FIBROBLAST GROWTH-FACTOR RECEPTOR (FGFR)-3 - ALTERNATIVE SPLICING IN IMMUNOGLOBULIN-LIKE DOMAIN-III CREATES A RECEPTOR HIGHLY SPECIFIC FOR ACIDIC FGF FGF-1

Fibroblast growth factors (FGF) regulate the growth and differentiatio n of cells through complex combinatorial signaling pathways. There are nine ligands that interact with a family of four tyrosine kinase FGF receptors (FGFR). Diversity in FGF signaling is determined in part by the affinity of specific ligand-receptor pairs. Alternative splicing i n the FGFR ligand binding domain generates additional receptor isoform s with novel ligand affinities. For example, splicing events in the li gand binding domain of FGFR2 dramatically increases its affinity for k eratinocyte growth factor (KGF/FGF-7). We have identified an alternati vely spliced form of the FGFR3 mRNA, corresponding to known splice var iants of FGFRs 1 and 2. We demonstrate both by binding studies on gene tically engineered soluble receptors and by the mitogenic response of growth factor-dependent cell lines that this splice variant of FGFR3 ( FGFR3 IIIb), by binding only acidic FGF (aFGF/FGF-1), has the most res tricted ligand binding properties of any FGFR thus far described. Furt hermore, by constructing a chimeric receptor that contains the homolog ous exon from FGFR2, we demonstrate that this single domain from FGFR2 is sufficient to confer upon FGFR3 the ability to bind KGF/FGF-7. The uniquely limited repertoire of ligands that interact with this recept or suggests that a novel ligand for FGFR3 IIIb exists.