A novel function of eIF2α kinases as inducers of the phosphoinositide-3 kinase signaling pathway
A novel function of eIF2α kinases as inducers of the phosphoinositide-3 kinase signaling pathway
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DOI：
10.1091/mbc.e07-01-0053
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发表时间：
2007-09-01
影响因子：
3.3
通讯作者：
Koromilas, Antonis E.
中科院分区：
文献类型：
--
作者：
Kazemi, Shirin;Mounir, Zineb;Koromilas, Antonis E.
磷脂酰肌醇-3激酶(PI3K)在信号转导中发挥重要作用，参与促进细胞增殖和存活的多种细胞刺激。真核细胞翻译起始因子eIF2的α亚基在Ser51发生磷酸化，以响应各种类型的环境应激，对翻译起始的调控是必不可少的。在这里，我们证明了条件激活形式的eIF2α激酶PKR作用于PI3K的上游，并启动Akt/PKB-FRAP/mTOR途径，导致S6和4E-BP1的磷酸化。此外，PI3K信号的诱导拮抗条件激活的PKR的凋亡和蛋白质合成抑制作用。此外，在PKR-/-或PERK-/-小鼠胚胎成纤维细胞(MEF)中，PI3K通路的诱导受到损害，以响应激活每个eIF2a激酶的各种刺激。从机制上讲，PI3K信号的激活是间接的，需要通过eIF2a磷酸化来抑制蛋白质合成，这一点可以通过小干扰RNA使内源性eIF2α失活或利用携带eIF2a Ser51Ala突变的MEF来证明。我们的数据揭示了eIF2a激酶作为PI3K信号和细胞生存激活剂的新特性。
Phosphoinositide-3 kinase (PI3K) plays an important role in signal transduction in response to a wide range of cellular stimuli involved in cellular processes that promote cell proliferation and survival. Phosphorylation of the a subunit of the eukaryotic translation initiation factor eIF2 at Ser51 takes place in response to various types of environmental stress and is essential for regulation of translation initiation. Herein, we show that a conditionally active form of the eIF2 alpha kinase PKR acts upstream of PI3K and turns on the Akt/PKB-FRAP/mTOR pathway leading to S6 and 4E-BP1 phosphorylation. Also, induction of PI3K signaling antagonizes the apoptotic and protein synthesis inhibitory effects of the conditionally active PKR. Furthermore, induction of the PI3K pathway is impaired in PKR-/- or PERK-/- mouse embryonic fibroblasts (MEFs) in response to various stimuli that activate each eIF2a kinase. Mechanistically, PI3K signaling activation is indirect and requires the inhibition of protein synthesis by eIF2a phosphorylation as demonstrated by the inactivation of endogenous eIF2 alpha by small interfering RNA or utilization of MEFs bearing the eIF2a Ser51Ala mutation. Our data reveal a novel property of eIF2a kinases as activators of PI3K signaling and cell survival.