Abstract
BackgroundCrosstalk 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 FindingsWe 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/SignificanceOur 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.
Highlights
Fibroblast growth factors (FGFs) constitute a family of heparinbinding polypeptides involved in the regulation of biological responses, such as growth, differentiation, and angiogenesis [1,2,3,4]
If Fibroblast Growth Factor-1 (FGF1) needs to bind to both fibroblast growth factor receptor (FGFR) and integrins for signaling, it is predicted that R50E that cannot bind to avb3 is defective in signaling but suppresses signaling induced by wild type (WT) FGF1 in a dominant-negative manner
We found that excess R50E blocked WT FGF1-induced BrdU incorporation in BaF3FGFR1c in a dose-dependent manner (Fig. 1B), suggesting that R50E acts as a dominant-negative antagonist of FGF1-induced DNA synthesis
Summary
Fibroblast growth factors (FGFs) constitute a family of heparinbinding polypeptides involved in the regulation of biological responses, such as growth, differentiation, and angiogenesis [1,2,3,4]. The biological effects of FGFs are mediated by four structurally related receptor tyrosine kinases denoted FGFR1, FGFR2, FGFR3, and FGFR4. The binding of FGF to its receptor results in receptor dimerization and subsequent transphosphorylation of specific tyrosine residues within the intracellular domain [1,2,3,4]. Activation of the receptor allows proteins containing Src homology-2 (SH2) or phosphotyrosine binding (PTB) domains to bind to sequence recognition motifs in the FGFR, resulting in phosphorylation and activation of these proteins [5]. This leads to the activation of intracellular signaling cascades. We recently discovered that 1) FGF1 directly binds to integrin avb3, 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 R50E still binds to FGFR and heparin and induces transient ERK1/2 activation
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