The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization
The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization
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DOI：
10.1128/mcb.23.16.5692-5705.2003
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发表时间：
2003-08-01
影响因子：
5.3
通讯作者：
Proud, CG
中科院分区：
文献类型：
--
作者：
Scheper, GC;Parra, JL;Proud, CG
帽结合真核起始因子eIF4E被促分裂原活化蛋白（MAP）激酶相互作用激酶（Mnk's）磷酸化。人类细胞中存在三种形式的Mnk：Mnk1，Mnk2a和Mnk2b。后两种基因通过选择性剪接来自同一基因，仅在C末端不同。虽然Mnk 2a在该区域包含MAP激酶结合位点，但Mnk 2b缺乏这样的序列，并且在体外不太容易被MAP激酶激活。Mnk2b在哺乳动物细胞中的表达导致eIF4E的磷酸化增加，表明其在体内充当eIF4E激酶。虽然Mnk2a是细胞质的，但在细胞核中发现了大量的Mnk2b。这两种酶在其N末端都含有一段碱性残基，其在与eIF4G结合中起作用，并作为核定位信号发挥作用。eIF4G的结合或核输入似乎受Mnk2a的C末端调节。此外，Mnk2a的MAP激酶结合位点调节核进入。在细胞核内，Mnk2b和存在于细胞核中的Mnk2a的某些变体与也结合eIF4E的早幼粒细胞白血病蛋白PML共定位。
The cap-binding eukaryotic initiation factor eIF4E is phosphorylated by the mitogen-activated protein (MAP) kinase-interacting kinases (Mnk's). Three forms of the Mnk's exist in human cells: Mnk1, Mnk2a, and Mnk2b. These last two are derived from the same gene by alternative splicing and differ only at their C termini. While Mnk2a contains a MAP kinase-binding site in this region, Mnk2b lacks such a sequence and is much less readily activated by MAP kinases in vitro. Expression of Mnk2b in mammalian cells leads to increased phosphorylation of eIF4E, showing that it acts as an eIF4E kinase in vivo. While Mnk2a is cytoplasmic, a substantial amount of Mnk2b is found in the nucleus. Both enzymes contain a stretch of basic residues in their N termini that plays a role in binding to eIF4G and functions as a nuclear localization signal. Binding of eIF4G or nuclear import appears to be regulated by the C terminus of Mnk2a. Furthermore, the MAP kinase-binding site of Mnk2a regulates nuclear entry. Within the nucleus, Mnk2b and certain variants of Mnk2a that are present in the nucleus colocalize with the promyelocytic leukemia protein PML, which also binds to eIF4E.