A search for novel histidine-based protein phosphatases and structural analysis of their substrate specificities

• Project/Area Number: 24659027
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Nagasaki University
• Principal Investigator: TAKEDA Kohsuke 長崎大学, 医歯(薬)学総合研究科, 教授 (10313230)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: シグナル伝達 / ストレス応答 / プロテインホスファターゼ

Research Abstract

We have recently identified PGAM5 as a novel type of protein phosphatase that relies on a histidine residue as a catalytic center; however, its mechanism of enzymatic action has not been revealed. In the current study, we found by structural analyses that the catalytic center of PGAM5 consists of two histidines and two arginines. We also found that PGAM5 forms a dimer and that the dimerization is required for the catalytic activity of PGAM5. These results provide important clues to the mechanism of action of the histidine-based protein phosphatases.

Research Products

• [Journal Article] The expression of Fn14 via mechanical stress-activated JNK contributes to apoptosis induction in osteoblasts (2014)
  • Author(s): Matsui, H., Fukuno, N., Kanda, Y., Kantoh, Y., Chida, T., Nagaura, Y., Suzuki, O., Nishitoh, H., Takeda, K., Ichijo, H., Sawada, Y., Sasaki, K., Kobayashi, T. and Tamura, S.
  • Journal Title: J. Biol. Chem. Volume: 289 Pages: 6138-6450
  • Peer Reviewed
• [Journal Article] The expression of Fn14 via mechanical stress-activated JNK contributes to apoptosis induction in osteoblasts. (2014)
  • Author(s): Matsui, H., Fukuno, N., Kanda, Y., Kantoh, Y., Chida, T., Nagaura, Y., Suzuki, O., Nishitoh, H., Takeda, K., Ichijo, H., Sawada, Y., Sasaki, K., Kobayashi, T. and Tamura, S.
  • Journal Title: J. Biol. Chem. Volume: 289 Issue: 10 Pages: 6438-6450
  • DOI: 10.1074/jbc.m113.536300
  • Peer Reviewed / Open Access
• [Journal Article] SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deficiency (2013)
  • Author(s): Homma, K., Fujisawa, T., Tsuburaya, N., Yamaguchi, N., Kadowaki, H., Takeda, K., Nishitoh, H., Matsuzawa, A., Naguro, I. and Ichijo, H.
  • Journal Title: Mol. Cell Volume: 52 Pages: 75-86
  • Peer Reviewed
• [Journal Article] Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreaticβcell exhaustion (2013)
  • Author(s): Yamaguchi, K., Takeda, K., Kadowaki, H., Ueda, I., Namba, Y., Ouchi, Y., Nishitoh, H. and Ichijo, H.
  • Journal Title: Biochim. Biophys. Acta Volume: 1830 Pages: 3656-3663
  • Peer Reviewed
• [Journal Article] Atypical protein phosphatases : emerging players in cellular signaling (2013)
  • Author(s): Sadatomi, D., Tanimura, S., Ozaki, K. and Takeda, K.
  • Journal Title: Int. J . Mol. Sci. Volume: 14 Pages: 4596-4612
  • Peer Reviewed
• [Journal Article] Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic s cell exhaustion (2013)
  • Author(s): Yamaguchi, K., Takeda, K., Kadowaki, H., Ueda, I., Namba, Y., Ouchi, Y. Nishitoh, H. and Ichijo, H.
  • Journal Title: Biochim. Biophys. Acta. Volume: 1830 Issue: 6 Pages: 3656-3663
  • DOI: 10.1016/j.bbagen.2013.01.029
  • Peer Reviewed
• [Journal Article] SOD1 as a molecular switch for initiating the homeostatic ER stress respouse under zinc deficiency. (2013)
  • Author(s): Homma, K., Fujisawa. T., Tsuburaya, N., Yamaguchi, N., Kadowaki, H., Takeda, K., Nishitoh, H., Matsuzawa, A., Naguro, I., and Ichijo, H.
  • Journal Title: Molecular Cell Volume: 52 Issue: 1 Pages: 75-86
  • DOI: 10.1016/j.molcel.2013.08.038
  • Peer Reviewed
• [Journal Article] Atypical protein phosphatases: emerging players in cellular signaling. (2013)
  • Author(s): Sadatomi, D. et al.
  • Journal Title: Int. J. Mol. Sci. Volume: 14 Issue: 3 Pages: 4596-4612
  • DOI: 10.3390/ijms14034596
  • Peer Reviewed
• [Journal Article] Therapeutic targets in the ASK1-dependent stress signalling pathways (2012)
  • Author(s): Hayakawa, R., Hayakawa, T., Takeda, K. and Ichijo, H.
  • Journal Title: Proc. J pn. Acad. Ser. B Phys. Biol. Sci. Volume: 88 Pages: 434-453
  • Peer Reviewed
• [Journal Article] The phosphorylation-dependent regulation of mitochondrial proteins in stress responses (2012)
  • Author(s): Kanamaru, Y., Sekine, S., Ichijo, H. and Takeda, K.
  • Journal Title: J. Signal Transduct. Volume: 2012 Pages: 931215-931215
  • Peer Reviewed
• [Journal Article] ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney (2012)
  • Author(s): Naguro, I., Umeda, T., Kobayashi, Y., Maruyama, J.
  • Journal Title: Nat. Commun. Volume: 3 Pages: 1285-1285
  • Peer Reviewed
• [Journal Article] The kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 activation by suppressing PP5 (2012)
  • Author(s): Sekine, Y., Hatanaka, R., Watanabe, T., Sono, N., Iemura, S., Natsume, T., Kuranaga, E., Miura, M., Takeda, K. and Ichijo, H.
  • Journal Title: Mol. Cell Volume: 48 Pages: 692-704
  • Peer Reviewed
• [Journal Article] Apoptosis signal-regulating kinase -1 inhibitor as a potent therapeutic drug for the treatment of gastric cancer (2012)
  • Author(s): Hayakawa, Y., Hirata, Y., Sakitani, K., Nakagawa, H., Nakata, W., Kinoshita, H., Takahashi, R., Takeda, K., Ichijo, H., Maeda, S. and Koike, K.
  • Journal Title: Cancer Sci Volume: 103 Pages: 2181-2185
  • Peer Reviewed
• [Journal Article] Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5 (2012)
  • Author(s): Sekine, S., Kanamaru, Y., Koike, M., Nishihara, A., Okada, M., Kinoshita, H., Kamiyama, M., Maruyama, J., Uchiyama, Y., Ishihara, N., Takeda, K. and Ichijo, H.
  • Journal Title: J. Biol. Chem. Volume: 287 Pages: 34635-34645
  • Peer Reviewed
• [Journal Article] A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants (2012)
  • Author(s): Fujisawa, T., Homma, K., Yamaguchi, N., Kadowaki, H., Tsuburaya, N., Naguro, I., Matsuzawa, A., Takeda, K., Takahashi, Y., Goto, J., Tsuji, S., Nishitoh, H. and Ichijo, H.
  • Journal Title: Ann. Neurol. Volume: 72 Pages: 739-749
  • Peer Reviewed
• [Journal Article] A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants. (2012)
  • Author(s): Fujisawa, T., Homma, K., et al.
  • Journal Title: Ann Neurol Volume: 72 Issue: 5 Pages: 739-749
  • DOI: 10.1002/ana.23668
  • Peer Reviewed
• [Journal Article] Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5 (2012)
  • Author(s): Sekine, S., et al.
  • Journal Title: J. Biol. Chem. Volume: 287 Issue: 41 Pages: 34635-34645
  • DOI: 10.1074/jbc.m112.357509
  • Peer Reviewed
• [Journal Article] Apoptosis signal-regulating kinase-1 inhibitor as a potent therapeutic drug for the treatment of gastric cancer. (2012)
  • Author(s): Hayakawa, Y., Hirata, Y., Sakitani, K., Nakagawa, H., Nakata, W., Kinoshita, H., Takahashi, R., Takeda, K., Ichijo, H., Maeda1, S. and Koike, K.
  • Journal Title: Cancer Sci. Volume: 103 Issue: 12 Pages: 2181-2185
  • DOI: 10.1111/cas.12024
  • Peer Reviewed
• [Journal Article] The kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 activation by suppressing PP5 (2012)
  • Author(s): Yusuke Sekine, Ryo Hatanaka, Takeshi Watanabe. Naoki Sono, Shun-ichiro Iemura, Tohru Natsume, Erina Kuranaga, Masayuki Miura, Kohsuke Takeda, and Hidenori Ichijo
  • Journal Title: Molecular Cell Volume: 48 Issue: 5 Pages: 1-13
  • DOI: 10.1016/j.molcel.2012.09.018
  • NAID: 120007150217
  • Peer Reviewed
• [Journal Article] ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney. (2012)
  • Author(s): Naguro I., et al.
  • Journal Title: Nature Communications Volume: 3 Issue: 1 Pages: 1285-1285
  • DOI: 10.1038/ncomms2283
  • Peer Reviewed
• [Journal Article] The Phosphorylation-Dependent Regulation of Mitochondrial Proteins in Stress Responses (2012)
  • Author(s): Kanamaru, Y., Sekine S., Ichijo, H. and Takeda, K.
  • Journal Title: J. Signal Transduc. Volume: 2012 Pages: 12-12
  • DOI: 10.1155/2012/931215
  • Peer Reviewed
• [Journal Article] Therapeutic targets in the ASK1-dependent stress signaling pathways (2012)
  • Author(s): Hayakawa, R., Hayakawa, T., Takeda, K. and Ichijo, H.
  • Journal Title: Proceedings of the Japan Academy, Series B Volume: 88 Issue: 8 Pages: 434-453
  • DOI: 10.2183/pjab.88.434
  • NAID: 130001924759
  • ISSN: 0386-2208, 1349-2896
  • Peer Reviewed
• [Presentation] Roles of mitochondrial sensing and responding to stress in inflammation regulation (2014)
  • Author(s): Takeda, K
  • Organizer: The 1st International Symposium Dejima Challenge for Therapeutic Innovation
  • Place of Presentation: 長崎
  • Year and Date: 2014-03-14
• [Presentation] ミトコンドリア局在プロテインホスファターゼPGAM5によるストレス応答制御 (2014)
  • Author(s): 武田弘資
  • Organizer: 第6回日本プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 三重
  • Year and Date: 2014-02-21
• [Presentation] ミトコンドリア局在プロテインホスファターゼPGAM5によるストレス応答制御 (2014)
  • Author(s): 武田弘資
  • Organizer: 第６回 日本プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 三重大学環境・情報科学館（津市）
• [Presentation] Microvesicles形成メカニズムの解明 (2013)
  • Author(s): 門田善法、竹之内彰吾、尾崎惠一、武田弘資、谷村進
  • Organizer: 第30回日本薬学会九州支部大会
  • Place of Presentation: 長崎
  • Year and Date: 2013-12-08
• [Presentation] ヒストン脱アセチル化酵素阻害剤に対する感受性におけるp21の役割 (2013)
  • Author(s): 田渕祐輔、小野真依、柿本貴子、谷村進、武田弘資、尾崎惠一
  • Organizer: 第30回日本薬学会九州支部大会
  • Place of Presentation: 長崎
  • Year and Date: 2013-12-07
• [Presentation] ミトコンドリア局在型フォスファターゼPGAM5は、インスリン受容体基質のセリン/スレオニンリン酸化と安定性の調節に機能しているミトコンドリア局在型フォスファターゼPGAM5は、インスリン受容体基質のセリン/スレオニンリン酸化と安定性の調節に機能している (2013)
  • Author(s): 米山鷹介、鋳延淳一、木田友佳子、福嶋俊明、関根史織、浅野知一郎、千田和広、武田弘資、高橋伸一郎
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 佐賀
  • Year and Date: 2013-12-05
• [Presentation] ミトコンドリアのストレス受容・応答機構と炎症制御 (2013)
  • Author(s): 武田弘資
  • Organizer: さきがけ研究報告会「炎症の慢性化機構の解明と制御」
  • Place of Presentation: 東京
  • Year and Date: 2013-11-10
• [Presentation] ミトコンドリアのストレス感知機構と細胞応答 (2013)
  • Author(s): 武田弘資
  • Organizer: 宮崎大学大学院特別セミナー
  • Place of Presentation: 宮崎
  • Year and Date: 2013-09-20
• [Presentation] ASK1は接触過敏における惹起相でのIL-17産生に重要である (2013)
  • Author(s): 水上潤哉、武田弘資、一條秀憲、坪井良治
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2013-09-13
• [Presentation] ゲノムワイドsiRNAスクリーニングによるミトコンドリア局在型ホスファターゼPGAM5の切断制御因子の網羅的探索 (2013)
  • Author(s): 金丸雄祐、関根史織、武田弘資、一條秀憲
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2013-09-12
• [Presentation] ミトコンドリア局在型プロテインホスファターゼPGAM5の膜内切断 (2013)
  • Author(s): 関根史織、武田弘資、一條秀憲
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2013-09-12
• [Presentation] Myosin1EはCaveolin1-Cavin1/3複合体の安定化を介して細胞運動を促進する (2013)
  • Author(s): 谷村進、浜松絢子、木原康孝、大山要、武田弘資、河野通明
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2013-09-11
• [Presentation] Myosin1E-SH3P2複合体による細胞運動制御の分子機構 (2013)
  • Author(s): 谷村進、木原康孝、大山要、中原康子、平田弦也、松丸由美、武田弘資、河野通明
  • Organizer: 平成25年度日本生化学会九州支部例会
  • Place of Presentation: 佐賀
  • Year and Date: 2013-05-18
• [Presentation] ミトコンドリア機能低下の感知システムとしてのプロテインホスファターゼPGAM5の膜内切断 (2013)
  • Author(s): 武田弘資
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-28
• [Presentation] ミトコンドリアのストレス受容・応答機構と炎症制御 (2013)
  • Author(s): 武田弘資
  • Organizer: 創薬シンポジウム : アカデミア創薬と探索医療
  • Place of Presentation: 長崎
  • Year and Date: 2013-03-19
• [Presentation] Role of mitochondrial protein phosphatase PGAM5 in inflammation (2013)
  • Author(s): Sadatomi, D. Takeda, K.
  • Organizer: 10th International Conference on Protein Phosphatase
  • Place of Presentation: 東京
  • Year and Date: 2013-02-28
• [Presentation] Role of mitochondrial phosphatase PGAM5 in inflammation (2013)
  • Author(s): Takeda, K
  • Organizer: JST-CREST International Symposium, Frontiers in Immunology and Inflammation : From Molecules to Disease
  • Place of Presentation: 東京
  • Year and Date: 2013-02-12
• [Presentation] Regulation of cellular stress response by mitochondrial protein phosphatase PGAM5 (2013)
  • Author(s): Takeda, K
  • Organizer: 1st International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling
  • Place of Presentation: 東京
  • Year and Date: 2013-02-01
• [Presentation] Myosin1E-SH3P2複合体による細胞運動制御の分子機構 (2013)
  • Author(s): 谷村進、木原康孝、大山要、中原康子、平田弦也、松丸由美、武田弘資、河野通明
  • Organizer: 平成25年度 日本生化学会九州支部例会
  • Place of Presentation: 佐賀大学農学部１号館（佐賀市）
• [Presentation] ミトコンドリア局在型プロテインホスファターゼPGAM5の膜内切断 (2013)
  • Author(s): 関根史織、武田弘資、一條秀憲
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] Myosin1EはCaveolin1-Cavin1/3複合体の安定化を介して細胞運動を促進する (2013)
  • Author(s): 谷村進、浜松絢子、木原康孝、大山要、武田弘資、河野通明
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] ASK1は接触過敏における惹起相でのIL-17産生に重要である (2013)
  • Author(s): 水上潤哉, 武田弘資, 一條秀憲, 坪井良治
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] ゲノムワイド siRNA スクリーニングによるミトコンドリア局在型ホスファターゼ PGAM5 の切断制御因子の網羅的探索 (2013)
  • Author(s): 金丸雄祐, 関根史織, 武田弘資, 一條秀憲
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] ミトコンドリア局在型フォスファターゼPGAM5は、インスリン受容体基質のセリン／スレオニンリン酸化と安定性の調節に機能している ミトコンドリア局在型フォスファターゼPGAM5は、インスリン受容体基質のセリン／スレオニンリン酸化と安定性の調節に機能している (2013)
  • Author(s): 米山鷹介、鋳延淳一、木田友佳子、福嶋俊明、関根史織、浅野知一郎、千田和広、武田弘資、高橋伸一郎
  • Organizer: 第36回 日本分子生物学会年会
  • Place of Presentation: 神戸国際展示場（神戸市）
• [Presentation] ヒストン脱アセチル化酵素阻害剤に対する感受性におけるp21の役割 (2013)
  • Author(s): 田渕祐輔、小野真依、柿本貴子、谷村進、武田弘資、尾崎惠一
  • Organizer: 第30回 日本薬学会九州支部大会
  • Place of Presentation: 長崎国際大学薬学部（佐世保市）
• [Presentation] Microvesicles形成メカニズムの解明 (2013)
  • Author(s): 門田善法、竹之内彰吾、尾崎惠一、武田弘資、谷村進
  • Organizer: 第30回 日本薬学会九州支部大会
  • Place of Presentation: 長崎国際大学薬学部（佐世保市）
• [Presentation] Role of mitochondrial phosphatase PGAM5 in inflammation (2013)
  • Author(s): Takeda, K.
  • Organizer: JST-CREST International Symposium, Frontiers in Immunology and Inflammation: From Molecules to Disease
  • Place of Presentation: 東京
• [Presentation] ミトコンドリアのストレス受容・応答機構と炎症制御 (2013)
  • Author(s): 武田 弘資
  • Organizer: 創薬シンポジウム：アカデミア創薬と探索医療
  • Place of Presentation: 長崎
• [Presentation] ミトコンドリア機能低下の感知システムとしてのプロテインホスファターゼ PGAM5の膜内切断 (2013)
  • Author(s): 武田 弘資
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] ミトコンドリア局在プロテインホスファターゼPGAM5によるストレス応答制御 (2012)
  • Author(s): 武田弘資
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-07
• [Presentation] Role of mitochondrial phosphatase PGAM5 in inflammation (2012)
  • Author(s): Takeda, K
  • Organizer: The 12th Biennial International Endotoxicin & Innate Immunity Society Meeting (IEIIS2012)
  • Place of Presentation: 東京
  • Year and Date: 2012-10-24
• [Presentation] Role of mitochondrial phosphatase PGAM5 in inflammation (2012)
  • Author(s): Takeda, K.
  • Organizer: The 12th Biennial International Endotoxin & Innate Immunity Society Meeting (IEIIS2012)
  • Place of Presentation: 東京
  • Invited
• [Presentation] ミトコンドリアのストレス感知機構と細胞応答
  • Author(s): 武田弘資
  • Organizer: 宮崎大学大学院特別セミナー
  • Place of Presentation: 宮崎大学医学部プレゼンテーションホール（宮崎市）
  • Invited
• [Presentation] ミトコンドリアのストレス受容・応答機構と炎症制御
  • Author(s): 武田弘資
  • Organizer: さきがけ研究報告会「炎症の慢性化機構の解明と制御」
  • Place of Presentation: 東京コンファレンスセンター品川（東京都）
• [Presentation] Roles of mitochondrial sensing and responding to stress in inflammation regulation.
  • Author(s): Takeda, K.
  • Organizer: The 1st International Symposium Dejima Challenge for Therapeutic Innovation
  • Place of Presentation: 長崎大学文教スカイホール（長崎市）
  • Invited
• [Book] Roles for the stress-responsive kinases ASK1 and ASK2 in tumorigenesis. Chembiomolecular Science : At the Frontier of Chemistry and Biology. (2012)
  • Author(s): Kamiyama, M., Sato, T., Takeda, K. and Ichijo, H.(eds Shibasaki, M., Iino, M. and Osada, H)
  • Publisher: Springer Japan
• [Book] がんと炎症, 「がん増殖と悪性化の分子機構」 (2012)
  • Author(s): 武田弘資
  • Publisher: 化学同人
• [Book] Roles for the stress-responsive kinases ASK1 and ASK2 in tumorigenesis. Chembiomolecular Science: At the Frontier of Chemistry and Biology, eds Shibasaki, M., Iino, M. and Osada, H. (2012)
  • Author(s): Kamiyama, M. et al.
  • Total Pages: 325
  • Publisher: Springer Japan
• [Book] がんと炎症．「がん増殖と悪性化の分子機構」 (2012)
  • Author(s): 武田 弘資
  • Total Pages: 280
  • Publisher: 化学同人
• [Remarks]
  • URL: http://www.ph.nagasaki-u.ac.jp/lab/cell/index-j.html
• [Remarks] 長崎大学大学院薬学系研究科 細胞制御学分野
  • URL: http://www.ph.nagasaki-u.ac.jp/lab/cell/index-j.html