An Essential Heparin-Binding Domain in the Fibroblast Growth Factor Receptor Kinase

• Published in: Science (American Association for the Advancement of Science) 1993-03, Vol.259 (5103), p.1918-1921
• Main Authors: Kan, Mikio, Wang, Fen, Xu, Jianming, Crabb, John W., Hou, Jinzhao, McKeehan, Wallace L.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Antibodies; Antibodies, Monoclonal; binding; Binding Sites; Biological and medical sciences; Cell receptors; Cell structures and functions; Complementary DNA; COS cells; domains; fibroblast growth factor receptor kinase; Fibroblast growth factor receptors; Fibroblast growth factors; Fibroblast Growth Factors - metabolism; Fundamental and applied biological sciences. Psychology; Hep G2 cells; Heparan Sulfate Proteoglycans; Heparin; Heparin - metabolism; Heparitin Sulfate - metabolism; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Humans; Immunohistochemistry; Ligands; Lysine - metabolism; man; Metalloendopeptidases - metabolism; Molecular and cellular biology; Molecular Sequence Data; Mutagenesis; Peptide Fragments - isolation & purification; Peptide Fragments - metabolism; point mutation; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proteoglycans - metabolism; Receptors; Receptors, Fibroblast Growth Factor - chemistry; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - metabolism; Recombinant Proteins - metabolism; Sodium Chloride - pharmacology; structure; Sulfates; Trypsin - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.8456318

Heparin or heparin-like heparan sulfate proteoglycans are obligatory for activity of the heparin-binding fibroblast growth factor (FGF) family. Heparin interacts independently of FGF ligand with a specific sequence (K18K) in one of the immunoglobulin-like loops in the extracellular domain of the FGF receptor tyrosine kinase transmembrane glycoprotein. A synthetic peptide corresponding to K18K inhibited heparin and heparin-dependent FGF binding to the receptor. K18K and an antibody to K18K were antagonists of FGF-stimulated cell growth. Point mutations of lysine residues in the K18K sequence abrogated both heparin- and ligand-binding activities of the receptor kinase. The results indicate that the FGF receptor is a ternary complex of heparan sulfate proteoglycan, tyrosine kinase transmembrane glycoprotein, and ligand.