Regulation of α-endosulfine, an inhibitor of protein phosphatase 2A, by multisite phosphorylation

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Satoru Mochida1

  • 1Priority Organization for Innovation and Excellence, Kumamoto University, Japan; Precursory Research for Embryonic Science and Technology (PRESTO) Program, Japan Science and Technology Agency, Tokyo, Japan.

The FEBS Journal
|December 21, 2013
PubMed

Insights

Alpha-endosulfine (ENSA) regulates cell cycle progression by inhibiting PP2A-B55. This study reveals ENSA has multiple phosphorylation sites that fine-tune PP2A-B55 inhibition, acting as a stepwise tuner rather than an on/off switch.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cell cycle progression into M phase requires PP2A-B55 inhibition and Cdk1 activation.
  • Alpha-endosulfine (ENSA) and ARPP-19 proteins inhibit PP2A-B55 when phosphorylated at S67 by Greatwall kinase.

Purpose of the Study:

  • To investigate the effects of additional phosphorylation sites on ENSA's inhibition of PP2A-B55.
  • To understand the regulatory mechanism of PP2A-B55 inhibition by ENSA during the cell cycle.

Main Methods:

  • Phosphorylation site analysis in Xenopus laevis cells and extracts.
  • In vitro inhibition assays of PP2A-B55 by ENSA.
  • Structural analysis of ENSA-PP2A-B55 interaction.

Main Results:

  • Endogenous kinases phosphorylate ENSA at T28 and S109 in addition to S67, with distinct kinetics.
  • These phosphorylations differentially modulate ENSA's inhibition of PP2A-B55 activity.
  • Structural data shows ENSA's middle region interacts with PP2A-B55 at the catalytic interface, and phosphorylations alter this interaction.

Conclusions:

  • ENSA acts as a stepwise tuner of PP2A-B55, regulated by multiple phosphorylation sites.
  • This multi-site regulation allows for nuanced control of PP2A-B55 activity by various cellular signals.
  • The findings provide a new perspective on cell cycle regulation beyond a simple on/off switch mechanism.
Keywords:
cell cyclecyclin-dependent kinasegreatwall kinaseprotein kinase Aprotein phosphatase 2A

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