title: Role for Tyrosine Phosphorylation of A-kinase Anchoring Protein 8 (AKAP8) in Its Dissociation from Chromatin and the Nuclear Matrix.
abstract: Protein-tyrosine phosphorylation regulates a wide variety of cellular processes at the plasma membrane. Recently, we showed that nuclear tyrosine kinases induce global nuclear structure changes, which we called chromatin structural changes. However, the mechanisms are not fully understood. In this study we identify protein kinase A anchoring protein 8 (AKAP8/AKAP95), which associates with chromatin and the nuclear matrix, as a nuclear tyrosine-phosphorylated protein. Tyrosine phosphorylation of AKAP8 is induced by several tyrosine kinases, such as Src, Fyn, and c-Abl but not Syk. Nucleus-targeted Lyn and c-Src strongly dissociate AKAP8 from chromatin and the nuclear matrix in a kinase activity-dependent manner. The levels of tyrosine phosphorylation of AKAP8 are decreased by substitution of multiple tyrosine residues on AKAP8 into phenylalanine. Importantly, the phenylalanine mutations of AKAP8 inhibit its dissociation from nuclear structures, suggesting that the association/dissociation of AKAP8 with/from nuclear structures is regulated by its tyrosine phosphorylation. Furthermore, the phenylalanine mutations of AKAP8 suppress the levels of nuclear tyrosine kinase-induced chromatin structural changes. In contrast, AKAP8 knockdown increases the levels of chromatin structural changes. Intriguingly, stimulation with hydrogen peroxide induces chromatin structural changes accompanied by the dissociation of AKAP8 from nuclear structures. These results suggest that AKAP8 is involved in the regulation of chromatin structural changes through nuclear tyrosine phosphorylation.
authors.affiliation: From the Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan and.
authors.forename: Sho
authors.initials: S
authors.lastname: Kubota
authors.affiliation: From the Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan and.
authors.forename: Mariko
authors.initials: M
authors.lastname: Morii
authors.affiliation: From the Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan and.
authors.forename: Ryuzaburo
authors.initials: R
authors.lastname: Yuki
authors.affiliation: From the Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan and.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yamaguchi
authors.affiliation: From the Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan and.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: From the Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan and.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Aoyama
authors.affiliation: Laboratory of Proteome Research, National Institute of Biomedical Innovation, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kuga
authors.affiliation: Laboratory of Proteome Research, National Institute of Biomedical Innovation, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tomonaga
authors.affiliation: From the Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan and nyama@faculty.chiba-u.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D015530:Nuclear Matrix / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; C485099:AKAP8 protein, human; D002843:Chromatin; D011505:Protein-Tyrosine Kinases
keywords: A-kinase Anchoring Protein (AKAP); AKAP8; Chromatin; Chromatin Remodeling; Chromatin Structural Changes; Global Nuclear Structure; Nuclear Matrix; Nuclear Tyrosine Phosphorylation Signals; Phosphotyrosine Signaling; Src-family Kinases