title: Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic Subunit.
abstract: Protein phosphatase 2A (PP2A) is a family of multifunctional serine/threonine phosphatases all composed of a catalytic C, a structural A, and a regulatory B subunit. Assembly of the complex with the appropriate B subunit forms the key to the functional specificity and regulation of PP2A. Emerging evidence suggests a crucial role for methylation and phosphorylation of the PP2A C subunit in this process. In this study, we show that PP2A C subunit methylation was not absolutely required for binding the PR61/B' and PR72/B'' subunit families, whereas binding of the PR55/B subunit family was determined by methylation and the nature of the C-terminal amino acid side chain. Moreover mutation of the phosphorylatable Tyr(307) or Thr(304) residues differentially affected binding of distinct B subunit family members. Down-regulation of the PP2A methyltransferase LCMT1 by RNA interference gradually reduced the cellular amount of methylated C subunit and induced a dynamic redistribution of the remaining methylated PP2A(C) between different PP2A trimers consistent with their methylation requirements. Persistent knockdown of LCMT1 eventually resulted in specific degradation of the PR55/B subunit and apoptotic cell death. Together these results establish a crucial foundation for understanding PP2A regulatory subunit selection.
authors.affiliation: Protein Phosphorylation and Proteomics Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, KULeuven, Herestraat 49 bus 901, B-3000 Leuven, Belgium.
authors.forename: Sari
authors.initials: S
authors.lastname: Longin
authors.affiliation: Protein Phosphorylation and Proteomics Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, KULeuven, Herestraat 49 bus 901, B-3000 Leuven, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Zwaenepoel
authors.affiliation: Protein Phosphorylation and Proteomics Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, KULeuven, Herestraat 49 bus 901, B-3000 Leuven, Belgium.
authors.forename: Justin V
authors.initials: JV
authors.lastname: Louis
authors.affiliation: Department of Metabolic Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Dilworth
authors.affiliation: Protein Phosphorylation and Proteomics Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, KULeuven, Herestraat 49 bus 901, B-3000 Leuven, Belgium.
authors.forename: Jozef
authors.initials: J
authors.lastname: Goris
authors.affiliation: Protein Phosphorylation and Proteomics Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, KULeuven, Herestraat 49 bus 901, B-3000 Leuven, Belgium. Electronic address: Veerle.Janssens@med.kuleuven.be.
authors.forename: Veerle
authors.initials: V
authors.lastname: Janssens
mesh_terms: D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D020134:Catalytic Domain; D002470:Cell Survival; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000502:physiology; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D013329:Structure-Activity Relationship
chemical_list: C432785:PPP2R1B protein, human; C086766:Ppp2r1b protein, mouse; D008780:Methyltransferases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2