Rote of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1
Rote of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1
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DOI：
10.1126/science.1103233
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发表时间：
2004-12-24
期刊：
影响因子：
56.9
通讯作者：
Kolch, W
中科院分区：
文献类型：
--
作者：
O'Neill, E;Rushworth, L;Kolch, W
尽管细胞外信号调节激酶正常调节，但蛋白激酶Raf-1的消融使细胞对细胞凋亡高度敏感，这表明细胞凋亡保护由不同的途径介导。我们使用Raf-1信号复合物的蛋白质组学分析表明Raf-1通过抑制哺乳动物不育20样激酶（MST 2）的激活来对抗细胞凋亡。Raf-1阻止MST 2激活环的二聚化和磷酸化，而与其蛋白激酶活性无关。从Raf-1（-1-）小鼠或人细胞中耗尽MST 2可消除对凋亡的敏感性，而MST 2的过表达可诱导凋亡。相反，从Raf-I（+/+）小鼠或人细胞中耗尽Raf-1导致MST 2活化和凋亡。Raf-1和MST 2的同时消耗阻止了细胞凋亡。
The ablation of the protein kinase Raf-1 renders cells hypersensitive to apoptosis despite normal regulation of extracellular signal-regulated kinases, which suggests that apoptosis protection is mediated by a distinct pathway. We used proteomic analysis of Raf-1 signaling complexes to show that Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (MST2). Raf-1 prevents dimerization and phosphorylation of the activation loop of MST2 independently of its protein kinase activity. Depletion of MST2 from Raf-1(-1-) mouse or human cells abrogated sensitivity to apoptosis, whereas overexpression of MST2 induced apoptosis. Conversely, depletion of Raf-1 from Raf-l(+/+) mouse or human cells led to MST2 activation and apoptosis. The concomitant depletion of both Raf-1 and MST2 prevented apoptosis.