Heparin differentially regulates the interaction of fibroblast growth factor-4 with FGF receptors 1 and 2.
Fibroblast growth factor-4 (FGF4), like other FGFs, shares a high affinity for the anionic glycosaminoglycans heparin and heparan sulfate (HS), which in turn enhance FGF-receptor (FGFR) binding and activation. Here we demonstrate using a cell free system that, at low concentrations of heparin, FGF4 binds only to FGFR-2, while much higher heparin levels are required for binding to FGFR-1. Chemical crosslinking of radiolabeled FGF4 to the soluble FGF receptors confirms the preferential formation of FGF4-FGFR-2 complexes under restricted heparin availability, with maximal ligand-receptor interactions at almost 20-fold lower heparin concentrations then those required for the affinity labeling of FGFR-1. In accordance, HS-deficient cells expressing FGFR-2 proliferate in response to FGF4 at extremely low exogenous heparin concentrations, while FGFR-1 expressing cells are completely unresponsive under the same conditions. We suggest that FGFR-2 is the preferred receptor for FGF4 under restricted HS conditions and that the bioavailability of structurally distinct HS motifs may differentially control receptor specificity of FGF4 in vivo.
Aviezer
D
D
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
Safran
M
M
Yayon
A
A
D000345:Affinity Labels; D002460:Cell Line; D002474:Cell-Free System; D002846:Chromatography, Affinity; D003432:Cross-Linking Reagents; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000302:isolation & purification / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D000345:Affinity Labels; D003432:Cross-Linking Reagents; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors; D006493:Heparin; D006497:Heparan Sulfate; D008024:Ligands; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins