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 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actomyosin / metabolism
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Animals
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Animals, Genetically Modified
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Apoptosis / physiology
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Caenorhabditis elegans
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism*
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Cell Death / physiology
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Cell Polarity / physiology
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Cytoskeletal Proteins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Myosin Type II / metabolism
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Neural Stem Cells / metabolism
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Neurons / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Snail Family Transcription Factors / genetics
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Snail Family Transcription Factors / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Caenorhabditis elegans Proteins
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Snail Family Transcription Factors
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Transcription Factors
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ces-1 protein, C elegans
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Actomyosin
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PIG-1 protein, C elegans
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Protein Serine-Threonine Kinases
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Myosin Type II
Grants and funding
This work was supported by LMU Munich (
https://www.uni-muenchen.de/index.html), the Deutsche Forschungsgemeinschaft (Center for Integrated Protein Science Munich – CIPSM, DFG EXC 114 to B.C.,
https://www.dfg.de/en/) and the European Research Council (
https://erc.europa.eu/) under the European Union’s Horizon 2020 research and innovation programme (grant agreement 640553 – ACTOMYO to A.X.C.). H.W. was supported by a predoctoral fellowship from the China Scholarship Council (
https://www.csc.edu.cn/). A.X.C. has a Principal Investigator position from the Fundação para a Ciência e Tecnologia (
https://www.fct.pt/) (CEECIND/01967/2017). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.