PKA negatively regulates PP2Cβ to activate NF-κB-mediated inflammatory signaling

Hyo-Kyung Choi; Soo-Yeon Park; Hye-Jeong Oh; Eun-Jeong Han; Yoo-Hyun Lee; Jeongmin Lee; Woo Jin Jun; Kyung-Chul Choi; Ho-Geun Yoon

doi:10.1016/j.bbrc.2013.05.129

PKA negatively regulates PP2Cβ to activate NF-κB-mediated inflammatory signaling

Biochem Biophys Res Commun. 2013 Jul 5;436(3):473-7. doi: 10.1016/j.bbrc.2013.05.129. Epub 2013 Jun 10.

Authors

Hyo-Kyung Choi¹, Soo-Yeon Park, Hye-Jeong Oh, Eun-Jeong Han, Yoo-Hyun Lee, Jeongmin Lee, Woo Jin Jun, Kyung-Chul Choi, Ho-Geun Yoon

Affiliation

¹ 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.

PMID: 23756813
DOI: 10.1016/j.bbrc.2013.05.129

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.

Keywords: Cytokines; Inflammation; NF-κB; Protein kinase A; Protein phosphatase 2Cβ; Ubiquitin-dependent proteasomal degradation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colforsin / pharmacology
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
Cyclic AMP-Dependent Protein Kinases / metabolism*
Enzyme Stability
Gene Expression Regulation, Enzymologic*
HEK293 Cells
Humans
Inflammation / immunology
Inflammation / pathology*
Intracellular Signaling Peptides and Proteins / pharmacology
Isoquinolines / pharmacology
NF-kappa B / immunology*
NF-kappa B / metabolism
Phosphoprotein Phosphatases / antagonists & inhibitors
Phosphoprotein Phosphatases / immunology*
Phosphorylation
Protein Phosphatase 2C
Proteolysis
Serine / metabolism
Signal Transduction
Sulfonamides / pharmacology
Tumor Necrosis Factor-alpha / pharmacology
Ubiquitin / metabolism

Substances

Intracellular Signaling Peptides and Proteins
Isoquinolines
NF-kappa B
Sulfonamides
Tumor Necrosis Factor-alpha
Ubiquitin
protein kinase modulator
Colforsin
Serine
Cyclic AMP-Dependent Protein Kinases
Phosphoprotein Phosphatases
Protein Phosphatase 2C
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide