CNOT3 interacts with the Aurora B and MAPK/ERK kinases to promote survival of differentiating mesendodermal progenitor cells |
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| Authors: | Moumita Sarkar Matteo Martufi Monica Roman-Trufero Yi-Fang Wang Chad Whilding Dirk Dormann Pierangela Sabbattini Niall Dillon |
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| Institution: | University of Texas, Austin;aGene Regulation and Chromatin Group, Imperial College London, London W12 0NN, UK;bBioinformatics and Computing, Imperial College London, London W12 0NN, UK;cMicroscopy Facility, MRC London Institute of Medical Sciences, Imperial College London, London W12 0NN, UK;dInstitute of Clinical Sciences, Imperial College London, London W12 0NN, UK |
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| Abstract: | Mesendoderm cells are key intermediate progenitors that form at the early primitive streak (PrS) and give rise to mesoderm and endoderm in the gastrulating embryo. We have identified an interaction between CNOT3 and the cell cycle kinase Aurora B that requires sequences in the NOT box domain of CNOT3 and regulates MAPK/ERK signaling during mesendoderm differentiation. Aurora B phosphorylates CNOT3 at two sites located close to a nuclear localization signal and promotes localization of CNOT3 to the nuclei of mouse embryonic stem cells (ESCs) and metastatic lung cancer cells. ESCs that have both sites mutated give rise to embryoid bodies that are largely devoid of mesoderm and endoderm and are composed mainly of cells with ectodermal characteristics. The mutant ESCs are also compromised in their ability to differentiate into mesendoderm in response to FGF2, BMP4, and Wnt3 due to reduced survival and proliferation of differentiating mesendoderm cells. We also show that the double mutation alters the balance of interaction of CNOT3 with Aurora B and with ERK and reduces phosphorylation of ERK in response to FGF2. Our results identify a potential adaptor function for CNOT3 that regulates the Ras/MEK/ERK pathway during embryogenesis. |
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