The Ki-67 and RepoMan mitotic phosphatases assemble via an identical, yet novel mechanism

Kumar, Ganesan Senthil; Gokhan, Ezgi; De Munter, Sofie; Bollen, Mathieu; Vagnarelli, Paola; Peti, Wolfgang; Page, Rebecca

doi:10.7554/elife.16539

The Ki-67 and RepoMan mitotic phosphatases assemble via an identical, yet novel mechanism

Journal Article · Tue Aug 30 00:00:00 EDT 2016 · eLife

DOI:https://doi.org/10.7554/elife.16539· OSTI ID:1628855

Kumar, Ganesan Senthil ^[1]; Gokhan, Ezgi ^[2]; De Munter, Sofie ^[3]; Bollen, Mathieu ^[3]; ^[2]; Peti, Wolfgang ^[4]; ^[5]

Brown Univ., Providence, RI (United States). Dept. of Molecular Pharmacology, Physiology and Biotechnology; DOE/OSTI
Brunel Univ., Middlesex (United Kingdom). Research Inst. for Environment, Health and Society. College of Health and Life Science
Katholieke Univ. Leuven, Heverlee (Belgium). Dept. of Cellular and Molecular Medicine. Lab. of Biosignaling and Therapeutics
Brown Univ., Providence, RI (United States). Dept. of Molecular Pharmacology, Physiology and Biotechnology
Brown Univ., Providence, RI (United States). Dept. of Molecular Biology, Cell Biology and Biochemistry

Ki-67 and RepoMan have key roles during mitotic exit. Previously, we showed that Ki-67 organizes the mitotic chromosome periphery and recruits protein phosphatase 1 (PP1) to chromatin at anaphase onset, in a similar manner as RepoMan. Here we show how Ki-67 and RepoMan form mitotic exit phosphatases by recruiting PP1, how they distinguish between distinct PP1 isoforms and how the assembly of these two holoenzymes are dynamically regulated by Aurora B kinase during mitosis. Unexpectedly, our data also reveal that Ki-67 and RepoMan bind PP1 using an identical, yet novel mechanism, interacting with a PP1 pocket that is engaged only by these two PP1 regulators. These findings not only show how two distinct mitotic exit phosphatases are recruited to their substrates, but also provide immediate opportunities for the design of novel cancer therapeutics that selectively target the Ki-67:PP1 and RepoMan:PP1 holoenzymes.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1628855

Journal Information:: eLife, Journal Name: eLife Vol. 5; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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