Direct binding of integrin αvβ3 to FGF1 plays a role in FGF1 signaling
Direct binding of integrin αvβ3 to FGF1 plays a role in FGF1 signaling
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DOI：
10.1074/jbc.m801213200
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发表时间：
2008-06-27
影响因子：
4.8
通讯作者：
Takada, Yoshikazu
中科院分区：
文献类型：
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作者：
Mori, Seiji;Wu, Chun-Yi;Takada, Yoshikazu
整合素通过与成纤维细胞生长因子受体（FGF receptor，FGFR）的相互作用在成纤维细胞生长因子（FGF）信号传导中发挥作用，但相互作用的机制尚不清楚。我们发现FGF 1直接与可溶性和细胞表面整合素α v β 3结合（KD约为1 μ M）。α v β 3的拮抗剂（单克隆抗体7 E3和环状RGDfV）阻断了这种相互作用。α v β 3如果不是唯一的，也是主要的与FGF 1结合的整联蛋白，因为FGF 1仅与几种测试的β 1整联蛋白弱结合。我们提供的证据表明，β 3配体结合位点内的CYDMKTTC序列（特异性环）在FGF 1结合中起作用。我们发现，整合素结合位点的FGF 1与肝素结合位点重叠，但从FGFR结合位点使用对接模拟和诱变是不同的。我们鉴定了一种FGF 1突变体（R50 E），其在整合素结合方面有缺陷，但仍与肝素和FGFR结合。R50 E在诱导DNA合成、细胞增殖、细胞迁移和趋化性方面有缺陷，表明整合素与FGF 1的直接结合对FGF信号传导至关重要。然而，R50 E诱导FGFR 1和FRS 2 α的磷酸化以及AKT和ERK 1/2的活化。这些结果表明，FGF信号传导中R50 E的缺陷不在于FGF信号传导途径组分的初始活化，而是在FGF信号传导的后续步骤中。我们建议，R50 E是一个有用的工具，以确定整联蛋白在FGF信号转导中的作用。
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 alpha v beta 3 (KD about 1 mu M). Antagonists to alpha v beta 3 (monoclonal antibody 7E3 and cyclic RGDfV) blocked this interaction. alpha v beta 3 was the predominant, if not the only, integrin that bound to FGF1, because FGF1 bound only weakly to several beta 1 integrins tested. We presented evidence that the CYDMKTTC sequence (the specificity loop) within the ligand-binding site of beta 3 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 alpha 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.