Department Biology II, Faculty of Biology, Ludwig-Maximilians-University Munich, Großhadener, Planegg-Martinsried, Germany.
Research Department of Cell and Developmental Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, United Kingdom.
PLoS Genet. 2020 Sep 18;16(9):e1008912. doi: 10.1371/journal.pgen.1008912. eCollection 2020 Sep.
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 MELK 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.
哺乳动物激酶 MELK 促进肿瘤发生的机制尚不清楚。我们发现 MELK 的秀丽隐杆线虫同源物 PIG-1 通过分配抗凋亡因子来促进细胞凋亡。秀丽隐杆线虫的 NSM 神经母细胞分裂产生一个较大的细胞，该细胞分化为神经元，而一个较小的细胞则死亡。我们发现，在这种情况下，PIG-1 MELK 对于 CES-1 Snail 的分配是必需的，CES-1 Snail 是促凋亡基因 egl-1 BH3-only 的转录抑制剂。pig-1 MELK 受 ces-1 Snail 和 par-4 LKB1 依赖的途径控制，并且可能通过磷酸化和皮质肌球蛋白 II 的富集在神经母细胞分裂之前发挥作用。我们提出，pig-1 MELK 诱导的肌动球蛋白网络的局部收缩性在获得凋亡命运中起着保守作用。我们的工作还揭示了一个自动调节回路，通过该回路，ces-1 Snail 通过形成 CES-1 Snail 蛋白的梯度来控制其自身的活性。
