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Studying Proteolysis of Cyclin B at the Single Cell Level in Whole Cell Populations
10:54

Studying Proteolysis of Cyclin B at the Single Cell Level in Whole Cell Populations

Published on: September 17, 2012

Role for the PP2A/B56delta phosphatase in regulating 14-3-3 release from Cdc25 to control mitosis

Seth S Margolis1, Jennifer A Perry, Craig M Forester

  • 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.

Cell
|November 18, 2006
PubMed

Insights

DNA damage checkpoints regulate cell division by controlling the mitotic activator Cdc25. This study reveals how PP2A/B56delta phosphatase and 14-3-3 protein interactions activate Cdc25 to promote cell cycle progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • DNA-responsive checkpoints are crucial for preventing cell-cycle progression after DNA damage.
  • The mitotic activator Cdc25 is regulated by inhibitory phosphorylation and 14-3-3 protein binding.
  • Mitotic entry requires the removal of 14-3-3 proteins and dephosphorylation of Cdc25 at Ser287.

Purpose of the Study:

  • To investigate the role of PP2A/B56delta phosphatase in DNA-responsive checkpoint control of Cdc25.
  • To elucidate the mechanism by which Cdc25 is activated to promote mitotic entry.

Main Methods:

  • Investigated the dephosphorylation of Cdc25 by PP2A/B56delta.
  • Analyzed the role of T138 phosphorylation in 14-3-3 binding to Cdc25.
  • Examined the formation of 14-3-3 "sinks" using intermediate filament proteins.

Main Results:

  • DNA-responsive checkpoints activate PP2A/B56delta to dephosphorylate Cdc25 at T138, distinct from Ser287.
  • T138 phosphorylation is necessary but not sufficient for 14-3-3 release from Cdc25.
  • A 14-3-3 "sink" formed by intermediate filament proteins and reduced Cdc25-14-3-3 affinity contribute to Cdc25 activation.

Conclusions:

  • PP2A/B56delta is a key effector of DNA-responsive checkpoints in regulating Cdc25.
  • A novel mechanism involving 14-3-3 "sinks" and altered protein affinity controls Cdc25 activation and mitotic entry.

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