CDK1-CCNB1 creates a spindle checkpoint-permissive state by enabling MPS1 kinetochore localization

Daniel Hayward, Tatiana Alfonso-Pérez, Michael J. Cundell, Michael Hopkins, James Holder, James Bancroft, Lukas H. Hutter, Bela Novak, Francis A. Barr*, Ulrike Gruneberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

Spindle checkpoint signaling is initiated by recruitment of the kinase MPS1 to unattached kinetochores during mitosis. We show that CDK1-CCNB1 and a counteracting phosphatase PP2A-B55 regulate the engagement of human MPS1 with unattached kinetochores by controlling the phosphorylation status of S281 in the kinetochore-binding domain. This regulation is essential for checkpoint signaling, since MPS1S281A is not recruited to unattached kinetochores and fails to support the recruitment of other checkpoint proteins. Directly tethering MPS1S281A to the kinetochore protein Mis12 bypasses this regulation and hence the requirement for S281 phosphorylation in checkpoint signaling. At the metaphase- anaphase transition, MPS1 S281 dephosphorylation is delayed because PP2A-B55 is negatively regulated by CDK1- CCNB1 and only becomes fully active once CCNB1 concentration falls below a characteristic threshold. This mechanism prolongs the checkpoint-responsive period when MPS1 can localize to kinetochores and enables a response to late-stage spindle defects. By acting together, CDK1-CCNB1 and PP2A-B55 thus create a spindle checkpoint-permissive state and ensure the fidelity of mitosis.

Original languageEnglish
Pages (from-to)1182-1199
Number of pages18
JournalJournal of Cell Biology
Volume218
Issue number4
DOIs
Publication statusPublished - 2019

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