Critical role for caspase-8 in epidermal growth factor signaling.
Critical role for caspase-8 in epidermal growth factor signaling.
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DOI：
10.1158/0008-5472.can-08-3731
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发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Vuori K
中科院分区：
文献类型：
--
作者：
Finlay D;Howes A;Vuori K
Caspase-8作为外源性细胞凋亡途径的顶端蛋白，具有明确的典型作用。然而，越来越多的证据表明，该蛋白还有许多其他非凋亡功能。我们先前已经证明，caspase-8是有效的黏附诱导ERK1/2通路激活所必需的。我们现在表明，caspase-8也是有效激活与表皮生长因子(EGF)信号相关的下游事件所必需的。这种对表皮生长因子诱导的Erk1/2激活的促进作用不依赖于Caspase-8‘S的蛋白水解性，并且可以仅使用该蛋白的前结构域来重新投降。此外，我们还确定了caspase-8“RXDLL基序”中对ERK途径激活至关重要的特定残基。此外，这些残基还参与与酪氨酸激酶Src形成复合体。与野生型蛋白重组细胞相比，caspase-8缺失细胞和携带这些关键氨基酸的点突变的caspase-8重组细胞也显示出EGF诱导的缺陷迁移。综上所述，我们首次提供了caspase-8作为生长因子信号的重要组成部分的证据，并认为这可能是由于它与Src有关。由于EGF/Src通路的活性已被证明可以促进致癌事件，我们的发现caspase-8是这些活动所必需的，这可能有助于解释为什么它在肿瘤中很少被缺失或沉默。
Caspase-8 has a well defined canonical role as an apical protease of the extrinsic apoptosis pathway. Evidence is growing, however, that the protein has numerous other non-apoptotic functions. We have previously demonstrated that caspase-8 is required for efficient adhesion-induced activation of the Erk 1/2 pathway. We now show that caspase-8 is also necessary for the efficient activation of downstream events associated with epidermal growth factor (EGF) signaling. This promotion of EGF-induced Erk 1/2 activation is independent of caspase-8’s proteolytic activity and can be re-capitulated using only the protein’s pro-domains. In addition, we identify specific residues within the caspase-8 “RXDLL motif” that are essential for Erk pathway activation. Furthermore, these residues are also involved in forming a complex with the tyrosine kinase Src. Caspase-8 null cells and cells re-constituted with caspase-8 harboring point mutations of these critical amino acids also show defective EGF-induced migration as compared to cells re-constituted with the wild-type protein. In sum, we provide the first evidence for caspase-8 as an essential component of growth factor signaling and suggest this may be due to its association with Src. As the EGF/Src pathway activity has been demonstrated to promote oncogenic events, our findings that caspase-8 is necessary for these activities may help explain why it is rarely deleted or silenced in tumors.