論文 - 久保田　翔

Formation of long and winding nuclear F-actin bundles by nuclear c-Abl tyrosine kinase 査読

Kazumasa Aoyama, Ryuzaburo Yuki, Yasuyoshi Horiike, Sho Kubota, Noritaka Yamaguchi, Mariko Morii, Kenichi Ishibashi, Yuji Nakayama, Takahisa Kuga, Yuuki Hashimoto, Takeshi Tomonaga, Naoto Yamaguchi

Experimental Cell Research   319 ( 20 )   3251 - 3268   2013年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

The non-receptor-type tyrosine kinase c-Abl is involved in actin dynamics in the cytoplasm. Having three nuclear localization signals (NLSs) and one nuclear export signal, c-Abl shuttles between the nucleus and the cytoplasm. Although monomeric actin and filamentous actin (F-actin) are present in the nucleus, little is known about the relationship between c-Abl and nuclear actin dynamics. Here, we show that nuclear-localized c-Abl induces nuclear F-actin formation. Adriamycin-induced DNA damage together with leptomycin B treatment accumulates c-Abl into the nucleus and increases the levels of nuclear F-actin. Treatment of c-Abl-knockdown cells with Adriamycin and leptomycin B barely increases the nuclear F-actin levels. Expression of nuclear-targeted c-Abl (NLS-c-Abl) increases the levels of nuclear F-actin even without Adriamycin, and the increased levels of nuclear F-actin are not inhibited by inactivation of Abl kinase activity. Intriguingly, expression of NLS-c-Abl induces the formation of long and winding bundles of F-actin within the nucleus in a c-Abl kinase activity-dependent manner. Furthermore, NLS-c-AblδC, which lacks the actin-binding domain but has the full tyrosine kinase activity, is incapable of forming nuclear F-actin and in particular long and winding nuclear F-actin bundles. These results suggest that nuclear c-Abl plays critical roles in actin dynamics within the nucleus. © 2013 Elsevier Inc.

DOI： 10.1016/j.yexcr.2013.09.003

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Nuclear ErbB4 signaling through H3K9me3 is antagonized by EGFR-activated c-Src 査読

Kenichi Ishibashi, Yasunori Fukumoto, Hitomi Hasegawa, Kohei Abe, Shoichi Kubota, Kazumasa Aoyama, Sho Kubota, Yuji Nakayama, Naoto Yamaguchi

JOURNAL OF CELL SCIENCE   126 ( 2 )   625 - 637   2013年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：COMPANY OF BIOLOGISTS LTD  

The ErbB family of receptor tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR)/ErbB1, HER2/ErbB2, ErbB3 and ErbB4, and plays roles in signal transduction at the plasma membrane upon ligand stimulation. Stimulation with neuregulin-1 (NRG-1) cleaves ErbB4 and releases the ErbB4 intracellular domain (4ICD) that translocates into the nucleus to control gene expression. However, little is known about the regulation of 4ICD nuclear signaling through tyrosine phosphorylation. We show here that 4ICD nuclear signaling is antagonized by EGF-induced c-Src activation through EGFR. Generation of 4ICD by NRG-1 leads to increased levels of trimethylated histone H3 on lysine 9 (H3K9me3) in a manner dependent on the nuclear accumulation of 4ICD and its tyrosine kinase activity. Once EGF activates c-Src downstream of EGFR concomitantly with NRG-1-induced ErbB4 activation, c-Src associates with phospho-Tyr950 and phospho-Tyr1056 on 4ICD, thereby decreasing nuclear accumulation of 4ICD and inhibiting an increase of H3K9me3 levels. Moreover, 4ICD-induced transcriptional repression of the human telomerase reverse transcriptase (hTERT) is inhibited by EGF-EGFR-Src signaling. Thus, our findings reveal c-Src-mediated inhibitory regulation of ErbB4 nuclear signaling upon EGFR activation.

DOI： 10.1242/jcs.116277

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Nuclear c-Abl-mediated tyrosine phosphorylation induces chromatin structural changes through histone modifications that include H4K16 hypoacetylation 査読

Kazumasa Aoyama, Yasunori Fukumoto, Kenichi Ishibashi, Sho Kubota, Takao Morinaga, Yasuyoshi Horiike, Ryuzaburo Yuki, Akinori Takahashi, Yuji Nakayama, Naoto Yamaguchi

EXPERIMENTAL CELL RESEARCH   317 ( 20 )   2874 - 2903   2011年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER INC  

c-Abl tyrosine kinase, which is ubiquitously expressed, has three nuclear localization signals and one nuclear export signal and can shuttle between the nucleus and the cytoplasm. c-Abl plays important roles in cell proliferation, adhesion, migration, and apoptosis. Recently, we developed a pixel imaging method for quantitating the level of chromatin structural changes and showed that nuclear Src-family tyrosine kinases are involved in chromatin structural changes upon growth factor stimulation. Using this method, we show here that nuclear c-Abl induces chromatin structural changes in a manner dependent on the tyrosine kinase activity. Expression of nuclear-targeted c-Abl drastically increases the levels of chromatin structural changes, compared with that of c-Abl. Intriguingly, nuclear-targeted c-Abl induces heterochromatic profiles of histone methylation and acetylation, including hypoacetylation of histone H4 acetylated on lysine 16 (H4K16Ac). The level of heterochromatic histone modifications correlates with that of chromatin structural changes. Adriamycin-induced DNA damage stimulates translocation of c-Abl into the nucleus and induces chromatin structural changes together with H4K16 hypoacetylation. Treatment with trichostatin A, a histone deacetylase inhibitor, blocks chromatin structural changes but not nuclear tyrosine phosphorylation by c-Abl. These results suggest that nuclear c-Abl plays an important role in chromatin dynamics through nuclear tyrosine phosphorylation-induced heterochromatic histone modifications. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yexcr.2011.09.013

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