Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States.
Biochemistry. 2011 Oct 11;50(40):8576-82. doi: 10.1021/bi200986f. Epub 2011 Sep 16.
Fibroblast growth factors (fgfs) play important roles in embryonic development and in adult life by controlling cell proliferation, differentiation, and migration. There are 18 known fgfs which activate four fibroblast growth factor receptors (FGFRs), with different isoforms due to alternative splicing. The physical basis behind the specificity of the biological responses mediated by different fgf-FGFR pairs is currently unknown. To gain insight into the specificity of FGFR3c, a membrane receptor which is critical for bone development, we studied, analyzed, and compared the activation of FGFR3c over a wide range of fgf1 and fgf2 concentrations. We found that while the strength of fgf2 binding to FGFR3c is lower than the strength of fgf1 binding, the fgf2-bound dimers exhibit higher phosphorylation of the critical tyrosines in the activation loop. As a result, fgf1 and fgf2 elicit a similar FGFR3c response at low, but not at high, concentrations. The results demonstrate the versatility of FGFR3c response to fgf1 and fgf2 and highlight the complexity in fgf signaling.
成纤维细胞生长因子（fgfs）在胚胎发育和成年期发挥着重要作用，通过控制细胞增殖、分化和迁移来发挥作用。目前已知有 18 种 fgfs，它们可以激活 4 种成纤维细胞生长因子受体（fgfrs），由于选择性剪接，这些受体具有不同的同工型。不同 fgf-FGFR 对介导的生物学反应的特异性的物理基础目前尚不清楚。为了深入了解对骨骼发育至关重要的膜受体 FGFR3c 的特异性，我们研究、分析和比较了 FGFR3c 在广泛的 fgf1 和 fgf2 浓度下的激活情况。我们发现，虽然 fgf2 与 FGFR3c 的结合强度低于 fgf1，但 fgf2 结合的二聚体在激活环中关键酪氨酸的磷酸化水平更高。因此，fgf1 和 fgf2 在低浓度下会引起类似的 FGFR3c 反应，但在高浓度下则不会。研究结果表明 FGFR3c 对 fgf1 和 fgf2 的反应具有多功能性，并强调了 fgf 信号的复杂性。
