title: Heparin can activate a receptor tyrosine kinase.
abstract: Heparin, a densely sulfated glycosaminoglycan produced by mast cells, is best known for its inhibitory effects on the blood coagulation system. Heparin or heparan sulfate proteoglycans are also essential cofactors for the interaction of fibroblast growth factors (FGFs) with their receptor tyrosine kinases (FGFRs). Here we show that heparin is a growth factor-independent activating ligand for FGFR-4. Heparin stimulates FGFR-4 autophosphorylation on transfected myoblasts, fibroblasts and lymphoid cells, and is most potent on cells lacking surface heparan proteoglycan. Two functional analogs of heparin, fucoidan and dextran sulfate, are also activators of FGFR-4, while neither heparin nor its analogs can stimulate FGFR-1 in the absence of FGF. A mutation in the FGFR-4 ectodomain which impairs receptor activation by FGFs does not interfere with activation by heparin, demonstrating that receptor domains required for heparin or FGF activation are not identical. Heparin activation of FGFR-4 or of a chimeric receptor bearing FGFR-4 ectodomain and FGFR-1 cytodomain triggers downstream tyrosine phosphorylation of several signaling proteins, and induces proliferation of cells bearing the chimeric receptor. Consistent with these findings, a soluble FGFR-4 ectodomain has strong FGF-independent affinity for immobilized heparin resin, while soluble FGFR-1 requires FGF for stable heparin interaction. Heparin activation of FGFR-4 is the first example of a mammalian polysaccharide serving as a signaling ligand.
authors.affiliation: Regeneron Pharmaceuticals Inc., Tarrytown, NJ 10591, USA.
authors.forename: G
authors.initials: G
authors.lastname: Gao
authors.forename: M
authors.initials: M
authors.lastname: Goldfarb
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D006025:Glycosaminoglycans / Q000378:metabolism / Q000494:pharmacology; D006493:Heparin / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000166:cytology; D008969:Molecular Sequence Data; D009132:Muscles / Q000166:cytology; D011134:Polysaccharides / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013463:Sulfuric Acid Esters / Q000494:pharmacology; D014162:Transfection
chemical_list: D006025:Glycosaminoglycans; D011134:Polysaccharides; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D013463:Sulfuric Acid Esters; D005346:Fibroblast Growth Factors; D006493:Heparin; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases