The Role of Insulin-Like Growth Factor Binding Proteins in Controlling the Expression of IGF Actions

  • David R. Clemmons


Although the insulin-like growth factors are secreted into blood and transported to peripheral tissues where they can act as traditional endocrine hormones, they are also synthesized and secreted by many types of cells and may exert their effects in the local microenvironment by autocrine or paracrine regulatory mechanisms. Specifically, IGF-I mRNA has been detected by in situ hybridization in connective tissue cells in several human tissues1. This mRNA appears to be translated and the peptide secreted since several types of cells in culture, such as fibroblasts, have been shown to secrete IGF-I2,3. Furthermore, blocking the binding of cell-secreted IGF-I to the type I IGF receptor will block mitogenic response in the fibroblasts that constitutively synthesize this peptide4. These data suggest that IGF-I is made by the connective tissue cell types within organs, and is secreted into interstitial fluids. Following secretion IGF-I not only binds to receptors on fibroblasts but it can bind also to receptors on cells of epithelial origin that contain receptors but do not contain IGF-I mRNA. Immunocytochemical localization studies have shown IGF-I to be present on the surfaces of many cell types that apparently do not synthesize and secrete this peptide5.


Growth Hormone Human Amniotic Fluid Placental Protein Somatomedin Binding Protein Connective Tissue Cell Type 
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  1. 1.
    Han, V.KM.; D’Ercole, A.J.; Lund, P.K.: Cellular location of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science 236: 193–197 (1987).PubMedCrossRefGoogle Scholar
  2. 2.
    Clemmons, D.R.; Elgin, R.G.; Han, V.KM.; Casella, S.J.; D’Ercole, A.J.; Van Wyk, J.J.: Cultured fibroblast monolayers secrete a protein that alters the cellular binding of somatomedin-C/insulin-like growth factor I. J.Clin.Invest. 77: 1548–1558 (1986).PubMedCrossRefGoogle Scholar
  3. 3.
    Hill, D.J.; Crace, C.J.; Fowler, L.; Holder A.T.; Milner D.G.: Cultured fetal rat myoblasts release peptide growth factors which are immunologically and biologically similar to somatomedin. J Cell Physiol 117: 349–358 (1984).CrossRefGoogle Scholar
  4. 4.
    Clemmons, D.R.; Van Wyk, J.J.: Evidence for a functional role of endogenously produced somatomedin-like peptide in the regulation of DNA synthesis in cultured human fibroblasts and porcine smooth muscle cells. J Clin Invest 75: 1914–1918 (1985).PubMedCrossRefGoogle Scholar
  5. 5.
    Han, V.K.M.; Hill, D.J.; Strain, A.J.; Towle, A.C.; Lauder, J.M.; Underwood, L.E.; D’Ercole, A.J.: Identification of somatomedin/insulin-like growth factor immunoreactive cells in the human fetus. Ped Res 22: 245–249 (1987).CrossRefGoogle Scholar
  6. 6.
    Nissley, S.P.; Rechler, M.M.: Insulin-like growth factors: biosynthesis, receptors and IGF-carrier proteins; in Li, C.H., ed. Hormonal Proteins and Peptides XII, pp. 127–203 (Academic Press, New York 1985).Google Scholar
  7. 7.
    Hintz, R.L.; Liu, F.: Demonstration of specific plasma protein binding sites for somatomedin. J. Clin. Endocrinol. Metab. 45: 988–995 (1977).PubMedCrossRefGoogle Scholar
  8. 8.
    Moses, A.C.; Freinkel, A.J.; Knowles, B.B.; Aden, D.P.: Demonstration that a human hepatoma cell line produces a specific insulin-like growth factor carrier protein. J.Clin.Endocrinol.Metab. 56: 1003–1008 (1983).PubMedCrossRefGoogle Scholar
  9. 9.
    Hill, D.J.; Clemmons, D.R.; Wilson, S.; Hall, V.K.M.; Strain, A.J.; Milner, D.G.: Immunological distribution of one form of insulin-like growth factor (IGF) binding protein and IGF peptides in human fetal tissues. J Mol Endo 3: 154–159 (1988).Google Scholar
  10. 10.
    Drop, S.LS.; Kortleve, D.J.; Guyda, H.J.: Isolation of a somatomedin binding protein from preterm human amniotic fluid: development of a radioimmunoassay. J.Clin.Endocrinol.Metab. 59: 899–905 (1984).PubMedCrossRefGoogle Scholar
  11. 11.
    Copeland, K.C.; Underwood, L.E.; Van Wyk, J.J.: Induction of immunoreactive somatomedin-C in human serum by growth hormone dose response relationships and effect on Chromatograph profiles. J Clin Endocrinol Metab 50: 690–698 (1980).PubMedCrossRefGoogle Scholar
  12. 12.
    Baxter, R.C.; Martin, J.L.: Radioimmunoassay of growth hormone dependent insulin-like growth factor binding protien in human plasma. J.Clin.Invest. 78: 1504–1512 (1986).PubMedCrossRefGoogle Scholar
  13. 13.
    Baxter, R.C.: Characterization of the acid labile subunit of the growth hormone dependent insulin like growth factor binding protein complex. J.Clin.Endocrinol.Metab. 67: 265–272 (1988).PubMedCrossRefGoogle Scholar
  14. 14.
    Wood, W.I.; Cathianes, G.; Henzel, W.J.; Winslow, G.A.; Spencer, S.A.; Hellmiss, R.; Martin, J.L.; Baxter, R.C.: Cloning and expression of the GH dependent insulin like growth factor binding protein. Mol.Endo. 2:1176–1185 (1988).CrossRefGoogle Scholar
  15. 15.
    Martin, J.L.; Baxter, R.C.: Insulin like growth factor binding protein from human plasma. Purification and characterization. J.Biol.Chem. 261: 8754–8760 (1988).Google Scholar
  16. 16.
    Wilkins, J.R.; D’Ercole, A.J.: Affinity labelled somatomedin-C insulin-like growth factor binding proteins: Evidence of growth hormone dependent subunit structures. J Clin Invest 75: 1350–1358 (1985).PubMedCrossRefGoogle Scholar
  17. 17.
    Hossenlopp, P.; Seurin, D.; Segovia, B.; Portolan, G.; Binoux, M.: Heterogeneity of insulin-like growth factor binding proteins and relationships between structure and affinity. 2 forms released by human and rat liver in culture. Eur.J.Biochem. 170: 133–142 (1987).PubMedCrossRefGoogle Scholar
  18. 18.
    Baxter, R.C.; Martin, J.L.; Wood, M.H.: Two immunoreactive binding proteins for insulin-like growth factors in human amniotic fluid: relationship to fetal maturity. J.Clin.Endocrin.Metabol. 65: 423–431 (1987).CrossRefGoogle Scholar
  19. 19.
    Drop, L.S.; Kortleve, D.J.; Guyda, H.J.; Posner, B.I.: Immunoassay of a somatomedin-binding protein from human amniotic fluid: levels in fetal, neonatal, and adult sera. J.Clin.Endocrinol.Metab. 59:908–915 (1984).PubMedCrossRefGoogle Scholar
  20. 20.
    Zapf, J.; Waldvogel, M.; Froesch, E.R.: Binding of nonsuppressible insulin-like activity to human serum: Evidence for a carrier protein. Arch.Biochem.Biophys. 168: 638–645 (1975).PubMedCrossRefGoogle Scholar
  21. 21.
    White, R.M.; Nissley, S.P.; Moses, A.C.; Rechler, M.M.; Johnsonbarvh, R.E.: The growth hormone dependence of somatomedin binding protein in human sera. J Clin Endocrinol Metab 53: 49–57 (1981).PubMedCrossRefGoogle Scholar
  22. 22.
    Koistinen, R.; Huhtala, M.L.; Stenman, U.H.; Seppala, M.: Purification of placental protein PP12 from human amniotic fluid and its comparison with PP12 from placenta by immunological, physicochemical and somatomedin-binding properties. Clin Chim Acta 164: 293–303 (1987).PubMedCrossRefGoogle Scholar
  23. 23.
    Povoa, G.; Enberg, G.; Jornvall, H.; Hall, K.: Isolation and characterization of a somatomedin binding protein from mid term human amniotic fluid. Eur.J.Biochem. 144: 199–204 (1984).PubMedCrossRefGoogle Scholar
  24. 24.
    Koistinen, R.; Kalkkinen, N.; Huhtala, M.L.; Seppala, M.; Bohn, H.; Rutanen, E.M.: Placental protein 12 is a decidual protein and has an identical N-terminal amino acid sequence with somatomedin binding protein in human amniotic fluid. Endocrinology 118: 1375–1184 (1986).PubMedCrossRefGoogle Scholar
  25. 25.
    Brewer, M.T.; Stetler, G.L.; Squires, C.H.; Thompson, R.C.; Busby, W.H.; Clemmons, D.R.: Cloning, characterization and expression of a human insulin- like growth factor binding protein. Biochem.Biophys.Res.Comm. 152: 1289–1297 (1988).PubMedCrossRefGoogle Scholar
  26. 26.
    Lee, Y.L.; Hintz, R.L.; James, D.M.; Lee, P.DK.; Shively, J.E.; Powell, D.R.: Insulin like growth factor IGF binding protein complementary deoxyribonucleic acid form human Hep G2 hepatoma cells: predicted protein sequence suggests an IGF binding domain different from those of IGF-I and IGF-II receptors. Mol.Endo. 3: 404–411 (1988).CrossRefGoogle Scholar
  27. 27.
    Julkunen, M.; Koistinen, R.; Setala, K.A.; Seppala, M.; Janne, O.; Kontula, K.: Primary structure of human insulin-like growth factor binding protein/placental protein 12 and tissue specific expression of its mRNA. FEBS Lett 236: 295–352 (1988).PubMedCrossRefGoogle Scholar
  28. 28.
    Rouslahti, E.; Pierschbacher, M.D.: Arg-Gly-Asp: A versatile recognition signal. Cell 44: 517–518 (1988).CrossRefGoogle Scholar
  29. 29.
    Shaw, G.; Kamen, R.P.: A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediating selective mRNA degradation. Cell 46: 659–667 (1986).PubMedCrossRefGoogle Scholar
  30. 30.
    Rutanen, E.-M.; Koistinen, R.; Wahlstrom, T.; Bohn, H.; Ranta, T.; Seppala, M.: Synthesis of placental protein 12 by human decidua. Endocrinol. 116: 1304–1309 (1985).CrossRefGoogle Scholar
  31. 31.
    Rutanen, E.-M.; Koistinen, R.; Sjoberg, J.; Julkunen, M.; Wahlstrom, T.; Bohn, H.; Seppala, M.: Synthesis of placental protein 12 by human endometrium. Endocrinol. 118: 1067–1071 (1986).CrossRefGoogle Scholar
  32. 32.
    Thrailkill, K.; Clemmons, D.R.; Handwerger, S.: Control of Secretion of IGF 25 kDa binding protein by human decidual cells. Annual Meeting of the American Society of Clinical Investigation. Washington, D.C.,: (1989).(Abstract)Google Scholar
  33. 33.
    Hill, D.J.; Camacho-Hubner, C.; Rashid, P.; Strain, A.J.; Clemmons, D.R.: Insulin like growth factor binding protein secretion by human fibroblasts: Dependency on cell density and IGF peptides. Journal of Endocrinology (1989).(in press)Google Scholar
  34. 34.
    Camacho-Hubner, C.; McCusker, R.H.; Clemmons, D.R.: Insulin like growth factor binding protein secretion by human tumor cells is horraonally regulated. 70th Annual Meeting of the Endocrine Society (1988). Abstract #526.Google Scholar
  35. 35.
    McCusker, R.M.; Clemmons, D.R.: Insulin like growth factor binding protein secretion by muscle cells: Effect of cellular differentiation and proliferation. J.Cell Physiol. 137: 505–512 (1988).PubMedCrossRefGoogle Scholar
  36. 36.
    McCusker, R.H.; Camacho-Hubner, C.; Clemmons, D.R.: Identification of the types of insulin like growth factor binding proteins that are secreted by muscle cells in vitro. J.Biol.Chem. in press: (1989).Google Scholar
  37. 37.
    Adams, S.O.; Kapadia, M.; Mills, B.; Daughaday, W.H.: Release of insulin-like growth factors and binding proteins into serum-free medium of cultured human fibroblasts. Endocrinol. 115: 520–526 (1984).CrossRefGoogle Scholar
  38. 38.
    Martin, J.L.; Baxter, R.C.: Insulin like growth factor binding proteins IGF-BP’s produced by human skin fibroblasts immunological relationship to other IGF-BP’s. J Clin Endocrinol Metab 123: 1907–1915 (1989).Google Scholar
  39. 39.
    Busby, W.H.; Snyder, D.K.; Clemmons, D.R.: Radioimmunoassay of a 26000 dalton plasma insulin like growth factor binding protein: Control by nutritional variables. J.Clin.Endocrinol.Metab. 67: 1231–1236 (1988).CrossRefGoogle Scholar
  40. 40.
    Baxter, R.C.; Colwell, C.T.: Diurnal rhythm of growth hormone dependent binding protein for insulin-like growth factors in human plasma. J.Clin.Endocrinol.Metab. 65: 432–440 (1987).PubMedCrossRefGoogle Scholar
  41. 41.
    Sukkari, A.M.; Koistinen, V.A.; Rutanen, E.M.; Jarvinen, H.; Karonen, S.L.; Seppala, M.: Insulin regulates serum levels of low molecular weight insulin like growth factor binding protein. J.Clin.Endocrinol.Metab. 66: 266–273 (1988).CrossRefGoogle Scholar
  42. 42.
    Sukkari, A.M.; Koivisto, V.A.; Koistinen, R.; Seppala, M.; Yki-Jarvinen, H.: Dose response characteristics for suppression of low molecular weight plasma insulin like growth factor binding proteins by insulin. J Clin Endocrinol Metab 68: 135–140 (1989).CrossRefGoogle Scholar
  43. 43.
    Povoa, G.; Roovete, A.; Hall, K.: Cross-reaction of serum somatomedin-binding protein in a radioimmunoassay developed for somatomedin-binding protein isolated from human amniotic fluid. Acta Endocrinol. 107: 563–570 (1984).PubMedGoogle Scholar
  44. 44.
    Iino, K.; Sjoberg, J.; Seppala, M.: Elevated circulating levels decidual protein placental protein 12 in preclampsia. Obst and Gyn 68: 58–60 (1986).Google Scholar
  45. 45.
    Iino, K.; Seppala, M.; Heinonen, P.K.; Scipponen, P.; Rutanen, E.M.: Elevated levels of somatomedin binding protein PP12 in patients with ovarian cancer. Cancer 58: 2294–3000 (1986).PubMedCrossRefGoogle Scholar
  46. 46.
    Rutanen, E.M.; Wahlstrom, T.; Koistinen, R.; Scipponen, P.; Jalanko, H.: Plancental protein 12 in primary liver cancer and cirrhosis. Tumor Biology 5: 95–102 (1984).PubMedGoogle Scholar
  47. 47.
    Elgin, R.G.; Busby, W.H.; Clemmons, D.R.: An insulin-like growth factor (IGF) binding protein enhances the biologic response to IGF-I. Proc.Natl.Acad.Sci. 84: 3254–3258 (1987).PubMedCrossRefGoogle Scholar
  48. 48.
    Busby, W.H.; Klapper, D.G.; Clemmons, D.R.: Purification of a 31000 dalton insulin like growth factor binding protein from human amniotic fluid. J.Biol.Chenu 263: 14203–14210 (1988).Google Scholar
  49. 49.
    De Mellow, J.SM.; Baxter, R.C.: Growth hormone dependent insulinlike growth factor binding protein both inhibits and potentiates IGF-I stimulated DNA synthesis in skin fibroblasts. Biochem. Biophys. Res. Commun. 156: 199–204 (1988).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • David R. Clemmons
    • 1
  1. 1.Division of Endocrinology, CB #7170University of North Carolina School of MedicineChapel HillUSA

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