Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation

Cell. 1994 Dec 16;79(6):1015-24. doi: 10.1016/0092-8674(94)90032-9.


Heparin is required for fibroblast growth factor (FGF) stimulation of biological responses. Using isothermal titration calorimetry, we show that acidic FGF (aFGF) forms a 1:1 complex with the soluble extracellular domain of FGF receptor (FGFR). Heparin exerts its effect by binding to many molecules of aFGF. The resulting aFGF-heparin complex can bind to several receptor molecules, leading to FGFR dimerization. In two cell lines lacking endogenous heparan sulfate, exogenous heparin is required for FGFR dimerization, tyrosine kinase activation, c-fos mRNA transcription, and cell proliferation. Moreover, a synthetic heparin analog that binds monovalently to aFGF blocks FGFR dimerization, activation, and signaling via FGFR. We propose that heparin causes oligomerization of aFGF such that its binding to FGFR results in dimerization and activation. This represents a novel mechanism for transmembrane signaling and may account for the action of many heparin-bound growth factors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CHO Cells
  • Calorimetry
  • Cell Division / drug effects
  • Cricetinae
  • Enzyme Activation
  • Fibroblast Growth Factor 1 / metabolism*
  • Heparin / metabolism*
  • Heparin / pharmacology
  • Models, Biological
  • Phosphorylation
  • Protein Binding / drug effects
  • Protein Conformation
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins c-fos / genetics
  • RNA, Messenger / analysis
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Recombinant Proteins / metabolism
  • Signal Transduction*


  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Receptors, Fibroblast Growth Factor
  • Recombinant Proteins
  • Fibroblast Growth Factor 1
  • Heparin
  • Protein-Tyrosine Kinases