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Elevated PME\u20101 protein levels are observed in neurodegenerative diseases and cancer, suggesting the involvement of dysregulation of PP2A\/PP4 methylation. However, PME\u20101 also forms stable complexes with the catalytic subunit of PP2A to interfere with phosphatase activity, and it remains unclear what roles the functions as a methylesterase and as a PP2A inhibitory protein each play in\u00a0vivo. This study generated PME\u20101 S156A and M335D knock\u2010in mice deficient in methylesterase and PP2A inhibitory activity, respectively. Each loss of function mutation compromised development in\u00a0vivo differently, with phenotypes distinct from the perinatal lethality of PME\u20101 null mice. The loss of methylesterase activity due to the S156A mutation resulted in systemic apoptosis characterized by brain atrophy: the layers of the cerebellum collapsed with fewer Purkinje cells and more microglia. Histological and gene expression analyses indicated increased inflammation and apoptosis. Primary embryonic fibroblasts isolated from S156A KI mice exhibited increased mitochondrial number, enhanced oxygen consumption rate, and elevated levels of reactive oxygen species. In contrast, M335D mutant pups did not appear deformed and had intact brains but died about two days after birth with a demonstrated loss of olfaction and apoptosis in the olfactory epithelium. Our data indicate that the action of PP2A\u2010type phosphatases is controlled in multiple ways by PME\u20101 and differentially contributes to mouse development.<\/jats:p>","DOI":"10.1096\/fj.202402617rr","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T04:01:14Z","timestamp":1746504074000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Two Distinct Mechanisms of\n                    <scp>PP2A<\/scp>\n                    Regulation by Methylesterase\n                    <scp>PME<\/scp>\n                    \u20101 Are Both Essential for Mouse Development"],"prefix":"10.1096","volume":"39","author":[{"given":"Shunta","family":"Ikeda","sequence":"first","affiliation":[{"name":"Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine Yamaguchi University  Yamaguchi 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