title: 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-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.
  
  
  RESULTS
  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.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.forename: Donmienne
authors.initials: D
authors.lastname: Leung
authors.forename: Scott
authors.initials: S
authors.lastname: Ficarro
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peters
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D020134:Catalytic Domain; D018390:Gene Targeting; D005804:Genes, Lethal; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D054648:Protein Phosphatase 2 / Q000378:metabolism*
chemical_list: D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; D054648:Protein Phosphatase 2