DCP1A, a MEK substrate, regulates the self-renewal and differentiation of mouse embryonic stem cells
Jiayu Yu,
Nannan Zhao,
Yuying Wang,
Nan Ding,
Zhenchang Guo,
Zichan He,
Qingye Zhang,
Jingai Zhang,
Xiaoqiong Yang,
Ming Zhang,
Xiaoling Du,
Kai Zhang,
Lingyi Chen
Affiliations
Jiayu Yu
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Nannan Zhao
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Yuying Wang
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Nan Ding
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Zhenchang Guo
Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300203, China
Zichan He
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Qingye Zhang
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Jingai Zhang
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Xiaoqiong Yang
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Ming Zhang
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Xiaoling Du
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Kai Zhang
Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300203, China
Lingyi Chen
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China; Corresponding author
Summary: 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.
