Direct binding of integrin alphavbeta3 to FGF1 plays a role in FGF1 signaling.
Integrins play a role in fibroblast growth factor (FGF) signaling through cross-talk with FGF receptors (FGFRs), but the mechanism underlying the cross-talk is unknown. We discovered that FGF1 directly bound to soluble and cell-surface integrin alphavbeta3 (K(D) about 1 microm). Antagonists to alphavbeta3 (monoclonal antibody 7E3 and cyclic RGDfV) blocked this interaction. alphavbeta3 was the predominant, if not the only, integrin that bound to FGF1, because FGF1 bound only weakly to several beta1 integrins tested. We presented evidence that the CYDMKTTC sequence (the specificity loop) within the ligand-binding site of beta3 plays a role in FGF1 binding. We found that the integrin-binding site of FGF1 overlaps with the heparin-binding site but is distinct from the FGFR-binding site using docking simulation and mutagenesis. We identified an FGF1 mutant (R50E) that was defective in integrin binding but still bound to heparin and FGFR. R50E was defective in inducing DNA synthesis, cell proliferation, cell migration, and chemotaxis, suggesting that the direct integrin binding to FGF1 is critical for FGF signaling. Nevertheless, R50E induced phosphorylation of FGFR1 and FRS2alpha and activation of AKT and ERK1/2. These results suggest that the defect in R50E in FGF signaling is not in the initial activation of FGF signaling pathway components, but in the later steps in FGF signaling. We propose that R50E is a useful tool to identify the role of integrins in FGF signaling.
Mori
Seiji
S
Department of Dermatology, School of Medicine, University of California Davis, Sacramento, CA 95817, USA.
Wu
Chun-Yi
CY
Yamaji
Satoshi
S
Saegusa
Jun
J
Shi
Biao
B
Ma
Zi
Z
Kuwabara
Yasuko
Y
Lam
Kit S
KS
Isseroff
R Rivkah
RR
Takada
Yoko K
YK
Takada
Yoshikazu
Y
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry*; D008954:Models, Biological; D009154:Mutation; D011485:Protein Binding; D015398:Signal Transduction; D020349:Surface Plasmon Resonance
D039302:Integrin alphaVbeta3; D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors