Integration of Kinase and Phosphatase Activities by BUBR1 Ensures Formation of Stable Kinetochore-Microtubule Attachments

SummaryMaintenance of chromosomal stability depends on error-free chromosome segregation. The pseudokinase BUBR1 is essential for this, because it is a core component of the mitotic checkpoint and is required for formation of stable kinetochore-microtubule attachments. We have identified a conserved and highly phosphorylated domain (KARD) in BUBR1 that is crucial for formation of kinetochore-microtubule attachments. Deletion of this domain or prevention of its phosphorylation abolishes formation of kinetochore microtubules, which can be reverted by inhibiting Aurora B activity. Phosphorylation of KARD by PLK1 promotes direct interaction of BUBR1 with the PP2A-B56α phosphatase that counters excessive Aurora B activity at kinetochores. As a result, removal of BUBR1 from mitotic cells or inhibition of PLK1 reduces PP2A-B56α kinetochore binding and elevates phosphorylation of Aurora B substrates on the outer kinetochore. We propose that PLK1 and BUBR1 cooperate to stabilize kinetochore-microtubule interactions by regulating PP2A-B56α-mediated dephosphorylation of Aurora B substrates at the kinetochore-microtubule interface.

Graphical AbstractFigure optionsDownload high-quality image (193 K)Download as PowerPoint slideHighlights
► Identification of kinetochore attachment regulatory domain (KARD) in BUBR1
► KARD is phosphorylated by PLK1 and recruits the PP2A-B56α phosphatase to kinetochores
► BUBR1-PP2A-B56α interaction counters phosphorylation of Aurora B substrates
► BUBR1-PP2A-B56α interaction is crucial for kinetochore-microtubule attachments