Growth and the Insulin-Like Growth Factor-1 Receptor (IGF1R)

  • Maria Belen Roldan Martin
  • Selma Feldman Witchel


The insulin-like growth factor-1 receptor (IGF-1R) is a membrane-bound tyrosine kinase receptor capable of auto-phosphorylation following ligand binding. While IGF-1 is the major ligand for this receptor, both IGF-2 and insulin can bind to the IGF-1R. Following ligand binding and IGF-1R auto-phosphorylation, the insulin receptor substrate (IRS) proteins are tyrosine phosphorylated by the IGF-1R. Following phosphorylation of the IRS proteins, one intracellular signaling cascade activates PI3K leading to increased PIP3 production. Another major intracellular signaling pathway involves the Shc proteins with subsequent activation of RAS, RAF, and the extracellular signal-regulated kinase (ERK) pathways. IGF-1R activates other members of the MAP kinase family. The IGF-1R has much structural homology with the insulin receptor leading to the presence of hybrid receptors in some cells. The IGF-1/IGF-1R system plays critical roles in prenatal and postnatal growth. One patient with a duplication of the IGF1R gene was reported as having large birth weight, coarse facial features, and dysmorphic features reminiscent of Beckwith–Wiedemann. Loss-of-function mutations in the IGF-1R gene have been associated with intrauterine growth retardation (IUGR). Clinical observations have demonstrated that IGF-1 concentrations increase during puberty. Dysregulation of the IGF-1/insulin/IGF-1R system may contribute to the pathophysiology of premature adrenarche (PA) and polycystic ovary syndrome (PCOS). Polymorphisms in the IGF-1R gene and its homologues have been associated with lifespan in humans and other organisms, respectively. Generation of transgenic mice has revealed the importance of IGF-1/IGF-1R signaling in multiple tissues including brain, bone, pancreatic β-cells, skin, and muscle. Elucidation of the role of IGF-1R in cell proliferation, survival, and apoptosis will be useful to develop novel therapies for cancer.


Congenital Adrenal Hyperplasia Adrenal Androgen Zona Reticularis Insulin Receptor Substrate Protein IGF1R Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Extracellular signal-regulated kinase


Growth hormone


Insulin-like growth factor


IGF-1 receptor


IGF-2 receptor


IGF-binding protein


Insulin receptor


Janus kinase 2


Mitogen-activated protein kinase


Premature adrenarche






Premature pubarche


Phosphatase and tensin homologue


Small for gestational age


Sex hormone-binding globulin


Signal transducer and activator of transcription


  1. 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.PubMedGoogle Scholar
  2. Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfäffle R, Raile K, Seidel B, Smith RJ, Chernausek SD; Intrauterine Growth Retardation (IUGR) Study Group. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003;349:2211–22.PubMedCrossRefGoogle Scholar
  3. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF; Task Force on the Phenotype of the Polycystic Ovary Syndrome of the Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91:456–88.PubMedCrossRefGoogle Scholar
  4. Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan K, Werbowetski-Ogilvie T, Ramos-Mejia V, Rouleau A, Yang J, Bossé M, Lajoie G, Bhatia M. IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature. 2007;448:1015–21.PubMedCrossRefGoogle Scholar
  5. Bonafè M, Barbieri M, Marchegiani F, Olivieri F, Ragno E, Giampieri C, Mugianesi E, Centurelli M, Franceschi C, Paolisso G. Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control. J Clin Endocrinol Metab. 2003;88:3299–304.PubMedCrossRefGoogle Scholar
  6. Bondy C, Werner H, Roberts Jr CT, LeRoith D. Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the rat brain: comparison with insulin-like growth factors I and II. Neuroscience. 1992;46:909–23.PubMedCrossRefGoogle Scholar
  7. Brown J, Jones EY, Forbes BE. Interactions of IGF-II with the IGF2R/cation-independent mannose-6-phosphate receptor mechanism and biological outcomes. Vitam Horm. 2009;80:699–19.PubMedCrossRefGoogle Scholar
  8. Chernausek SD, Jacobs S, Van Wyk JJ. Structural similarities between human receptors for somatomedin C and insulin: analysis by affinity labeling. Biochemistry. 1981;20:7345–50.PubMedCrossRefGoogle Scholar
  9. Choi JH, Kang M, Kim GH, Hong M, Jin HY, Lee BH, Park JY, Lee SM, Seo EJ, Yoo HW. Clinical and functional characteristics of a novel heterozygous mutation of the IGF1R gene and IGF1R haploinsufficiency due to terminal 15q26.2->qter deletion in patients with intrauterine growth retardation and postnatal catch-up growth failure. J Clin Endocrinol Metab. 2011;96(1):E130–4.Google Scholar
  10. Denburg MR, Silfen ME, Manibo AM, Chin D, Levine LS, Ferin M, McMahon DJ, Go C, Oberfield SE. Insulin sensitivity and the insulin-like growth factor system in prepubertal boys with premature adrenarche. J Clin Endocrinol Metab. 2002;87:5604–9.PubMedCrossRefGoogle Scholar
  11. Escobar-Morreale HF, Luque-Ramírez M, San Millán JL. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev. 2005;26:251–82.PubMedCrossRefGoogle Scholar
  12. Fang P, Schwartz ID, Johnson BD, Derr MA, Roberts CT Jr, Hwa V, Rosenfeld RG. Familial short stature caused by haploinsufficiency of the insulin-like growth factor i receptor due to nonsense-mediated messenger ribonucleic acid decay. J Clin Endocrinol Metab. 2009;94:1740–7.PubMedCrossRefGoogle Scholar
  13. Fernández AM, Kim JK, Yakar S, Dupont J, Hernandez-Sanchez C, Castle AL, Filmore J, Shulman GI, Le Roith D. Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes Dev. 2001;15:1926–34.PubMedCrossRefGoogle Scholar
  14. Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002;23:824–54.PubMedCrossRefGoogle Scholar
  15. Himpe E, Kooijman R. Insulin-like growth factor-I receptor signal transduction and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway. Biofactors. 2009;35:76–81.PubMedCrossRefGoogle Scholar
  16. Hiney JK, Srivastava V, Nyberg CL, Ojeda SR, Dees WL. Insulin-like growth factor I of peripheral origin acts centrally to accelerate the initiation of female puberty. Endocrinology. 1996;137:3717–28.PubMedCrossRefGoogle Scholar
  17. Hiney JK, Srivastava VK, Pine MD, Dees WL. Insulin-like growth factor-I activates KiSS-1 gene expression in the brain of the prepubertal female rat. Endocrinology. 2009;150:376–84.PubMedCrossRefGoogle Scholar
  18. Holzenberger M. The GH/IGF-I axis and longevity. Eur J Endocrinol. 2004;151:S23–7.PubMedCrossRefGoogle Scholar
  19. Hwangbo DS, Gersham B, Tu MP, Palmer M, Tatar M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature. 2004;429:562–6.PubMedCrossRefGoogle Scholar
  20. Ibañez L, DiMartino-Nardi J, Potau N, Saenger P. Premature adrenarche – normal variant or forerunner of adult disease? Endocr Rev. 2000;21:671–96.PubMedCrossRefGoogle Scholar
  21. Inagaki K, Tiuppakov A. Rubtsov P, Sverdlova P, Peterkiva V, Yakar S, Terekhov S, LeRoith D. A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization. J Clin Endocrinol Metab. 2007;92:1542–8.PubMedCrossRefGoogle Scholar
  22. Kappeler L, De Magalhaes Filho CM, Dupont J, Leneuve P, Cervera P, Périn L, Loudes C, Blaise A, Klein R, Epelbaum J, Le Bouc Y, Holzenberger M. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol. 2008;6;e254.PubMedCrossRefGoogle Scholar
  23. Kawashima Y, Kanzaki S, Yang F, Kinoshita T, Hanaki K, Nagaishi J, Ohtsuka Y, Hisatome I, Ninomoya H, Nanba E, Fukushima T, Takahashi S. Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J Clin Endocrinol Metab. 2005;90:4679–87.PubMedCrossRefGoogle Scholar
  24. Keniry M, Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene. 2008;27:5477–85.PubMedCrossRefGoogle Scholar
  25. Kulkarni RN, Holzenberger M, Shih DQ, Ozcan U, Stoffel M, Magnuson MA, Kahn CR. Beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat Genet. 2002;31:111–5.PubMedGoogle Scholar
  26. Laviola L, Perrini S, Belsanti G, Natalicchio A, Montrone C, Leonardini A, Vimercati A, Scioscia M, Selvaggi L, Giorgino R, Greco P, Giorgino F. Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling. Endocrinology. 2005;146:1498–505.PubMedCrossRefGoogle Scholar
  27. Lewy VD, Danadian K, Witchel SF, Arslanian S. J Pediatr. 2001;138:38–44.PubMedCrossRefGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. Liu W, Ye P, O’Kusky JR, D’Ercole AJ. Type 1 insulin-like growth factor receptor signaling is essential for the development of the hippocampal formation and dentate gyrus. J Neurosci Res. 2009;87:2821–32.PubMedCrossRefGoogle Scholar
  30. Löfqvist C, Andersson E, Gelander L, Rosberg S, Blum WF, Albertsson Wikland K. Reference values for IGF-I throughout childhood and adolescence: a model that accounts simultaneously for the effect of gender, age, and puberty. J Clin Endocrinol Metab. 2001;86:5870–5876.Google Scholar
  31. Nakamura Y, Gang HX, Suzuki T, Sasano H, Rainey WE. Adrenal changes associated with adrenarche. Rev Endocr Metab Disord. 2009;10:19–26.PubMedCrossRefGoogle Scholar
  32. Okubo Y, Siddle K, Firth H, O’Rahilly S, Wilson LC, Willatt L, Fukushima T, Takahashi S, Petry CJ, Saukkonen T, Stanhope R, Dunger DB. Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene. J Clin Endocrinol Metab. 2003;88:5981–8.PubMedCrossRefGoogle Scholar
  33. Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, Joyner AH, Schork NJ, Hsueh WC, Reiner AP, Psaty BM, Atzmon G, Barzilai N, Cummings SR, Browner WS, Kwok PY, Ziv E. Study of Osteoporotic Fractures. Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell. 2009;8:460–72.PubMedCrossRefGoogle Scholar
  34. Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocr Rev. 1999;20:535–82.PubMedCrossRefGoogle Scholar
  35. Raile K, Klammt J, Schneider A, Keller A, Laue S, Smith R, Pfäffle R, Kratzsch J, Keller E, Kiess W. Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor i receptor (IGF1R) mutation: implications for a gene dosage effect of the human IGF1R. J Clin Endocrinol Metab. 2006;91:2264–71.PubMedCrossRefGoogle Scholar
  36. Roldan MB, White C, Witchel SF. Association of the GAA1013–>GAG polymorphism of the insulin-like growth factor-1 receptor (IGF1R) gene with premature pubarche. Fertil Steril. 2007;88:410–7.PubMedCrossRefGoogle Scholar
  37. Rosenfeld RG, Hwa V. The growth hormone cascade and its role in mammalian growth. Horm Res. 2009;71 Suppl 2:36–40.PubMedCrossRefGoogle Scholar
  38. Sadagurski M, Yakar S, Weingarten G, Holzenberger M, Rhodes CJ, Breitkreutz D, Leroith D, Wertheimer E. Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation. Mol Cell Biol. 2006;26:2675–87.PubMedCrossRefGoogle Scholar
  39. San Millán JL, Cortón M, Villuendas G, Sancho J, Peral B, Escobar-Morreale HF. Association of the polycystic ovary syndrome with genomic variants related to insulin resistance, type 2 diabetes mellitus, and obesity. J Clin Endocrinol Metab. 2004;89:2640–6.PubMedCrossRefGoogle Scholar
  40. Silfen ME, Manibo AM, Ferin M, McMahon DJ, Levine LS, Oberfield SE. Elevated free IGF-I levels in prepubertal Hispanic girls with premature adrenarche: relationship with hyperandrogenism and insulin sensitivity. J Clin Endocrinol Metab. 2002;87:398–403.PubMedCrossRefGoogle Scholar
  41. Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci USA. 2008;105:3438–42.PubMedCrossRefGoogle Scholar
  42. Tam CS, de Zegher F, Garnett SP, Baur LA, Cowell CT. Opposing influences of prenatal and postnatal growth on the timing of menarche. J Clin Endocrinol Metab. 2006;91:4369–673.PubMedCrossRefGoogle Scholar
  43. Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals. Science. 2003;299:1346–51.PubMedCrossRefGoogle Scholar
  44. Todd BJ, Fraley GS, Peck AC, Schwartz GJ, Etgen AM. Central insulin-like growth factor 1 receptors play distinct roles in the control of reproduction, food intake, and body weight in female rats. Biol Reprod. 2007;77:492–503.PubMedCrossRefGoogle Scholar
  45. Utriainen P, Voutilainen R, Jääskeläinen J. Girls with premature adrenarche have accelerated early childhood growth. J Pediatr. 2009;154:882–7.PubMedCrossRefGoogle Scholar
  46. Walenkamp MJ, van der Kamp HJ, Pereira AM, Kant SG, van Duyvenvoorde HA, Kruithof MF, Breuning MH, Romijn JA, Karperien M, Wit JM. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. J Clin Endocrinol Metab. 2006;91:3062–70.PubMedCrossRefGoogle Scholar
  47. Wang Y, Nishida S, Boudignon BM, Burghardt A, Elalieh HZ, Hamilton MM, Majumdar S, Halloran BP, Clemens TL, Bikle DD. IGF-I receptor is required for the anabolic actions of parathyroid hormone on bone. J Bone Miner Res. 2007;22:1329–37.PubMedCrossRefGoogle Scholar
  48. Werner H, Bruchim I. The insulin-like growth factor-I receptor as an oncogene. Arch Physiol Biochem. 2009;115:58–71.PubMedCrossRefGoogle Scholar
  49. Weroha SJ, Haluska P. IGF-1 receptor inhibitors in clinical trials–early lessons. J Mammary Gland Biol Neoplasia. 2008;13:471–83.PubMedCrossRefGoogle Scholar
  50. Witchel SF. Puberty and polycystic ovary syndrome. Mol Cell Endocrinol. 2006;254–255:146–53.PubMedCrossRefGoogle Scholar
  51. Yakar S, Rosen CJ. From mouse to man: redefining the role of insulin-like growth factor-I in the acquisition of bone mass. Exp Biol Med (Maywood). 2003;228:245–52.Google Scholar
  52. Zeger M, Popken G, Zhang J, Xuan S, Lu QR, Schwab MH, Nave KA, Rowitch D, D’Ercole AJ, Ye P. Insulin-like growth factor type 1 receptor signaling in the cells of oligodendrocyte lineage is required for normal in vivo oligodendrocyte development and myelination. Glia. 2007;55:400–11.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Maria Belen Roldan Martin
    • 1
  • Selma Feldman Witchel
    • 2
  1. 1.Division of Pediatric EndocrinologyGregorio Marañón Hospital, Complutense University of MadridMadridSpain
  2. 2.Division of Pediatric EndocrinologyChildren’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations