Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene.

Abstract

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.

The expression of RET and its multiple splice forms in developing human kidney

“…When such events occur near the 5' end of the gene, ligand-binding domains may be a ected resulting in altered ligandbinding speci®cities. In the case of ®broblast growth factor receptor type 2, for example, alternative exon usage in the immunoglobulin-like loop region results in receptor variants with di erent ligand-binding a nities (Miki et al, 1992;Yayon et al, 1992). These transcripts are expressed in a tissue-and developmental stage-speci®c fashion (Orr-Urtreger et al, 1993;McDonald, 1994;Shi et al, 1994).…”

Exon III splicing switch of fibroblast growth factor (FGF) receptor-2 and -3 can be induced by FGF-1 or FGF-2

“…Though FGF-2 does not induce exon III switch in NBT-II, it stimulates cell growth on these cells (Valle s et al, 1990). This is most probably correlated to the fact that although FGFR-2/IIIb is a high a nity receptor for FGF-1 and FGF-7, it also binds FGF-2 with lower a nity (Miki et al, 1992).…”

“…Alternative splicing of IIIb or IIIc exons of the FGFR-2 also results in di erential a nities for FGF ligands. The IIIb variant of FGFR-2, also called keratinocyte growth factor receptor (KGFR) is a high a nity receptor for FGF-1 and FGF-7, while use of the IIIc exon yields a receptor (also called BEK) with high a nity for FGF-1 and FGF-2, but not for FGF-7 (Dionne et al, 1990;Houssaint et al, 1990;ChampionArnaud et al, 1991;Miki et al, 1992;Yayon et al, 1992;Yan et al, 1993). Distinct a nities for the FGFs have also been described for the variants of the FGFR-3: the IIIc variant preferentially binds FGF-1 and FGF-4, with very little response to FGF-2 and no response to FGF-5 (Ornitz and Leder, 1992), while the IIIb variant binds only FGF-1 (Chellaiah et al, 1994).…”

“…It was established by di erent groups that the choice between IIIb and IIIc exons of the FGFR-2 is a mutually exclusive alternative splicing choice, so that the two receptors, BEK and KGFR, seem never to be expressed together on the cell surface (ChampionArnaud et al, 1991;Miki et al, 1992;Yan et al, 1993). In fact, the IIIb/IIIc choice is strictly correlated to the cell phenotype.…”

Agonist-induced formation of FGFR1 homodimers and signaling differ among members of the FGF family

“…However, FGF ligand-FGFR1 binding properties are the most critical mechanism for the control of FGFR1 signaling. FGFR1 binds members of the FGF family with different affinities and capabilities to produce activation, and alternative mRNA splicing leads to isoforms of FGFR1 having special ligand binding properties [4]. In addition, FGF ligand/FGF ligand and FGFR1/FGFR1 dimerization may expand the spectrum of interactions between FGFs and FGFR affecting their binding and signaling properties [5].…”