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首页> 外文期刊>Molecular and Cellular Biology >Phosphorylation of the Cap-Binding Protein Eukaryotic Translation Initiation Factor 4E by Protein Kinase Mnk1 In Vivo
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Phosphorylation of the Cap-Binding Protein Eukaryotic Translation Initiation Factor 4E by Protein Kinase Mnk1 In Vivo

机译：蛋白激酶Mnk1体内的帽结合蛋白真核翻译起始因子4E的磷酸化。

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Eukaryotic translation initiation factor 4E (eIF4E) binds to the mRNA 5′ cap and brings the mRNA into a complex with other protein synthesis initiation factors and ribosomes. The activity of mammalian eIF4E is important for the translation of capped mRNAs and is thought to be regulated by two mechanisms. First, eIF4E is sequestered by binding proteins, such as 4EBP1, in quiescent cells. Mitogens induce the release of eIF4E by stimulating the phosphorylation of 4EBP1. Second, mitogens and stresses induce the phosphorylation of eIF4E at Ser 209, increasing the affinity of eIF4E for capped mRNA and for an associated scaffolding protein, eIF4G. We previously showed that a mitogen- and stress-activated kinase, Mnk1, phosphorylates eIF4E in vitro at the physiological site. Here we show that Mnk1 regulates eIF4E phosphorylation in vivo. Mnk1 binds directly to eIF4G and copurifies with eIF4G and eIF4E. We identified activating phosphorylation sites in Mnk1 and developed dominant-negative and activated mutants. Expression of dominant-negative Mnk1 reduces mitogen-induced eIF4E phosphorylation, while expression of activated Mnk1 increases basal eIF4E phosphorylation. Activated mutant Mnk1 also induces extensive phosphorylation of eIF4E in cells overexpressing 4EBP1. This suggests that phosphorylation of eIF4E is catalyzed by Mnk1 or a very similar kinase in cells and is independent of other mitogenic signals that release eIF4E from 4EBP1.
机译：真核翻译起始因子4E（eIF4E）与mRNA 5'帽结合，并使mRNA与其他蛋白质合成起始因子和核糖体形成复合体。哺乳动物eIF4E的活性对于加帽的mRNA的翻译很重要，并被认为受两种机制调控。首先，在静止细胞中，eIF4E被结合蛋白（例如4EBP1）隔离。丝裂原通过刺激4EBP1的磷酸化诱导eIF4E的释放。其次，促细胞分裂剂和应激诱导eIF4E在Ser 209磷酸化，增加了eIF4E对加帽的mRNA和相关支架蛋白eIF4G的亲和力。我们以前显示有丝分裂原和应激激活的激酶Mnk1在体外在生理部位磷酸化eIF4E。在这里，我们显示Mnk1在体内调节eIF4E磷酸化。 Mnk1直接绑定到eIF4G，并与eIF4G和eIF4E共纯化。我们确定了Mnk1中的激活磷酸化位点，并开发了显性的负性和激活性突变体。显性负性Mnk1的表达减少有丝分裂原诱导的eIF4E磷酸化，而活化的Mnk1的表达则增加基础eIF4E的磷酸化。活化的突变体Mnk1在过表达4EBP1的细胞中也诱导eIF4E广泛磷酸化。这表明eIF4E的磷酸化被细胞中的Mnk1或非常相似的激酶催化，并且独立于其他有丝分裂信号，这些信号从4EBP1释放eIF4E。

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