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J. Biol. Chem., Vol. 283, Issue 26, 18066-18075, June 27, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/26/18066    most recent M801213200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mori, S. Articles by Takada, Y. Search for Related Content PubMed PubMed Citation Articles by Mori, S. Articles by Takada, Y. Social Bookmarking                      What's this?

Direct Binding of Integrin vβ3 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, and Yoshikazu Takada¹

From the Departments of Dermatology and Hematology-Oncology, School of Medicine, University of California, Davis, Sacramento, California 95817

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 vβ3 (K_D about 1 µM). Antagonists to vβ3 (monoclonal antibody 7E3 and cyclic RGDfV) blocked this interaction. vβ3 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 FRS2 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.

Received for publication, February 14, 2008 , and in revised form, April 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA113298 and CA093373 (to Y. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Research III Ste. 3300, 4645 Second Ave., Sacramento, CA 95817. Tel.: 916-734-7443; Fax: 916-734-7505; E-mail: ytakada{at}ucdavis.edu.

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