title: Protein Phosphatase Methyl-Esterase PME-1 Protects Protein Phosphatase 2A from Ubiquitin/Proteasome Degradation.
abstract: Protein phosphatase 2A (PP2A) is a conserved essential enzyme that is implicated as a tumor suppressor based on its central role in phosphorylation-dependent signaling pathways. Protein phosphatase methyl esterase (PME-1) catalyzes specifically the demethylation of the C-terminal Leu309 residue of PP2A catalytic subunit (PP2Ac). It has been shown that PME-1 affects the activity of PP2A by demethylating PP2Ac, but also by directly binding to the phosphatase active site, suggesting loss of PME-1 in cells would enhance PP2A activity. However, here we show that PME-1 knockout mouse embryonic fibroblasts (MEFs) exhibit lower PP2A activity than wild type MEFs. Loss of PME-1 enhanced poly-ubiquitination of PP2Ac and shortened the half-life of PP2Ac protein resulting in reduced PP2Ac levels. Chemical inhibition of PME-1 and rescue experiments with wild type and mutated PME-1 revealed methyl-esterase activity was necessary to maintain PP2Ac protein levels. Our data demonstrate that PME-1 methyl-esterase activity protects PP2Ac from ubiquitin/proteasome degradation.
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, 753-8515, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Yabe
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, 753-8515, Japan.
authors.forename: Akane
authors.initials: A
authors.lastname: Miura
authors.affiliation: Laboratory of Veterinary Toxicology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, 753-8515, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Usui
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, 1030, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Mudrak
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, 1030, Austria.
authors.forename: Egon
authors.initials: E
authors.lastname: Ogris
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, 753-8515, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohama
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, 753-8515, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism* / Q000502:physiology; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism* / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000378:metabolism* / Q000502:physiology; D059748:Proteolysis; D060888:Real-Time Polymerase Chain Reaction; D025801:Ubiquitin / Q000378:metabolism* / Q000502:physiology
chemical_list: D025801:Ubiquitin; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; D054648:Protein Phosphatase 2; D046988:Proteasome Endopeptidase Complex