Molecular mechanism for the Shp-2 tyrosine phosphatase function in promoting growth factor stimulation of Erk activity
Molecular mechanism for the Shp-2 tyrosine phosphatase function in promoting growth factor stimulation of Erk activity
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DOI：
10.1128/mcb.20.5.1526-1536.2000
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发表时间：
2000-03-01
影响因子：
5.3
通讯作者：
Feng, GS
中科院分区：
文献类型：
--
作者：
Shi, ZQ;Yu, DH;Feng, GS
我们之前已经表明，在表达SH2-N结构域中缺乏65个氨基酸的突变型Shp-2分子Shp-2(Delta 46-110)的小鼠成纤维细胞中，表皮生长因子(EGF)处理对细胞外信号调节激酶(Erk)的激活显着降低。为了阐明Shp-2在介导Erk诱导中积极作用的分子机制，我们评估了Shp-2突变细胞中Erk上游信号成分的激活，EGF刺激的Ras、Raf和Mek激活在Shp-2突变细胞中显着减弱，表明Shp-2起到促进Ras激活或抑制激活Ras下调的作用。生化分析表明，在 EGF 刺激下，Shp-2 被招募到在 Gab1 对接分子上组装的多蛋白复合物中，并且 Shp-2 似乎通过特异性去磷酸化复合物中未识别的 90 kDa 分子来发挥其生物学功能。突变型Shp-2(Delta 46-110)分子未能参与Gab1组织的p90去磷酸化复合物，这与EGF处理的Shp-2突变细胞中Ras-Raf-Mek-Erk级联的激活缺陷相关。还有证据表明，Shp-2 似乎不会通过 Shc、Grb2 和 Sos 蛋白调节从 EGF 受体到 Ras 的信号传递。这些结果开始阐明Shp-2在受体酪氨酸激酶下游发挥作用以促进Ras-Erk通路激活的机制，在癌症治疗中具有潜在的治疗应用。
We have previously shown that activation of extracellular signal-regulated kinase (Erk) by epidermal growth factor (EGF) treatment was significantly decreased in mouse fibroblast cells expressing a mutant Shp-2 molecule lacking 65 amino acids in the SH2-N domain, Shp-2(Delta 46-110). To address the molecular mechanism for the positive role of Shp-2 in mediating Erk induction, we evaluated the activation of signaling components upstream of Erk in Shp-2 mutant cells, EGF-stimulated Ras, Raf, and Mek activation was significantly attenuated in Shp-2 mutant cells, suggesting that Shp-2 acts to promote Ras activation or to suppress the down-regulation of activated Ras. Biochemical analyses indicate that upon EGF stimulation, Shp-2 is recruited into a multiprotein complex assembled on the Gab1 docking molecule and that Shp-2 seems to exert its biological function by specifically dephosphorylating an unidentified molecule of 90 kDa in the complex. The mutant Shp-2(Delta 46-110) molecule failed to participate in the Gab1-organized complex for dephosphorylation of p90, correlating with a defective activation of the Ras-Raf-Mek-Erk cascade in EGF-treated Shp-2 mutant cells. Evidence is also presented that Shp-2 does not appear to modulate the signal relay from EGF receptor to Ras through the Shc, Grb2, and Sos proteins. These results begin to elucidate the mechanism of Shp-2 function downstream of a receptor tyrosine kinase to promote the activation of the Ras-Erk pathway, with potential therapeutic applications in cancer treatment.