Protein Phosphatase Methyl-Esterase PME-1 Protects Protein Phosphatase 2A from Ubiquitin/Proteasome Degradation

PLoS One. 2015 Dec 17;10(12):e0145226. doi: 10.1371/journal.pone.0145226. eCollection 2015.

Abstract

Protein phosphatase 2A (PP2A) is a conserved essential enzyme that is implicated as a tumor suppressor based on its central role in phosphorylation-dependent signaling pathways. Protein phosphatase methyl esterase (PME-1) catalyzes specifically the demethylation of the C-terminal Leu309 residue of PP2A catalytic subunit (PP2Ac). It has been shown that PME-1 affects the activity of PP2A by demethylating PP2Ac, but also by directly binding to the phosphatase active site, suggesting loss of PME-1 in cells would enhance PP2A activity. However, here we show that PME-1 knockout mouse embryonic fibroblasts (MEFs) exhibit lower PP2A activity than wild type MEFs. Loss of PME-1 enhanced poly-ubiquitination of PP2Ac and shortened the half-life of PP2Ac protein resulting in reduced PP2Ac levels. Chemical inhibition of PME-1 and rescue experiments with wild type and mutated PME-1 revealed methyl-esterase activity was necessary to maintain PP2Ac protein levels. Our data demonstrate that PME-1 methyl-esterase activity protects PP2Ac from ubiquitin/proteasome degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxylic Ester Hydrolases / metabolism*
  • Carboxylic Ester Hydrolases / physiology
  • Immunoblotting
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Endopeptidase Complex / physiology
  • Protein Phosphatase 2 / metabolism*
  • Protein Phosphatase 2 / physiology
  • Proteolysis
  • Real-Time Polymerase Chain Reaction
  • Ubiquitin / metabolism*
  • Ubiquitin / physiology

Substances

  • Ubiquitin
  • Carboxylic Ester Hydrolases
  • protein phosphatase methylesterase-1
  • Protein Phosphatase 2
  • Proteasome Endopeptidase Complex

Grant support

Thus study was supported by Japan Society for the Promotion of Science (JSPS); Grant number and the funder's URLs are: (https://www.jsps.go.jp/english/index.html) Grant Number 25660227: TO, 15K14856: TO, 15J07273: RY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.