Shp2 regulates Src family kinase activity and Ras/Erk activation by controlling Csk recruitment
Shp2 regulates Src family kinase activity and Ras/Erk activation by controlling Csk recruitment
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DOI：
10.1016/s1097-2765(04)00050-4
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发表时间：
2004-02-13
期刊：
影响因子：
16
通讯作者：
Neel, BG
中科院分区：
文献类型：
--
作者：
Zhang, SQ;Yang, WT;Neel, BG
蛋白酪氨酸磷酸酶Shp2在生长因子和整合素信号转导中起重要作用，Shp2突变导致发育缺陷和/或恶性。以前的工作已经把Shp2放在RAS的上游。然而，Shp2的作用机制及其底物(S)尚不清楚。还提出了在RAS/ERK激活下游或平行于RAS/ERK激活的额外Shp2功能。在这里，我们表明Shp2通过调节CSK调节因子PAG/CBP的磷酸化，从而控制CSK对SFK的访问，促进了Src家族激酶(SFK)的激活。在Shp2缺失的细胞中，SFK抑制的C末端酪氨酸被过度磷酸化，包括PlcGamma1在内的多种SFK底物的酪氨酸磷酸化水平降低。PlcGamma1磷酸化降低导致膜上RAS激活缺陷，并可能有助于解释Shp2缺陷细胞中ERK活性受损的原因。其他SFK底物的磷酸化/激活减少可能解释Shp2缺乏的其他后果，包括细胞伸展、应力纤维、焦点粘连和运动性改变。
The protein-tyrosine phosphatase Shp2 plays an essential role in growth factor and integrin signaling, and Shp2 mutations cause developmental defects and/or malignancy. Previous work has placed Shp2 upstream of Ras. However, the mechanism of Shp2 action and its substrate(s) are poorly defined. Additional Shp2 functions downstream of, or parallel to, Ras/Erk activation also are proposed. Here, we show that Shp2 promotes Src family kinase (SFK) activation by regulating the phosphorylation of the Csk regulator PAG/Cbp, thereby controlling Csk access to SFKs. In Shp2-deficient cells, SFK inhibitory C-terminal tyrosines are hyperphosphorylated, and the tyrosyl phosphorylation of multiple SFK substrates, including Plcgamma1, is decreased. Decreased Plcgamma1 phosphorylation leads to defective Ras activation on endomembranes, and may help account for impaired Erk activation in Shp2-deficient cells. Decreased phosphorylation/activation of other SFK substrates may explain additional consequences of Shp2 deficiency, including altered cell spreading, stress fibers, focal adhesions, and motility.