Mutations uncouple human fibroblast growth factor (FGF)-7 biological activity and receptor binding and support broad specificity in the secondary receptor binding site of FGFs
I. Sher et al., Mutations uncouple human fibroblast growth factor (FGF)-7 biological activity and receptor binding and support broad specificity in the secondary receptor binding site of FGFs, J BIOL CHEM, 274(49), 1999, pp. 35016-35022
The fibroblast growth factor (FGF) family plays a key role in a multitude o
f physiological and pathological processes. The activities of FGFs are medi
ated by a family of tyrosine kinase receptors, designated FGFRs, The mechan
ism by which FGFs induce receptor activation is controversial. Despite thei
r structural similarity, FGFs display distinct receptor binding characteris
tics and cell type specificity. Previous studies with FGF-2 identified a lo
w affinity receptor binding site that is located within a loop connecting i
ts 9th and 10th beta-strands, The corresponding residues in the other famil
y members are highly variable, and it was proposed that the variability mig
ht confer on FGFs unique receptor binding characteristics. We studied the r
ole of this loop in FGF-7 by both site-directed mutagenesis and loop replac
ement. Unlike the other members of the FGF family, FGF-7 recognizes only on
e FGFR isoform and is, therefore, ideal for studies of how the specificity
in the FGF-FGFR interaction is conferred at the structural level, Point mut
ations in the loop of FGF-7 did not change receptor binding affinity but re
sulted in reduced mitogenic potency and reduced ability to induce receptor-
mediated phosphorylation events. These results suggest that the loop of FGF
-I? fulfills the role of low affinity binding site required for receptor ac
tivation. The observation that it is possible to uncouple FGF-7 receptor bi
nding and biological activity favors a bivalent model for FGFR dimerization
, and it may be clinically relevant to the design of FGF-7 antagonists. Rec
iprocal loop replacement between FGF-7 and FGF-S had no effect on their kno
wn receptor binding affinities nor did it alter their known specificity in
eliciting a mitogenic response. In conclusion, these results suggest that,
despite the diversity in the loop structure of FGF-2 and FGF-7, the loop ha
s a similar function in both growth factors.