Zhang Si Qing, Yang Wentian, Kontaridis Maria I, Bivona Trever G, Wen Gengyun, Araki Toshiyuki, Luo Jincai, Thompson Julie A, Schraven Burkhart L, Philips Mark R, Neel Benjamin G
Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, MA 02115 USA.
Mol Cell. 2004 Feb 13;13(3):341-55. doi: 10.1016/s1097-2765(04)00050-4.
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.
蛋白酪氨酸磷酸酶Shp2在生长因子和整合素信号传导中起重要作用，Shp2突变会导致发育缺陷和/或恶性肿瘤。先前的研究已将Shp2置于Ras上游。然而，Shp2的作用机制及其底物尚不清楚。也有人提出Shp2在Ras/Erk激活的下游或与之平行的其他功能。在这里，我们表明Shp2通过调节Csk调节因子PAG/Cbp的磷酸化来促进Src家族激酶（SFK）的激活，从而控制Csk与SFK的结合。在缺乏Shp2的细胞中，SFK抑制性C末端酪氨酸过度磷酸化，包括Plcgamma1在内的多种SFK底物的酪氨酸磷酸化减少。Plcgamma1磷酸化减少导致内膜上Ras激活缺陷，这可能有助于解释缺乏Shp2的细胞中Erk激活受损的原因。其他SFK底物磷酸化/激活的减少可能解释了Shp2缺乏的其他后果，包括细胞铺展、应力纤维、粘着斑和运动性的改变。
