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Protein phosphatase 4 is phosphorylated and inactivated by Cdk in response to spindle toxins and interacts with

Martin Voss1, Kathryn Campbell, Nastja Saranzewa

  • 1Medical Research Council Protein Phosphorylation and Ubiquitylation Unit; College of Life Sciences; University of Dundee; Dundee, Scotland, UK.

Cell Cycle (Georgetown, Tex.)
|August 23, 2013
PubMed

Insights

Cancer drugs targeting cell cycle dynamics inhibit the protein phosphatase 4 (Ppp4) complex during mitosis. This inhibition regulates microtubule organization, suggesting Ppp4 complex inhibition may aid cancer treatment.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Cancer therapeutics often target cell cycle regulation and mitotic spindle dynamics.
  • Paclitaxel, a chemotherapy agent, stabilizes microtubules, impacting cell division.
  • The protein phosphatase 4 (Ppp4) complex plays a role in cellular processes.

Purpose of the Study:

  • To investigate the regulation and activity of the Ppp4 complex (Ppp4c-R2-R3A) in cells treated with spindle-targeting drugs.
  • To determine the role of Ppp4 complex in microtubule organization during mitosis.
  • To explore the potential of Ppp4 complex inhibition as a cancer therapy strategy.

Main Methods:

  • Cell cycle arrest using nocodazole or paclitaxel.
  • Phosphorylation analysis of Ppp4 complex regulatory subunits.
  • Immunofluorescence to detect Ppp4 complex localization at centrosomes.
  • In vitro kinase and phosphatase assays using recombinant proteins.

Main Results:

  • Ppp4 complex (Ppp4c-R2-R3A) undergoes inhibitory phosphorylation on regulatory subunits during mitosis.
  • Cdk1-cyclin B is implicated as the kinase mediating these phosphorylations.
  • Ppp4 complex activity is inhibited from G1/S to G2/M phase.
  • Ppp4 complex interacts with gamma-tubulin and gamma-tubulin complex protein 2 at centrosomes.
  • Ppp4 complex dephosphorylates gamma-tubulin in vitro.

Conclusions:

  • The Ppp4 complex regulates microtubule organization at centrosomes in response to spindle toxins.
  • Inhibition of the Ppp4 complex during mitotic stress is a key regulatory mechanism.
  • Targeting Ppp4 complex inhibition could be a promising strategy for certain cancer treatments.
Keywords:
Cdk1cell cyclecentrosomenocodazolepaclitaxelprotein phosphatase 4γ-tubulin

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