title: PKA negatively regulates PP2Cβ to activate NF-κB-mediated inflammatory signaling.
abstract: Protein phosphatase 2Cβ (PP2Cβ) was found to act as a negative regulator of NF-κB-mediated inflammatory signaling; however, its regulatory mechanism has not been examined. Here, we show that protein kinase A (PKA) phosphorylates the PP2Cβ, which was inhibited by PKA-specific inhibitor, H89. Mutation analysis of serine residues in PP2Cβ revealed that Ser-195 in PP2Cβ is phosphorylated by PKA. Importantly, PKA inhibition by H89 abrogated the Forskolin-induced destabilization of PP2Cβ against ubiquitin-dependent proteosomal degradation pathway. Furthermore, H89 treatment efficiently reversed the negative effect of Forskolin on the anti-inflammatory function of PP2Cβ. Collectively, these data suggest that PKA destabilizes PP2Cβ upon inflammatory stimuli via phosphorylation of Ser-195 in PP2Cβ.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, South Korea.
authors.forename: Hyo-Kyung
authors.initials: HK
authors.lastname: Choi
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Hye-Jeong
authors.initials: HJ
authors.lastname: Oh
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Han
authors.forename: Yoo-Hyun
authors.initials: YH
authors.lastname: Lee
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Lee
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Jun
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.forename: Ho-Geun
authors.initials: HG
authors.lastname: Yoon
mesh_terms: D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004795:Enzyme Stability; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000276:immunology*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D059748:Proteolysis; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D016328:NF-kappa B; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; C015482:protein kinase modulator; D005576:Colforsin; D012694:Serine; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Cytokines; Inflammation; NF-κB; Protein kinase A; Protein phosphatase 2Cβ; Ubiquitin-dependent proteasomal degradation