Targeted disruption of the PME-1 gene causes loss of demethylated PP2A and perinatal lethality in mice

PLoS One. 2008 Jul 2;3(7):e2486. doi: 10.1371/journal.pone.0002486.

Abstract

Background: Phosphoprotein phosphatase 2A (PP2A), a major serine-threonine protein phosphatase in eukaryotes, is an oligomeric protein comprised of structural (A) and catalytic (C) subunits to which a variable regulatory subunit (B) can associate. The C subunit contains a methyl ester post-translational modification on its C-terminal leucine residue, which is removed by a specific methylesterase (PME-1). Methylesterification is thought to control the binding of different B subunits to AC dimers, but little is known about its physiological significance in vivo.

Methodology/principal findings: Here, we show that targeted disruption of the PME-1 gene causes perinatal lethality in mice, a phenotype that correlates with a virtually complete loss of the demethylated form of PP2A in the nervous system and peripheral tissues. Interestingly, PP2A catalytic activity over a peptide substrate was dramatically reduced in PME-1(-/-) tissues, which also displayed alterations in phosphoproteome content.

Conclusions: These findings suggest a role for the demethylated form of PP2A in maintenance of enzyme function and phosphorylation networks in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxylic Ester Hydrolases / genetics*
  • Catalytic Domain
  • Gene Targeting
  • Genes, Lethal
  • Methylation
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Protein Phosphatase 2 / metabolism*

Substances

  • Carboxylic Ester Hydrolases
  • protein phosphatase methylesterase-1
  • Protein Phosphatase 2