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

J Cell Biol. 2019 Apr 1;218(4):1182-1199. doi: 10.1083/jcb.201808014. Epub 2019 Jan 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Aurora Kinase B / genetics
  • Aurora Kinase B / metabolism
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Nucleus / enzymology*
  • Cell Nucleus / genetics
  • Cyclin B1 / genetics
  • Cyclin B1 / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Kinetochores / enzymology*
  • M Phase Cell Cycle Checkpoints*
  • Phosphorylation
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Retinal Pigment Epithelium / enzymology
  • Signal Transduction
  • Time Factors

Substances

  • CCNB1 protein, human
  • Cell Cycle Proteins
  • Cyclin B1
  • PPP2R2A protein, human
  • Protein-Tyrosine Kinases
  • AURKB protein, human
  • Aurora Kinase B
  • Protein Serine-Threonine Kinases
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • TTK protein, human
  • Protein Phosphatase 2