COLOCALIZATION OF HEPARIN AND RECEPTOR-BINDING SITES ON KERATINOCYTE GROWTH-FACTOR

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family. FGFs are also known as heparin-binding growth fac tors because they bind to heparin and their physical and biological pr operties are modulated by heparin. Consistent with a role as a paracri ne effector, KGF is produced by cells of mesenchymal origin but is act ive primarily, if not exclusively, on epithelial cells. KGF is involve d in a variety of physiological processes, including proliferation, di fferentiation, wound healing, and cytoprotection. To identify regions in KGF that contribute to heparin and tyrosine kinase receptor interac tions, nine peptides spanning defined motifs in the predicted structur e of KGF were synthesized, and their heparin and receptor binding prop erties were analyzed. Peptides at the amino and carboxyl termini bound heparin, and one peptide showed relative binding comparable to that o f KGF, Competitive binding studies showed that this peptide along with two other overlapping peptides specifically displaced KGF bound to th e KGF receptor. These three peptides were also selectively recognized by a neutralizing monoclonal antibody against KGF, though only in the presence of heparin, Together, these data suggest that the sites for h eparin and receptor binding both reside in the amino and carboxyl term ini of KGF, which are spatially juxtaposed in the predicted three-dime nsional structure of this molecule.