Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1983 Oct;72(4):1459–1469. doi: 10.1172/JCI111102

Antireceptor antibodies as probes of insulinlike growth factor receptor structure.

M Kasuga, N Sasaki, C R Kahn, S P Nissley, M M Rechler
PMCID: PMC370430  PMID: 6313762

Abstract

Insulin receptors and Type I insulinlike growth factor (IGF) receptors have a similar structure with a major binding subunit of Mr approximately 130,000 linked by disulfide bonds to other membrane proteins to form a Mr greater than 300,000 complex. Both insulin and Type I IGF receptors also interact with both insulin and IGF, although with different binding affinities. We used a panel of human and rabbit sera containing antibodies to insulin receptors to determine whether these sera also interact with Type I IGF receptors. Immunoglobulins from five of five human sera inhibited binding of 125I-insulin and 125I-IGF-I to insulin receptors and Type I IGF receptors in human placenta and human lymphocytes. The rank order of reactivity with both receptors was the same; two sera, however, appeared to be selectively less reactive with the Type I IGF receptor, especially in placenta. Sera from five of seven patients and from a rabbit immunized with purified insulin receptor effectively immunoprecipitated both placental insulin receptors and Type I IGF receptors. Of the remaining sera, one had only a low titer against the insulin receptor and did not immunoprecipitate the IGF receptor, whereas the second serum effectively immunoprecipitated cross-linked and surface-iodinated insulin receptors, but had negligible reactivity against the Type I IGF receptor. These results suggest that most antisera to the insulin receptor also contain antibodies to Type I IGF receptors. Whether both specificities are inherent in the same or different antibody molecules remains to be determined. These data support the hypothesis that the insulin and IGF-I receptors are separate but related molecules, although there remains a small possibility that both receptors are domains on the same protein.

Full text

PDF
1464

Images in this article

1462Image
on p.1462
1463Image
on p.1463
1463Image
on p.1463
1465Image
on p.1465

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. 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]
  3. Deschatrette J., Moore E. E., Dubois M., Cassio D., Weiss M. C. Dedifferentiated variants of a rat hepatoma: analysis by cell hybridization. Somatic Cell Genet. 1979 Nov;5(6):697–718. doi: 10.1007/BF01542636. [DOI] [PubMed] [Google Scholar]
  4. Ey P. L., Prowse S. J., Jenkin C. R. Isolation of pure IgG1, IgG2a and IgG2b immunoglobulins from mouse serum using protein A-sepharose. Immunochemistry. 1978 Jul;15(7):429–436. doi: 10.1016/0161-5890(78)90070-6. [DOI] [PubMed] [Google Scholar]
  5. Flier J. S., Kahn C. R., Jarrett D. B., Roth J. Characterization of antibodies to the insulin receptor: a cause of insulin-resistant diabetes in man. J Clin Invest. 1976 Dec;58(6):1442–1449. doi: 10.1172/JCI108600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hintz R. L., Clemmons D. R., Underwood L. E., Van Wyk J. J. Competitive binding of somatomedin to the insulin receptors of adipocytes, chondrocytes, and liver membranes. Proc Natl Acad Sci U S A. 1972 Aug;69(8):2351–2353. doi: 10.1073/pnas.69.8.2351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Jacobs S., Chang K. J., Cuatrecasas P. Antibodies to purified insulin receptor have insulin-like activity. Science. 1978 Jun 16;200(4347):1283–1284. doi: 10.1126/science.663609. [DOI] [PubMed] [Google Scholar]
  8. Jonas H. A., Baxter R. C., Harrison L. C. Structural differences between insulin and somatomedin-C/insulin-like growth factor-1 receptors revealed by autoantibodies to the insulin receptor. Biochem Biophys Res Commun. 1982 Nov 30;109(2):463–470. doi: 10.1016/0006-291x(82)91744-2. [DOI] [PubMed] [Google Scholar]
  9. Kahn C. R., Baird K. L., Flier J. S., Grunfeld C., Harmon J. T., Harrison L. C., Karlsson F. A., Kasuga M., King G. L., Lang U. C. Insulin receptors, receptor antibodies, and the mechanism of insulin action. Recent Prog Horm Res. 1981;37:477–538. doi: 10.1016/b978-0-12-571137-1.50015-3. [DOI] [PubMed] [Google Scholar]
  10. Kahn C. R., Flier J. S., Bar R. S., Archer J. A., Gorden P., Martin M. M., Roth J. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976 Apr 1;294(14):739–745. doi: 10.1056/NEJM197604012941401. [DOI] [PubMed] [Google Scholar]
  11. Kasuga M., Kahn C. R., Hedo J. A., Van Obberghen E., Yamada K. M. Insulin-induced receptor loss in cultured human lymphocytes is due to accelerated receptor degradation. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6917–6921. doi: 10.1073/pnas.78.11.6917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kasuga M., Van Obberghen E., Nissley S. P., Rechler M. M. Demonstration of two subtypes of insulin-like growth factor receptors by affinity cross-linking. J Biol Chem. 1981 Jun 10;256(11):5305–5308. [PubMed] [Google Scholar]
  13. Kasuga M., Van Obberghen E., Nissley S. P., Rechler M. M. Structure of the insulin-like growth factor receptor in chicken embryo fibroblasts. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1864–1868. doi: 10.1073/pnas.79.6.1864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kasuga M., van Obberghen E., Yamada K. M., Harrison L. C. Autoantibodies against the insulin receptor recognize the insulin binding subunits of an oligomeric receptor. Diabetes. 1981 Apr;30(4):354–357. doi: 10.2337/diab.30.4.354. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  17. Marshall R. N., Underwood L. E., Voina S. J., Foushee D. B., Van Wyk J. J. Characterization of the insulin and somatomedin-C receptors in human placental cell membranes. J Clin Endocrinol Metab. 1974 Aug;39(2):283–292. doi: 10.1210/jcem-39-2-283. [DOI] [PubMed] [Google Scholar]
  18. Massagué J., Blinderman L. A., Czech M. P. The high affinity insulin receptor mediates growth stimulation in rat hepatoma cells. J Biol Chem. 1982 Dec 10;257(23):13958–13963. [PubMed] [Google Scholar]
  19. 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]
  20. Megyesi K., Kahn C. R., Roth J., Froesch E. R., Humbel R. E., Zapf J., Neville D. M., Jr Insulin and non-suppressible insulin-like activity (NSILA-s): evidence for separate plasma membrane receptor sites. Biochem Biophys Res Commun. 1974 Mar 15;57(1):307–315. doi: 10.1016/s0006-291x(74)80391-8. [DOI] [PubMed] [Google Scholar]
  21. Moses A. C., Nissley S. P., Short P. A., Rechler M. M., Podskalny J. M. Purification and characterization of multiplication-stimulating activity. Insulin-like growth factors purified from rat-liver-cell-conditioned medium. Eur J Biochem. 1980 Jan;103(2):387–400. doi: 10.1111/j.1432-1033.1980.tb04325.x. [DOI] [PubMed] [Google Scholar]
  22. Nissley S. P., Rechler M. M. Multiplication-stimulating activity (MSA): a somatomedin-like polypeptide from cultured rat liver cells. Natl Cancer Inst Monogr. 1978 May;(48):167–177. [PubMed] [Google Scholar]
  23. Pilch P. F., Czech M. P. The subunit structure of the high affinity insulin receptor. Evidence for a disulfide-linked receptor complex in fat cell and liver plasma membranes. J Biol Chem. 1980 Feb 25;255(4):1722–1731. [PubMed] [Google Scholar]
  24. Posner B. I. Insulin receptors in human and animal placental tissue. Diabetes. 1974 Mar;23(3):209–217. doi: 10.2337/diab.23.3.209. [DOI] [PubMed] [Google Scholar]
  25. Rechler M. M. Leprechaunism and related syndromes with primary insulin resistance: heterogeneity of molecular defects. Prog Clin Biol Res. 1982;97:245–281. [PubMed] [Google Scholar]
  26. Rechler M. M., Zapf J., Nissley S. P., Froesch E. R., Moses A. C., Podskalny J. M., Schilling E. E., Humbel R. E. Interactions of insulin-like growth factors I and II and multiplication-stimulating activity with receptors and serum carrier proteins. Endocrinology. 1980 Nov;107(5):1451–1459. doi: 10.1210/endo-107-5-1451. [DOI] [PubMed] [Google Scholar]
  27. Rinderknecht E., Humbel R. E. Primary structure of human insulin-like growth factor II. FEBS Lett. 1978 May 15;89(2):283–286. doi: 10.1016/0014-5793(78)80237-3. [DOI] [PubMed] [Google Scholar]
  28. Rinderknecht E., Humbel R. E. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem. 1978 Apr 25;253(8):2769–2776. [PubMed] [Google Scholar]
  29. Rosenfeld R. G., Baldwin D., Jr, Dollar L. A., Hintz R. L., Olefsky J. M., Rubenstein A. Simultaneous inhibition of insulin and somatomedin-C binding to cultured IM-9 lymphocytes by naturally occurring antireceptor antibodies. Diabetes. 1981 Nov;30(11):979–982. doi: 10.2337/diab.30.11.979. [DOI] [PubMed] [Google Scholar]
  30. Roth R. A., Maddux B., Wong K. Y., Styne D. M., Van Vliet G., Humbel R. E., Goldfine I. D. Interactions of a monoclonal antibody to the insulin receptor with receptors for insulin-like growth factors. Endocrinology. 1983 May;112(5):1865–1867. doi: 10.1210/endo-112-5-1865. [DOI] [PubMed] [Google Scholar]
  31. Sasaki N., Okabe T., Imai Y., Matsuzaki F., Kosaka K., Wakai K., Tsushima T. Basic peptide with insulin-like activity in human serum. Endocrinol Jpn. 1981 Apr;28(2):157–167. doi: 10.1507/endocrj1954.28.157. [DOI] [PubMed] [Google Scholar]
  32. Taylor S. I., Dons R. F., Hernandez E., Roth J., Gorden P. Insulin resistance associated with androgen excess in women with autoantibodies to the insulin receptor. Ann Intern Med. 1982 Dec;97(6):851–855. doi: 10.7326/0003-4819-97-6-851. [DOI] [PubMed] [Google Scholar]
  33. Van Wyk J. J., Svoboda M. E., Underwood L. E. Evidence from radioligand assays that somatomedin-C and insulin-like growth factor-I are similar to each other and different from other somatomedins. J Clin Endocrinol Metab. 1980 Jan;50(1):206–208. doi: 10.1210/jcem-50-1-206. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES