Role of Insulin-like Growth Factor Binding Proteins in Modulating Insulin-like Growth Factor Action

  • D. R. Clemmons
Conference paper


The insulin-like growth factor (IGF) binding proteins are high affinity, soluble carrier proteins that are present in all extracellular fluids. Six structurally distinct forms of IGF binding proteins have been cloned and their cDNA sequences determined (Shimasaki et al. 1991). Although all six share structural homology many of their features appear to be distinct. Structural characterization and purification of these proteins has made it possible to more rationally discern the molecular mechanisms by which they function to modify IGF actions. All six proteins have been shown to contain a highly conserved cysteine pattern and disruption of any of the disulfide linkages appears to lead to a substantial loss in IGF binding capacity, suggesting that the cysteine linkage pattern is necessary to form the correct tertiary structure for maximum IGF binding (Brinkman et al. 1991). Structural characterization has also shown that numerous post-translational modifications of these proteins can occur. Specifically IGFBP-1 through 5 have been shown to be proteolytically cleaved. These proteases exist in a variety of physiologic fluids and therefore are capable of modifying binding protein activity by eliminating IGF binding following proteolytic cleavage. In addition each of these proteins appears to be glycosylated. The functional significance of glycosylation has not been determined at the present time. Finally several of the proteins appear to be phosphorylated. The biologic significance of phosphorylation has been determined in the case of IGFBP-1 where it has been shown to modulate both IGF binding affinity and cellular responsiveness to this growth factor.


Breast Tumor Epithelial Cell Normal Connective Tissue Cell Conserve Cysteine Pattern 
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. Bar RS, Boes M, Clemmons DR et al. (1990a) Insulin differentially alters transcapillary movement of intravascular IGFBP-1, IGFBP-2 and endothelial cell IGF binding proteins in rat heart. Endocrinology 127:497–499.PubMedCrossRefGoogle Scholar
  2. Bar RS, Clemmons DR, Boes M et al. (1990b) Transcapillary permeability and subendothelial distribution of endothelial and amniotic fluid IGF-binding proteins in rat heart. Endocrinology 127:1078–1086.PubMedCrossRefGoogle Scholar
  3. Baxter RC (1990) Criculating levels and molecular distribution of the acid-labile (alpha) subunit of the high molecular weight insulin-like growth factor binding protein complex. J Clin Endocrinol Metab 70:1347–1353.PubMedCrossRefGoogle Scholar
  4. Baxter RC, Martin JL (1986) Radioimmunoassay of growth hormone dependent insulin-like growth factor binding protein in human plasma. J Clin Invest 78:1504–1512.PubMedCrossRefGoogle Scholar
  5. Baxter RC, Martin JL (1989) Structure of the Mr 140000 growth hormone-dependent insulin-like growth factor binding protein complex: determination by reconstitution and affinity labeling. Proc Natl Acad Sci USA 86:6898–6902.PubMedCrossRefGoogle Scholar
  6. Baxter RC, Martin JL, Beniac VA (1989) High molecular weight insulin-like growth factor binding protein complex: purification and properties of the acid-labile subunit from human serum. J Biol Chem 264:11843–11848.PubMedGoogle Scholar
  7. Brinkman A, Korfleve DJ, Zwarthoff EC, Drop SLS (1991) Mutation in the c-terminal part of insulin-like growth factor binding protein-1 results in diminished function and loss of binding capacity. Mol Endocrinol 5:987–994.PubMedCrossRefGoogle Scholar
  8. Camacho-Hubner C, Busby WH, McCusker RH, Wright G, Clemmons DR (1992) Identification of the forms of insulin-like growth factor binding proteins produced by human fibroblasts and the mechanisms that regulate their secretion. J Biol Chem 267:11949–11956.PubMedGoogle Scholar
  9. Clemmons DR, Elgin RG, Han VKM, Casella SJ, D’Ercole AJ, Van Wyk JJ (1986) Cultured fibroblast monolayers secrete a protein that alters the cellular binding of somatomedin-C/insulin-like growth factor I. J Clin Invest 77:1548–1556.PubMedCrossRefGoogle Scholar
  10. Clemmons DR, Thissen JR, Maes M, Ketelslegers JM, Underwood LE (1989) Insulin-like growth factor-I (IGF-I) infusion into hypophysectomized or protein-deprived rats induces specific IGF binding proteins in serum. Endocrinology 125:2967–2972.PubMedCrossRefGoogle Scholar
  11. Clemmons DR, Camacho-Hubner C, Coronado EB, Osborne CK (1990) Insulin-like growth factor binding protein secretion by breast carcinoma cell lines: correlation with estrogen receptor status. Endocrinology 127:2679–2686.PubMedCrossRefGoogle Scholar
  12. Conover CA (1992) Potentiation of insulin-like growth factor IGF action by IGF binding protein-3. Studies of an underlying mechanism. Endocrinology 130:3191–3200.PubMedCrossRefGoogle Scholar
  13. Davenport ML, Clemmons DR, Miles MV, Camacho-Hubner C, D’Ercole AJ, Underwood LE (1990) Regulation of serum insulin-like growth factor I (IGF-I) and IGF binding proteins during rat pregnancy. Endocrinology 127:1278–1286.PubMedCrossRefGoogle Scholar
  14. Davenport ML, Isley WI, Pucilowska J et al. (1992a) Insulin-like growth factor binding protein-3 proteolysis is induced following elective surgery. J Clin Endocrinol Metab 130:2505–2512.Google Scholar
  15. Davenport ML, Pucilowska J, Clemmons DR, Lundblad R, Spencer JA, Underwood LE (1992b) Tissue specific expression of IGFBP-3 protease activity during rat pregnancy. Endocrinology 75:590–595.Google Scholar
  16. De Mellow JSM, Baxter RC (1988) Growth hormone dependent insulin-like growth factor binding protein both inhibits and potentiates IGF-I stimulated DNA synthesis in skin fibroblasts. Biochem Biophys Res Commun 156:199–204.PubMedCrossRefGoogle Scholar
  17. Fontana JA, Burrows-Mezu A, Clemmons DR, LeRoith D (1991) Retinoid modulation of insulin-like growth factor binding proteins and inhibition of breast carcinoma proliferation. Endocrinology 128:1115–1122.PubMedCrossRefGoogle Scholar
  18. Fowlkes J, Freemark M (1992) Regulation of high affinity insulin-like growth factor binding proteins: a novel IGF dependant protease regulating IGFBP-4. Endocrinology 131:2071–2076.PubMedCrossRefGoogle Scholar
  19. Frost JP, Tseng LT (1991) Insulin-like growth factor binding protein-1 is phosphorylated by cultured human endometrial cells and multiple protein kinases in vitro. J Biol Chem 266:18082–18088.PubMedGoogle Scholar
  20. Guidice LC, Farrell EM, Pham M, Lawson G, Rosenfeld RE (1990) Insulin like growth factor binding protein-3 in maternal serum throughout gestation and in the puerperium: effects of pregnancy associated protease activity. J Clin Endocrinol Metab 77:806–816.CrossRefGoogle Scholar
  21. Hardouin S, Hossenlopp P, Segovia B, Portolan G, Lassarre C, Binoux M (1987) Heterogeneity of insulin-like growth factor binding proteins and relationships between structure and affinity. 1. Circulating forms in man. Eur J Biochem 170:121–132.PubMedCrossRefGoogle Scholar
  22. Holly JMP, Smith CP, Dunger DB et al. (1989) Relationship between the pubertal fall in sex hormone binding globulin and insulin-like growth factor binding protein-1. A synchronized approach to pubertal development? Clin Endocrinol 31:277–284.CrossRefGoogle Scholar
  23. Hossenlopp P, Sergovia B, Vaparre C, Rohgarri M, Bredon M, Buoix M (1990) Binding proteins in the 150k complex in pregnancy. J Clin Endocrinol Metab 71:797–805.PubMedCrossRefGoogle Scholar
  24. Jones JI, D’Ercole AJ, Camacho-Hubner C, Clemmons DR (1991) Phosphorylation of insulin-like growth factor binding protein in cell culture and in vivo: effects on affinity for IGF-I. Proc Natl Acad Sci USA 88:7481–7485.PubMedCrossRefGoogle Scholar
  25. Jones JI, Gockerman A, Clemmons DR (1993) Insulin like growth factor binding protein-5 binds to extracellular matrix and is phosphoylated. 74th annual meeting of the Endocrine Society, abstract no 1284, San Antonio (Texas).Google Scholar
  26. Martin JL, Baxter RC (1992) Insulin like growth factor binding protein-3 biochemistry and physiology. Growth Regul 2:80–87.Google Scholar
  27. McCusker RH, Camacho-Hubner C, Bayne ML, Cascieri MA, Clemmons DR (1990) 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 144:244–253.PubMedCrossRefGoogle Scholar
  28. Moser DR, LoweWL, Dubie BL, Booth BA, Clemmons DR, Bar RS (1992) Endothelial cells express insulin-like growth factor binding proteins 2 to 6. Mol Endocrinol (in press).Google Scholar
  29. Mukku VA, Courter RG, Gorman C, Parker M, Larsen B, Wood WI (1989) Expression, purification and characterization of recombinant BP-53, the GH-dependent IGF binding protein. In: Drop SLS, Hintz RL (eds) Insulin-like growth factor binding proteins. Elsevier, Amsterdam, pp 65–72 (Congress series 881)Google Scholar
  30. Rechler MM, Brown AL (1992) Insulin like growth factor binding proteins: Gene structure and expression. Growth Regul 2:55–68.PubMedGoogle Scholar
  31. Ritvos O, Ranta T, Jalkanen J et al. (1988) 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.PubMedCrossRefGoogle Scholar
  32. Rouslahti E, Pierschbaker MD (1988) New perspectives in cell adhesion: RGD and integrins. Science 238:491–497.CrossRefGoogle Scholar
  33. Schmid C, Rutishauser J, Schlapfer I, Froesch ER, Zapf J (1991) Intact but not truncated insulin-like growth factor binding protein-3 blocks IGF-I induced stimulation of osteoblasts: control of IGF signalling to bone cells by IGFBP-3 specific proteolysis. Biochem Biophys Res Commun 179:579–585.PubMedCrossRefGoogle Scholar
  34. Shimasaki S, Shimonaka M, Ling N (1991) Identification of five different insulin-like growth factor binding proteins (IGFBPs) from adult rat serum and molecular cloning of a novel IGFBP in rat and human. J Biol Chem 266:10646–10653.PubMedGoogle Scholar
  35. Suikkari AM, Baxter RC (1991) Insulin like growth factor binding protein-3 in pregnancy serum binding native IGF-I but not iodo-IGF-I. J Clin Endocrinol Metab 73:1337–1379.CrossRefGoogle Scholar
  36. Thrailkill KM, Clemmons DR, Busby WH, Handwerger SR (1990) Differential regulation of insulin-like growth factor binding protein secretion from human decidual cells by IGF-I, insulin and relaxin. J Clin Invest 86:878–883.CrossRefGoogle Scholar
  37. Yee D, Favoni RE, Lupu R et al. (1989) The insulin-like growth factor binding protein BP-25 is expressed by human breast cancer cells. Biochem Biophys Res Commun 158:38–44.PubMedCrossRefGoogle Scholar
  38. Zapf J, Schmid C, Guler HP et al. (1990) Regulation of binding proteins for insulin-like growth factors in humans: increased expression of IGF binding proteins during treatment of healthy adults and in patients with extrapancreatic tumors. J Clin Invest 86:952–961.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • D. R. Clemmons

There are no affiliations available

Personalised recommendations