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首页> 外文期刊>Oncogene >Differential phosphorylation of the docking protein Gab1 by c-Src and the hepatocyte growth factor receptor regulates different aspects of cell functions
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Differential phosphorylation of the docking protein Gab1 by c-Src and the hepatocyte growth factor receptor regulates different aspects of cell functions

机译：c-Src和肝细胞生长因子受体对接蛋白Gab1的差异磷酸化调节细胞功能的不同方面

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摘要

The docking protein Grb2-associated binder1 (Gab1) has a central role in the integration of the growth-factor signaling. In this study, we aimed to examine the significance of Src-mediated Gab1 phosphorylation in the hepatocyte growth factor (HGF) signaling. Using both mutagenesis and mass spectrometry approaches, Y242, Y259, Y317, Y373 and Y627 of Gab1 were identified to be phosphorylated by c-Src. It is interesting to note that the binding of the tyrosine phosphatase SHP2 to the Y627 antagonized the effect of c-Src on the phosphorylation of the other four tyrosine residues. Moreover, the tyrosine residues predominantly phosphorylated by c-Src were different from those predominantly phosphorylated by the HGF receptor. Gab1 overexpression potentiated both mitogenic and motogenic activities of HGF. However, a Gab1 mutant with substitutions of the Src phosphorylation sites (Y242, Y259, Y317 and Y373) failed to promote HGF-induced DNA synthesis, but retained its ability to facilitate HGF-induced chemotaxis. Taken together, our results not only suggest that the phosphorylation of Gab1 by c-Src is important for HGF-induced DNA synthesis, but also provide an example to illustrate how a docking protein (for example, Gab1) is differentially phosphorylated by c-Src and a receptor tyrosine kinase to emanate full spectrum of signals to the downstream.
机译：对接蛋白Grb2相关的binder1（Gab1）在整合生长因子信号中起着核心作用。在这项研究中，我们旨在检查肝细胞生长因子（HGF）信号传导中Src介导的Gab1磷酸化的重要性。使用诱变和质谱方法，鉴定Gab1的Y242，Y259，Y317，Y373和Y627被c-Src磷酸化。有趣的是，酪氨酸磷酸酶SHP2与Y627的结合拮抗了c-Src对其他四个酪氨酸残基磷酸化的影响。此外，主要被c-Src磷酸化的酪氨酸残基不同于主要被HGF受体磷酸化的酪氨酸残基。 Gab1的过表达增强了HGF的促有丝分裂和促运动活性。但是，具有Src磷酸化位点（Y242，Y259，Y317和Y373）取代的Gab1突变体不能促进HGF诱导的DNA合成，但保留了其促进HGF诱导的趋化性的能力。综上所述，我们的结果不仅表明c-Src对Gab1的磷酸化对于HGF诱导的DNA合成很重要，而且还提供了一个示例来说明对接蛋白（例如Gab1）如何被c-Src差异磷酸化和受体酪氨酸激酶向下游发出全光谱信号。

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