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 a subunit of casein kinase II (CK2a), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-kB 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 CK2a associated with BCR. We found the BCR functions are mediated by CK2a. Indeed, CK2a associated with adaptor molecules of TNF-aR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-a stimulation. Notably, p65 S529 phosphorylation by CK2a 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 CK2a, and the BCR-CK2a complex could be a novel therapeutic target for various inflammatory diseases.
ASJC Scopus subject areas
- Immunology and Allergy