Insulin-Like Growth Factor Binding Protein Control Secretion and Mechanisms of Action

  • David R. Clemmons
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 293)


The insulin-like growth factors are present in extracellular fluids bound to high affinity soluble binding proteins. This localization of IGF-I and II in the pericellular microenvironment in association with IGF binding proteins suggests a role for these proteins in controlling the amount of IGF that is transported to specific cell types and the amount of growth factor that is available to associate with type I and II IGF receptors. This theory has recently been strengthened by the observation that each of the IGF binding proteins that have been purified has an affinity constant that is higher than the type I IGF receptor.1 Therefore these proteins have the capacity to partition IGF-I and II between receptors and the extracellular fluid compartment. Other proposed functions of the IGF binding proteins include acting as a high affinity carriers in plasma and preventing uncontrolled efflux of the IGFs from the vascular space. In blood IGF-I and II form a 150 kilodalton complex with IGF binding protein-3 (IGFBP-3)2. The complex is not transported across intact capillaries and forms a reservoir of IGF that is available for utilization by peripheral tissues. Since IGF-I and II are believed to be secreted into blood and utilized by peripheral tissues at a relatively constant rate, the binding protein in the vascular compartment may provide a means for maintaining a sustained amount of growth factor that is available for transport into extracellular fluids.


Growth Hormone Decidual Cell Acid Labile Subunit Extracellular Fluid Compartment Pericellular Microenvironment 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Baxter, R.C. and Martin, J.L., Binding proteins for insulin like growth factors: Structure, Regulation and Function, Prog. Growth. Fact. Res. 1:49–68 (1989).CrossRefGoogle Scholar
  2. 2.
    Baxter, R.C., Martin, J.L. and Beniac, V.A., High molecular weight insulin-like growth factor binding protein complex: purification and properties of the acid-labile subunit from human serum, J Biol Chem264:11843–11848 (1989).PubMedGoogle Scholar
  3. 3.
    Bar, R.S., Clemmons, D.R., Busby, W.H., et al, Transcapillary permeability and subendothelial distribution of endothelial and amniotic fluid (IGFBP-1) IGF-binding proteins in the rat heart, Endocrinology 127: 1078–1086 (1990).PubMedCrossRefGoogle Scholar
  4. 4.
    Bar, R.S., Boes, M., Clemmons, D.R., et al, Insulin differentially alters transcapillary movement of intravascular IGFBP-1, IGFBP-2 and endothelial cell IGF binding proteins in rat heart, Endocrinology127:497–499 (1990).PubMedCrossRefGoogle Scholar
  5. 5.
    Bar, R.S., Boes, M., Dake, B.L., et al., Tissue localization of perfused endothelial cell IGF bindign protein is markedly altered by association with IGF-I. Endocrinol. 127:3243–3245 (1990).CrossRefGoogle Scholar
  6. 6.
    Brewer, M.T., Stetler, G.L., Squires, C.H., et al, Cloning, characterization and expression of a human insulin-like growth factor binding protein, Biochem.Biophys.Res.Comm. 152:1289–1297 (1988).PubMedCrossRefGoogle Scholar
  7. 7.
    Brown, A.L., Chairiotti, L., Orlowski, C.C., et al, Nucleotide sequence and expression of a cDNA cloning encoding a fetal rat binding protein for insulin-like growth factors, J.Biol.Chem. 264: 5148–5154 (1989).PubMedGoogle Scholar
  8. 8.
    Wood, W.I., \Cachianes, G., Henzel, W.J., et al, Cloning and expression of the GH dependent insulin like growth factor binding protein, Mol. Endo. 2:1176–1185 (1988).CrossRefGoogle Scholar
  9. 9.
    Shimasaki, S., Shimonaka, M., Ui, M., et al, Structural characterization of a follicle-stimulating hormone action inhibitor in porcine ovarian follicular fluid.’ Its identification as the insulinlike growth factor-binding protein, J. Biol. Chem. 265: 2198–2202 (1990).PubMedGoogle Scholar
  10. 10.
    Zapf, J., Bom, W., Chang, J.Y., et al, Isolation and NH2-terminal amino acid sequences of rat serum carrier proteins for insulin-like growth factors, Biochem.Biophys.Res.Comm. 156: 1187–1194 (1988).PubMedCrossRefGoogle Scholar
  11. 11.
    Baxter, R.C. and Martin, J.L., Radioimmunoassay of growth hormone dependent insulin-like growth factor binding protein in human plasma, J.Clin.Invest. 78:1504–1512 (1986).PubMedCrossRefGoogle Scholar
  12. 12.
    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
  13. 13.
    Baxter, R.C. and Martin, J. L., Structure of the Mr 140,000 growth hormone-dependent insulin-like growth factor binding protein complex: determination by reconstitution and affinity labeling, PNAS 86:6898– 6902 (1989).PubMedCrossRefGoogle Scholar
  14. 14.
    Van Wyk, J.J. The somatomedins: Biological actions and physiological control mechanisms. In: Hormonal proteins and peptides ,edited by Li, C.H. Orlando: Academic Press, 1985, p. 81–125.Google Scholar
  15. 15.
    Clemmons, D.R., Thissen, J.P., Maes, M., et al, Insulin-like growth factor-I (IGF-I) infusion into hypophysectomized or protein-deprived rats induces specific IGF binding proteins in serum, Endocrinology125:2967–2972 (1989).PubMedCrossRefGoogle Scholar
  16. 16.
    Thissen, J. P., Underwood, L. E., Maiter, D., et al, Failure of IGF-I infusion to promote growth in protein restricted rats despite normalization of serum IGF-I concnetrations, Endocrinology, in press (1991).Google Scholar
  17. 17.
    Suikkari, A.M., Koivisto, V.A., Koistinen, R., et al, Dose response characteristics for suppression of low molecular weight plasma insulin like growth factor binding protein by insulin, J. Clin. Endocrinol. Metab. 68:135–140 (1989).PubMedCrossRefGoogle Scholar
  18. 18.
    Busby, W.H., Snyder, D.K. and Clemmons, D.R., Radioimmunoassay of a 26,000 dalton plasma insulin like growth factor binding protein: Control by nutritional variables, J.CIin.Endocrinol.Metab. 67: 1225– 1230 (1988).CrossRefGoogle Scholar
  19. 19.
    Lewitt, M.S. and Baxter, R.C., Inhibitors of glucose uptake stimulate the production of insulin-like growth factor-binding protein (IGFBP-1) by human fetal liver, Endocrinol. 126: 1527–1533 (1990).CrossRefGoogle Scholar
  20. 20.
    Snyder, D.K. and Clemmons, D.R.,Insulin dependent regulation of IGFBP-1, J. Clin. Endocrinol. Metab. 71:1632–1638 (1990).PubMedCrossRefGoogle Scholar
  21. 21.
    Conover, CA.,Regulation of insulin-like growth factor (IGF)-binding protein synthesis by insulin and IGF-I in cultured bovine fibroblasts, Endocrinology 126: 3139–3145 (1990).PubMedCrossRefGoogle Scholar
  22. 22.
    Ooi, G.T., Orlowski, C.C., Brown, A.L., et al,Different tissue distribution and hormonal regulation of messenger RNAs encoding rat insulin-like growth factor binding proteins-1 and 2, Mol. Endo. 4:321– 328 (1990).CrossRefGoogle Scholar
  23. 23.
    Unterman, T.G., Patel, K., Kumar Mahathre, V., et al, Regulation of low molecular weight insulin-like growth factor binding proteins in experimental diabetes mellitus, Endocrinol. 126:2614–2626 (1990).CrossRefGoogle Scholar
  24. 24.
    Orlowski, C.C., Brown, A.L., Ooi, G.T., et al, Tissue, developmental and metabolic regulation of messenger ribonucleic acid encoding a rat insulin-like growth factor-binding protein, Endocrinology 126:644–652 (1990).PubMedCrossRefGoogle Scholar
  25. 25.
    Hardouin, S., Gourmelen, M., Noguiez, P., et al, Molecular forms of serum insulin-like growth factor (IGF)-binding proteins in man: relationship with growth hormone and IGFs and physiological significance, J. Clin. Endocrinol. Metab. 69:1291–1301 (1989).PubMedCrossRefGoogle Scholar
  26. 26.
    Cohick, W. S., Busby, W. H., Clemmons, D. R. and Bauman, D. E., Insulin-like growth factor binding proteins (IGFBP) in serum of lactating cows treated with recombinant in-methionlyl bovine somatotropin (BST). Presented to the Annual Meeting of the American Society of Animal Science, Ames Iowa, July, 1990.Google Scholar
  27. 27.
    McCusker, R.H., Campion, D.R., Jones, W.K. and Clemmons, D.R., The insulin-like growth factor-binding proteins of porcine serum: Endocrine and nutritional regulation, Endocrinology 125:501–509 (1989).PubMedCrossRefGoogle Scholar
  28. 28.
    Martin, J.L. and Baxter, R.C., Insulin like growth factor binding proteins IGF-BP’s produced by human skin fibroblasts immunological relationship to other human IGF-BP’s, Endocrinology 123: 1907–1915 (1988).PubMedCrossRefGoogle Scholar
  29. 29.
    Hill, D.J., Cajmacho-Hubner, C., Rashid, P., et al, Insulin like growth factor binding protein secretion by human fibroblasts: Dependence on cell density and IGF peptides, J. Endocrinol. 122:87–98 (1989).PubMedCrossRefGoogle Scholar
  30. 30.
    McCusker, R.H. and Clemmons, D.R., Insulin-like growth factor-binding proteins (IGF-BPs) secretion by muscle cells: Effect of cellular differentiation and proliferation, J. Cell. Physiol. 137:505–512 (1988).PubMedCrossRefGoogle Scholar
  31. 31.
    Tollefsen, S.E., Lajara, R., McCusker, R.H., et al, Insulin-like growth factors (IGF) in muscle development, J.Biol.Chem. 264:13810– 13817 (1989).PubMedGoogle Scholar
  32. 32.
    Thrailkill, K.M., Clemmons, D.R., Busby, W.H. and Handwerger, S.R., Differential regulation of IGF binding protein (IGFBP) secretion from human decidual cells by IGF-I, insulin and relaxin, J. Clin. Invest. 86:878–883 (1990).CrossRefGoogle Scholar
  33. 33.
    Clemmons, D.R., Thrailkill, K.M., Handwerger, S.R. and Busby, W.H., Three distinct forms of insulin-like growth factor binding proteins are released by decidual cells in culture, Endocrinology 127:643–650 (1990).PubMedCrossRefGoogle Scholar
  34. 34.
    Melby, A. E., Mohn, K. L., Laz, T., et al, The gene encoding the rat low molecular weight IGF binding protein gene is highly expressed immediate early gene in liver regeneration, Mol. Cell. Biol. in press (1991).Google Scholar
  35. 35.
    Clemmons, D.R., Camacho-Hubner, C., Coronado, E. and Osborne, C.K., Insulin-like growth factor binding protein secretion by breast carcinoma cell lines: Correlation with estrogen receptor status, Endocrinology 127:2679–2686 (1990).PubMedCrossRefGoogle Scholar
  36. 36.
    Camacho-Hubner, C., McCusker, R.H. and Clemmons, D.R., Regulation of insulin-like growth factor binding protein secretion by human tumor cells in vitro, J. Cell. Physiol. submitted.Google Scholar
  37. 37.
    McCusker, R. H., Busby, W. H., Dehoff, M., et al, Insulin-like growth factors (IGF) binding to cell monolayers is modulated by the addition of binding proteins (IGFBPs), Presented to the Endocrine Society, Atlanta, GH, June 22, 1990.Google Scholar
  38. 38.
    McCusker, R.H., Camacho-Hubner, C., Bayne, M.L., et al, Insulin-like growth factor (IGF) binding to human fibroblast and glioblastoma cells: The modulating effect of cell released IGF binding proteins (IGFBPs), J. Cell. Physiol. 144:244–254 (1990).PubMedCrossRefGoogle Scholar
  39. 18.39.
    Elgin, R.G., Busby, W.H. and Clemmons, D.R., An insulin-like growth factor binding protein enhances the biogic response to IGF-I, Proc.Natl.Acad.Sci. 84:3313–3318 (1987).CrossRefGoogle Scholar
  40. 40.
    Bourner, M.J., Busby, W.H., Siegel, N.R., et al, Purification, structural determination and characterization of biologic and binding activity of bovine insulin-like growth factor binding protein-2, J. Biol. Chem. in press (1991).Google Scholar
  41. 41.
    Busby, W.H., Klapper, D.G. and Clemmons, D.R., Purification of a 31000 dalton insulin like growth factor binding protein from human amniotic fluid, J.Biol.Chem. 263:14203–14210 (1988).PubMedGoogle Scholar
  42. 42.
    Ritvos, O., Ranta, T., Jalkanen, J., et al, Insulin-like growth factor (IGF) binding protein from human decidua inhibits the binding and biological action of IGF-I in cultured choriocarcinoma cells, Endocrinology 122: 2150–2157 (1988).PubMedCrossRefGoogle Scholar
  43. 43.
    Busby, W.H., Hossenlopp, P., Binoux, M. and Clemmons, D.R., Purified preparations of the amniotic fluid IGF binding protein contain multimeric forms that are biologically active, Endocrinol. 125:773–777 (1989).CrossRefGoogle Scholar
  44. 44.
    Mukku, V.R., and Chu, H., Phosphorylation of insulin-like growth factor binding protein by mammalian cells, Presented to the Endocrine Society Meeting, Abstract 190, 1990.Google Scholar
  45. 45.
    Jones, J.I., and Clemmons, D.R., The bioactivity of an insulin-like growth factor binding protein is modulated by serine phosphorylation, To Be Presented to the Southern Society for Clinical Investigation Meeting, 1991.Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • David R. Clemmons
    • 1
  1. 1.Division of EndocrinologyUniversity of North CarolinaChapel HillUSA

Personalised recommendations