Skip to main content
SpringerLink
Log in

The INSR/IGF1R Receptor Family

  • Chapter
Receptor Tyrosine Kinases: Family and Subfamilies

Abstract

The insulin/insulin-like growth factors (IGFs) constitute a network of ligands, cell-surface receptors, and binding proteins involved in the regulation of multiple physiological and pathological processes, including metabolic, nutritional, growth, and aging events. Although the insulin receptor (INSR) and IGF1 receptor (IGF1R) share the vast majority of their downstream cytoplasmic mediators, most evidence is consistent with the notion that INSR activation (mainly by insulin) leads primarily to metabolic activities, whereas IGF1R activation (mainly by IGF1 or IGF2) leads to proliferative and differentiative events. INSR/IGF1R receptors display a remarkable similarity in genomic organization. Thus, 12 exons of the IGF1R gene are identical in size with the homologous exons of INSR, the main difference being that the IGF1R gene does not contain an equivalent of the alternatively spliced INSR exon 11. This splicing event leads to the generation of two isoforms, INSR-A and INSR-B, which lack or contain, respectively, exon 11. Overexpression of the IGF1R constitutes a typical hallmark of most types of cancer. The IGF1R exhibits a potent anti-apoptotic activity which confers upon IGF1R-expressing cells enhanced survivability, a key hallmark of cancer cells. The IGF1R emerged in recent years as a promising therapeutic target in cancer. Likewise, INSR-A seems to play an important role in proliferation and recent studies have established a role for this specific isoform in breast cancer etiology. The recognition that the INSR-A isoform is an important player in breast cancer might imply that dual (i.e., INSR and IGF1R) targeted therapy offers advantages over single receptor targeting.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hwa V, Tomasini-Sprenger C, Bermejo AL, Rosenfeld RG, Plymate SR. Characterization of insulin-like growth factor-binding protein-related protein-1 in prostate cells. J Clin Endocrinol Metab. 1998;83:4355–62.

    CAS  PubMed  Google Scholar 

  2. Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev. 2009;30:586–623.

    Article  CAS  PubMed  Google Scholar 

  3. Sandhu MS, Luben R, Day NE, Khaw KT. Self-reported birth weight and subsequent risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2002;11:935–8.

    PubMed  Google Scholar 

  4. Werner H, Bruchim I. Basic and clinical significance of IGF-I-induced signatures in cancer. BMC Med. 2010;8:2.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Frasca F, Pandini G, Scalia R, Sciacca L, Mineo R, Constantino A, et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol. 1999;19:3278–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Sarfstein R, Maor S, Reizner N, Abramovitch S, Werner H. Transcriptional regulation of the insulin-like growth factor-I receptor gene in breast cancer. Mol Cell Endocrinol. 2006; 252:241–6.

    Article  CAS  PubMed  Google Scholar 

  7. Werner H, Woloschak M, Adamo M, Shen-Orr Z, Roberts Jr CT, LeRoith D. Developmental regulation of the rat insulin-like growth factor I receptor gene. Proc Natl Acad Sci USA. 1989;86:7451–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Belfiore A. The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des. 2007;13:671–86.

    Article  CAS  PubMed  Google Scholar 

  9. Denley A, Wallace JC, Cosgrove LJ, Forbes BE. The insulin receptor isoform exon 11- (IR-A) in cancer and other diseases: a review. Horm Metab Res. 2003;35:778–85.

    Article  CAS  PubMed  Google Scholar 

  10. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505–18.

    Article  CAS  PubMed  Google Scholar 

  11. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569–78.

    Article  PubMed  Google Scholar 

  12. Venkateswaran V, Haddad AQ, Fleshner NE, Fan R, Sugar LM, Nam R, et al. Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts. J Natl Cancer Inst. 2007;99:1793–800.

    Article  PubMed  Google Scholar 

  13. Pandini G, Wurch T, Akla B, Corvaia N, Belfiore A, Goetsch L. Functional responses and in vivo anti-tumour activity of h7C10: a humanised monoclonal antibody with neutralising activity against the insulin-like growth factor-1 (IGF-1) receptor and insulin/IGF-1 hybrid receptors. Eur J Cancer. 2007;43:1318–27.

    Article  CAS  PubMed  Google Scholar 

  14. Werner H. Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer. Oncogene. 2012;31:2703–14.

    Article  CAS  PubMed  Google Scholar 

  15. Harrington EA, Bennett MR, Fanidi A, Evan GI. c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J. 1994;13:3286–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. O’Connor R, Kauffmann-Zeh A, Liu Y, Lehar S, Evan GI, Baserga R, et al. Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis. Mol Cell Biol. 1997;17:427–35.

    PubMed Central  PubMed  Google Scholar 

  17. Resnicoff M, Abraham D, Yutanawiboonchai W, Rotman HL, Kajstura J, Rubin R, et al. The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo. Cancer Res. 1995;55:2463–9.

    CAS  PubMed  Google Scholar 

  18. Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R. Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc Natl Acad Sci USA. 1993;90:11217–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Sell C, Dumenil G, Deveaud C, Miura M, Coppola D, DeAngelis T, et al. Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol Cell Biol. 1994;14:3604–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Bentov I, Werner H. IGF, IGF receptor and overgrowth syndromes. Pediatr Endocrinol Rev. 2004;1:352–60.

    PubMed  Google Scholar 

  21. Christofori G, Naik P, Hanahan D. A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature. 1994;369:414–8.

    Article  CAS  PubMed  Google Scholar 

  22. Bruchim I, Attias Z, Werner H. Targeting the IGF1 axis in cancer proliferation. Expert Opin Ther Targets. 2009;13:1179–92.

    Article  CAS  PubMed  Google Scholar 

  23. Scotlandi K, Picci P. Targeting insulin-like growth factor 1 receptor in sarcomas. Curr Opin Oncol. 2008;20:419–27.

    Article  CAS  PubMed  Google Scholar 

  24. Yuen JSP, Macaulay VM. Targeting the type 1 insulin-like growth factor receptor as a treatment for cancer. Expert Opin Ther Targets. 2008;12:589–603.

    Article  CAS  PubMed  Google Scholar 

  25. Gualberto A, Pollak M. Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene. 2009; 28: 3009–21.

    Article  CAS  PubMed  Google Scholar 

  26. Belfiore A, Frasca F. IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:381–406.

    Article  PubMed  Google Scholar 

  27. Araki E, Shichiri M. Characterization and expression of the insulin receptor gene and its promoter. Nihon Rinsho. 1994;52:2623–8.

    CAS  PubMed  Google Scholar 

  28. Seino S, Seino M, Nishi S, Bell GI. Structure of the human insulin receptor gene and characterization of its promoter. Proc Natl Acad Sci USA. 1989;86:114–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Webster NJ, Resnik JL, Reichart DB, Strauss B, Haas M, Seely BL. Repression of the insulin receptor promoter by the tumor suppressor gene product p53: a possible mechanism for receptor overexpression in breast cancer. Cancer Res. 1996;56:2781–8.

    CAS  PubMed  Google Scholar 

  30. Mamula PW, Wong KY, Maddux BA, McDonald AR, Goldfine ID. Sequence and analysis of promoter region of human insulin-receptor gene. Diabetes. 1988;37:1241–6.

    Article  CAS  PubMed  Google Scholar 

  31. McKeon C, Moncada V, Pham T, Salvatore P, Kadowaki T, Accili D, et al. Structural and functional analysis of the insulin receptor promoter. Mol Endocrinol. 1990;4:647–56.

    Article  CAS  PubMed  Google Scholar 

  32. Tewari DS, Cook DM, Taub R. Characterization of the promoter region and 3′ end of the human insulin receptor gene. J Biol Chem. 1989;264:16238–45.

    CAS  PubMed  Google Scholar 

  33. Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, et al. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature. 1985;313:756–61.

    Article  CAS  PubMed  Google Scholar 

  34. Zick Y. The insulin receptor: structure and function. Crit Rev Biochem Mol Biol. 1989; 24:217–69.

    Article  CAS  PubMed  Google Scholar 

  35. Finn FM, Ridge KD, Hofmann K. Labile disulfide bonds in human placental insulin receptor. Proc Natl Acad Sci USA. 1990;87:419–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Olson TS, Bamberger MJ, Lane MD. Post-translational changes in tertiary and quaternary structure of the insulin proreceptor. Correlation with acquisition of function. J Biol Chem. 1988;263:7342–51.

    CAS  PubMed  Google Scholar 

  37. Cosgrove L, Lovrecz GO, Verkuylen A, Cavaleri L, Black LA, Bentley JD, et al. Purification and properties of insulin receptor ectodomain from large-scale mammalian cell culture. Protein Expr Purif. 1995;6:789–98.

    Article  CAS  PubMed  Google Scholar 

  38. Adams TE, Epa VC, Garrett TP, Ward CW. Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci. 2000;57:1050–93.

    Article  CAS  PubMed  Google Scholar 

  39. White MF, Kahn CR. The insulin signaling system. J Biol Chem. 1994;269:1–4.

    CAS  PubMed  Google Scholar 

  40. Bandyopadhyay D, Kusari A, Kenner KA, Liu F, Chernoff J, Gustafson TA, et al. Protein-tyrosine phosphatase 1B complexes with the insulin receptor in vivo and is tyrosine-phosphorylated in the presence of insulin. J Biol Chem. 1997;272:1639–45.

    Article  CAS  PubMed  Google Scholar 

  41. Dickens M, Tavare JM. Analysis of the order of autophosphorylation of human insulin receptor tyrosines 1158, 1162 and 1163. Biochem Biophys Res Commun. 1992;186:244–50.

    Article  CAS  PubMed  Google Scholar 

  42. Mosthaf L, Grako K, Dull TJ, Coussens L, Ullrich A, McClain DA. Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J. 1990;9:2409–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Tavare JM, Denton RM. Studies on the autophosphorylation of the insulin receptor from human placenta. Analysis of the sites phosphorylated by two-dimensional peptide mapping. Biochem J. 1988;252:607–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Sarfstein R, Pasmanik-Chor M, Yeheskel A, Edry L, Shomron N, Warman N, et al. Insulin-like growth factor-I receptor (IGF-IR) translocates to nucleus and autoregulates IGF-IR gene expression in breast cancer cells. J Biol Chem. 2012;287:2766–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Hay RT. SUMO: a history of modification. Mol Cell. 2005;18:1–12.

    Article  CAS  PubMed  Google Scholar 

  46. Ahmed Z, Smith BJ, Kotani K, Wilden P, Pillay TS. APS, an adapter protein with a PH and SH2 domain, is a substrate for the insulin receptor kinase. Biochem J. 1999;341:665–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Ahmed Z, Smith B, Pillay TS. The APS adapter protein couples the insulin receptor to the phosphorylation of c-Cbl and facilitates ligand-stimulated ubiquitination of the insulin receptor. FEBS Lett. 2000;475:31–4.

    Article  CAS  PubMed  Google Scholar 

  48. Zheng N, Wang P, Jeffrey PD, Pavletich NP. Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell. 2000;102:533–9.

    Article  CAS  PubMed  Google Scholar 

  49. Hedo JA, Collier E, Watkinson A. Myristyl and palmityl acylation of the insulin receptor. J Biol Chem. 1987;262:954–7.

    CAS  PubMed  Google Scholar 

  50. Feener EP, Backer JM, King GL, Wilden PA, Sun XJ, Kahn CR, et al. Insulin stimulates serine and tyrosine phosphorylation in the juxtamembrane region of the insulin receptor. J Biol Chem. 1993;268:11256–64.

    CAS  PubMed  Google Scholar 

  51. Tavare JM, O’Brien RM, Siddle K, Denton RM. Analysis of insulin-receptor phosphorylation sites in intact cells by two-dimensional phosphopeptide mapping. Biochem J. 1988;253:783–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Tornqvist HE, Pierce MW, Frackelton AR, Nemenoff RA, Avruch J. Identification of insulin receptor tyrosine residues autophosphorylated in vitro. J Biol Chem. 1987;262:10212–9.

    CAS  PubMed  Google Scholar 

  53. Ando A, Momomura K, Tobe K, Yamamoto-Honda R, Sakura H, Tamori Y, et al. Enhanced insulin-induced mitogenesis and mitogen-activated protein kinase activities in mutant insulin receptors with substitution of two COOH-terminal tyrosine autophosphorylation sites by phenylalanine. J Biol Chem. 1992;267:12788–96.

    CAS  PubMed  Google Scholar 

  54. Maegawa H, McClain DA, Freidenberg G, Olefsky JM, Napier M, Lipari T, et al. Properties of a human insulin receptor with a COOH-terminal truncation. II. Truncated receptors have normal kinase activity but are defective in signaling metabolic effects. J Biol Chem. 1988;263:8912–7.

    CAS  PubMed  Google Scholar 

  55. McClain DA, Maegawa H, Levy J, Huecksteadt T, Dull TJ, Lee J, et al. Properties of a human insulin receptor with a COOH-terminal truncation. I. Insulin binding, autophosphorylation, and endocytosis. J Biol Chem. 1988;263:8904–11.

    CAS  PubMed  Google Scholar 

  56. Myers MG, Backer JM, Siddle K, White MF. The insulin receptor functions normally in Chinese hamster ovary cells after truncation of the C terminus. J Biol Chem. 1991; 266:10616–23.

    CAS  PubMed  Google Scholar 

  57. White MF, Livingston JN, Backer JM, Lauris V, Dull TJ, Ullrich A, et al. Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell. 1988;54:641–9.

    Article  CAS  PubMed  Google Scholar 

  58. Katzen HM, Stetten Jr D. Hepatic glutathione-insulin transhydrogenase. Diabetes. 1962;11:271–80.

    CAS  PubMed  Google Scholar 

  59. Varandani PT, Shroyer LA, Nafz MA. Sequential degradation of insulin by rat liver homogenates. Proc Natl Acad Sci USA. 1972;69:1681–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Brush JS. Purification and characterization of a protease with specificity for insulin from rat muscle. Diabetes. 1971;20:140–5.

    Article  CAS  Google Scholar 

  61. Duckworth WC, Heinemann MA, Kitabchi AE. Purification of insulin-specific protease by affinity chromatography. Proc Natl Acad Sci USA. 1972;69:3698–702.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Morrione A, Valentinis B, Xu SQ, Yumet G, Louvi A, Efstratiadis A, et al. Insulin-like growth factor II stimulates cell proliferation through the insulin receptor. Proc Natl Acad Sci USA. 1997;94:3777–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Bailyes EM, Nave BT, Soos MA, Orr SR, Hayward AC, Siddle K. Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: quantification of individual receptor species by selective immunoprecipitation and immunoblotting. Biochem J. 1997; 327:209–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Federici M, Porzio O, Zucaro L, Giovannone B, Borboni P, Marini MA, et al. Increased abundance of insulin/IGF-I hybrid receptors in adipose tissue from NIDDM patients. Mol Cell Endocrinol. 1997;135:41–7.

    Article  CAS  PubMed  Google Scholar 

  65. Baserga R. The decline and fall of the IGF-I receptor. J Cell Physiol. 2013;228:675–9.

    Article  CAS  PubMed  Google Scholar 

  66. Sandhu MS, Dunger DB, Giovannucci EL. Insulin, insulin-like growth factor-I, IGF binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst. 2002;94:972–80.

    Article  CAS  PubMed  Google Scholar 

  67. Bevan P. Insulin signalling. J Cell Sci. 2001;114:1429–30.

    CAS  PubMed  Google Scholar 

  68. Cohen P. The twentieth century struggle to decipher insulin signalling. Nat Rev Mol Cell Biol. 2006;7:867–73.

    Article  CAS  PubMed  Google Scholar 

  69. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7:85–96.

    Article  CAS  PubMed  Google Scholar 

  70. Talbot K, Wang H-Y, Kazi H, Han L-Y, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122:1316–38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12:159–69.

    CAS  PubMed  Google Scholar 

  72. Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Gen. 2002;11:1465–75.

    Article  CAS  PubMed  Google Scholar 

  73. Abbott AM, Bueno R, Pedrini MT, Murray JM, Smith RJ. Insulin-like growth factor I receptor gene structure. J Biol Chem. 1992;267:10759–63.

    CAS  PubMed  Google Scholar 

  74. Lowe Jr WL, Adamo M, Werner H, Roberts Jr CT, LeRoith D. Regulation by fasting of rat insulin-like growth factor I and its receptor. Effects on gene expression and binding. J Clin Invest. 1989;84:619–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, et al. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J. 1986;5:2503–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Werner H, Woloschak M, Stannard B, Shen-Orr Z, Roberts Jr CT, LeRoith D. Insulin-like growth factor receptor: molecular biology, heterogeneity, and regulation. In: LeRoith D, editor. Insulin-like growth factors: molecular and cellular aspects. Boca Raton, FL: CRC Press; 1991. p. 17–47.

    Google Scholar 

  77. Werner H, Bach MA, Stannard B, Roberts Jr CT, LeRoith D. Structural and functional analysis of the insulin-like growth factor I receptor gene promoter. Mol Endocrinol. 1992;6:1545–58.

    CAS  PubMed  Google Scholar 

  78. Sarfstein R, Belfiore A, Werner H. Identification of IGFR gene promoter binding proteins in estrogen receptor positive and ER-depleted breast cancer cells. Cancers. 2010;2:233–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Werner H, Bruchim I. IGF-1 and BRCA1 signalling pathways in familial cancer. Lancet Oncol. 2012;13:e537–44.

    Article  CAS  PubMed  Google Scholar 

  80. Werner H, Karnieli E, Rauscher FJ, LeRoith D. Wild-type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. Proc Natl Acad Sci USA. 1996;93:8318–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Yuen JSP, Cockman ME, Sullivan M, Protheroe A, Turner GDH, Roberts IS, et al. The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma. Oncogene. 2007;26:6499–508.

    Article  CAS  PubMed  Google Scholar 

  82. Boone DN, Lee AV. Targeting the insulin-like growth factor receptor: developing biomarkers from gene expression profiling. Crit Rev Oncog. 2012;17:161–73.

    Article  PubMed Central  PubMed  Google Scholar 

  83. Andersen AS, Kjeldsen T, Wiberg FC, Christensen PM, Rasmussen JS, Norris K, et al. Changing the insulin receptor to possess insulin-like growth factor I ligand specificity. Biochemistry. 1990;29:7363–6.

    Article  CAS  PubMed  Google Scholar 

  84. Kjeldsen T, Andersen AS, Wiberg FC, Rasmussen JS, Schäffer L, Balschmidt P, et al. The ligand specificities of the insulin receptor and the insulin-like growth factor I receptor reside in different regions of a common binding site. Proc Natl Acad Sci USA. 1991;88:4404–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. LeRoith D, Werner H, Beitner-Johnson D, Roberts Jr CT. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 1995;16:143–63.

    Article  CAS  PubMed  Google Scholar 

  86. Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988;241:42–52.

    Article  CAS  PubMed  Google Scholar 

  87. Favelyukis S, Till JH, Hubbard SR, Miller WT. Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Biol. 2001;8:1058–63.

    Article  CAS  PubMed  Google Scholar 

  88. Lopaczynski W, Terry C, Nissley P. Autophosphorylation of the insulin-like growth factor I receptor cytoplasmic domain. Biochem Biophys Res Commun. 2000;279:955–60.

    Article  CAS  PubMed  Google Scholar 

  89. Pautsch A, Zoephel A, Ahorn H, Spevak W, Hauptmann R, Nar H. Crystal structure of bisphosphorylated IGF-1 receptor kinase: insight into domain movements upon kinase activation. Structure. 2001;9:955–65.

    Article  CAS  PubMed  Google Scholar 

  90. Tollefsen SE, Stoszek RM, Thompson K. Interaction of the alpha beta dimers of the insulin-like growth factor I receptor is required for receptor autophosphorylation. Biochemistry. 1991;30:48–54.

    Article  CAS  PubMed  Google Scholar 

  91. Sehat B, Tofigh A, Lin Y, Trocme E, Liljedahl U, Lagergren J, et al. SUMOylation mediates the nuclear translocation and signaling of the IGF-1 receptor. Sci Signal. 2010;3:ra10.

    Article  PubMed  CAS  Google Scholar 

  92. Girnita L, Girnita A, Larsson O. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci USA. 2003;100:8247–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Sehat B, Andersson S, Girnita L, Larsson O. Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis. Cancer Res. 2008;68:5669–77.

    Article  CAS  PubMed  Google Scholar 

  94. Vecchione A, Marchese A, Henry P, Rotin D, Morrione A. The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol Cell Biol. 2003;23:3363–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Mao Y, Shang Y, Pham VC, Ernst JA, Lill JR, Scales SJ, et al. Polyubiquitination of insulin-like growth factor I receptor (IGF-IR) activation loop promotes antibody-induced receptor internalization and down-regulation. J Biol Chem. 2011;286:41852–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Gronborg M, Wulff BS, Rasmussen JS, Kjeldsen T, Gammeltoft S. Structure-function relationship of the insulin-like growth factor-I receptor tyrosine kinase. J Biol Chem. 1993;268:23435–40.

    CAS  PubMed  Google Scholar 

  97. Hernandez-Sanchez C, Blakesley V, Kalebic T, Helman L, LeRoith D. The role of the tyrosine kinase domain of the insulin-like growth factor-I receptor in intracellular signaling, cellular proliferation, and tumorigenesis. J Biol Chem. 1995;270:29176–81.

    Article  CAS  PubMed  Google Scholar 

  98. Baserga R. The IGF-I receptor in cancer research. Exp Cell Res. 1999;253:1–6.

    Article  CAS  PubMed  Google Scholar 

  99. Baserga R. Insulin-like growth factor I receptor signalling in prostate cancer cells. Growth Horm IGF Res. 2000;10(Suppl A):S43–4.

    Article  PubMed  Google Scholar 

  100. LeRoith D, Werner H, Neuenschwander S, Kalebic T, Helman LJ. The role of the insulin-like growth factor-I receptor in cancer. Ann NY Acad Sci. 1995;766:402–8.

    Article  CAS  PubMed  Google Scholar 

  101. Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000;92:1472–89.

    Article  CAS  PubMed  Google Scholar 

  102. Chan SJ, Nagamatsu S, Cao QP, Steiner DF. Structure and evolution of insulin and insulin-like growth factors in chordates. Prog Brain Res. 1992;92:15–24.

    Article  CAS  PubMed  Google Scholar 

  103. Werner H, LeRoith D. The role of the insulin-like growth factor system in human cancer. Adv Cancer Res. 1996;68:183–223.

    Article  CAS  PubMed  Google Scholar 

  104. Rosenblum JS, Kozarich JW. Prolyl peptidases: a serine protease subfamily with high potential for drug discovery. Curr Opin Chem Biol. 2003;7:496–504.

    Article  CAS  PubMed  Google Scholar 

  105. Lin C-T, Tang H-Y, Han Y-S, Liu H-P, Huang S-F, Chien C-H, et al. Downregulation of signaling-active IGF1 by dipeptidyl peptidase IV. Int J Biomed Sci. 2010;6:301–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Sepp-Lorenzino L. Structure and function of the insulin-like growth factor I receptor. Breast Cancer Res Treat. 1998;47:235–53.

    Article  CAS  PubMed  Google Scholar 

  107. Baserga R, Hongo A, Rubini M, Prisco M, Valentinis B. The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta. 1997;1332:F105–26.

    CAS  PubMed  Google Scholar 

  108. Dupont J, LeRoith D. Insulin and insulin-like growth factor-I receptors: similarities and differences in signal transduction. Horm Res. 2001;55 Suppl 2:22–6.

    Article  CAS  PubMed  Google Scholar 

  109. Myers Jr MG, Sun X-J, Cheatham B, Jachna BR, Glasheen EM, Backer JM, et al. IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3′-kinase. Endocrinology. 1993;132:1421–30.

    CAS  PubMed  Google Scholar 

  110. Galvan V, Logvinova A, Sperandio S, Ichijo H, Bredesen DE. Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis signal-regulating kinase 1 (ASK1). J Biol Chem. 2003;278:13325–32.

    Article  CAS  PubMed  Google Scholar 

  111. Zong CS, Chan J, Levy D, Horvath C, Sadowski HB, Wang LH. Mechanism of STAT3 activation by insulin-like growth factor I receptor. J Biol Chem. 2000;275:15099–105.

    Article  CAS  PubMed  Google Scholar 

  112. Werner H, Weinstein D, Bentov I. Similarities and differences between insulin and IGF-I: structures, receptors, and signaling pathways. Arch Physiol Biochem. 2008;114:17–22.

    Article  CAS  PubMed  Google Scholar 

  113. Klotz DM, Hewitt SC, Ciana P, Raviscioni M, Lindzey JK, Foley J, et al. Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk. J Biol Chem. 2002;277:8531–7.

    Article  CAS  PubMed  Google Scholar 

  114. van der Veeken J, Oliveira S, Schiffelers RM, Storm G, van Bergen En Henegouwen PM, Roovers RC. Crosstalk between epidermal growth factor receptor- and insulin-like growth factor-1 receptor signaling: implications for cancer therapy. Curr Cancer Drug Targets. 2009;9:748–60.

    Article  PubMed  Google Scholar 

  115. Pandini G, Mineo R, Frasca F, Roberts Jr CT, Marcelli M, Vigneri R, et al. Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. Cancer Res. 2005;65:1849–57.

    Article  CAS  PubMed  Google Scholar 

  116. Plymate SR, Tennant MK, Culp SH, Woodke L, Marcelli M, Colman I, et al. Androgen receptor (AR) expression in AR-negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors. Prostate. 2004;61:276–90.

    Article  CAS  PubMed  Google Scholar 

  117. Sayeed A, Alam N, Trerotola M, Languino LR. Insulin-like growth factor 1 stimulation of androgen receptor activity requires beta(1A) integrins. J Cell Physiol. 2012;227:751–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  118. Wu JD, Haugk K, Woodke L, Nelson P, Coleman I, Plymate SR. Interaction of IGF signaling and the androgen receptor in prostate cancer progression. J Cell Biochem. 2006;99:392–401.

    Article  CAS  PubMed  Google Scholar 

  119. Charalambous M, Smith FM, Bennett WR, Crew TE, Mackenzie F, Ward A. Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism. Proc Natl Acad Sci USA. 2003;100:8292–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  120. Heron-Milhavet L, LeRoith D. Insulin-like growth factor I induces MDM2-dependent degradation of p53 via the p38 MAPK pathway in response to DNA damage. J Biol Chem. 2002;277:15600–6.

    Article  CAS  PubMed  Google Scholar 

  121. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, et al. β-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem. 2005;280:24412–9.

    Article  CAS  PubMed  Google Scholar 

  122. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Vasilcanu D, Girnita A, et al. β-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression. J Biol Chem. 2007;282:11329–38.

    Article  CAS  PubMed  Google Scholar 

  123. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 1993;75:59–72.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Rive Sarfstein & Haim Werner

Authors
  1. Rive Sarfstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haim Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haim Werner .

Editor information

Editors and Affiliations

  1. School of Medicine and Public Health Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA

    Deric L. Wheeler

  2. Department of Biological Regulation, Rehovot, Israel

    Yosef Yarden

Receptor at a glance: INSR

Receptor at a glance: INSR

Chromosome location

19

Gene size (bp)

>130 kb

Intron/exon numbers

21/22. Two isoforms, INSR-A and –B, are generated by alternative splicing of exon 11

mRNA size (5′, ORF, 3′)

~5–10 kb

Amino acid number

1,370

kDa

Precursor, 200 kDa; mature receptor, 97 kDa

Posttranslational modifications

Glycosylation, phosphorylation and desphosphorylation, SUMOylation, ubiquitination, and lipidation

Domains

Ligand-binding domain in the extracellular α-subunit; tyrosine kinase domain in the cytoplasmic portion of the transmembrane β-subunit

Ligands

Insulin and IGF2 (mainly at INSR-A)

Known dimerizing partners

Preformed heterotetramer composed of two α and two β subunits

Pathways activated

PI3K/AKT and MAPK pathways

Tissues expressed

INSR-A predominantly expressed in fetal tissues and InsR-B predominately expressed in adult tissues, particularly liver, muscle, and adipocytes

Human diseases

Type 2 diabetes mellitus. May affect the onset of Alzheimer’s disease, Donohue syndrome or leprechaunism, and Rabson–Mendenhall syndrome

Knockout mouse phenotype

Severe hyperglycemia, hyperketonemia, and growth retardation. KO mice die as a result of diabetic ketoacidosis within 48–72 h

Receptor at a glance: IGF1R

Chromosome location

15

Gene size (bp)

>100 kb

Intron/exon numbers

20/21

mRNA size (5′, ORF, 3′)

~11 kb with an additional band at ~7 kb

Amino acid number

1,337

kDa

Precursor, 200 kDa; mature receptor, 97 kDa

Posttranslational modifications

Glycosylation, phosphorylation and desphosphorylation, SUMOylation, and ubiquitination

Domains

Ligand-binding domain in the extracellular α-subunit; tyrosine kinase domain in the cytoplasmic portion of the transmembrane β-subunit

Ligands

IGF1, IGF2, and insulin (with low affinity)

Known dimerizing partners

Preformed heterotetramer composed of two α and two β subunits

Pathways activated

PI3K/AKT and MAPK pathways

Tissues expressed

Low levels in adipose tissue and high levels in brain. Highly expressed in most cancers

Human diseases

Mutations (very rare) of the IGF1R lead to intrauterine and postnatal growth failure, microcephaly, mental retardation, and deafness

Knockout mouse phenotype

Lethal condition with severe growth retardation. KO mice have anomalies in CNS, skin, and other organs

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Sarfstein, R., Werner, H. (2015). The INSR/IGF1R Receptor Family. In: Wheeler, D., Yarden, Y. (eds) Receptor Tyrosine Kinases: Family and Subfamilies. Springer, Cham. https://doi.org/10.1007/978-3-319-11888-8_7

Download citation

Publish with us

Policies and ethics

Search

Navigation