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Functional regulation of proteins by Cys phosphorylation

Research Project

Project/Area Number 16K14723
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Cell biology
Research InstitutionOsaka University

Principal Investigator

Miki Hiroaki  大阪大学, 微生物病研究所, 教授 (80302602)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywords蛋白質 / シグナル伝達 / ストレス / 癌
Outline of Final Research Achievements

We investigated the phosphorylation that occurs on Cys residue in oncogenic protein PRL. When magnesium ion was depleted from the culture medium, PRL was rapidly dephosphorylated and its protein levels were increased. PRL knockdown under this magnesium ion-depleted condition resulted in promotion of cell death, indicating the biological importance of this response. Moreover, the investigation of the phosphorylation mechanism revealed the possible role of phosphate-containing molecules, such as ATP, as phosphate donor.

Academic Significance and Societal Importance of the Research Achievements

リン酸化はタンパク質の主要な翻訳後修飾として知られるが、システイン残基のリン酸化はこれまでにバクテリアでの事例が一つしか知られていないユニークなものである。本研究では発がん因子PRLでのシステインリン酸化に関する解析を進め、細胞の環境応答の仕組みとしてダイナミックに制御されており、それが細胞の生死に関わることを明らかにした。タンパク質機能制御の新たな仕組みとして今後の研究の発展が期待できる。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (59 results)

All 2020 2019 2018 2017 2016 Other

All Int'l Joint Research (6 results) Journal Article (14 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 14 results,  Open Access: 7 results,  Acknowledgement Compliant: 4 results) Presentation (39 results) (of which Int'l Joint Research: 5 results,  Invited: 22 results)

  • [Int'l Joint Research] McGill University(カナダ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Fudan University(中国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] McGill University(カナダ)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Fudan University(中国)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] McGill大学(カナダ)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] McGill University(Canada)

    • Related Report
      2016 Research-status Report
  • [Journal Article] Excessive Mg 2+ Impairs Intestinal Homeostasis by Enhanced Production of Adenosine Triphosphate and Reactive Oxygen Species2020

    • Author(s)
      Osamu Hashizume , Yosuke Funato , Daisuke Yamazaki, Hiroaki Miki
    • Journal Title

      Antioxid Redox Signal .

      Volume: - Issue: 1 Pages: 20-34

    • DOI

      10.1089/ars.2019.7951

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Control of Protein Function Through Oxidation and Reduction of Persulfidated States2020

    • Author(s)
      E Doka, T Ida, M Dagnell, Y Abiko, N C Luong, N Balog, T Takata, B Espinosa, A Nishimura, Q Cheng, Y Funato, H Miki, J M Fukuto, J R Prigge, E E Schmidt, E S J Arner, Y Kumagai, T Akaike, P Nagy
    • Journal Title

      Sci Adv

      Volume: 6 Issue: 1 Pages: 8358-8358

    • DOI

      10.1126/sciadv.aax8358

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Phosphatase of regenerating liver sensitizes MET to functional activation by hepatocyte growth factor.2019

    • Author(s)
      Kojima T, Funato Y, Miki H
    • Journal Title

      Biochem J

      Volume: 476 Issue: 10 Pages: 1419-1431

    • DOI

      10.1042/bcj20190071

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cnnm4 deficiency suppresses Ca2+ signaling and promotes cell proliferation in the colon epithelia2019

    • Author(s)
      Yamazaki D, Hasegawa A, Funato Y, Tran HN, Mori MX, Mori Y, Sato T, Miki H
    • Journal Title

      Oncogene

      Volume: - Issue: 20 Pages: 3962-3969

    • DOI

      10.1038/s41388-019-0682-0

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Molecular function and biological importance of CNNM family Mg2+ transporters.2019

    • Author(s)
      Funato Y, Miki H
    • Journal Title

      J Biochem

      Volume: 165 Issue: 3 Pages: 219-225

    • DOI

      10.1093/jb/mvy095

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The cyclic nucleotide-binding homology domain of the integral membrane protein CNNM mediates dimerization and is required for Mg2+ efflux activity.2018

    • Author(s)
      Chen YS, Kozlov G, Fakih R, Funato Y, Miki H, Gehring K
    • Journal Title

      J Biol Chem

      Volume: 293 Issue: 52 Pages: 19998-20007

    • DOI

      10.1074/jbc.ra118.005672

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Phosphatase of regenerating liver maintains cellular magnesium homeostasis2018

    • Author(s)
      Yoshida A, Funato Y, Miki H
    • Journal Title

      Biochem J.

      Volume: 475 Issue: 6 Pages: 1129-1139

    • DOI

      10.1042/bcj20170756

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] CrossTalk proposal: CNNM proteins are Na+/Mg2+exchangers playing a central role in transepithelial Mg2+(re)absorption2018

    • Author(s)
      Funato Y, Furutani K, Kurachi Y, Miki H
    • Journal Title

      J Physiol.

      Volume: 596 Issue: 5 Pages: 743-746

    • DOI

      10.1113/jp275248

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Visualization of long-term Mg2+ dynamics in apoptotic cells using a novel targetable fluorescent probe2017

    • Author(s)
      Matsui Y, Funato Y, Imamura H, Miki H, Mizukami S, Kikuchi K
    • Journal Title

      Chem Sci.

      Volume: 8 Issue: 12 Pages: 8255-8264

    • DOI

      10.1039/c7sc03954a

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Renal function of cyclin M2 Mg2+ transporter maintains blood pressure.2017

    • Author(s)
      Funato Y, Yamazaki D, Miki H.
    • Journal Title

      J Hypertens.

      Volume: 35 Issue: 3 Pages: 585-592

    • DOI

      10.1097/hjh.0000000000001211

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis.2016

    • Author(s)
      Gulerez I, Funato Y, Wu H, Yang M, Kozlov G, Miki H, Gehring K.
    • Journal Title

      EMBO Rep.

      Volume: 17 Issue: 12 Pages: 1890-1900

    • DOI

      10.15252/embr.201643393

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Mg<sup>2+</sup> Extrusion from Intestinal Epithelia by CNNM Proteins Is Essential for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis elegans2016

    • Author(s)
      Ishii T, Funato Y, Hashizume O, Yamazaki D, Hirata Y, Nishiwaki K, Kono N, Arai H, Miki H.
    • Journal Title

      PLoS Genet.

      Volume: 12 Issue: 8 Pages: e1006276-e1006276

    • DOI

      10.1371/journal.pgen.1006276

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Complementary role of CNNM2 in sperm motility and Ca(2+) influx during capacitation.2016

    • Author(s)
      Yamazaki D, Funato Y, Miyata H, Ikawa M, Miki H.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 474 Issue: 3 Pages: 441-446

    • DOI

      10.1016/j.bbrc.2016.05.001

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The Mg2+ transporter CNNM4 regulates sperm Ca2+ homeostasis and it is essential for reproduction2016

    • Author(s)
      Daisuke Yamazaki, Haruhiko Miyata, Yosuke Funato, Yoshitaka Fujihara, Masahito Ikawa, Hiroaki Miki
    • Journal Title

      Journal of Cell Science

      Volume: 未定 Issue: 9 Pages: 1940-1949

    • DOI

      10.1242/jcs.182220

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Lysosomal exocytosisを介した細胞の酸性環境への依存2020

    • Author(s)
      船戸洋佑、橋爪脩、山崎大輔、三木裕明
    • Organizer
      2019年度・先端モデル動物支援プラットフォーム成果発表会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 細胞内マグネシウムイオンによるエネルギー代謝調節と活性酸素産生2019

    • Author(s)
      三木裕明、船戸洋佑、橋爪脩、山崎大輔
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] CNNM4は腸管上皮細胞の増殖と分化を制御する2019

    • Author(s)
      山崎大輔、長谷川綾郁、船戸洋佑、三木裕明
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Lysosomal exocytosisを介した細胞の酸性環境への適応2019

    • Author(s)
      船戸洋佑、橋爪脩、山崎大輔、三木裕明
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] PRLはHGFによるMETの機能的活性化を増強する2019

    • Author(s)
      兒島卓也、船戸洋佑、三木裕明
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] MDCK細胞におけるPRLによる密度依存的な細胞死2019

    • Author(s)
      ロハニスウェクサ、船戸洋佑、三木裕明
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 細胞内でのマグネシウム蓄積が引き起こす過剰なROSとATP産生2019

    • Author(s)
      橋爪脩、船戸洋佑、三木裕明
    • Organizer
      ミトコンドリアサイエンスワークショップ2019
    • Related Report
      2019 Annual Research Report
  • [Presentation] 腎臓でのマグネシウム輸送体を介した血圧調節機構の解明2019

    • Author(s)
      船戸洋佑、三木裕明
    • Organizer
      公益財団法人ソルト・サイエンス研究財団 第31回助成研究発表会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] PRLはHGFによるMETの機能的活性化を増強する2019

    • Author(s)
      兒島卓也、船戸洋佑、三木裕明
    • Organizer
      2019年度若手支援技術講習会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Regulation of Mg2+ levels and ROS generation by PRL/CNNM complexes2019

    • Author(s)
      Hiroaki Miki
    • Organizer
      The Kick-off Symposium of Advanced Graduate Program for Future Medicine and Health Care
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] がん細胞のエネルギー代謝における細胞の環境pH応答の制御2019

    • Author(s)
      船戸洋佑、吉田篤、山崎大輔、三木裕明
    • Organizer
      第1回SGH若手がん研究者ワークショップ
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 過剰なマグネシウムが引き起こすミトコンドリアでの活性酸素種とATPの過剰産生2018

    • Author(s)
      橋爪 脩, 船戸 洋佑, 三木 裕明
    • Organizer
      第18回日本ミトコンドリア学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Regulation of Mg2+ homeostasis and cancer progression by Phosphatase of Regenerating Liver (PRL)2018

    • Author(s)
      Yosuke Funato, Daisuke Yamazaki, Hiroaki Miki
    • Organizer
      Workshop on Frontiers in Phosphatase Research and Drug Discovery
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Overproduction of ATP and Reactive Oxygen Species in Mitochondria by Excessive Magnesium2018

    • Author(s)
      Osamu Hashizume, Yosuke Funato, Hiroaki Miki
    • Organizer
      The Joint Symposium of the 13th International Symposium of the Institute Network for Biomedical Sciences and the 28th Hot Spring Harbor
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] PRL高発現によるMetチロシンリン酸化の亢進と細胞内局在変化2018

    • Author(s)
      兒島 卓也, 船戸 洋佑, 三木 裕明
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] がん悪性化のドライバー蛋白質PRLによる染色体制御の異常2018

    • Author(s)
      Kajung Ryu, 吉田 篤, 船戸 洋佑, 山崎 大輔, 三木 裕明
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] 過剰なマグネシウムが引き起こすミトコンドリアでのATPとROSの過剰産生2018

    • Author(s)
      橋爪 脩, 船戸 洋佑, 三木 裕明
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] 酸化・還元依存的なマグネシウム恒常性の維持機構とその破綻による疾患・老化2018

    • Author(s)
      船戸 洋佑, 橋爪 脩, 山崎 大輔, 三木 裕明
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Mg2+トランスポーターCNNM4は大腸での発がんを抑制する2018

    • Author(s)
      山崎 大輔, 長谷川 綾郁, 船戸 洋佑, 三木 裕明
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] PRL/CNNM複合体によるマグネシウムイオン排出の調節とミトコンドリアでの活性酸素産生2018

    • Author(s)
      船戸 洋佑, 橋爪 脩, 山崎 大輔, 三木 裕明
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] PRLによる細胞外pH環境依存的な 細胞死2018

    • Author(s)
      船戸洋佑、吉田篤、柳嘉晶、山崎大輔、三木裕明
    • Organizer
      第27回日本Celldeath学会学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Mg2+排出タンパク質CNNMによる マグネシウム恒常性維持と寿命制御2018

    • Author(s)
      船戸洋佑、 橋爪脩、山崎大輔、三木裕明
    • Organizer
      第13回トランスポーター研究会年会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] マグネシウム再吸収と共役した血圧調節機構の解明2018

    • Author(s)
      船戸洋佑、山崎大輔、三木裕明
    • Organizer
      ソルト・サイエンス研究財団 第30回 助成研究発表会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Overproduction of ATP and reactive oxygen species in mitochondria by excessive magnesium2018

    • Author(s)
      Hiroaki Miki
    • Organizer
      WCP2018 KYOTO Satellite Symposia "Regulating cell homeostasis: from small molecules (drugs, O2, ROS, and NO) to ion channels, receptors, and systems.”
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 細胞内マグネシウムイオンの調節とミトコンドリアでの活性酸素産生2018

    • Author(s)
      三木裕明
    • Organizer
      第71回日本酸化ストレス学会/第18回日本NO学会 合同学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] PRL/CNNM複合体によるMg2+排出の調節とPRLのCysリン酸化2018

    • Author(s)
      三木裕明
    • Organizer
      生体分子コバレント修飾の革新的解析拠点形成 シンポジウム
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Mg2+の不足によるPRLの転写活性化2017

    • Author(s)
      Yoshida A, Funato Y, Miki H
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Mg2+トランスポーターCNNM4は大腸での発がんを抑制する2017

    • Author(s)
      Yamazaki D, Hasegawa A, Funato Y, Miki H
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Mg2+トランスポーターCNNMは線虫でROSレベルと寿命を調節する2017

    • Author(s)
      Hashizume O, Funato Y, Miki H
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Presentation] PRLによる酸性微小環境への適応2017

    • Author(s)
      Funato Y, Yoshida A, Yamazaki D, Miki H
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Presentation] がんの浸潤運動におけるPRLの役割2017

    • Author(s)
      船戸洋佑, 山崎大輔, 吉田篤, 三木裕明
    • Organizer
      第69回日本細胞生物学会大会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] がんの悪性化と酸性環境適応の分子機構2017

    • Author(s)
      船戸洋佑, 山崎大輔, 吉田篤, 三木裕明
    • Organizer
      第44回日本毒性学会学術年会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] CNNM magnesium transporters in health and disease2017

    • Author(s)
      Yosuke Funato, Daisuke Yamazaki, Hiroaki Miki
    • Organizer
      IUPS 38th world congress
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] PRLによる細胞内Mg2+量の調節とその破綻によるがん悪性化2016

    • Author(s)
      船戸 洋佑、山崎 大輔、三木 裕明
    • Organizer
      第89回日本生化学会大会シンポジウム
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] PRLによるがん悪性化とpH依存性の細胞死2016

    • Author(s)
      三木 裕明
    • Organizer
      第25回日本Cell Death学会学術集会シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2016-09-09
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] PRLによる細胞内マグネシウムイオン量のレドックス制御2016

    • Author(s)
      船戸 洋佑、山崎 大輔、三木 裕明
    • Organizer
      第43回日本毒性学会学術年会シンポジウム
    • Place of Presentation
      名古屋
    • Year and Date
      2016-06-29
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] PRLによるがん悪性化と上皮組織内の細胞間相互作用2016

    • Author(s)
      船戸 洋佑、山崎 大輔、三木 裕明
    • Organizer
      第68回日本細胞生物学会大会シンポジウム
    • Place of Presentation
      京都
    • Year and Date
      2016-06-15
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 細胞内マグネシウム調節の異常とがん悪性化2016

    • Author(s)
      三木 裕明
    • Organizer
      タイムシグナルと制御シンポジウム
    • Place of Presentation
      下田
    • Year and Date
      2016-06-11
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 細胞内マグネシウム調節とがん悪性化2016

    • Author(s)
      三木 裕明
    • Organizer
      第53回日本臨床分子医学会学術集会シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2016-04-15
    • Related Report
      2016 Research-status Report
    • Invited

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Published: 2016-04-21   Modified: 2021-02-19  

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