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Gene Review

IRS4  -  insulin receptor substrate 4

Homo sapiens

Synonyms: 160 kDa phosphotyrosine protein, IRS-4, Insulin receptor substrate 4, PY160, Phosphoprotein of 160 kDa, ...
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Disease relevance of IRS4


High impact information on IRS4

  • In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states [5].
  • Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation [5].
  • In order to distinguish common and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually in 32D myeloid progenitor cells containing the human insulin receptor (32D(IR)) [6].
  • IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis [6].
  • These data suggest that IRS-4 is insulin-/IGF-1-activated by phosphorylation and not by translocation, inducing the recruitment of SH2 domain-containing proteins and PKC zeta to the membrane [7].

Biological context of IRS4


Anatomical context of IRS4


Associations of IRS4 with chemical compounds

  • The phosphotyrosine form of PY160 was purified from insulin-treated HEK 293 cells by anti-phosphotyrosine immunoaffinity chromatography, the sequences of peptides determined, and its cDNA cloned [11].
  • IRS-4 was found to be associated with two src homology 2 (SH2) domain-containing proteins, phosphatidylinositol 3-kinase and Grb2, the adaptor to the guanine nucleotide exchange factor for Ras [12].
  • Interestingly, none of these four tyrosines was individually critical for the interaction between Crk-II and IRS-4, but when all four tyrosines were simultaneously mutated to phenylalanine, the IGF-I induced interaction between these molecules was abolished [13].
  • The available data are consistent with the notion that both IRS-1 and IRS-2 are important for insulin action and glucose homeostasis in vivo, whereas IRS-and IRS-4 appear to play a redundant role in the IRS signalling system [14].
  • In summary, we showed that Ins induces tyr-phosphorylation of IRS-4, an effect modulated by Ang II [15].

Regulatory relationships of IRS4

  • On the other hand, overexpression of IRAS enhanced IRS-4-dependent insulin stimulation of the extracellularly regulated kinase [16].
  • Nevertheless, as demonstrated in this study, both IRS-3 and IRS-4 can also stimulate translocation of GLUT4 [17].

Other interactions of IRS4


Analytical, diagnostic and therapeutic context of IRS4


  1. Interaction between Brk kinase and insulin receptor substrate-4. Qiu, H., Zappacosta, F., Su, W., Annan, R.S., Miller, W.T. Oncogene (2005) [Pubmed]
  2. Candida albicans IRS4 contributes to hyphal formation and virulence after the initial stages of disseminated candidiasis. Badrane, H., Cheng, S., Nguyen, M.H., Jia, H.Y., Zhang, Z., Weisner, N., Clancy, C.J. Microbiology (Reading, Engl.) (2005) [Pubmed]
  3. Genetic diversity of bacterial agents detected in ticks removed from asymptomatic patients in northeastern Italy. Sanogo, Y.O., Parola, P., Shpynov, S., Camicas, J.L., Brouqui, P., Caruso, G., Raoult, D. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  4. Common amino acid substitutions in insulin receptor substrate-4 are not associated with Type II diabetes mellitus or insulin resistance. Almind, K., Frederiksen, S.K., Ahlgren, M.G., Urhammer, S., Hansen, T., Clausen, J.O., Pedersen, O. Diabetologia (1998) [Pubmed]
  5. Differential roles of insulin receptor substrates in brown adipocyte differentiation. Tseng, Y.H., Kriauciunas, K.M., Kokkotou, E., Kahn, C.R. Mol. Cell. Biol. (2004) [Pubmed]
  6. 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]
  7. Insulin receptor substrate-4 signaling in quiescent rat hepatocytes and in regenerating rat liver. Escribano, O., Fernández-Moreno, M.D., Zueco, J.A., Menor, C., Fueyo, J., Ropero, R.M., Diaz-Laviada, I., Román, I.D., Guijarro, L.G. Hepatology (2003) [Pubmed]
  8. Insulin receptor substrate-4 is expressed in muscle tissue without acting as a substrate for the insulin receptor. Schreyer, S., Ledwig, D., Rakatzi, I., Klöting, I., Eckel, J. Endocrinology (2003) [Pubmed]
  9. Phylogenetic analysis of spotted fever group rickettsiae based on gltA, 17-kDa, and rOmpA genes amplified by nested PCR from ticks in Japan. Ishikura, M., Ando, S., Shinagawa, Y., Matsuura, K., Hasegawa, S., Nakayama, T., Fujita, H., Watanabe, M. Microbiol. Immunol. (2003) [Pubmed]
  10. Tyrosine phosphoproteomics of fibroblast growth factor signaling: a role for insulin receptor substrate-4. Hinsby, A.M., Olsen, J.V., Mann, M. J. Biol. Chem. (2004) [Pubmed]
  11. A novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family. Lavan, B.E., Fantin, V.R., Chang, E.T., Lane, W.S., Keller, S.R., Lienhard, G.E. J. Biol. Chem. (1997) [Pubmed]
  12. Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells. Fantin, V.R., Sparling, J.D., Slot, J.W., Keller, S.R., Lienhard, G.E., Lavan, B.E. J. Biol. Chem. (1998) [Pubmed]
  13. The insulin-like growth factor I receptor-induced interaction of insulin receptor substrate-4 and Crk-II. Karas, M., Koval, A.P., Zick, Y., LeRoith, D. Endocrinology (2001) [Pubmed]
  14. Insulin receptor substrate polymorphisms and type 2 diabetes mellitus. Sesti, G. Pharmacogenomics (2000) [Pubmed]
  15. Angiotensin II modulates tyr-phosphorylation of IRS-4, an insulin receptor substrate, in rat liver membranes. Villarreal, R.S., Alvarez, S.E., Ayub, M.J., Ciuffo, G.M. Mol. Cell. Biochem. (2006) [Pubmed]
  16. Insulin receptor substrate 4 associates with the protein IRAS. Sano, H., Liu, S.C., Lane, W.S., Piletz, J.E., Lienhard, G.E. J. Biol. Chem. (2002) [Pubmed]
  17. Action of insulin receptor substrate-3 (IRS-3) and IRS-4 to stimulate translocation of GLUT4 in rat adipose cells. Zhou, L., Chen, H., Xu, P., Cong, L.N., Sciacchitano, S., Li, Y., Graham, D., Jacobs, A.R., Taylor, S.I., Quon, M.J. Mol. Endocrinol. (1999) [Pubmed]
  18. Protein phosphatase 4 interacts with and down-regulates insulin receptor substrate 4 following tumor necrosis factor-alpha stimulation. Mihindukulasuriya, K.A., Zhou, G., Qin, J., Tan, T.H. J. Biol. Chem. (2004) [Pubmed]
  19. Cloning, tissue expression, and chromosomal location of the mouse insulin receptor substrate 4 gene. Fantin, V.R., Lavan, B.E., Wang, Q., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Keller, S.R., Lienhard, G.E. Endocrinology (1999) [Pubmed]
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