Abstract

eIF4E plays key roles in protein synthesis and tumorigenesis. It is phosphorylated by the kinases MNK1 and MNK2. Binding of MNKs to eIF4G enhances their ability to phosphorylate eIF4E. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G. These effects provide a novel mechanism by which mTORC1 signaling impairs the function of MNK2 and thereby decreases eIF4E phosphorylation. MNK2[S74A] knock-in cells show enhanced phosphorylation of eIF4E and S6K1 (i.e., increased mTORC1 signaling), enlarged cell size, and increased invasive and transformative capacities. MNK2[Ser74] phosphorylation was inversely correlated with disease progression in human prostate tumors. MNK inhibition exerted anti-proliferative effects in prostate cancer cells in vitro. These findings define a novel feedback loop whereby mTORC1 represses MNK2 activity and oncogenic signaling through eIF4E phosphorylation, allowing reciprocal regulation of these two oncogenic pathways.

中文翻译：

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mTORC1 和 MNK2 之间的相互信号传导控制细胞生长和肿瘤发生

 抽象的

eIF4E 在蛋白质合成和肿瘤发生中发挥关键作用。它被激酶 MNK1 和 MNK2 磷酸化。 MNK 与 eIF4G 的结合增强了它们磷酸化 eIF4E 的能力。在这里，我们发现 mTORC1（mRNA 翻译和肿瘤发生的关键调节因子）直接磷酸化 Ser74 上的 MNK2。这会抑制 MNK2 活性并损害 MNK2 与 eIF4G 的结合。这些效应提供了一种新机制，mTORC1 信号传导可通过该机制损害 MNK2 的功能，从而降低 eIF4E 磷酸化。 MNK2[S74A] 敲入细胞表现出 eIF4E 和 S6K1 磷酸化增强（即 mTORC1 信号传导增强）、细胞尺寸增大以及侵袭和转化能力增强。 MNK2[Ser74] 磷酸化与人类前列腺肿瘤的疾病进展呈负相关。 MNK 抑制在体外前列腺癌细胞中发挥抗增殖作用。这些发现定义了一个新的反馈环路，mTORC1 通过 eIF4E 磷酸化抑制 MNK2 活性和致癌信号传导，从而允许这两种致癌途径的相互调节。