Targeted disruption of the PME-1 gene causes loss of demethylated PP2A and perinatal lethality in mice.
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.
Ortega-Gutiérrez
Silvia
S
The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America.
Leung
Donmienne
D
Ficarro
Scott
S
Peters
Eric C
EC
Cravatt
Benjamin F
BF
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*
D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; D054648:Protein Phosphatase 2