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Wei, Hai; Lambie, Eric J.; Osorio, Daniel S.; Carvalho, Ana X. and Conradt, Barbara (2020): PIG-1 MELK-dependent phosphorylation of nonmuscle myosin II promotes apoptosis through CES-1 Snail partitioning.
In: PLOS Genetics 16(9), e1008912 [PDF, 4MB]


The mechanism(s) through which mammalian kinase MELK promotes tumorigenesis is not understood. We find that theC.elegansorthologue of MELK, PIG-1, promotes apoptosis by partitioning an anti-apoptotic factor. TheC.elegansNSM neuroblast divides to produce a larger cell that differentiates into a neuron and a smaller cell that dies. We find that in this context, PIG-1 is required for partitioning of CES-1 Snail, a transcriptional repressor of the pro-apoptotic geneegl-1BH3-only.pig-1MELK is controlled by both aces-1Snail- andpar-4LKB1-dependent pathway, and may act through phosphorylation and cortical enrichment of nonmuscle myosin II prior to neuroblast division. We propose thatpig-1MELK-induced local contractility of the actomyosin network plays a conserved role in the acquisition of the apoptotic fate. Our work also uncovers an auto-regulatory loop through whichces-1Snail controls its own activity through the formation of a gradient of CES-1 Snail protein. Author summary Apoptosis is critical for the elimination of 'unwanted' cells. What distinguishes wanted from unwanted cells in developing animals is poorly understood. We report that in theC.elegansNSM neuroblast lineage, the level of CES-1, a Snail-family member and transcriptional repressor of the pro-apoptotic geneegl-1, contributes to this process. In addition, we demonstrate thatC.elegansPIG-1, the orthologue of mammalian proto-oncoprotein MELK, plays a critical role in controlling CES-1(Snail)levels. Specifically, during NSM neuroblast division, PIG-1(MELK)controls partitioning of CES-1(Snail)into one but not the other daughter cell thereby promoting the making of one wanted and one unwanted cell. Furthermore, we present evidence that PIG-1(MELK)acts prior to NSM neuroblast division by locally activating the actomyosin network.

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