title: 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.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Jing-Jing
authors.identifier: 0000-0002-4570-797X
authors.initials: JJ
authors.lastname: Jiang
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Atsumi
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Bando
authors.affiliation: Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okuyama
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Lavannya
authors.initials: L
authors.lastname: Sabharwal
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Ikuma
authors.identifier: 0000-0002-8115-548X
authors.initials: I
authors.lastname: Nakagawa
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Higuchi
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Mitsutoshi
authors.identifier: 0000-0002-7108-9730
authors.initials: M
authors.lastname: Ota
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Okawara
authors.affiliation: Department of Biological Sciences, Graduate School of Sciences, University of Tokyo, Tokyo 113-0032, Japan; and.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Ishitani
authors.affiliation: Department of Biological Sciences, Graduate School of Sciences, University of Tokyo, Tokyo 113-0032, Japan; and.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
authors.affiliation: Thermo Fisher Scientific, Yokohama 221-0022, Japan.
authors.forename: Daisuke
authors.identifier: 0000-0002-4696-4505
authors.initials: D
authors.lastname: Higo
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Arima
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ogura
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamimura
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan; murakami@igm.hokudai.ac.jp.
authors.forename: Masaaki
authors.identifier: 0000-0001-7159-7279
authors.initials: M
authors.lastname: Murakami
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics*; D001169:Arthritis, Experimental / Q000235:genetics; D047390:Casein Kinase II / Q000378:metabolism*; D002460:Cell Line; D002853:Chromatography, Liquid; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D016313:Genes, abl / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010677:Philadelphia Chromosome; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D053719:Tandem Mass Spectrometry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D016044:Fusion Proteins, bcr-abl; D047390:Casein Kinase II; D051562:Proto-Oncogene Proteins c-bcr