Control of growth factor networks by heparan sulfate proteoglycans

Ann Biomed Eng. 2008 Dec;36(12):2134-48. doi: 10.1007/s10439-008-9575-z. Epub 2008 Oct 7.


Growth factor binding to transmembrane protein receptors is generally understood to initiate cell signaling. Receptor binding of heparin-binding growth factors (HB-GFs), such as fibroblast growth factor-2 (FGF-2), is regulated by interactions with heparan sulfate proteoglycans. While there is some specificity for binding to heparan sulfate, overlap in sites for different growth factors may allow for cross regulation. Here we demonstrate, using experiments and computer simulations, that the HB-GFs FGF-2 and heparin-binding EGF-like growth factor (HB-EGF) can cross regulate receptor binding of the other despite having unique receptors. The ability of HSPG to stabilize HB-GF receptor binding is critical for competing growth factors to modulate receptor binding with both enhanced and reduced binding possible depending on this stabilization process. HSPG density and affinity for HB-GF are also critical factors for HB-GF cross regulation. Simulations further reveal that HB-GF can regulate receptor binding of non-HB-GFs such as EGF even when the two proteins share no binding sites when other HB-GF are present within the network. Proliferation studies demonstrate potentiation of HB-EGF-induced growth by FGF-2 indicating that competition networks can alter biological response. Exogenous manipulation of cellular responses to growth factors in complex living systems will require understanding the HSPG-controlled network.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acid Phosphatase / metabolism
  • Animals
  • Aorta / cytology
  • Cattle
  • Cell Count
  • Cells, Cultured
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Fibroblast Growth Factor 2 / genetics
  • Fibroblast Growth Factor 2 / metabolism*
  • Heparan Sulfate Proteoglycans / metabolism*
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Iodine Radioisotopes / metabolism
  • Models, Biological*
  • Myocytes, Smooth Muscle / enzymology
  • Myocytes, Smooth Muscle / metabolism*
  • Recombinant Proteins / metabolism


  • HBEGF protein, human
  • Heparan Sulfate Proteoglycans
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Iodine Radioisotopes
  • Recombinant Proteins
  • Fibroblast Growth Factor 2
  • ErbB Receptors
  • Acid Phosphatase