Cdk1 orders mitotic events through coordination of a chromosome-associated phosphatase switch

Nat Commun. 2015 Dec 17;6:10215. doi: 10.1038/ncomms10215.

Abstract

RepoMan is a scaffold for signalling by mitotic phosphatases at the chromosomes. During (pro)metaphase, RepoMan-associated protein phosphatases PP1 and PP2A-B56 regulate the chromosome targeting of Aurora-B kinase and RepoMan, respectively. Here we show that this task division is critically dependent on the phosphorylation of RepoMan by protein kinase Cyclin-dependent kinase 1 (Cdk1), which reduces the binding of PP1 but facilitates the recruitment of PP2A-B56. The inactivation of Cdk1 in early anaphase reverses this phosphatase switch, resulting in the accumulation of PP1-RepoMan to a level that is sufficient to catalyse its own chromosome targeting in a PP2A-independent and irreversible manner. Bulk-targeted PP1-RepoMan also inactivates Aurora B and initiates nuclear-envelope reassembly through dephosphorylation-mediated recruitment of Importin β. Bypassing the Cdk1 regulation of PP1-RepoMan causes the premature dephosphorylation of its mitotic-exit substrates in prometaphase. Hence, the regulation of RepoMan-associated phosphatases by Cdk1 is essential for the timely dephosphorylation of their mitotic substrates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase
  • Aurora Kinase B / metabolism*
  • CDC2 Protein Kinase
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Chromosomes / metabolism
  • Cyclin-Dependent Kinases / genetics*
  • Cyclin-Dependent Kinases / metabolism
  • Fluorescent Antibody Technique
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Microscopy, Confocal
  • Mitosis / genetics*
  • Nuclear Envelope / metabolism
  • Nuclear Proteins / metabolism*
  • Phosphoric Monoester Hydrolases
  • Prometaphase
  • Protein Phosphatase 1 / metabolism*
  • Protein Phosphatase 2 / metabolism*
  • beta Karyopherins / metabolism*

Substances

  • CDCA2 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Nuclear Proteins
  • beta Karyopherins
  • AURKB protein, human
  • Aurora Kinase B
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases
  • Protein Phosphatase 1
  • Protein Phosphatase 2
  • Phosphoric Monoester Hydrolases