003) [Pubmed]
  24. Effect of receptor phosphorylation on the binding between IRS-1 and IGF-1R as revealed by surface plasmon resonance biosensor. Huang, M., Lai, W.P., Wong, M.S., Yang, M. FEBS Lett. (2001) [Pubmed]
  25. Myosin motor Myo1c and its receptor NEMO/IKK-gamma promote TNF-alpha-induced serine307 phosphorylation of IRS-1. Nakamori, Y., Emoto, M., Fukuda, N., Taguchi, A., Okuya, S., Tajiri, M., Miyagishi, M., Taira, K., Wada, Y., Tanizawa, Y. J. Cell Biol. (2006) [Pubmed]
  26. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. Stephens, J.M., Lee, J., Pilch, P.F. J. Biol. Chem. (1997) [Pubmed]
  27. An essential role of the JIP1 scaffold protein for JNK activation in adipose tissue. Jaeschke, A., Czech, M.P., Davis, R.J. Genes Dev. (2004) [Pubmed]
  28. Impairment of bone healing by insulin receptor substrate-1 deficiency. Shimoaka, T., Kamekura, S., Chikuda, H., Hoshi, K., Chung, U.I., Akune, T., Maruyama, Z., Komori, T., Matsumoto, M., Ogawa, W., Terauchi, Y., Kadowaki, T., Nakamura, K., Kawaguchi, H. J. Biol. Chem. (2004) [Pubmed]
  29. Nuclear translocation of insulin receptor substrate-1 by the insulin receptor in mouse embryo fibroblasts. Wu, A., Sciacca, L., Baserga, R. J. Cell. Physiol. (2003) [Pubmed]
  30. Interruption of growth hormone signaling via SHC and ERK in 3T3-F442A preadipocytes upon knockdown of insulin receptor substrate-1. Wang, X., Yang, N., Deng, L., Li, X., Jiang, J., Gan, Y., Frank, S.J. Mol. Endocrinol. (2009) [Pubmed]
  31. Insulin signaling in insulin receptor substrate (IRS)-1-deficient brown adipocytes: requirement of IRS-1 for lipid synthesis. Valverde, A.M., Kahn, C.R., Benito, M. Diabetes (1999) [Pubmed]
  32. Interleukin-9 induces tyrosine phosphorylation of insulin receptor substrate-1 via JAK tyrosine kinases. Yin, T., Keller, S.R., Quelle, F.W., Witthuhn, B.A., Tsang, M.L., Lienhard, G.E., Ihle, J.N., Yang, Y.C. J. Biol. Chem. (1995) [Pubmed]
  33. Interleukin-1alpha inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes. He, J., Usui, I., Ishizuka, K., Kanatani, Y., Hiratani, K., Iwata, M., Bukhari, A., Haruta, T., Sasaoka, T., Kobayashi, M. Mol. Endocrinol. (2006) [Pubmed]
  34. Low insulin-like growth factor binding protein-2 expression is responsible for increased insulin receptor substrate-1 phosphorylation in mesangial cells from mice susceptible to glomerulosclerosis. Fornoni, A., Rosenzweig, S.A., Lenz, O., Rivera, A., Striker, G.E., Elliot, S.J. Endocrinology (2006) [Pubmed]
  35. Control of cell size through phosphorylation of upstream binding factor 1 by nuclear phosphatidylinositol 3-kinase. Drakas, R., Tu, X., Baserga, R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  36. Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302. Werner, E.D., Lee, J., Hansen, L., Yuan, M., Shoelson, S.E. J. Biol. Chem. (2004) [Pubmed]
  37. 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]
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