Regulation of Early Events in Integrin Signaling by Protein Tyrosine Phosphatase SHP-2
Regulation of Early Events in Integrin Signaling by Protein Tyrosine Phosphatase SHP-2
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DOI：
10.1128/mcb.19.4.3205
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发表时间：
1999-04
影响因子：
5.3
通讯作者：
E. Oh;Haihua Gu;T. M. Saxton;J. Timms;S. Hausdorff;E. Frevert;B. Kahn;T. Pawson;B. Neel;Sheila M. Thomas
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文献类型：
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作者：
E. Oh;Haihua Gu;T. M. Saxton;J. Timms;S. Hausdorff;E. Frevert;B. Kahn;T. Pawson;B. Neel;Sheila M. Thomas
摘要 非跨膜蛋白酪氨酸磷酸酶 SHP-2 在生长因子和细胞因子信号通路中发挥着关键作用。先前的研究表明，一部分 SHP-2 在整合素接合后移动到焦点接触处，并且 SHP-2 与 SHP 底物 1 (SHPS-1)/SIRP-1α 结合，SHP 底物 1 (SHPS-1)/SIRP-1α 是一种具有粘附分子特征的跨膜糖蛋白 (Y. Fujioka 等人，Mol. Cell. Biol. 16:6887–6899, 1996；M. Tsuda 等人，J. Biol. Chem. 16:6887-6899, 1996)。 273：13223–13229）。因此，我们询问 SHP2-SHPS-1 复合物是否参与整合素信号传导。将小鼠成纤维细胞铺板到特定的细胞外基质上后，SHPS-1 酪氨酰磷酸化增加。体外和体内研究均表明 SHPS-1 酪氨酰磷酸化是由 Src 家族蛋白酪氨酸激酶 (PTK) 催化的。 293 细胞中 SHPS-1 的过度表达增强了整合素诱导的丝裂原激活蛋白激酶 (MAPK) 的激活，而增强作用需要功能性 SHP-2。为了进一步探讨 SHP-2 在整合素信号传导中的作用，我们分析了 SHP-2 外显子 3−/− 和野生型细胞系对铺在纤连蛋白上的反应。整合素诱导的 Src 家族 PTK 激活、几种粘着斑蛋白的酪氨酰磷酸化、MAPK 激活以及在纤连蛋白上扩散的能力在 SHP-2 突变成纤维细胞中均存在缺陷，但在 SHP-2 表达后恢复。我们的数据表明了一个正反馈模型，其中，在整合素参与时，c-Src 活性的基础水平催化 SHPS-1 的酪氨酰磷酸化，从而将 SHP-2 招募到质膜，其中，也许通过进一步激活 Src PTK，SHP-2 为下游事件（例如 MAPK 激活和细胞形状变化）转导正信号。
ABSTRACT The nontransmembrane protein tyrosine phosphatase SHP-2 plays a critical role in growth factor and cytokine signaling pathways. Previous studies revealed that a fraction of SHP-2 moves to focal contacts upon integrin engagement and that SHP-2 binds to SHP substrate 1 (SHPS-1)/SIRP-1α, a transmembrane glycoprotein with adhesion molecule characteristics (Y. Fujioka et al., Mol. Cell. Biol. 16:6887–6899, 1996; M. Tsuda et al., J. Biol. Chem. 273:13223–13229). Therefore, we asked whether SHP2–SHPS-1 complexes participate in integrin signaling. SHPS-1 tyrosyl phosphorylation increased upon plating of murine fibroblasts onto specific extracellular matrices. Both in vitro and in vivo studies indicate that SHPS-1 tyrosyl phosphorylation is catalyzed by Src family protein tyrosine kinases (PTKs). Overexpression of SHPS-1 in 293 cells potentiated integrin-induced mitogen-activated protein kinase (MAPK) activation, and potentiation required functional SHP-2. To further explore the role of SHP-2 in integrin signaling, we analyzed the responses of SHP-2 exon 3−/− and wild-type cell lines to being plated on fibronectin. Integrin-induced activation of Src family PTKs, tyrosyl phosphorylation of several focal adhesion proteins, MAPK activation, and the ability to spread on fibronectin were defective in SHP-2 mutant fibroblasts but were restored upon SHP-2 expression. Our data suggest a positive-feedback model in which, upon integrin engagement, basal levels of c-Src activity catalyze the tyrosyl phosphorylation of SHPS-1, thereby recruiting SHP-2 to the plasma membrane, where, perhaps by further activating Src PTKs, SHP-2 transduces positive signals for downstream events such as MAPK activation and cell shape changes.