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首页> 外文期刊>Molecular and Cellular Biology >Negative Regulation of Protein Translation by Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2
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Negative Regulation of Protein Translation by Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2

机译：丝裂原激活的蛋白激酶相互作用激酶1和2的蛋白质翻译的负调控。

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Eukaryotic initiation factor 4E (eIF4E) is a key component of the translational machinery and an important modulator of cell growth and proliferation. The activity of eIF4E is thought to be regulated by interaction with inhibitory binding proteins (4E-BPs) and phosphorylation by mitogen-activated protein (MAP) kinase-interacting kinase (MNK) on Ser209 in response to mitogens and cellular stress. Here we demonstrate that phosphorylation of eIF4E via MNK1 is mediated via the activation of either the Erk or p38 pathway. We further show that expression of active mutants of MNK1 and MNK2 in 293 cells diminishes cap-dependent translation relative to cap-independent translation in a transient reporter assay. The same effect on cap-dependent translation was observed when MNK1 was activated by the Erk or p38 pathway. In line with these findings, addition of recombinant active MNK1 to rabbit reticulocyte lysate resulted in a reduced protein synthesis in vitro, and overexpression of MNK2 caused a decreased rate of protein synthesis in 293 cells. By using CGP 57380, a novel low-molecular-weight kinase inhibitor of MNK1, we demonstrate that eIF4E phosphorylation is not crucial to the formation of the initiation complex, mitogen-stimulated increase in cap-dependent translation, and cell proliferation. Our results imply that activation of MNK by MAP kinase pathways does not constitute a positive regulatory mechanism to cap-dependent translation. Instead, we propose that the kinase activity of MNKs, eventually through phosphorylation of eIF4E, may serve to limit cap-dependent translation under physiological conditions.
机译：真核起始因子4E（eIF4E）是翻译机制的关键组成部分，是细胞生长和增殖的重要调节剂。 eIF4E的活性被认为是通过与抑制性结合蛋白（4E-BPs）相互作用以及Ser209对有丝分裂原和细胞应激的有丝分裂原活化蛋白（MAP）激酶相互作用激酶（MNK）磷酸化来调节的。在这里，我们证明通过ENK或p38途径的激活介导通过MNK1的eIF4E的磷酸化。我们进一步显示，在瞬时报告基因分析中，相对于不依赖于帽的翻译，293细胞中MNK1和MNK2活性突变体的表达减少了依赖于帽的翻译。当通过Erk或p38途径激活MNK1时，观察到了与帽依赖性翻译相同的效果。与这些发现一致，向兔网织红细胞裂解物中添加重组活性MNK1导致体外蛋白质合成减少，而MNK2的过表达导致293细胞中蛋白质合成的速率降低。通过使用CGP 57380，MNK1的新型低分子量激酶抑制剂，我们证明eIF4E磷酸化对于起始复合物的形成，有丝分裂原刺激的盖帽依赖性翻译和细胞增殖的形成不是至关重要的。我们的结果表明，通过MAP激酶途径激活MNK并不构成依赖于帽的翻译的积极调控机制。相反，我们提出，最终通过eIF4E的磷酸化作用，MNKs的激酶活性可能会在生理条件下限制帽依赖性翻译。

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