Mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors are widely applied to maintain pluripotency, while prolonged MEK inhibition compromises the developmental potential of mouse embryonic stem cells (ESCs). To understand the mechanism of MEK in pluripotency maintenance, we first demonstrated that MEK regulates gene expression at post-transcriptional steps. Consistently, many of the 66 MEK substrates identified by quantitative phosphoproteomics analysis are involved in RNA processing. We further confirmed that MEK1 phosphorylates S563 of DCP1A, an mRNA decapping cofactor and processing body (P body) component. DCP1A, as well as two other P body components, EDC4 and DCP2, are required for the self-renewal and differentiation of ESCs, indicating the role of P bodies in ESCs. Dephosphorylation of DCP1A S563 facilitates both self-renewal and differentiation of ESCs through promoting P body formation and RNA storage. In summary, our study identified 66 MEK substrates supporting the extracellular signal-regulated kinase (ERK)-independent function of MEK and revealed that DCP1A, phosphorylated by MEK, regulates ESC self-renewal and differentiation through modulating P body formation.
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