Integration of kinase and phosphatase activities by BUBR1 ensures formation of stable kinetochore-microtubule attachments

Dev Cell. 2012 Oct 16;23(4):745-55. doi: 10.1016/j.devcel.2012.09.005.

Abstract

Maintenance 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase B
  • Aurora Kinases
  • Cell Cycle Proteins / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Kinetochores / metabolism*
  • Microtubules / metabolism*
  • Phosphorylation
  • Protein Phosphatase 2 / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Tumor Cells, Cultured

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • BUB1 protein, human
  • Bub1 spindle checkpoint protein
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • PP2A-B56alpha protein, human
  • Protein Phosphatase 2