Nck-1 selectively modulates eIF2αSer51 phosphorylation by a subset of eIF2α-kinases
Nck-1 selectively modulates eIF2αSer51 phosphorylation by a subset of eIF2α-kinases
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DOI：
10.1111/j.1742-4658.2007.06110.x
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发表时间：
2007-11-01
期刊：
影响因子：
5.4
通讯作者：
Larose, Louise
中科院分区：
文献类型：
--
作者：
Cardin, Eric;Latreille, Mathieu;Larose, Louise
真核起始因子2（eIF 2）的α亚基在Ser 51上的磷酸化是与在翻译水平上下调蛋白质合成和启动转录程序相关的早期事件。这构成了克服各种压力条件的有效机制。在哺乳动物中，在特定应激后激活的四种eIF 2 α-激酶[PKR样内质网激酶（PERK）、dsRNA激活的蛋白激酶（PKR）、血红素调节抑制剂（HRI）和一般控制非去抑制蛋白-2（GCN 2）]已被证明参与了这一过程。在这篇文章中，我们报告说，普遍表达的衔接蛋白NCK，仅组成的Src同源结构域和经典的细胞信号转导激活质膜受体酪氨酸激酶，调制eIF 2 α-激酶介导的eIF 2 α Ser 51磷酸化的特定方式。我们的研究结果表明，Nck不仅可以阻止PERK激活后的eIF 2 α磷酸化，如前所述，还可以减少导致PKR和HRI激活的条件下的eIF 2 α磷酸化。相比之下，哺乳动物细胞中Nck的过表达不能减弱eIF 2 α Ser 51磷酸化对氨基酸饥饿的响应，这是一种众所周知的激活GCN 2的应激。通过显示Nck不能改变酿酒酵母中eIF 2 α Ser 51磷酸化进一步证实了这一观察结果，其中唯一的eIF 2 α-激酶是Gcn 2 p。我们的研究结果表明，存在一种新的机制，特别是调节eIF 2 α的磷酸化Ser 51在各种压力条件下。
Phosphorylation of the alpha-subunit of the eukaryotic initiation factor 2 (eIF2) on Ser51 is an early event associated with the down-regulation of protein synthesis at the level of translation and initiation of a transcriptional program. This constitutes a potent mechanism to overcome various stress conditions. In mammals, four eIF2 alpha-kinases [PKR-like endoplasmic reticulum kinase (PERK), dsRNA-activated protein kinase (PKR), heme regulated inhibitor (HRI) and general control nonderepressible-2 (GCN2)], activated following specific stresses, have been shown to be involved in this process. In this article, we report that the ubiquitously expressed adaptor protein Nck, composed only of Src homology domains and classically implicated in cell signaling by activated plasma membrane receptor tyrosine kinases, modulates eIF2 alpha-kinase-mediated eIF2 alpha Ser51 phosphorylation in a specific manner. Our results show that Nck not only prevents eIF2 alpha phosphorylation upon PERK activation, as reported previously, but also reduces eIF2 alpha phosphorylation in conditions leading to PKR and HRI activation. By contrast, the overexpression of Nck in mammalian cells fails to attenuate eIF2 alpha Ser51 phosphorylation in response to amino acid starvation, a stress well known to activate GCN2. This observation is further confirmed by showing that Nck fails to alter eIF2 alpha Ser51 phosphorylation in Saccharomyces cerevisiae, for which the sole eIF2 alpha-kinase is Gcn2p. Our results suggest the existence of a novel mechanism that specifically modulates the phosphorylation of eIF2 alpha on Ser51 under various stress conditions.