PIG-1 MELK-dependent phosphorylation of nonmuscle myosin II promotes apoptosis through CES-1 Snail partitioning

Abstract

The mechanism(s) through which mammalian kinase MELK promotes tumorigenesis is not understood. We find that the C. elegans orthologue of MELK, PIG-1, promotes apoptosis by partitioning an anti-apoptotic factor. The C. elegans NSM 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 gene egl-1 BH3-only. pig-1 MELK is controlled by both a ces-1 Snail- and par-4 LKB1-dependent pathway, and may act through phosphorylation and cortical enrichment of nonmuscle myosin II prior to neuroblast division. We propose that pig-1 MELK-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 which ces-1 Snail controls its own activity through the formation of a gradient of CES-1 Snail protein. Significance StatementApoptosis is critical for the elimination of unwanted cells. What distinguishes wanted from unwanted cells in developing animals is poorly understood. We report that in the C. elegans NSM neuroblast lineage, the level of CES-1, a Snail-family member and transcriptional repressor of the pro-apoptotic gene egl-1, contributes to this process. In addition, we demonstrate that C. elegans PIG-1, the orthologue of mammalian proto-oncoprotein MELK, plays a critical role in controlling CES-1Snail levels. Specifically, during NSM neuroblast division, PIG-1MELK controls partitioning of CES-1Snail 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-1MELK acts prior to NSM neuroblast division by locally activating the actomyosin network.