Breakpoint Cluster Region-Mediated Inflammation Is Dependent on Casein Kinase II

The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the alpha subunit of casein kinase II (CK2 alpha), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-kappa B activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography-tandem mass spectrometry analysis showed that CK2 alpha associated with BCR. We found the BCR functions are mediated by CK2 alpha. Indeed, CK2 alpha associated with adaptor molecules of TNF-alpha R and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-alpha stimulation. Notably, p65 S529 phosphorylation by CK2 alpha creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2 alpha, and the BCR-CK2 alpha complex could be a novel therapeutic target for various inflammatory diseases.