A PP1-PP2A phosphatase relay controls mitotic progression

Nature. 2015 Jan 1;517(7532):94-98. doi: 10.1038/nature14019. Epub 2014 Dec 10.

Abstract

The widespread reorganization of cellular architecture in mitosis is achieved through extensive protein phosphorylation, driven by the coordinated activation of a mitotic kinase network and repression of counteracting phosphatases. Phosphatase activity must subsequently be restored to promote mitotic exit. Although Cdc14 phosphatase drives this reversal in budding yeast, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) activities have each been independently linked to mitotic exit control in other eukaryotes. Here we describe a mitotic phosphatase relay in which PP1 reactivation is required for the reactivation of both PP2A-B55 and PP2A-B56 to coordinate mitotic progression and exit in fission yeast. The staged recruitment of PP1 (the Dis2 isoform) to the regulatory subunits of the PP2A-B55 and PP2A-B56 (B55 also known as Pab1; B56 also known as Par1) holoenzymes sequentially activates each phosphatase. The pathway is blocked in early mitosis because the Cdk1-cyclin B kinase (Cdk1 also known as Cdc2) inhibits PP1 activity, but declining cyclin B levels later in mitosis permit PP1 to auto-reactivate. PP1 first reactivates PP2A-B55; this enables PP2A-B55 in turn to promote the reactivation of PP2A-B56 by dephosphorylating a PP1-docking site in PP2A-B56, thereby promoting the recruitment of PP1. PP1 recruitment to human, mitotic PP2A-B56 holoenzymes and the sequences of these conserved PP1-docking motifs suggest that PP1 regulates PP2A-B55 and PP2A-B56 activities in a variety of signalling contexts throughout eukaryotes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • CDC2 Protein Kinase / metabolism
  • Chromosome Segregation
  • Conserved Sequence
  • Cyclin B / metabolism
  • Enzyme Activation
  • HeLa Cells
  • Holoenzymes / metabolism
  • Humans
  • Isoenzymes / metabolism
  • Mitosis*
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Phosphatase 1 / metabolism*
  • Protein Phosphatase 2 / chemistry
  • Protein Phosphatase 2 / metabolism*
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Schizosaccharomyces / cytology*
  • Schizosaccharomyces / enzymology*
  • Schizosaccharomyces pombe Proteins / chemistry
  • Schizosaccharomyces pombe Proteins / metabolism
  • Signal Transduction

Substances

  • Cyclin B
  • Holoenzymes
  • Isoenzymes
  • Protein Subunits
  • Schizosaccharomyces pombe Proteins
  • CDC2 Protein Kinase
  • Protein Phosphatase 1
  • Protein Phosphatase 2