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

Abstract

Background: Phosphoprotein phosphatase 2A (PP2A), a major serine-theonine 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-transnational modification on its C-terminal 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 activity over a peptide substrate was dramatically reduced in PME-1 (/) tissues, which also displayed alterations in phosphoproteome content. Conclusions: These findings suggest s role for the demethylated form of PP2A in maintenance of enzyme function and phosphorylation networks in vivo. © 2008 Ortega-Gutierrez et al.