A novel fibroblast growth factor-1 (FGF1) mutant that acts as an FGF antagonist

Satoshi Yamaji, Jun Saegusa, Katsuaki Ieguchi, Masaaki Fujita, Seiji Mori, Yoko K. Takada, Yoshikazu Takada

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: Crosstalk between integrins and FGF receptors has been implicated in FGF signaling, but the specifics of the crosstalk are unclear. We recently discovered that 1) FGF1 directly binds to integrin αvβ3, 2) the integrin-binding site and FGF receptor (FGFR) binding site are distinct, and 3) the integrin-binding-defective FGF1 mutant (R50E) is defective in inducing FGF signaling although R50E still binds to FGFR and heparin and induces transient ERK1/2 activation. Principal Findings: We tested if excess R50E affect DNA synthesis and cell survival induced by WT FGF1 in BaF3 mouse pro- B cells expressing human FGFR1. R50E suppressed DNA synthesis and cell proliferation induced by WT FGF1. We tested if WT FGF1 and R50E generate integrin-FGF1-FGFR ternary complex. WT FGF1 induced ternary complex formation (integrin- FGF-FGFR1) and recruitment of SHP-2 to the complex in NIH 3T3 cells and human umbilical endothelial cells, but R50E was defective in these functions. It has been reported that sustained ERK1/2 activation is integrin-dependent and crucial to cell cycle entry upon FGF stimulation. We thus determined the time-course of ERK1/2 activation induced by WT FGF1 and R50E. We found that WT FGF1 induced sustained activation of ERK1/2, but R50E was defective in this function. Conclusions/Significance: Our results suggest that 1) R50E is a dominant-negative mutant, 2) Ternary complex formation is involved in FGF signaling, 3) The defect of R50E to bind to integrin may be directly related to the antagonistic action of R50E. Taken together, these results suggest that R50E has potential as a therapeutic in cancer.

Original languageEnglish
Article numbere10273
JournalPLoS One
Volume5
Issue number4
DOIs
Publication statusPublished - 2010
Externally publishedYes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Yamaji, S., Saegusa, J., Ieguchi, K., Fujita, M., Mori, S., Takada, Y. K., & Takada, Y. (2010). A novel fibroblast growth factor-1 (FGF1) mutant that acts as an FGF antagonist. PLoS One, 5(4), [e10273]. https://doi.org/10.1371/journal.pone.0010273