Translational control of ERK signalling pathway by the mRNA cap-binding protein 4EHP

microRNA (miRNA)-mediated gene silencing is commonly deregulated in a wide variety of diseases. Therefore, a better understanding of how miRNAs govern the translation and stability of mRNAs is of paramount importance. We recently demonstrated that the cap-binding protein 4EHP is recruited by the miRNA machinery to effect translational repression. However, the impact of 4EHP on regulation of endogenous mRNAs and its role in cell biology is debated. Herein, using the ribosome profiling assay, we identify a subset of endogenous mRNAs that are sensitive to translational repression by 4EHP. We show that expression of DUSP6, a phosphatase that reverses ERK1/2 phosphorylation, is regulated by 4EHP. This regulation, which occurs exclusively at the level of mRNA translation, without affecting the stability of Dusp6 mRNA, is engendered through 4EHP- and miRNA-dependent elements in Dusp6 3´UTR. Consequently, 4EHP protein controls ERK1/2 phosphorylation, promotes cell growth and inhibits apoptosis. Our data reveal a crucial role for translational control mechanisms in the regulation of the ERK pathway. Ribosome profiling and mRNA-seq in 4EHP KO and WT MEFs.