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Gene Review

INSR  -  insulin receptor

Homo sapiens

Synonyms: CD220, HHF5, IR, Insulin receptor
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Disease relevance of INSR


Psychiatry related information on INSR

  • CONCLUSION: LTPA appears to reduce the risk of IR and IGT, an effect which is not explained by the current level of physical activity, and only partially explained by the BMI history preceding and subsequent to the assessment of LTPA [6].
  • Abnormal insulin/IR levels and activities are seen in Alzheimer's dementia, whereas administration of insulin significantly improves the cognitive performance of these patients [7].
  • To determine the impact of the severity of depressive symptoms on the putative association between IR and depression in young adult males, we were given access to the Northern Finland 1966 Birth Cohort database [8].
  • Food deprivation induced a decrease in PTP1B and a trend toward lowered IR gene expression in LD but not in SD [9].
  • The goal of this study was to further explore potential mechanisms through which diabetogenic dietary conditions that result in promotion of insulin resistance (IR), a feature of non-insulin dependant diabetes mellitus (type-2 diabetes), may influence Alzheimer's disease (AD) [10].

High impact information on INSR

  • Here we demonstrate that alternative splicing of the insulin receptor (IR) pre-mRNA is aberrantly regulated in DM1 skeletal muscle tissue, resulting in predominant expression of the lower-signaling nonmuscle isoform (IR-A) [11].
  • Insulin stimulates the autophosphorylation of tyrosine residues of the beta subunit of the insulin receptor (IR); this modified insulin-independent kinase has increased activity toward exogenous substrates in vitro [12].
  • In vivo, these mutations not only result in a substantial decrease in insulin-stimulated IR autophosphorylation but also in a parallel decrease in the insulin-activated uptake of 2-deoxyglucose [12].
  • The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man [13].
  • Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity [14].

Chemical compound and disease context of INSR

  • Via activation of the IR tyrosine kinase IGF-II stimulated breast cancer cell growth [15].
  • AIMS/HYPOTHESIS: We examined the properties of a mutant insulin receptor (IR) with an Arg(252) to Cys (IR(R252C)) substitution in the alpha-subunit originally identified in a patient with extreme insulin resistance and acanthosis nigricans [16].
  • Furthermore, antagonists to the RTKs that are endogenously expressed in C6 glioma cells (insulin receptor (IR) and platelet-derived growth factor receptor (PDGFR)) were unable to reduce opioid-mediated ERK activation [17].
  • 3. A marked association was observed between hypertension and insertion alleles of polymorphisms of the insulin receptor gene (INSR) (P < 0.0040) and the dipeptidyl carboxypeptidase-1 (angiotensin I-converting enzyme; kininase II) gene (DCP1) (P < 0.0018) [18].
  • Since the main site of insulin resistance in hypertension is glycogen synthesis in skeletal muscle, genes that encode molecules involved in this pathway, i.e. insulin receptor (INSR), insulin-responsive glucose transporter (GLUT4) and glycogen synthase (GSY), were studied [19].

Biological context of INSR

  • The human insulin receptor gene, INSR, and its promoter region have been isolated and characterized [20].
  • INSR gene mutations have been described in multiple individuals with extreme insulin resistance, but the INSR gene has not been implicated in familial NIDDM [21].
  • Pedigree members were typed for presence or absence of the Met985 substitution by hybridization of PCR-amplified exon 17 DNA to allele-specific oligonucleotide probes, and typing was confirmed by segregation of INSR haplotypes and by SSCP analysis [21].
  • We previously have screened members of 18 familial NIDDM pedigrees for mutations in exons encoding the tyrosine kinase domain of the INSR gene (exons 13-21) by SSCP [21].
  • Using a cloned gene probe for INSR, we have studied its linkage relationships with the DM locus and other chromosome 19 markers [3].

Anatomical context of INSR


Associations of INSR with chemical compounds

  • Genotypes for insulin hypervariable region (HVR), insulin-like growth factor II (IGF2), insulin receptor (INSR), and glucose transporter (GLUT1) RFLPs were studied in 96 GDM and 164 control subjects, matched to GDM for race, age, and gravidity [4].
  • Insulin receptor and insulin receptor substrate (IRS)-1 serine hyperphosphorylation by an unidentified kinase(s) contributes to this defect [25].
  • Previous data suggest that IR-mediated serine/threonine phosphorylation of the Ras guanine nucleotide exchange factor Sos correlates with its decreased affinity for the adapter protein Grb2 [26].
  • Alanine substitution for the positively charged residues in the C- and D-regions of IGF-1 led to 15- and 10-fold losses, respectively, in binding potency for the human IGF-1R, but they increased the potency of binding to the human IR 29- and 6-fold, respectively [27].
  • The effect of metformin was completely blocked by an IR inhibitor [28].

Physical interactions of INSR

  • In this study, we used the sensitive two-hybrid assay of protein-protein interaction to demonstrate that SHC interacts directly with the IR [29].
  • Here we demonstrate the existence of a second novel domain within Grb10 that interacts with the IR and insulin-like growth factor receptor in a kinase-dependent manner [30].
  • Coimmunoprecipitation experiments and in vitro binding assays demonstrated that FLNa binds constitutively to IR and that neither insulin nor depolymerization of actin by cytochalasin D affected this interaction [31].
  • However, 55PIK and SOCS-2 also interact with the IR in the yeast two hybrid system [32].
  • Lastly, we show that hMAD2 can be coimmunoprecipitated with the IR from Chinese hamster ovary IR cell lysates, suggesting that this interaction occurs in vivo in cells of mammalian origin [33].

Enzymatic interactions of INSR

  • We found that the SH2 domain of CSK binds to the tyrosine-phosphorylated form of IGF-IR and IR [34].
  • We found that IR can directly phosphorylate FRS2 [35].
  • Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro [36].
  • These results suggest that PTP-1B appears not only to interact with and dephosphorylate the insulin-stimulated IR in a perinuclear endosome compartment but is also involved in maintaining the IR in a dephosphorylated state during its biosynthesis [37].
  • Insulin receptor beta subunit autophosphorylation occurs in an intramolecular trans-reaction in which one beta subunit phosphorylates the adjacent beta subunit within an alpha 2 beta 2 holoreceptor complex (Frattali, A. L., Treadway, J. L., and Pessin, J. E. (1992) J. Biol. Chem. 267, 19521-19528) [38].

Regulatory relationships of INSR


Other interactions of INSR

  • The SHC proteins have been implicated in insulin receptor (IR) signaling [29].
  • In cultured breast cancer cells and human breast cancer specimens, the expression of AP-2 was significantly higher than that observed in cells and tissues derived from normal breast, and this overexpression paralleled the increase in IR expression [43].
  • The interaction of this protein with the IR has been shown to be mediated in part by the Src homology 2 (SH2) domain of Grb10 [30].
  • We observed that the IGF-IR and IR associated with the C-terminal Src kinase (CSK) following ligand stimulation [34].
  • Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism [15].

Analytical, diagnostic and therapeutic context of INSR


  1. Antisense gene therapy of brain cancer with an artificial virus gene delivery system. Zhang, Y., Zhu, C., Pardridge, W.M. Mol. Ther. (2002) [Pubmed]
  2. Mapping of the 19p13 breakpoint in an ovarian carcinoma between the INSR and TCF3 loci. Aman, P., Pejovic, T., Wennborg, A., Heim, S., Mitelman, F. Genes Chromosomes Cancer (1993) [Pubmed]
  3. Linkage relationships of the insulin receptor gene with the complement component 3, LDL receptor, apolipoprotein C2 and myotonic dystrophy loci on chromosome 19. Shaw, D.J., Meredith, A.L., Brook, J.D., Sarfarzi, M., Harley, H.G., Huson, S.M., Bell, G.I., Harper, P.S. Hum. Genet. (1986) [Pubmed]
  4. Increased risk for gestational diabetes mellitus associated with insulin receptor and insulin-like growth factor II restriction fragment length polymorphisms. Ober, C., Xiang, K.S., Thisted, R.A., Indovina, K.A., Wason, C.J., Dooley, S. Genet. Epidemiol. (1989) [Pubmed]
  5. Human genome--chromosome no. 19. Sokol, L., Prchal, J.T. Cas. Lek. Cesk. (1995) [Pubmed]
  6. Long-term effects of leisure time physical activity on risk of insulin resistance and impaired glucose tolerance, allowing for body weight history, in Danish men. Berentzen, T., Petersen, L., Pedersen, O., Black, E., Astrup, A., Sørensen, T.I. Diabet. Med. (2007) [Pubmed]
  7. Role of insulin and insulin receptor in learning and memory. Zhao, W.Q., Alkon, D.L. Mol. Cell. Endocrinol. (2001) [Pubmed]
  8. Depressive symptoms and insulin resistance in young adult males: results from the Northern Finland 1966 birth cohort. Timonen, M., Rajala, U., Jokelainen, J., Kein??nen-Kiukaanniemi, S., Meyer-Rochow, V.B., R??s??nen, P. Mol. Psychiatry (2006) [Pubmed]
  9. Photoperiodic regulation of insulin receptor mRNA and intracellular insulin signaling in the arcuate nucleus of the Siberian hamster, Phodopus sungorus. Tups, A., Helwig, M., Stöhr, S., Barrett, P., Mercer, J.G., Klingenspor, M. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2006) [Pubmed]
  10. Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance- associated promotion of Alzheimer's disease beta-amyloid neuropathology. Zhao, Z., Ho, L., Wang, J., Qin, W., Festa, E.D., Mobbs, C., Hof, P., Rocher, A., Masur, S., Haroutunian, V., Pasinetti, G.M. FASEB J. (2005) [Pubmed]
  11. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Savkur, R.S., Philips, A.V., Cooper, T.A. Nat. Genet. (2001) [Pubmed]
  12. Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucose. Ellis, L., Clauser, E., Morgan, D.O., Edery, M., Roth, R.A., Rutter, W.J. Cell (1986) [Pubmed]
  13. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. Kahn, C.R., Flier, J.S., Bar, R.S., Archer, J.A., Gorden, P., Martin, M.M., Roth, J. N. Engl. J. Med. (1976) [Pubmed]
  14. Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Foti, D., Chiefari, E., Fedele, M., Iuliano, R., Brunetti, L., Paonessa, F., Manfioletti, G., Barbetti, F., Brunetti, A., Croce, C.M., Fusco, A., Brunetti, A. Nat. Med. (2005) [Pubmed]
  15. Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism. Sciacca, L., Costantino, A., Pandini, G., Mineo, R., Frasca, F., Scalia, P., Sbraccia, P., Goldfine, I.D., Vigneri, R., Belfiore, A. Oncogene (1999) [Pubmed]
  16. An arginine to cysteine(252) mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events. Hamer, I., Foti, M., Emkey, R., Cordier-Bussat, M., Philippe, J., De Meyts, P., Maeder, C., Kahn, C.R., Carpentier, J.L. Diabetologia (2002) [Pubmed]
  17. Delta opioid activation of the mitogen-activated protein kinase cascade does not require transphosphorylation of receptor tyrosine kinases. Kramer, H.K., Onoprishvili, I., Andria, M.L., Hanna, K., Sheinkman, K., Haddad, L.B., Simon, E.J. BMC Pharmacol. (2002) [Pubmed]
  18. Independent, marked associations of alleles of the insulin receptor and dipeptidyl carboxypeptidase-I genes with essential hypertension. Morris, B.J., Zee, R.Y., Ying, L.H., Griffiths, L.R. Clin. Sci. (1993) [Pubmed]
  19. Analysis of candidate genes for insulin resistance in essential hypertension. Ikegami, H., Yamato, E., Fujisawa, T., Hamada, Y., Fujioka, Y., Rakugi, H., Higaki, J., Murakami, H., Shimamoto, K., Ogihara, T. Hypertens. Res. (1996) [Pubmed]
  20. Structure of the human insulin receptor gene and characterization of its promoter. Seino, S., Seino, M., Nishi, S., Bell, G.I. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  21. Methionine for valine substitution in exon 17 of the insulin receptor gene in a pedigree with familial NIDDM. Elbein, S.C., Sorensen, L.K., Schumacher, M.C. Diabetes (1993) [Pubmed]
  22. Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. Goodyear, L.J., Giorgino, F., Sherman, L.A., Carey, J., Smith, R.J., Dohm, G.L. J. Clin. Invest. (1995) [Pubmed]
  23. Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3-kinase. Mèndez, R., Myers, M.G., White, M.F., Rhoads, R.E. Mol. Cell. Biol. (1996) [Pubmed]
  24. Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Schnarr, B., Strunz, K., Ohsam, J., Benner, A., Wacker, J., Mayer, D. Int. J. Cancer (2000) [Pubmed]
  25. Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome. Corbould, A., Zhao, H., Mirzoeva, S., Aird, F., Dunaif, A. Diabetes (2006) [Pubmed]
  26. Insulin receptor-mediated dissociation of Grb2 from Sos involves phosphorylation of Sos by kinase(s) other than extracellular signal-regulated kinase. Zhao, H., Okada, S., Pessin, J.E., Koretzky, G.A. J. Biol. Chem. (1998) [Pubmed]
  27. Positively charged side chains in the insulin-like growth factor-1 C- and D-regions determine receptor binding specificity. Zhang, W., Gustafson, T.A., Rutter, W.J., Johnson, J.D. J. Biol. Chem. (1994) [Pubmed]
  28. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. Gunton, J.E., Delhanty, P.J., Takahashi, S., Baxter, R.C. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  29. Phosphotyrosine-dependent interaction of SHC and insulin receptor substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 domain. Gustafson, T.A., He, W., Craparo, A., Schaub, C.D., O'Neill, T.J. Mol. Cell. Biol. (1995) [Pubmed]
  30. Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains. He, W., Rose, D.W., Olefsky, J.M., Gustafson, T.A. J. Biol. Chem. (1998) [Pubmed]
  31. Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway. He, H.J., Kole, S., Kwon, Y.K., Crow, M.T., Bernier, M. J. Biol. Chem. (2003) [Pubmed]
  32. Differential regulation of signaling pathways for insulin and insulin-like growth factor I. Lopaczynski, W. Acta Biochim. Pol. (1999) [Pubmed]
  33. Interaction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR. Evidence for release from the insulin receptor after activation. O'Neill, T.J., Zhu, Y., Gustafson, T.A. J. Biol. Chem. (1997) [Pubmed]
  34. C-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-I receptor. Arbet-Engels, C., Tartare-Deckert, S., Eckhart, W. J. Biol. Chem. (1999) [Pubmed]
  35. Potential involvement of FRS2 in insulin signaling. Delahaye, L., Rocchi, S., Van Obberghen, E. Endocrinology (2000) [Pubmed]
  36. Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro. Maegawa, H., Ugi, S., Adachi, M., Hinoda, Y., Kikkawa, R., Yachi, A., Shigeta, Y., Kashiwagi, A. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
  37. Protein tyrosine phosphatase-1B dephosphorylation of the insulin receptor occurs in a perinuclear endosome compartment in human embryonic kidney 293 cells. Romsicki, Y., Reece, M., Gauthier, J.Y., Asante-Appiah, E., Kennedy, B.P. J. Biol. Chem. (2004) [Pubmed]
  38. Relationship between alpha subunit ligand occupancy and beta subunit autophosphorylation in insulin/insulin-like growth factor-1 hybrid receptors. Frattali, A.L., Pessin, J.E. J. Biol. Chem. (1993) [Pubmed]
  39. Correlation of type I insulin-like growth factor receptor (IGF-I-R) and insulin receptor-related receptor (IRR) messenger RNA levels in tumor cell lines from pediatric tumors of neuronal origin. Elmlinger, M.W., Rauschnabel, U., Koscielniak, E., Haenze, J., Ranke, M.B., Berthold, A., Klammt, J., Kiess, W. Regul. Pept. (1999) [Pubmed]
  40. Alpha 1,3-fucosyltransferase-VII regulates the signaling molecules of the insulin receptor pathway. Wang, Q.Y., Zhang, Y., Chen, H.J., Shen, Z.H., Chen, H.L. FEBS J. (2007) [Pubmed]
  41. Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. Maddux, B.A., Goldfine, I.D. Diabetes (2000) [Pubmed]
  42. Inhibition of insulin receptor catalytic activity by the molecular adapter Grb14. Béréziat, V., Kasus-Jacobi, A., Perdereau, D., Cariou, B., Girard, J., Burnol, A.F. J. Biol. Chem. (2002) [Pubmed]
  43. Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer. Paonessa, F., Foti, D., Costa, V., Chiefari, E., Brunetti, G., Leone, F., Luciano, F., Wu, F., Lee, A.S., Gulletta, E., Fusco, A., Brunetti, A. Cancer Res. (2006) [Pubmed]
  44. A C/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovary syndrome. Siegel, S., Futterweit, W., Davies, T.F., Concepcion, E.S., Greenberg, D.A., Villanueva, R., Tomer, Y. Fertil. Steril. (2002) [Pubmed]
  45. Insulin and epidermal growth factor receptors contain the cysteine repeat motif found in the tumor necrosis factor receptor. Ward, C.W., Hoyne, P.A., Flegg, R.H. Proteins (1995) [Pubmed]
  46. Substitution of Leu for Pro-193 in the insulin receptor in a patient with a genetic form of severe insulin resistance. Carrera, P., Cordera, R., Ferrari, M., Cremonesi, L., Taramelli, R., Andraghetti, G., Carducci, C., Dozio, N., Pozza, G., Taylor, S.I. Hum. Mol. Genet. (1993) [Pubmed]
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