Regulation of ephexin1, a guanine nucleotide exchange factor of Rho family GTPases, by fibroblast growth factor receptor-mediated tyrosine phosphorylation
Regulation of ephexin1, a guanine nucleotide exchange factor of Rho family GTPases, by fibroblast growth factor receptor-mediated tyrosine phosphorylation
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DOI：
10.1074/jbc.m704430200
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发表时间：
2007-10-19
影响因子：
4.8
通讯作者：
Sakaguchi, Kazushige
中科院分区：
文献类型：
--
作者：
Zhang, Yueqiang;Sawada, Takahiro;Sakaguchi, Kazushige
成纤维细胞生长因子（FGF）信号不仅与细胞增殖有关，还与细胞迁移和形态变化有关。 Ras/ERK 通路下游的几种不同的 Rho 家族 GTPases 被认为介导后一种功能。然而，尚未发现任何一种可以直接与 FGF 受体 (FGFR) 偶联。我们之前报道过 EphA4 和 FGFR 通过其胞质结构域异源寡聚化，相互反式激活，并通过对接蛋白 FRS2 α 转导细胞增殖信号（Yokote, H.、Fujita, K.、Jing, X.、Sawada, T.、Liang, S.、Yao, L.、Yan, X.、Zhang, Y.、Schlessinger, J. 和 Sakaguchi, K.） (2005) 国家科学院。102, 18866-18871)。在这里，我们发现 ephexin1（Rho 家族 GTPases 的鸟嘌呤核苷酸交换因子）构成了受体复合物的另一个下游组件。 Ephexin1 主要通过其 DH 和 PH 结构域直接与 FGFR 的激酶结构域结合。当 FGFR 被激活时，结合似乎会变弱并仅限于 DH 结构域。 FGFR 介导的 ephexin1 磷酸化增强了对 RhoA 的鸟嘌呤核苷酸交换活性，而不影响对 Rac1 或 Cdc42 的活性。 FGFR介导的酪氨酸磷酸化包括但不限于由Src家族激酶磷酸化的残基(Tyr-87)，已知其在EphA4激活后被激活。在一些假定的 FGFR 介导的磷酸化位点中模拟酪氨酸磷酸化的 Tyr-to-Asp 突变增加了 RhoA 的核苷酸交换活性，而不改变 Rac1 或 Cdc42 的活性。从这些结果中，我们得出结论，ephexin1 位于 EphA4-FGFR 复合物的紧下游，并且其功能因 FGFR 介导的多个位点酪氨酸磷酸化而改变。
Fibroblast growth factor (FGF) signal is implicated in not only cell proliferation, but cell migration and morphological changes. Several different Rho family GTPases downstream of the Ras/ERK pathway are postulated to mediate the latter functions. However, none have been recognized to be directly coupled to FGF receptors (FGFRs). We have previously reported that EphA4 and FGFRs hetero-oligomerize through their cytoplasmic domains, trans-activate each other, and transduce a signal for cell proliferation through a docking protein, FRS2 alpha (Yokote, H., Fujita, K., Jing, X., Sawada, T., Liang, S., Yao, L., Yan, X., Zhang, Y., Schlessinger, J., and Sakaguchi, K. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 18866-18871). Here, we have found that ephexin1, a guanine nucleotide exchange factor for Rho family GTPases, constitutes another downstream component of the receptor complex. Ephexin1 directly binds to the kinase domain of FGFR mainly through its DH and PH domains. The binding appears to become weaker and limited to the DH domain when FGFRs become activated. FGFR-mediated phosphorylation of ephexin1 enhances the guanine nucleotide exchange activity toward RhoA without affecting the activity to Rac1 or Cdc42. The FGFR-mediated tyrosine phosphorylation includes, but is not limited to, the residue (Tyr-87) phosphorylated by Src family kinase, which is known to be activated following EphA4 activation. The Tyr-to-Asp mutations that mimic the tyrosine phosphorylation in some of the putative FGFR-mediated phosphorylation sites increase the nucleotide exchange activity for RhoA without changing the activity for Rac1 or Cdc42. From these results, we conclude that ephexin1 is located immediately downstream of the EphA4-FGFR complex and the function is altered by the FGFR-mediated tyrosine phosphorylation at multiple sites.