Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1986 Oct;5(10):2503–2512. doi: 10.1002/j.1460-2075.1986.tb04528.x

Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity.

A Ullrich, A Gray, A W Tam, T Yang-Feng, M Tsubokawa, C Collins, W Henzel, T Le Bon, S Kathuria, E Chen, et al.
PMCID: PMC1167146  PMID: 2877871

Abstract

To identify structural characteristics of the closely related cell surface receptors for insulin and IGF-I that define their distinct physiological roles, we determined the complete primary structure of the human IGF-I receptor from cloned cDNA. The deduced sequence predicts a 1367 amino acid receptor precursor, including a 30-residue signal peptide, which is removed during translocation of the nascent polypeptide chain. The 1337 residue, unmodified proreceptor polypeptide has a predicted Mr of 151,869, which compares with the 180,000 Mr IGF-I receptor precursor. In analogy with the 152,784 Mr insulin receptor precursor, cleavage of the Arg-Lys-Arg-Arg sequence at position 707 of the IGF-I receptor precursor will generate alpha (80,423 Mr) and beta (70,866 Mr) subunits, which compare with approximately 135,000 Mr (alpha) and 90,000 Mr (beta) fully glycosylated subunits.

Full text

PDF
2503

Images in this article

2504Fig. 1.
on p.2504
2507Fig. 4.
on p.2507
2508Fig. 5.
on p.2508
2509Fig. 6.
on p.2509

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bhaumick B., Bala R. M., Hollenberg M. D. Somatomedin receptor of human placenta: solubilization, photolabeling, partial purification, and comparison with insulin receptor. Proc Natl Acad Sci U S A. 1981 Jul;78(7):4279–4283. doi: 10.1073/pnas.78.7.4279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brown S., Oie H. K., Gazdar A. F., Minna J. D., Francke U. Requirement of human chromosomes 19, 6 and possibly 3 for infection of hamster x human hybrid cells with baboon M7 type C virus. Cell. 1979 Sep;18(1):135–143. doi: 10.1016/0092-8674(79)90362-3. [DOI] [PubMed] [Google Scholar]
  3. Cathala G., Savouret J. F., Mendez B., West B. L., Karin M., Martial J. A., Baxter J. D. A method for isolation of intact, translationally active ribonucleic acid. DNA. 1983;2(4):329–335. doi: 10.1089/dna.1983.2.329. [DOI] [PubMed] [Google Scholar]
  4. Champion M. J., Brown J. A., Shows T. B. Assignment of cytoplasmic alpha-mannosidase (MANA) and confirmation of mitochondrial isocitrate dehydrogenase (IDHM) to the q11 leads to qter region of chromosome 15 in man. Cytogenet Cell Genet. 1978;22(1-6):498–502. doi: 10.1159/000131007. [DOI] [PubMed] [Google Scholar]
  5. Chern C. J., Croce C. M. Confirmation of the synteny of the human genes for mannose phosphate isomerase and pyruvate kinase and of their assignment to chromosome 15. Cytogenet Cell Genet. 1975;15(5):299–305. doi: 10.1159/000130527. [DOI] [PubMed] [Google Scholar]
  6. Chernausek S. D., Jacobs S., Van Wyk J. J. Structural similarities between human receptors for somatomedin C and insulin: analysis by affinity labeling. Biochemistry. 1981 Dec 22;20(26):7345–7350. doi: 10.1021/bi00529a004. [DOI] [PubMed] [Google Scholar]
  7. Coussens L., Van Beveren C., Smith D., Chen E., Mitchell R. L., Isacke C. M., Verma I. M., Ullrich A. Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature. 1986 Mar 20;320(6059):277–280. doi: 10.1038/320277a0. [DOI] [PubMed] [Google Scholar]
  8. Coussens L., Yang-Feng T. L., Liao Y. C., Chen E., Gray A., McGrath J., Seeburg P. H., Libermann T. A., Schlessinger J., Francke U. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985 Dec 6;230(4730):1132–1139. doi: 10.1126/science.2999974. [DOI] [PubMed] [Google Scholar]
  9. Crea R., Horn T. Synthesis of oligonucleotides on cellulose by a phosphotriester method. Nucleic Acids Res. 1980 May 24;8(10):2331–2348. doi: 10.1093/nar/8.10.2331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ebina Y., Ellis L., Jarnagin K., Edery M., Graf L., Clauser E., Ou J. H., Masiarz F., Kan Y. W., Goldfine I. D. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell. 1985 Apr;40(4):747–758. doi: 10.1016/0092-8674(85)90334-4. [DOI] [PubMed] [Google Scholar]
  11. Flier J. S., Usher P., Moses A. C. Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts. Proc Natl Acad Sci U S A. 1986 Feb;83(3):664–668. doi: 10.1073/pnas.83.3.664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Froesch E. R., Schmid C., Schwander J., Zapf J. Actions of insulin-like growth factors. Annu Rev Physiol. 1985;47:443–467. doi: 10.1146/annurev.ph.47.030185.002303. [DOI] [PubMed] [Google Scholar]
  13. Fujita-Yamaguchi Y., Choi S., Sakamoto Y., Itakura K. Purification of insulin receptor with full binding activity. J Biol Chem. 1983 Apr 25;258(8):5045–5049. [PubMed] [Google Scholar]
  14. Gould K. L., Woodgett J. R., Cooper J. A., Buss J. E., Shalloway D., Hunter T. Protein kinase C phosphorylates pp60src at a novel site. Cell. 1985 Oct;42(3):849–857. doi: 10.1016/0092-8674(85)90281-8. [DOI] [PubMed] [Google Scholar]
  15. Grunfeld C., Shigenaga J. K., Ramachandran J. Urea treatment allows dithiothreitol to release the binding subunit of the insulin receptor from the cell membrane: implications for the structural organization of the insulin receptor. Biochem Biophys Res Commun. 1985 Dec 17;133(2):389–396. doi: 10.1016/0006-291x(85)90918-0. [DOI] [PubMed] [Google Scholar]
  16. Harper M. E., Franchini G., Love J., Simon M. I., Gallo R. C., Wong-Staal F. Chromosomal sublocalization of human c-myb and c-fes cellular onc genes. Nature. 1983 Jul 14;304(5922):169–171. doi: 10.1038/304169a0. [DOI] [PubMed] [Google Scholar]
  17. Harper M. E., Saunders G. F. Localization of single copy DNA sequences of G-banded human chromosomes by in situ hybridization. Chromosoma. 1981;83(3):431–439. doi: 10.1007/BF00327364. [DOI] [PubMed] [Google Scholar]
  18. Heffetz D., Zick Y. Receptor aggregation is necessary for activation of the soluble insulin receptor kinase. J Biol Chem. 1986 Jan 15;261(2):889–894. [PubMed] [Google Scholar]
  19. Hildebrand C. E., Gonzalez F. J., McBride O. W., Nebert D. W. Assignment of the human 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible cytochrome P1-450 gene to chromosome 15. Nucleic Acids Res. 1985 Mar 25;13(6):2009–2016. doi: 10.1093/nar/13.6.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hunkapiller M. W., Lujan E., Ostrander F., Hood L. E. Isolation of microgram quantities of proteins from polyacrylamide gels for amino acid sequence analysis. Methods Enzymol. 1983;91:227–236. doi: 10.1016/s0076-6879(83)91019-4. [DOI] [PubMed] [Google Scholar]
  21. Hunter T., Ling N., Cooper J. A. Protein kinase C phosphorylation of the EGF receptor at a threonine residue close to the cytoplasmic face of the plasma membrane. Nature. 1984 Oct 4;311(5985):480–483. doi: 10.1038/311480a0. [DOI] [PubMed] [Google Scholar]
  22. Ingram P. H., Bruns G. A., Regina V. M., Eisenman R. E., Gerald P. S. Expression of alpha-D-mannosidase in man-hamster somatic cell hybrids. Biochem Genet. 1977 Jun;15(5-6):455–476. doi: 10.1007/BF00520191. [DOI] [PubMed] [Google Scholar]
  23. Jacobs S., Cuatrecasas P. Phosphorylation of receptors for insulin and insulin-like growth factor I. Effects of hormones and phorbol esters. J Biol Chem. 1986 Jan 15;261(2):934–939. [PubMed] [Google Scholar]
  24. Jacobs S., Kull F. C., Jr, Cuatrecasas P. Monensin blocks the maturation of receptors for insulin and somatomedin C: identification of receptor precursors. Proc Natl Acad Sci U S A. 1983 Mar;80(5):1228–1231. doi: 10.1073/pnas.80.5.1228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jacobs S., Kull F. C., Jr, Earp H. S., Svoboda M. E., Van Wyk J. J., Cuatrecasas P. Somatomedin-C stimulates the phosphorylation of the beta-subunit of its own receptor. J Biol Chem. 1983 Aug 25;258(16):9581–9584. [PubMed] [Google Scholar]
  26. Jacobs S., Sahyoun N. E., Saltiel A. R., Cuatrecasas P. Phorbol esters stimulate the phosphorylation of receptors for insulin and somatomedin C. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6211–6213. doi: 10.1073/pnas.80.20.6211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Karlsson F. A., Grunfeld C., Kahn C. R., Roth J. Regulation of insulin receptors and insulin responsiveness in 3T3-L1 fatty fibroblasts. Endocrinology. 1979 May;104(5):1383–1392. doi: 10.1210/endo-104-5-1383. [DOI] [PubMed] [Google Scholar]
  28. Kozak M. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucleic Acids Res. 1984 Jan 25;12(2):857–872. doi: 10.1093/nar/12.2.857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kull F. C., Jr, Jacobs S., Su Y. F., Svoboda M. E., Van Wyk J. J., Cuatrecasas P. Monoclonal antibodies to receptors for insulin and somatomedin-C. J Biol Chem. 1983 May 25;258(10):6561–6566. [PubMed] [Google Scholar]
  30. Kyte J., Doolittle R. F. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982 May 5;157(1):105–132. doi: 10.1016/0022-2836(82)90515-0. [DOI] [PubMed] [Google Scholar]
  31. LeBon T. R., Jacobs S., Cuatrecasas P., Kathuria S., Fujita-Yamaguchi Y. Purification of insulin-like growth factor I receptor from human placental membranes. J Biol Chem. 1986 Jun 15;261(17):7685–7689. [PubMed] [Google Scholar]
  32. Lehrach H., Diamond D., Wozney J. M., Boedtker H. RNA molecular weight determinations by gel electrophoresis under denaturing conditions, a critical reexamination. Biochemistry. 1977 Oct 18;16(21):4743–4751. doi: 10.1021/bi00640a033. [DOI] [PubMed] [Google Scholar]
  33. Massagué J., Czech M. P. The subunit structures of two distinct receptors for insulin-like growth factors I and II and their relationship to the insulin receptor. J Biol Chem. 1982 May 10;257(9):5038–5045. [PubMed] [Google Scholar]
  34. Neckameyer W. S., Wang L. H. Nucleotide sequence of avian sarcoma virus UR2 and comparison of its transforming gene with other members of the tyrosine protein kinase oncogene family. J Virol. 1985 Mar;53(3):879–884. doi: 10.1128/jvi.53.3.879-884.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Phillips I. R., Shephard E. A., Povey S., Davis M. B., Kelsey G., Monteiro M., West L. F., Cowell J. A cytochrome P-450 gene family mapped to human chromosome 19. Ann Hum Genet. 1985 Oct;49(Pt 4):267–274. doi: 10.1111/j.1469-1809.1985.tb01702.x. [DOI] [PubMed] [Google Scholar]
  36. Rechler M. M., Nissley S. P. The nature and regulation of the receptors for insulin-like growth factors. Annu Rev Physiol. 1985;47:425–442. doi: 10.1146/annurev.ph.47.030185.002233. [DOI] [PubMed] [Google Scholar]
  37. Ronnett G. V., Knutson V. P., Kohanski R. A., Simpson T. L., Lane M. D. Role of glycosylation in the processing of newly translated insulin proreceptor in 3T3-L1 adipocytes. J Biol Chem. 1984 Apr 10;259(7):4566–4575. [PubMed] [Google Scholar]
  38. Rubin C. S., Hirsch A., Fung C., Rosen O. M. Development of hormone receptors and hormonal responsiveness in vitro. Insulin receptors and insulin sensitivity in the preadipocyte and adipocyte forms of 3T3-L1 cells. J Biol Chem. 1978 Oct 25;253(20):7570–7578. [PubMed] [Google Scholar]
  39. Rubin J. B., Shia M. A., Pilch P. F. Stimulation of tyrosine-specific phosphorylation in vitro by insulin-like growth factor I. 1983 Sep 29-Oct 5Nature. 305(5933):438–440. doi: 10.1038/305438a0. [DOI] [PubMed] [Google Scholar]
  40. Sherr C. J., Rettenmier C. W., Sacca R., Roussel M. F., Look A. T., Stanley E. R. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell. 1985 Jul;41(3):665–676. doi: 10.1016/s0092-8674(85)80047-7. [DOI] [PubMed] [Google Scholar]
  41. Takayama S., White M. F., Lauris V., Kahn C. R. Phorbol esters modulate insulin receptor phosphorylation and insulin action in cultured hepatoma cells. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7797–7801. doi: 10.1073/pnas.81.24.7797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Taylor J. M., Illmensee R., Summers J. Efficeint transcription of RNA into DNA by avian sarcoma virus polymerase. Biochim Biophys Acta. 1976 Sep 6;442(3):324–330. doi: 10.1016/0005-2787(76)90307-5. [DOI] [PubMed] [Google Scholar]
  43. Ullrich A., Bell J. R., Chen E. Y., Herrera R., Petruzzelli L. M., Dull T. J., Gray A., Coussens L., Liao Y. C., Tsubokawa M. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. 1985 Feb 28-Mar 6Nature. 313(6005):756–761. doi: 10.1038/313756a0. [DOI] [PubMed] [Google Scholar]
  44. Ullrich A., Berman C. H., Dull T. J., Gray A., Lee J. M. Isolation of the human insulin-like growth factor I gene using a single synthetic DNA probe. EMBO J. 1984 Feb;3(2):361–364. doi: 10.1002/j.1460-2075.1984.tb01812.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Ullrich A., Coussens L., Hayflick J. S., Dull T. J., Gray A., Tam A. W., Lee J., Yarden Y., Libermann T. A., Schlessinger J. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. 1984 May 31-Jun 6Nature. 309(5967):418–425. doi: 10.1038/309418a0. [DOI] [PubMed] [Google Scholar]
  46. Wessel D., Flügge U. I. A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal Biochem. 1984 Apr;138(1):141–143. doi: 10.1016/0003-2697(84)90782-6. [DOI] [PubMed] [Google Scholar]
  47. Yamamoto T., Davis C. G., Brown M. S., Schneider W. J., Casey M. L., Goldstein J. L., Russell D. W. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984 Nov;39(1):27–38. doi: 10.1016/0092-8674(84)90188-0. [DOI] [PubMed] [Google Scholar]
  48. Yang-Feng T. L., Floyd-Smith G., Nemer M., Drouin J., Francke U. The pronatriodilatin gene is located on the distal short arm of human chromosome 1 and on mouse chromosome 4. Am J Hum Genet. 1985 Nov;37(6):1117–1128. [PMC free article] [PubMed] [Google Scholar]
  49. Yang-Feng T. L., Francke U., Ullrich A. Gene for human insulin receptor: localization to site on chromosome 19 involved in pre-B-cell leukemia. Science. 1985 May 10;228(4700):728–731. doi: 10.1126/science.3873110. [DOI] [PubMed] [Google Scholar]
  50. Zick Y., Sasaki N., Rees-Jones R. W., Grunberger G., Nissley S. P., Rechler M. M. Insulin-like growth factor-I (IGF-I) stimulates tyrosine kinase activity in purified receptors from a rat liver cell line. Biochem Biophys Res Commun. 1984 Feb 29;119(1):6–13. doi: 10.1016/0006-291x(84)91610-3. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES