Cellular signals that influence Cap-dependent translation have assumed significant relevance in the backdrop of their enforced dysregulation during oncogenesis. Eukaryotic initiation factor 4E(eIF4E), the mRNA cap-binding protein, has emerged as a key player to facilitate tumor progression through upregulated cap-dependent translation synchronized with enhanced cell division. We provide evidence that eIF4E phosphorylation is regulated by mTORC1 by virtue of its interaction with Raptor through a novel TPTPNPP motif and consequent phosphorylation invitro and in vivo in a Rapamycin-sensitive manner. While we show that phosphorylation pattern of eIF4E responds faithfully to Rapamycin inhibition, the prolonged exposure to Rapamycin rescues the loss of eIF4E phosphorylation through Mnk1 activation. We also present evidence that eIF4E interacts with the amino terminal domain of S6K1 in a phospho-dependent manner, and this interaction is instrumental in overriding Rapamycin inhibition of S6K1. The data endorses eIF4E as a regulatory subunit that modulates the functional attributes of mTOR effectors to synchronize cap-dependent translation with growth assertion.

中文翻译：

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真核生物起始因子4E是与Mnk1发生串扰的mTORC1信号通路的新型效应子。

影响Cap依赖性翻译的细胞信号在其在肿瘤发生过程中被强制失调的背景下具有重要意义。mRNA帽结合蛋白真核起始因子4E（eIF4E）已成为通过上调帽依赖性翻译与增强细胞分裂同步促进肿瘤进展的关键参与者。我们提供的证据表明，eIF4E的磷酸化受mTORC1的调节，这是由于其与Raptor的相互作用（通过新型TPTPNPP基序）以及随后在体内和体内对雷帕霉素敏感的方式进行的磷酸化。尽管我们显示eIF4E的磷酸化模式忠实地响应了雷帕霉素的抑制作用，但长时间暴露于雷帕霉素可通过Mnk1激活来挽救eIF4E磷酸化的损失。我们还提供了证据，证明eIF4E与S6K1的氨基末端结构域以磷酸依赖的方式相互作用，并且这种相互作用在抑制雷帕霉素对S6K1的抑制作用中发挥了作用。数据认可eIF4E作为调节性亚基，可调节mTOR效应子的功能属性，以使瓶盖依赖性翻译与生长断言同步。