targeted disruption of the pme-1 gene causes loss of demethylated pp2a and perinatal lethality in micepme-1基因的靶向破坏造成的损失脱甲基pp2a和围产期死亡率在老鼠身上.pdf

Targeted Disruption of the PME-1 Gene Causes Loss of Demethylated PP2A and Perinatal Lethality in Mice ´ 1,2 1,2 3 3 1,2 Silvia Ortega-Gutierrez , Donmienne Leung , Scott Ficarro , Eric C. Peters , Benjamin F. Cravatt * 1The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America, 2 The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, California, United States of America, 3 The Genomics Institute for the Novartis Foundation, San Diego, California, United States of America 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(2/ 2) tissues, which also displayed alterations in phosphoproteome content. Conclusions: These findings suggest