Wip1 controls the translocation of the chromosomal passenger complex to the central spindle for faithful mitotic exit
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Wip1 controls the translocation of the chromosomal passenger complex to the central spindle for faithful mitotic exit Xianghua Zhang1 · Ji Eun Park1 · Eun Ho Kim2 · Jihee Hong1 · Ki‑Tae Hwang3 · Young A. Kim4 · Chang‑Young Jang1 Received: 10 March 2020 / Revised: 12 August 2020 / Accepted: 5 October 2020 © Springer Nature Switzerland AG 2020
Abstract Dramatic cellular reorganization in mitosis critically depends on the timely and temporal phosphorylation of a broad range of proteins, which is mediated by the activation of the mitotic kinases and repression of counteracting phosphatases. The mitosis-to-interphase transition, which is termed mitotic exit, involves the removal of mitotic phosphorylation by protein phosphatases. Although protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) drive this reversal in animal cells, the phosphatase network associated with ordered bulk dephosphorylation in mitotic exit is not fully understood. Here, we describe a new mitotic phosphatase relay in which Wip1/PPM1D phosphatase activity is essential for chromosomal passenger complex (CPC) translocation to the anaphase central spindle after release from the chromosome via PP1-mediated dephosphorylation of histone H3T3. Depletion of endogenous Wip1 and overexpression of the phosphatase-dead mutant disturbed CPC translocation to the central spindle, leading to failure of cytokinesis. While Wip1 was degraded in early mitosis, its levels recovered in anaphase and the protein functioned as a Cdk1-counteracting phosphatase at the anaphase central spindle and midbody. Mechanistically, Wip1 dephosphorylated Thr-59 in inner centromere protein (INCENP), which, subsequently bound to MKLP2 and recruited other components to the central spindle. Furthermore, Wip1 overexpression is associated with the overall survival rate of patients with breast cancer, suggesting that Wip1 not only functions as a weak oncogene in the DNA damage network but also as a tumor suppressor in mitotic exit. Altogether, our findings reveal that sequential dephosphorylation of mitotic phosphatases provides spatiotemporal regulation of mitotic exit to prevent tumor initiation and progression. Keywords DNA damage response · Aurora B · Homeostasis · Checkpoint · MKLP1 Xianghua Zhang, Ji Eun Park and Eun Ho Kim contributed equally to this study. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03665-x) contains supplementary material, which is available to authorized users. * Young A. Kim [email protected] * Chang‑Young Jang [email protected] 1
Drug Information Research Institute, College of Pharmacy, Sookmyung Women’s University, Seoul 04310, Republic of Korea
2
Department of Biochemistry, School of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea
3
Department of Surgery, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea
4
Department of Pathology, Seoul National University Boram
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