Engagement of Gab1 and Gab2 in erythropoietin signaling
Engagement of Gab1 and Gab2 in erythropoietin signaling
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DOI：
10.1074/jbc.274.35.24469
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发表时间：
1999-08-27
影响因子：
4.8
通讯作者：
Platanias, LC
中科院分区：
文献类型：
--
作者：
Wickrema, A;Uddin, S;Platanias, LC
在促红细胞生成素受体的参与期间激活若干信号传导级联以介导促红细胞生成素的生物学效应。胰岛素受体底物（IRS）蛋白家族的成员通过充当信号传导元件的SH 2结构域的对接蛋白，将细胞因子受体连接到不同的下游途径，在各种生长因子受体和细胞因子的信号传导中发挥核心作用。在本研究中，我们提供的证据表明，最近克隆的IRS相关蛋白，Gab 1和Gab 2，Gab家族的蛋白质，在促红细胞生成素治疗的促红细胞生成素反应细胞的酪氨酸迅速磷酸化，并提供对接网站的参与SHP 2磷酸酶和磷脂酰肌醇3 '-激酶的p85亚基。此外，我们的数据表明，Gab 1是在原代红系祖细胞中由促红细胞生成素激活的主要IRS相关蛋白。在鉴定促红细胞生成素受体结构域所需的Gab蛋白激活的研究中，我们发现促红细胞生成素受体胞质结构域中的酪氨酸425和367是Gab 2磷酸化所需的。总之，我们的数据表明，Gab蛋白参与促红细胞生成素信号传导介导的SHP 2和磷脂酰肌醇3 '-激酶途径的下游激活，并可能参与促红细胞生成素诱导的促有丝分裂反应的产生。
Several signaling cascades are activated during engagement of the erythropoietin receptor to mediate the biological effects of erythropoietin, The members of the insulin receptor substrate (IRS) family of proteins play a central role in signaling for various growth factor receptors and cytokines by acting as docking proteins for the SH2 domains of signaling elements, linking cytokine receptors to diverse downstream pathways. In the present study we provide evidence that the recently cloned IRS-related proteins, Gab1 and Gab2, of the Gab family of proteins, are rapidly phosphorylated on tyrosine during erythropoietin treatment of erythropoietin-responsive cells and provide docking sites for the engagement of the SHP2 phosphatase and the p85 subunit of the phosphatidylinositol 3'-kinase. Furthermore, our data show that Gab1 is the primary IRS-related protein activated by erythropoietin in primary erythroid progenitor cells, In studies to identify the erythropoietin receptor domains required for activation of Gab proteins, we found that tyrosines 425 and 367 in the cytoplasmic domain of the erythropoietin receptor are required for the phosphorylation of Gab2. Taken together, our data demonstrate that Gab proteins are engaged in erythropoietin signaling to mediate downstream activation of the SHP2 and phosphatidylinositol 3'-kinase pathways and possibly participate in the generation of the erythropoietin-induced mitogenic responses.