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Expression cDNA cloning and structural analysis of the human keratinocyte growth factor receptor (KGFR) revealed identity with one of the fibroblast growth factor (FGF) receptors encoded by the bek gene (FGFR-2), except for a divergent stretch of 49 amino acids in their extracellular domains. Binding assays demonstrated that the KGFR was a high-affinity receptor for both KGF and acidic FGF, while FGFR-2 showed high affinity for basic and acidic FGF but no detectable binding by KGF. Genomic analysis of the bek gene revealed two alternative exons responsible for the region of divergence between the two receptors. The KGFR transcript was specific to epithelial cells, and it appeared to be differentially regulated with respect to the alternative FGFR-2 transcript. Thus, two growth factor receptors with different ligand-binding specificities and expression patterns are encoded by alternative transcripts of the same gene.

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Fibroblast growth factors (FGFs) constitute a large family of at least nine distinct polypeptide growth factors (7,31,34). FGFs play an important role in the regulation of cell growth, differentiation, embryogenesis, and angiogenesis (34). Like other growth factors, FGFs exert their action by binding to and activating a distinct family of growth factor receptors that has been previously classified as subclass IV (20, 74). The FGF receptor family consists of at least four distinct gene products, each composed of an extracellular ligand-binding domain that contains three immunoglobulin-like domains, a single transmembrane domain, and a cytoplasmic domain that contains protein tyrosine kinase activity (interrupted by an insertion of 14 amino acids in the kinase domain). One of the characteristic features of the FGF receptor family is the occurrence of numerous receptor isoforms that are produced from alternatively spliced transcripts in both the intracellular and extracellular domains (9,14,27,32,33). As with other growth factors, binding of FGF to FGF receptors leads to receptor dimerization (3, 70, 73) and subsequent tyrosine autophosphorylation and phosphorylation of target substrates (6, 13, 23). Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanism, as seen with the insulin receptor (22,63,81,84,86). Also, many autophosphorylation sites serve as binding sites for signaling proteins that contain Src homology 2 (SH2) domains or the recently identified phosphotyrosine interaction (also called phosphotyrosine-binding [PTB]) domains (4,5,8,35,36,39,48,56,57). Binding of SH2 or PTB domain-containing proteins to activated growth factor receptors has been shown to be important for the activation of downstream signaling molecules. For example, binding of Shc and phospholipase C␥ (PLC␥) through PTB and SH2 domains, respectively, to the activated nerve growth factor receptor (Trk) has been shown to be required for the nerve growth factor-induced activation of Ras signaling pathways and neuronal differentiation of PC12 cells (16,55,72). Several studies have demonstrated that mutation of autophosphorylation sites in platelet-derived growth factor (PDGF) receptor and in colony-stimulating factor 1 receptor can impair mitogenic signaling in some cell lines (19,76,77).Very little is known about the cellular substrates and target proteins involved in signaling processes that lead to FGFmediated mitogenesis. So far only PLC␥ has been shown to associate with the activated FGF receptor 1 (FGFR1) (flg); the identities of other targets remain unclear. We have previously identified tyrosine 766 of FGFR1 as the major autophosphorylation site and have shown that this tyrosine and its flanking sequences represent a high affinity binding site for one of the SH2 domains of PLC␥ (52). Mutation of this tyrosine to phenylalanine results in a receptor that is no longer able to stimulate phosphatidylinosito...

The fibroblast growth factor (FGF) family consists of at least seven closely related polypeptide mitogens which exert their activities by binding and activation of specific cell surface receptors. Unanswered questions have been whether there are multiple FGF receptors and what factors determine binding specificity and biological response. We report the complete cDNA cloning of two human genes previously designated flg and bek. These genes encode two similar but distinct cell surface receptors comprised of an extracellular domain with three immunoglobulin‐like regions, a single transmembrane domain, and a cytoplasmic portion containing a tyrosine kinase domain with a typical kinase insert. The expression of these two cDNAs in transfected NIH 3T3 cells led to the biosynthesis of proteins of 150 kd and 135 kd for flg and bek, respectively. Direct binding experiments with radiolabeled acidic FGF (aFGF) or basic FGF (bFGF), inhibition of binding with native growth factors, and Scatchard analysis of the binding data indicated that bek and flg bind either aFGF or bFGF with dissociation constants of (2‐15) x 10(‐11) M. The high affinity binding of two distinct growth factors to each of two different receptors represents a unique double redundancy without precedence among polypeptide growth factor‐receptor interactions.