Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors.

Abstract

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.

Overexpression of vascular endothelial growth factor induces cell transformation in cooperation with fibroblast growth factor 2

“…RPE cells express FGF receptors and respond to the mitogenic e ect of FGF-2 (Leschey et al, 1990). Among the four receptors, FGFR-1 and 2 have a high a nity for FGF-2 (Dionne et al, 1990). In contrast, FGFR-3 preferentially binds FGF-1 (Ornitz and Leder, 1992), and FGFR-4 binds FGF-1 with high a nity but shows low a nity for FGF-2 (Vainikka et al, 1992).…”

“…Analysis of FGF receptors indicated that such cells overexpress ®broblast growth factor receptor-1 (FGFR-1). Most probably, FGFR-1, which is a high a nity receptor for FGF-2 (Dionne et al, 1990), mediates the transforming e ect induced by this growth factor.…”

Ligand-independent activation of fibroblast growth factor receptor-2 by carboxyl terminal alterations

“…The FGFs elicit their biological responses through high a nity binding and activation of a family of receptor tyrosine kinases, the ®broblast growth factor receptors (FGFRs). Four members of structurally related FGFRs (FGFR1/Flg, FGFR2/Bek, FGFR3 and FGFR4) have been characterized (Dionne et al, 1990;Miki et al, 1991;Keegan et al, 1991;Partanen et al, 1991;Ron et al, 1993). Extracelluarly, the receptors are composed of two or three immunoglobulin (Ig)-like domains which mediate ligand binding and interaction with heparin proteoglycans Gao and Goldfarb, 1995).…”

The community effect in FGF-1 mediated tumor progression of a rat bladder carcinoma does not involve a direct paracrine signaling

“…The pFlg expression vector contains the entire cDNA coding sequence for the human FGFR1 receptor (Dionne et al, 1990). We have generated a mutant termed pDFlg by deleting the region encompassing the whole tyrosine kinase domain of the transmembrane receptor.…”