{{Short description|Protein-coding gene in the species Homo sapiens}} {{Redirect|IRS2|the chemical IrS<sub>2</sub>|Iridium disulfide}} {{Infobox_gene}} '''Insulin receptor substrate 2''' is a [[protein]] that in humans is encoded by the ''IRS2'' [[gene]].<ref name="pmid9312143">{{cite journal |vauthors=Ogihara T, Isobe T, Ichimura T, Taoka M, Funaki M, Sakoda H, Onishi Y, Inukai K, Anai M, Fukushima Y, Kikuchi M, Yazaki Y, Oka Y, Asano T | title = 14-3-3 protein binds to insulin receptor substrate-1, one of the binding sites of which is in the phosphotyrosine binding domain | journal = J Biol Chem | volume = 272 | issue = 40 | pages = 25267–74 |date=Oct 1997 | pmid = 9312143 | doi =10.1074/jbc.272.40.25267 | doi-access = free }}</ref>
== Function ==
This gene encodes the insulin receptor substrate 2, a cytoplasmic signaling molecule that mediates effects of [[insulin]], [[insulin-like growth factor 1]], and other [[cytokine]]s by acting as a molecular adaptor between diverse [[receptor tyrosine kinase]]s and downstream effectors. The product of this gene is [[phosphorylated]] by the insulin receptor tyrosine kinase upon receptor stimulation, as well as by an [[IRAK1|interleukin 4 receptor-associated kinase]] in response to [[interleukin-4|IL4]] treatment.<ref>{{cite web | title = Entrez Gene: IRS2 insulin receptor substrate 2| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=8660}}</ref>
Mice lacking IRS2 have a diabetic phenotype<ref name="pmid15467829">{{cite journal |vauthors=Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y, White MF | title = Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes | journal = J. Clin. Invest. | volume = 114 | issue = 7 | pages = 908–16 |date=October 2004 | pmid = 15467829 | pmc = 518668 | doi = 10.1172/JCI22217 }}</ref> as well as a 40% reduction in brain mass.<ref name="pmid12904469">{{cite journal |vauthors=Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL, Farhang-Fallah J, Dikkes P, Warot XM, Rio C, Corfas G, White MF | title = Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation | journal = J. Neurosci. | volume = 23 | issue = 18 | pages = 7084–92 |date=August 2003 | pmid = 12904469 | pmc = 6740672 | doi = 10.1523/JNEUROSCI.23-18-07084.2003}}</ref>
== Interactions ==
IRS2 has been shown to [[Protein-protein interaction|interact]] with: * [[PLCG1]],<ref name="pmid9535722">{{cite journal |vauthors=Sozzani P, Hasan L, Séguélas MH, Caput D, Ferrara P, Pipy B, Cambon C | title = IL-13 induces tyrosine phosphorylation of phospholipase C gamma-1 following IRS-2 association in human monocytes: relationship with the inhibitory effect of IL-13 on ROI production | journal = Biochem. Biophys. Res. Commun. | volume = 244 | issue = 3 | pages = 665–70 |date=March 1998 | pmid = 9535722 | doi = 10.1006/bbrc.1998.8314 }}</ref> * [[Suppressor of cytokine signaling 1|SOCS1]],<ref name="pmid12228220">{{cite journal |vauthors=Rui L, Yuan M, Frantz D, Shoelson S, White MF | title = SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2 | journal = J. Biol. Chem. | volume = 277 | issue = 44 | pages = 42394–8 |date=November 2002 | pmid = 12228220 | doi = 10.1074/jbc.C200444200 | doi-access = free }}</ref> and * [[PIK3R1]],<ref name="pmid8910607">{{cite journal |vauthors=Argetsinger LS, Norstedt G, Billestrup N, White MF, Carter-Su C | title = Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling | journal = J. Biol. Chem. | volume = 271 | issue = 46 | pages = 29415–21 |date=November 1996 | pmid = 8910607 | doi = 10.1074/jbc.271.46.29415 | doi-access = free }}</ref><ref name="pmid9334184">{{cite journal |vauthors=Verdier F, Chrétien S, Billat C, Gisselbrecht S, Lacombe C, Mayeux P | title = Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2. An alternate pathway for erythropoietin-induced phosphatidylinositol 3-kinase activation | journal = J. Biol. Chem. | volume = 272 | issue = 42 | pages = 26173–8 |date=October 1997 | pmid = 9334184 | doi = 10.1074/jbc.272.42.26173 | doi-access = free }}</ref><ref name="pmid9852124">{{cite journal |vauthors=Kim B, Cheng HL, Margolis B, Feldman EL | title = Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling | journal = J. Biol. Chem. | volume = 273 | issue = 51 | pages = 34543–50 |date=December 1998 | pmid = 9852124 | doi = 10.1074/jbc.273.51.34543 | doi-access = free }}</ref><ref name="pmid12107746">{{cite journal |vauthors=Hamer I, Foti M, Emkey R, Cordier-Bussat M, Philippe J, De Meyts P, Maeder C, Kahn CR, Carpentier JL | title = An arginine to cysteine(252) mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events | journal = Diabetologia | volume = 45 | issue = 5 | pages = 657–67 |date=May 2002 | pmid = 12107746 | doi = 10.1007/s00125-002-0798-5 | doi-access = free }}</ref>
==References== {{reflist}}
==Further reading== {{refbegin | 2}} *{{cite journal | author=White MF |title=The IRS-signalling system: a network of docking proteins that mediate insulin action. |journal=Mol. Cell. Biochem. |volume=182 |issue= 1–2 |pages= 3–11 |year= 1999 |pmid= 9609109 |doi=10.1023/A:1006806722619 |s2cid=32623861 }} *{{cite journal |vauthors=Jiang H, Harris MB, Rothman P |title=IL-4/IL-13 signaling beyond JAK/STAT. |journal=J. Allergy Clin. Immunol. |volume=105 |issue= 6 Pt 1 |pages= 1063–70 |year= 2000 |pmid= 10856136 |doi=10.1067/mai.2000.107604 |doi-access=free }} *{{cite journal |vauthors=Sesti G, Federici M, Hribal ML, etal |title=Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. |journal=FASEB J. |volume=15 |issue= 12 |pages= 2099–111 |year= 2001 |pmid= 11641236 |doi= 10.1096/fj.01-0009rev |s2cid=6429338 |doi-access=free }} *{{cite journal |vauthors=Gibson SL, Ma Z, Shaw LM |title=Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis. |journal=Cell Cycle |volume=6 |issue= 6 |pages= 631–7 |year= 2007 |pmid= 17361103 |doi= 10.4161/cc.6.6.3987|doi-access=free }} *{{cite journal |vauthors=Dearth RK, Cui X, Kim HJ, etal |title=Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2. |journal=Cell Cycle |volume=6 |issue= 6 |pages= 705–13 |year= 2007 |pmid= 17374994 |doi= 10.4161/cc.6.6.4035|doi-access=free }} *{{cite journal |vauthors=Johnston JA, Wang LM, Hanson EP, etal |title=Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. |journal=J. Biol. Chem. |volume=270 |issue= 48 |pages= 28527–30 |year= 1996 |pmid= 7499365 |doi=10.1074/jbc.270.48.28527 |doi-access=free }} *{{cite journal |vauthors=Patti ME, Sun XJ, Bruening JC, etal |title=4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice. |journal=J. Biol. Chem. |volume=270 |issue= 42 |pages= 24670–3 |year= 1995 |pmid= 7559579 |doi=10.1074/jbc.270.42.24670 |doi-access=free }} *{{cite journal |vauthors=Sun XJ, Wang LM, Zhang Y, etal |title=Role of IRS-2 in insulin and cytokine signalling. |journal=Nature |volume=377 |issue= 6545 |pages= 173–7 |year= 1995 |pmid= 7675087 |doi= 10.1038/377173a0 |bibcode=1995Natur.377..173S |s2cid=4336107 }} *{{cite journal |vauthors=Ridderstråle M, Degerman E, Tornqvist H |title=Growth hormone stimulates the tyrosine phosphorylation of the insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase in primary adipocytes. |journal=J. Biol. Chem. |volume=270 |issue= 8 |pages= 3471–4 |year= 1995 |pmid= 7876077 |doi=10.1074/jbc.270.8.3471 |doi-access=free }} *{{cite journal |vauthors=Platanias LC, Uddin S, Yetter A, etal |title=The type I interferon receptor mediates tyrosine phosphorylation of insulin receptor substrate 2. |journal=J. Biol. Chem. |volume=271 |issue= 1 |pages= 278–82 |year= 1996 |pmid= 8550573 |doi=10.1074/jbc.271.1.278 |doi-access=free }} *{{cite journal |vauthors=Beitner-Johnson D, Blakesley VA, Shen-Orr Z, etal |title=The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS. Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling. |journal=J. Biol. Chem. |volume=271 |issue= 16 |pages= 9287–90 |year= 1996 |pmid= 8621590 |doi= 10.1074/jbc.271.16.9287|doi-access=free }} *{{cite journal |vauthors=Sawka-Verhelle D, Tartare-Deckert S, White MF, Van Obberghen E |title=Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786. |journal=J. Biol. Chem. |volume=271 |issue= 11 |pages= 5980–3 |year= 1996 |pmid= 8626379 |doi=10.1074/jbc.271.11.5980 |doi-access=free }} *{{cite journal |vauthors=He W, Craparo A, Zhu Y, etal |title=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. |journal=J. Biol. Chem. |volume=271 |issue= 20 |pages= 11641–5 |year= 1996 |pmid= 8662806 |doi= 10.1074/jbc.271.20.11641|doi-access=free }} *{{cite journal |vauthors=Zhang WR, Li PM, Oswald MA, Goldstein BJ |title=Modulation of insulin signal transduction by eutopic overexpression of the receptor-type protein-tyrosine phosphatase LAR. |journal=Mol. Endocrinol. |volume=10 |issue= 5 |pages= 575–84 |year= 1996 |doi=10.1210/mend.10.5.8732688 |pmid= 8732688 |s2cid=42128485 |doi-access=free }} *{{cite journal |vauthors=Argetsinger LS, Norstedt G, Billestrup N, etal |title=Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling. |journal=J. Biol. Chem. |volume=271 |issue= 46 |pages= 29415–21 |year= 1997 |pmid= 8910607 |doi=10.1074/jbc.271.46.29415 |doi-access=free }} *{{cite journal |vauthors=Thiselton DL, Hampson RM, Nayudu M, etal |title=Mapping the RP2 locus for X-linked retinitis pigmentosa on proximal Xp: a genetically defined 5-cM critical region and exclusion of candidate genes by physical mapping. |journal=Genome Res. |volume=6 |issue= 11 |pages= 1093–102 |year= 1997 |pmid= 8938433 |doi=10.1101/gr.6.11.1093 |doi-access=free }} *{{cite journal |vauthors=Izuhara K, Harada N |title=Interleukin-4 activates two distinct pathways of phosphatidylinositol-3 kinase in the same cells. |journal=Biochem. Biophys. Res. Commun. |volume=229 |issue= 2 |pages= 624–9 |year= 1997 |pmid= 8954948 |doi= 10.1006/bbrc.1996.1854 }} *{{cite journal |vauthors=Vanhaesebroeck B, [[Melanie Welham|Welham MJ]], Kotani K, etal |title=P110delta, a novel phosphoinositide 3-kinase in leukocytes. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 9 |pages= 4330–5 |year= 1997 |pmid= 9113989 |doi=10.1073/pnas.94.9.4330 | pmc=20722 |bibcode=1997PNAS...94.4330V |doi-access=free }} *{{cite journal |vauthors=Sawka-Verhelle D, Baron V, Mothe I, etal |title=Tyr624 and Tyr628 in insulin receptor substrate-2 mediate its association with the insulin receptor. |journal=J. Biol. Chem. |volume=272 |issue= 26 |pages= 16414–20 |year= 1997 |pmid= 9195949 |doi=10.1074/jbc.272.26.16414 |doi-access=free }} *{{cite journal |vauthors=Algenstaedt P, Antonetti DA, Yaffe MB, Kahn CR |title=Insulin receptor substrate proteins create a link between the tyrosine phosphorylation cascade and the Ca2+-ATPases in muscle and heart. |journal=J. Biol. Chem. |volume=272 |issue= 38 |pages= 23696–702 |year= 1997 |pmid= 9295312 |doi=10.1074/jbc.272.38.23696 |doi-access=free }} {{refend}}