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Heparin-binding growth factors and their receptors

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Abstract

Heparin-binding growth factors modulate diverse biological activities including cellular proliferation, cellular differentiation, morphogenesis, and angiogenesis. Biochemical characterization for two members of the heparin-binding growth factor family, acidic and basic fibroblast growth factors, is extensive, while characterization of the remaining five members is forthcoming. Cell surface receptors have been identified for acidic and basic fibroblast growth factors, but little is known concerning their sites of action in vivo or the mechanisms involved in transducing the energy of growth factor binding to a biological response. An understanding of the biological basis for the diversity of the heparin binding growth factor family and the in vivo actions of these factors will prove a major challenge to future research efforts.

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References

  1. Abraham JA, Mergia A, Whang JL, Tumolo A, Friedman J, Hjerrild KA, Gospodarowicz D and Fiddes JC (1986) Nucleotide sequence of a bovine clone encoding the angiogenic protein, basic fibroblast growth factor. Science 233: 545–8.

    Google Scholar 

  2. Baird A, Esch F, Mormede P, Ueno N, Ling N, Bohlen P, Ying SY, Wehrenberg WB and Guillemin R (1986) Molecular characterization of fibroblast growth factor: distribution and biological activities in various tissues. Recent Prog. Horm. Res. 42: 143–205.

    Google Scholar 

  3. Bashkin P, Doctrow S, Klagsbrun M, Svahn CM, Folkman J and Vlodavsky I (1989) Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules. Biochemistry 28: 1737–1743.

    Google Scholar 

  4. Blam SB, Mitchell R, Tischer E, Rubin JS, Silva M, Silver S, Fiddes JC, Abraham JA and Aaronson SA (1988) Addition of growth hormone secretion signal to basic fibroblast growth factor results in cell transformation and secretion of aberrant forms of the protein. Proc. Natl. Acad. Sci. USA. 85: 6992–6.

    Google Scholar 

  5. Banquet PR, Patte C, Fayein N and Courtois Y (1989) Identification and isolation from bovine epithelial lens cells of two basic fibroblast growth factor receptors that possess bFGF-enhanced phosphorylation activities. Biochem. Biophys. Res. Commun. 160: 1124–1131.

    Google Scholar 

  6. Bohlen P, Baird A, Esch F, Ling N and Gospodarowicz D (1984) Isolation and partial molecular characterization of pituitary fibroblast growth factor. Proc. Natl. Acad. Sci. Usa. 81: 5364–8.

    Google Scholar 

  7. Braunhut S, Gudas L, Kurokawa T, Sasse J and D'Amore P (1989) Expression of fibroblast growth factor by F9 terato-carcinoma cells as a function of differentiation. J. Cell Biol. 108: 2467–2476.

    Google Scholar 

  8. Brown KD, Blakeley DM and Brigstock DR (1989) Stimulation of polyphosphoinositide hydrolysis in Swiss 3T3 cells by recombinant fibroblast growth factors. Febs. Lett. 247: 227–231.

    Google Scholar 

  9. Burgess W and Maciag T (1989) The heparin-binding (fibroblast) growth factor family of proteins. Annu. Rev. Biochem. 58: 575–606.

    Google Scholar 

  10. Burrus L and Olwin B (1989) Isolation of a receptor for acidic and basic fibroblast growth factor from embryonic chick. J. Biol. Chem. (In press)

  11. Clegg CH, Linkhart TA, Olwin BB and Hauschka SD (1987) Growth factor control of skeletal muscle differentiation: commitment to terminal differentiation occurs in G1 phase and is repressed by fibroblast growth factor. J. Cell Biol. 105: 949–56.

    Google Scholar 

  12. Coughlin SR, Barr PJ, Cousens LS, Fretto LJ and Williams LT (1988) Acidic and basic fibroblast growth factors stimulate tyrosine kinase activity in vivo. J. Biol. Chem. 263: 988–93.

    Google Scholar 

  13. Courty J, Dauchel MC, Mereau A, Sadet J and Barritault D (1988) Presence of basic fibroblast growth factor receptors in bovine brain membranes. J. Biol. Chem. 263: 11217–20.

    Google Scholar 

  14. Damon DH, Lobb RR, D'Amore PA and Wagner JA (1989) Heparin potentiates the action of acidic fibroblast growth factor by prolonging its biological half-life. J. Cell Physiol. 138: 221–226.

    Google Scholar 

  15. Delli-Bovi P, Curatola AM, Kern FG, Greco A, Ittmann M and Basilico C (1987) An oncogene isolated by transfection of Kaposi's sarcoma DNA encodes a growth factor that is a member of the FGF family. Cell 50: 729–37.

    Google Scholar 

  16. Deuel T (1987) Polypeptide growth factors: Roles in normal and abnormal cell growth. Ann. Rev. Cell Biol. 3: 443–492.

    Google Scholar 

  17. Dickson C and Peters G (1987) Potential oncogene product related to growth factors [letter]. Nature (Lond.) 326: 833.

    Google Scholar 

  18. DiMario J, Buffinger N, Yamada S and Strohman RC (1989) Fibroblast growth factor in the extracellular matrix of dystrophic (mdx) mouse muscle. Science 244: 688–690.

    Google Scholar 

  19. DiSorbo D, Shi EG and McKeehan WL (1988) Purification from human hepatoma cells of a 130-kDa membrane glycoprotein with properties of the heparin-binding growth factor receptor. Biochem. Biophys. Res. Commun. 157: 1007–1014.

    Google Scholar 

  20. Feige JJ and Baird A (1988) Glycosylation of the basic fibroblast growth factor receptor. The contribution of carbohydrate to receptor function. J. Cell Biol. 107: 1611–9.

    Google Scholar 

  21. Finch PW, Rubin JS, Miki T, Ron D and Aaronson SA (1989) Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science (USA) 245: 752–755.

    Google Scholar 

  22. Florkiewicz R and Sommer A (1989) Human basic fibroblast growth factor gene encodes four polypeptides: Three initiate translation from non-AUG codons. Proc. Natl. Acad. Sci. USA 86: 3978–3981.

    Google Scholar 

  23. Folkman J and Klagsburn M (1987) Angiogenic factors. Science 235: 442–7.

    Google Scholar 

  24. Friesel R, Burgess W, Mehlman T and Maciag T (1986) The characterization of the receptor for endothelial cell growth factor by covalent ligand attachment. J. Biol. Chem. 261: 7581–7584.

    Google Scholar 

  25. Friesel R, Burgess WH and Maciag T (1989) Heparin-binding growth factor 1 stimulates tyrosine phosphorylation in NIH 3T3 cells. Mol. Cell Biol. 9: 1857–1865.

    Google Scholar 

  26. Gillespie LL, Paterno GD and Slack J (1989) Analysis of competence: Receptors for fibroblast growth factor in early Xenopus embryos. Development 106: 203–208.

    Google Scholar 

  27. Gospodarowicz D and Cheng J (1986) Heparin protects basic and acidic FGF from inactivation. J. Cell Physiol. 128: 475–84.

    Google Scholar 

  28. Gospodarowicz D, Neufeld G and Schweigerer L (1987) Fibroblast growth factor: structural and biological properties. J. Cell Physiol. Suppl. 5: 15–26.

    Google Scholar 

  29. Hart CE, Forstrom JW, Kelly JD, Seifert RA, Smith RA, Ross R, Murray M and Bowen-Pope DF (1988) Two classes of PDGF receptor recognize different isoforms of PDGF. Science 240: 1529–1531.

    Google Scholar 

  30. Heldin CH, Backstrom G, Ostman A, Hammacher A, Ronstrand L, Rubin K, Nister M and Westermark B (1988) Binding of dimeric forms of PDGF to human fibroblasts: evidence for two separate receptor types. EMBO J. 7: 1387–1393.

    Google Scholar 

  31. Huang S and Huang J (1986) Association of Bovine Brain-Derived Growth Factor Receptor with Protein Tyrosine Kinase Activity. J. Biol. Chem. 261: 9568–9571.

    Google Scholar 

  32. Huang JS, Huang SS and Kuo MD (1986) Bovine brain-derived growth factor. Purification and characterization of its interaction with responsive cells. J. Biol. Chem. 261 (25): 11600–7.

    Google Scholar 

  33. Imamura T, Tokita Y and Mitsui Y (1988) Purification of basic FGF receptors from rat brain. Biochem. Biophys. Res. Comm. 155: 583–590.

    Google Scholar 

  34. Jakobovits A, Shackleford G, Varmus H and Martin G (1985) Embryonal carcinoma-derived growth factors: Specific growth-promoting and differentiation inhibiting activities. In: J. Feramisco, B. Ozanne and C. Stiles (eds) Cancer Cells, Growth Factors and Transformation. (393–399), Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.

    Google Scholar 

  35. Jaye M, Howk R, Burgess W, Ricca G, Chiu I-M, Ravera M, O'Brien S, Modi W, Maciag T and Drohan W (1986) Human Endothelial Cell Growth Factor: Cloning, Nucleotide Sequence and Chromosome Localization. Science 233: 541–545.

    Google Scholar 

  36. Joseph-Silverstein J, Consigli S, Lyser K and VerPault C (1989) Basic fibroblast growth factor in the chick embryo: Immunolocalization to striated muscle cells and their precursors. J. Cell Biol. 108: 2459–2466.

    Google Scholar 

  37. Kan M, DiSorbo D, Hou J, Hoshi H, Mansson P-E and McKeehan W (1988) High and low affinity binding of heparin-binding growth factor to a 130-kDa receptor correlates with stimulation and inhibition of growth of a differentiated human hepatoma cell. J. Biol. Chem. 263: 11306–11313.

    Google Scholar 

  38. Kimelman D and Kirschner M (1987) Synergistic induction of mesoderm by FGF and TGF-beta and the identification of an mRNA coding for FGF in the early Xenopus embryo. Cell 51: 869–77.

    Google Scholar 

  39. Kimelman D, Abraham JA, Haaparanta T, Palisi TM and Kirschner MW (1988) The presence of fibroblast growth factor in the frog egg: its role as a natural mesoderm inducer. Science (USA) 242: 1053–1056.

    Google Scholar 

  40. Klagsbrun M, Smith S, Sullivan R, Shing Y, Davidson S, Smith JA and Sasse J (1987) Multiple forms of basic fibroblast growth factor: amino-terminal cleavages by tumor cell- and brain cell-derived acid proteinases. Proc. Natl. Acad. Sci USA. 84: 2292–6.

    Google Scholar 

  41. Kurokawa M, Doctrow SR and Klagsbrun M (1989) Neutralizing antibodies inhibit the binding of basic fibroblast growth factor to its receptor but not to heparin. J. Biol. Chem. 264: 7686–7691.

    Google Scholar 

  42. Lathrop B, Thomas K and Glaser L (1985) Control of myogenic differentiation by fibroblast growth factor is mediated by position in the G1 phase of the cell cycle. J. Cell Biol. 101: 2194–8.

    Google Scholar 

  43. Lee P, Johnson D, Cousens L, Fried V and Williams L (1989) Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. Science 245: 57–60.

    Google Scholar 

  44. Linkhart T, Clegg C and Hauschka S (1981) Myogenic differentiation in permanent clonal myoblast cell lines: regulation by macromolecular growth factors in the culture medium. Dev. Biol. 86: 19–30.

    Google Scholar 

  45. Lobb R and Fett J (1984) Purification of two distinct growth factors from bovine neural tissue by heparin affinity chromatography. Biochemistry 23: 6294–6299.

    Google Scholar 

  46. Lobb R, Harper J and Fett J (1986) Purification of heparin-binding growth factors. Anal. Biochem. 154: 1–14.

    Google Scholar 

  47. Magnaldo I, LAllemain G, Chambard JC, Moenner M, Barritault D and Pouyssegur J (1986) The mitogenic signaling pathway of fibroblast growth factor is not mediated through polyphosphoinositide hydrolysis and protein kinase C activation in hamster fibroblasts. J. Biol Chem. 261: 16916–22.

    Google Scholar 

  48. Mansson PE, Adams P, Kan M and McKeehan WL (1989) Heparin-binding growth factor gene expression and receptor characteristics in normal rat prostate and two transplantable rat prostate tumors. Cancer Res. 49 (9): 2485–2494.

    Google Scholar 

  49. Marics I, Adelaide J, Rayband F, Mattei MG, Coulier F, Planche J, De LO and Birnbaum D (1989) Characterization of the HST-related FGF 6 gene, a new member of the fibroblast growth factor gene family. Oncogene 4: 335–340.

    Google Scholar 

  50. Martin G (1980) Teratocarcinomas and mammalian embryogenesis. Science 209: 768–776.

    Google Scholar 

  51. Matsui T, Heidaran M, Miki T, Popescu N, La Rochelle W, Kraus M, Pierce J and Aaronson S (1989) Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes. Science 243: 800–804.

    Google Scholar 

  52. Moenner M, Chevalier B, Badet J and Barritault D (1986) Evidence and characterization of the receptor to eye-derived growth factor I, the retinal form of basic fibroblast growth factor, on bovine epithelial lens cells. Proc. Natl. Acad. Sci. USA 83 (14): 5024–8.

    Google Scholar 

  53. Moscatelli D (1987) High and low affinity binding sites for basic fibroblast growth factor on cultured cells: absence of a role for low affinity binding in the stimulation of plasminogen activator production by bovine capillary endothelial cells. J. Cell Physiol. 131: 131–40.

    Google Scholar 

  54. Moscatelli D (1988) Metabolism of receptor-boud and matrix-bound basic fibroblast growth factor by bovine capillary endothelial cells. J. Cell Biol. 107: 1199–205.

    Google Scholar 

  55. Moscatelli DA, Rifkin DB and Jaffe EA (1985) Production of latent collagenase by human umbilical vein endothelial cells in response to angiogenic preparations. Exp. Cell Res. 156: 379–90.

    Google Scholar 

  56. Navre M and Ringold GM (1988) A growth factor-repressible gene associated with protein kinase C-mediated inhibition of adipocyte differentiation. J. Cell Biol. 107: 279–86.

    Google Scholar 

  57. Neufeld G and Gospodarowicz D (1985) The identification and partial characterization of the fibroblast growth factor receptor of baby hamster kidney cells. J. Biol. Chem. 260: 13860–13868.

    Google Scholar 

  58. Neufeld G and Gospodarowicz D (1986) Basic and acidic fibroblast growth factors interact with the same cell surface receptors. J. Biol. Chem. 261: 5631–7.

    Google Scholar 

  59. Neufeld G, Mitchell R, Ponte P and Gospodarowicz D (1988) Expression of human basic fibroblast growth factor cDNA in baby hamster kidney-derived cells results in autonomous cell growth. J. Cell Biol. 106: 1385–94.

    Google Scholar 

  60. Olwin BB and Hauschka SD (1986) Identification of the fibroblast growth factor receptor of Swiss 3T3 cells and mouse skeletal muscle myoblasts. Biochemistry 25: 3487–92.

    Google Scholar 

  61. Olwin BB and Hauschka SD (1988) Cell surface fibroblast growth factor and epidermal growth factor receptors are permanently lost during skeletal muscle terminal differentiation in culture. J. Cell Biol. 107: 761–9.

    Google Scholar 

  62. Olwin BB and Hauschka SD (1989) Cell type and tissue distribution of the fibroblast growth factor receptor. J. Cell Biochem. 39: 443–454.

    Google Scholar 

  63. Olwin BB and Hauschka SD. Fibroblast growth factor receptor levels decrease during chick embryogenesis. J. Cell Biol. (in press).

  64. Pasquale E, Maher P and Singer S (1988) Comparative study of the tyrosine phosphorylation of proteins in Swiss 3T3 fibroblasts stimulated by a variety of mitogenic agents. J. Cell Phys. 137: 146–156.

    Google Scholar 

  65. Paterno GD, Gillespie LL, Dixon MS, Slack J and Heath JK (1989) Mesoderm inducing properties of INT-2 and kFGF: Two oncogene-encoded growth factors related to FGF. Development 106: 79–83.

    Google Scholar 

  66. Pelech SL, Olwin BB and Krebs EG (1986) Fibroblast growth factor treatment of Swiss 3T3 cells activates a subunit S6 kinase that phosphorylates a synthetic peptide substrate. Proc. Natl. Acad. Sci. USA 83: 5968–72.

    Google Scholar 

  67. Prats H, Kaghad M, Prats AC, Klagsbrun M, Lelias JM, Liauzun P, Chalon P, Tauber JP, Amalric F, Smith JA et al (1989) High molecular mass forms of basic fibroblast growth factor are initiated by alternative CUG codons. Proc. Natl. Acad. Sci. 86: 1836–1840.

    Google Scholar 

  68. Rizzino A, Kuszynski C, Ruff E and Tiesman J (1988) Production and utilization of growth factors related to fibroblast growth factor by embryonal carcinoma cells and their differentiated cells. Dev. Biol. 129: 61–67.

    Google Scholar 

  69. Rogelj S, Weinberg RA, Fanning P and Klagsbrun M (1989) Characterization of tumors produced by signal peptide-basic fibroblast growth factor-transformed cells. Nature (Lond.) 331: 173–175.

    Google Scholar 

  70. Rubin J, Osada H, Finch P, Taylor W, Rudikoff S and Aaronson S (1989) Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc. Natl. Acad. Sci. USA. 86: 802–806.

    Google Scholar 

  71. Saksela O, Moscatelli D, Sommer A and Rifkin DB (1988) Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation. J. Cell Biol. 107: 753–9.

    Google Scholar 

  72. Sasada R, Kurokawa T, Iwane M and Igarashi K (1988) Transformation of mouse BALB/c 3T3 cells with human basic fibroblast growth factor cDNA. Mol. Cell Biol. 8: 588–94.

    Google Scholar 

  73. Sato Y and Rifkin DB (1988) Autocrine activities of basic fibroblast growth factor: regulation of endothelial cell movement, plasminogen activator synthesis, and DNA synthesis. J. Cell Biol. 107: 1199–1205.

    Google Scholar 

  74. Schreiber A, Kenney J, Kowalski W, Friesel R, Mehlman T and Maciag T (1985) Interaction of endothelial cell growth factor with heparin: Characterization by receptor and antibody recognition. Proc. Natl. Acad. Sci. USA 82: 6138–6142.

    Google Scholar 

  75. Shing Y, Folkman J, Sullivan R, Butterfield C, Murray J and Klagsbrun M (1984) Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science 223: 1296–1298.

    Google Scholar 

  76. Shipley GD, Keeble WW, Hendrickson JE, Coffey RJ and Pittelkow MR (1989) Growth of normal human keratinocytes and fibroblasts in serum-free medium is stimulated by acidic and basic fibroblast growth factor. J. Cell Physiol. 138: 511–518.

    Google Scholar 

  77. Slack JM, Darlington BG, Heath JK and Godsave SF (1987) Mesoderm induction in early Xenopus embryos by heparin-binding growth factors. Nature, Lond. 326: 197–200.

    Google Scholar 

  78. Smith R, Peters G and Dickson C (1988) Multiple RNAs expressed from the int-2 gene in mouse embryonal carcinoma cell lines encode a protein with homology to fibroblast growth factors. EMBO J. 7: 959–62.

    Google Scholar 

  79. Thomas KA, Rios CM and Fitzpatrick S (1984) Purification and characterization of acidic fibroblast growth factor from bovine brain. Proc. Natl. Acad. Sci. USA 81: 357–61.

    Google Scholar 

  80. Tiara M, Yoshida T, Miagawa K, Sakamoto H, Terada M and Sugimura T (1987) cDNA sequence of human transforming gene hst and identification of the coding sequence required for transforming activity. Proc. Natl. Acad. Sci. 84: 2980–2984.

    Google Scholar 

  81. Tiesman J, Meyer A, Hines RN and Rizzino A (1988) Production of growth factors related to fibroblast growth factor and platelet-derived growth factor by human embryonal carcinoma cells. In vitro Cell Dev. Biol. 24: 1209–1216.

    Google Scholar 

  82. Togari A, Dickens G, Kuzuya H and Guroff G (1985) The effect of fibroblast growth factor on PC12 cells. J. Neurosci. 5: 307–16.

    Google Scholar 

  83. Tsuda T, Kaibuchi K, Kawahara Y, Fukuzaki H and Takai Y (1985) Induction of protein kinase C activation and Ca2+ mobilization by fibroblast growth factor in Swiss 3T3 cells. Febs. Lett. 191: 205–10.

    Google Scholar 

  84. Tucker RW, Chang DT and Meade CK (1989) Effects of platelet-derived growth factor and fibroblast growth factor on free intracellular calcium and mitogenesis. J. Cell Biochem. 39: 139–151.

    Google Scholar 

  85. Vigny M, Ollier HMP, Lavigne M, Fayein N, Jeanny JC, Laurent M and Courtois Y (1988) Specific binding of basic fibroblast growth factor to basement membrane-like structures and to purified heparan sulfate proteoglycan of the EHS tumor. J. Cell Physiol. 137: 588–92.

    Google Scholar 

  86. Walicke P, Cowan WM, Ueno N, Baird A and Guillemin R (1986) Fibroblast growth factor promotes survival of dissociated hippocampal neurons and enhances neurite extension. Proc. Natl. Acad. Sci. USA 83: 3012–6.

    Google Scholar 

  87. Walicke PA, Feige JJ and Baird A (1989) Characterization of the neuronal receptor for basic fibroblast growth factor and comparison to receptors on mesenchymal cells. J. Biol. Chem. 264 (7): 4120–4126.

    Google Scholar 

  88. Wilkinson DG, Peters G, Dickson C and McMahon AP (1988) Expression of the FGF-related proto-oncogene int-2 during gastrulation and neurulation in the mouse. EMBO J. 7: 691–5.

    Google Scholar 

  89. Yarden Y and Ullrich A (1988) Growth factor receptor tyrosine kinases. Annu. Rev. Biochem. 57: 443–478.

    Google Scholar 

  90. Yoshida T, Miyagawa K, Odagiri H, Sakamoto H, Little PF, Terada M and Sugimura T (1987) Genomic sequence of hst, a transforming gene encoding a protein homologous to fibroblast growth factors and the int-2-encoded protein. Proc. Natl. Acad. Sci. USA 84: 7305–9.

    Google Scholar 

  91. Zhan X, Bates B, Hu XG and Goldfarb M (1988) The human FGF-5 oncogene encodes a novel protein related to fibroblast growth factors. Mol. Cell Biol. 8: 3487–3495.

    Google Scholar 

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Olwin, B.B. Heparin-binding growth factors and their receptors. Cytotechnology 2, 351–365 (1989). https://doi.org/10.1007/BF00364998

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