Abstract
Regulation of mitosis secures cellular integrity and its failure critically contributes to the development, maintenance, and treatment resistance of cancer. In yeast, the dual phosphatase Cdc14 controls mitotic progression by antagonizing Cdk1-mediated protein phosphorylation. By contrast, specific mitotic functions of the mammalian Cdc14 orthologue CDC14B have remained largely elusive. Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms’ tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. We further demonstrate that WT1 functions as a mitotic transcription factor and specify CXCL8/IL-8 as a target gene of WT1 that conveys mitotic survival. Together, we describe a ubiquitin-dependent signaling pathway that directs a mitosis-specific transcription program to regulate mitotic survival.
Highlights
Regulation of mitosis secures cellular integrity and its failure critically contributes to the development, maintenance, and treatment resistance of cancer
Given the function of CDC14B as a phosphatase, we thought to investigate whether USP9X undergoes CDC14B-dependent mitotic phosphorylation/dephosphorylation and whether such an event has regulatory effects on USP9X activity
We carried out an unbiased quantitative phospho-proteomic screen of USP9X using Stable Isotope Labeling of Amino Acids in Culture (SILAC) in control or CDC14B overexpressing mitotic cells
Summary
Regulation of mitosis secures cellular integrity and its failure critically contributes to the development, maintenance, and treatment resistance of cancer. The dual phosphatase Cdc[14] controls mitotic progression by antagonizing Cdk1-mediated protein phosphorylation. Essential mitotic regulators include the polo-like kinase 1 (PLK1), and cyclin-dependent kinases (CDK), as well as the anaphase-promoting complex/cyclosome (APC/C), a large ubiquitin ligase complex whose ubiquitylation activity is determined by the SAC and controls mitotic exit[4,5]. Cdc[14] is the major mitotic exit phosphatase in budding yeast by virtue of its antagonizing activity on Cdk1-mediated phosphorylation of Cdh[1], a coactivator of the APC/C6–8. This function of Cdc[14] is not conserved. Neither USP9Xregulatory upstream mechanisms nor its mitosis-specific downstream pathways have been well defined
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