Abstract
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 αvβ3 (KD about 1 μM). Antagonists to αvα3 (monoclonal antibody 7E3 and cyclic RGDfV) blocked this interaction. αvβ3 was the predominant, if not the only, integrin that bound to FGF1, because FGF1 bound only weakly to several β1 integrins tested. We presented evidence that the CYDMKTTC sequence (the specificity loop) within the ligand-binding site of β3 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 FRS2α 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.
| Original language | English |
|---|---|
| Pages (from-to) | 18066-18075 |
| Number of pages | 10 |
| Journal | Journal of Biological Chemistry |
| Volume | 283 |
| Issue number | 26 |
| DOIs | |
| Publication status | Published - Jun 27 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
Direct binding of integrin αvβ3 to FGF1 plays a role in FGF1 signaling. / Mori, Seiji; Wu, Chun Yi; Yamaji, Satoshi; Saegusa, Jun; Shi, Biao; Ma, Zi; Kuwabara, Yasuko; Lam, Kit S.; Isseroff, R. Rivkah; Takada, Yoko K.; Takada, Yoshikazu.
In: Journal of Biological Chemistry, Vol. 283, No. 26, 27.06.2008, p. 18066-18075.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Direct binding of integrin αvβ3 to FGF1 plays a role in FGF1 signaling
AU - Mori, Seiji
AU - Wu, Chun Yi
AU - Yamaji, Satoshi
AU - Saegusa, Jun
AU - Shi, Biao
AU - Ma, Zi
AU - Kuwabara, Yasuko
AU - Lam, Kit S.
AU - Isseroff, R. Rivkah
AU - Takada, Yoko K.
AU - Takada, Yoshikazu
PY - 2008/6/27
Y1 - 2008/6/27
N2 - 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 αvβ3 (KD about 1 μM). Antagonists to αvα3 (monoclonal antibody 7E3 and cyclic RGDfV) blocked this interaction. αvβ3 was the predominant, if not the only, integrin that bound to FGF1, because FGF1 bound only weakly to several β1 integrins tested. We presented evidence that the CYDMKTTC sequence (the specificity loop) within the ligand-binding site of β3 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 FRS2α 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.
AB - 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 αvβ3 (KD about 1 μM). Antagonists to αvα3 (monoclonal antibody 7E3 and cyclic RGDfV) blocked this interaction. αvβ3 was the predominant, if not the only, integrin that bound to FGF1, because FGF1 bound only weakly to several β1 integrins tested. We presented evidence that the CYDMKTTC sequence (the specificity loop) within the ligand-binding site of β3 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 FRS2α 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.
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U2 - 10.1074/jbc.M801213200
DO - 10.1074/jbc.M801213200
M3 - Article
VL - 283
SP - 18066
EP - 18075
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 26
ER -