Protein phosphatase 2C beta (PP2C beta) was found to act as a negative regulator of NF-kappa B-mediated inflammatory signaling: however, its regulatory mechanism has not been examined. Here, we show that protein kinase A (MA) phosphorylates the PP2C beta, which was inhibited by PICA-specific inhibitor, H89. Mutation analysis of serine residues in PP2C beta revealed that Ser-195 in PP2C beta is phosphorylated by PICA. Importantly, PKA inhibition by H89 abrogated the Forskolin-induced destabilization of PP2C beta against ubiquitin-dependent proteosomal degradation pathway. Furthermore, H89 treatment efficiently reversed the negative effect of Forskolin on the anti-inflammatory function of PP2C beta. Collectively, these data suggest that PICA destabilizes PP2C beta upon inflammatory stimuli via phosphorylation of Ser-195 in PP2C beta. (C) 2013 Elsevier Inc. All rights reserved.