Although FGF19 has been shown to activate multiple FGFRs in the presence of the coreceptor KLB in vitro, contribution of each FGFR to the in vivo activity of FGF19 has been poorly defined.
When FGFs bind to the FGFRs, dimerization results from a complex of two FGFs, two FGFRs, and two heparin sulfate chains (Fig. 1) and ultimately leads to FGFR activation, with the adaptor protein FGFR substrate two serving to recruit the Ras/mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K /protein kinase B (Akt) pathways 18.
In fibroblasts, FGFs bind to FGFRs and activate the intracellular ERK1/2 cascade to maintain cell proliferation.
If FGF1 needs to bind to both FGFR and integrins for signaling, it is predicted that R50E that cannot bind to αvβ3 is not only defective in signaling but suppresses signaling induced by WT FGF1 in a dominant-negative manner.
Fibroblast growth factor-1, -3, -7, -10, and -22 bind to FGFR-2 IIIb with high affinity, whereas FGF-1, -2, -4, -6, -9, -17, and -18 bind to FGFR-2 IIIc with high affinity.
If the integrin αvβ3-binding site in FGF1 is distinct from that of FGFR1 [12], FGF1 can simultaneously bind to αvβ3 and FGFR (ternary complex formation).
Based on the notion that NCAM binds to FGFR and modulates FGFR activity (see Introduction Section), we asked whether this interplay is involved in the NCAM-dependent migration of MOVCAR cells.
An ad hoc host molecule is tailored to bind to glucose by multiple hydrogen bonds.
FGF21 activates FGFRs only when recruited to the FGFR/KLB complex through its C-terminal KLB-binding tail, while the determinants for FGFR-specificity reside in its N-terminal region, which likely binds to FGFRs via a low affinity interaction (Fig. 1B) (Micanovic et al., 2009, Yie et al., 2009).
FRS2 not only binds to FGFRs, but also to the TrkA, VEGF and RET receptors suggesting a broad role in signal transduction [ 11, 12].
