1. FGF1 Suppresses Allosteric Activation of β3 Integrins by FGF2: A Potential Mechanism of Anti-Inflammatory and Anti-Thrombotic Action of FGF1
- Author
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Takada, Yoko K, Wu, Xuesong, Wei, David, Hwang, Samuel, and Takada, Yoshikazu
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Animals ,Humans ,Fibroblast Growth Factor 1 ,Fibroblast Growth Factor 2 ,Integrin beta3 ,Anti-Inflammatory Agents ,Allosteric Regulation ,Binding Sites ,Allosteric Site ,Protein Binding ,FGF1 ,FGF2 ,anti-inflammatory action ,anti-thrombotic action ,integrin ,Biochemistry and cell biology ,Bioinformatics and computational biology ,Medical biotechnology - Abstract
Several inflammatory cytokines bind to the allosteric site (site 2) and allosterically activate integrins. Site 2 is also a binding site for 25-hydroxycholesterol, an inflammatory lipid mediator, and is involved in inflammatory signaling (e.g., TNF and IL-6 secretion) in addition to integrin activation. FGF2 is pro-inflammatory and pro-thrombotic, and FGF1, homologous to FGF2, has anti-inflammatory and anti-thrombotic actions, but the mechanism of these actions is unknown. We hypothesized that FGF2 and FGF1 bind to site 2 of integrins and regulate inflammatory signaling. Here, we describe that FGF2 is bound to site 2 and allosterically activated β3 integrins, suggesting that the pro-inflammatory action of FGF2 is mediated by binding to site 2. In contrast, FGF1 bound to site 2 but did not activate these integrins and instead suppressed integrin activation induced by FGF2, indicating that FGF1 acts as an antagonist of site 2 and that the anti-inflammatory action of FGF1 is mediated by blocking site 2. A non-mitogenic FGF1 mutant (R50E), which is defective in binding to site 1 of αvβ3, suppressed β3 integrin activation by FGF2 as effectively as WT FGF1.
- Published
- 2024