I. Sher et al., Identification of residues important both for primary receptor binding andspecificity in fibroblast growth factor-7, J BIOL CHEM, 275(45), 2000, pp. 34881-34886
Fibroblast growth factors (FGFs) mediate a multitude of physiological and p
athological processes by activating a family of tyrosine kinase receptors (
FGFRs), Each FGFR binds to a unique subset of FGFs and ligand binding speci
ficity is essential in regulating FGF activity, FGF-7 recognizes one FGFR i
soform known as the FGFR2 IIIb isoform or keratinocyte growth factor recept
or (KGFR), whereas FGF-2 binds well to FGFR1, FGFR2, and FGFR4 but interact
s poorly with KGFR, Previously, mutations in FGF-2 identified a set of resi
dues that are important for high affinity receptor binding, known as the pr
imary receptor-binding site. FGF-7 contains this primary site as well as a
region that restricts interaction with FGFR1. The sequences that confer on
FGF-7 its specific binding to KGFR have not been identified. By utilizing d
omain swapping and site-directed mutagenesis we have found that the loop co
nnecting the beta4-beta5 strands of FGF-7 contributes to high affinity rece
ptor binding and is critical for KGFR recognition. Replacement of this loop
with the homologous loop from FGF-2 dramatically reduced both the affinity
of FGF-7 for KGFR and its biological potency but did not result in the abi
lity to bind FGFR1. Point mutations in residues comprising this loop of FGF
-7 reduced both binding affinity and biological potency. The reciprocal loo
p replacement mutant (FGF2-L4/7) retained FGF-2 like affinity for FGFR1 and
for KGFR, Our results show that topologically similar regions in these two
FGFs have different roles in regulating receptor binding specificity and s
uggest that specificity may require the concerted action of distinct region
s of an FGF.