Direct binding of integrin αvβ3 to FGF1 plays a role in FGF1 signaling

Seiji Mori, Chun Yi Wu, Satoshi Yamaji, Jun Saegusa, Biao Shi, Zi Ma, Yasuko Kuwabara, Kit S. Lam, R. Rivkah Isseroff, Yoko K. Takada, Yoshikazu Takada

Research output: Contribution to journalArticle

80 Citations (Scopus)

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 languageEnglish
Pages (from-to)18066-18075
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number26
DOIs
Publication statusPublished - Jun 27 2008
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Mori, S., Wu, C. Y., Yamaji, S., Saegusa, J., Shi, B., Ma, Z., Kuwabara, Y., Lam, K. S., Isseroff, R. R., Takada, Y. K., & Takada, Y. (2008). Direct binding of integrin αvβ3 to FGF1 plays a role in FGF1 signaling. Journal of Biological Chemistry, 283(26), 18066-18075. https://doi.org/10.1074/jbc.M801213200