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

Abstract

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 α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB 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 CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α 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 CK2α, and the BCR-CK2α complex could be a novel therapeutic target for various inflammatory diseases.

• Authors: Jie Meng, Jing-Jing Jiang, Toru Atsumi, Hidenori Bando, Yuko Okuyama, Lavannya Sabharwal, Ikuma Nakagawa, Haruka Higuchi, Mitsutoshi Ota, Momoko Okawara, Ryuichiro Ishitani, Osamu Nureki, Daisuke Higo, Yasunobu Arima, Hideki Ogura, Daisuke Kamimura, Masaaki Murakami
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 197 Issue 8 Pg. 3111-3119 (10 15 2016) ISSN: 1550-6606 [Electronic] United States
• PMID: 27630163 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 by The American Association of Immunologists, Inc.

Chemical References

• Interleukin-6
• NF-kappa B
• RNA, Small Interfering
• Tumor Necrosis Factor-alpha
• Fusion Proteins, bcr-abl
• Casein Kinase II
• Proto-Oncogene Proteins c-bcr

Topics

• Animals
• Arthritis (genetics)
• Arthritis, Experimental (genetics)
• Casein Kinase II (metabolism)
• Cell Line
• Chromatography, Liquid
• Fusion Proteins, bcr-abl (genetics, metabolism)
• Genes, abl (genetics)
• Humans
• Interleukin-6 (metabolism)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Philadelphia Chromosome
• Proto-Oncogene Proteins c-bcr (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Tandem Mass Spectrometry
• Tumor Necrosis Factor-alpha (metabolism)