Cysteine phosphorylation: elucidating the mechanism and significance of a novel post-translational modification

• Project/Area Number: 17K19396
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Biology of Cells to Organisms, and related fields
• Research Institution: Osaka University
• Principal Investigator: Yosuke Funato 大阪大学, 微生物病研究所, 助教 (60505775)
• Project Period (FY): 2017-06-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Cysリン酸化 / システイン / リン酸化 / PRL / 翻訳後修飾 / lysosomal exocytosis / pH応答 / 細胞密度 / CNNM / 酸性適応 / シグナル伝達

Outline of Final Research Achievements

In this study, we investigated the properties and physiological significance of a novel post-translational modification, the phosphorylation of cysteine residues (Cys). We clarified the relationship between Cys phosphorylation and oxidation, a previously known post-translational modification of Cys residues, and the biological importance of this Cys residue in cancer malignancy through its binding to the Mg2+ transporter CNNM.

Academic Significance and Societal Importance of the Research Achievements

これまでセリン/スレオニンやチロシン残基のリン酸化は、その仕組みや意義が深く研究されている一方で、システイン残基のリン酸化はその存在を示す報告すら殆どない状態であった。本研究によりその存在だけでなく重要性も一定レベルで示すことができたことは、この新しいタイプの翻訳後修飾が認知され、今後さらに研究が進展してゆく上で大きな意味のあるステップだったと位置づけられる。

Research Products

• [Int'l Joint Research] The University of Oxford(英国)
• [Int'l Joint Research] Fudan University(中国)
• [Int'l Joint Research] McGill University(カナダ)
• [Journal Article] Structural basis for the Mg2+ recognition and regulation of the CorC Mg2+ transporter (2021)
  • Author(s): Huang Yichen、Jin Fei、Funato Yosuke、Xu Zhijian、Zhu Weiliang、Wang Jing、Sun Minxuan、Zhao Yimeng、Yu Ye、Miki Hiroaki、Hattori Motoyuki
  • Journal Title: Science Advances Volume: 7 Issue: 7
  • DOI: 10.1126/sciadv.abe6140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Magnesium efflux from Drosophila Kenyon cells is critical for normal and diet-enhanced long-term memory (2020)
  • Author(s): Wu Yanying、Funato Yosuke、Meschi Eleonora、Jovanoski Kristijan D、Miki Hiroaki、Waddell Scott
  • Journal Title: eLife Volume: 9
  • DOI: 10.7554/elife.61339
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Oncogenic PRL Protein Causes Acid Addiction of Cells by Stimulating Lysosomal Exocytosis. (2020)
  • Author(s): Yosuke Funato, Atsushi Yoshida, Yusuke Hirata, Osamu Hashizume, Daisuke Yamazaki, Hiroaki Miki
  • Journal Title: Developmental cell Volume: 55 Issue: 4 Pages: 387-397
  • DOI: 10.1016/j.devcel.2020.08.009
  • Peer Reviewed / Open Access
• [Journal Article] PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth (2020)
  • Author(s): Kozlov Guennadi、Funato Yosuke、Chen Yu Seby、Zhang Zhidian、Illes Katalin、Miki Hiroaki、Gehring Kalle
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 33 Pages: 11682-11692
  • DOI: 10.1074/jbc.ra120.014464
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Excessive Mg 2+ Impairs Intestinal Homeostasis by Enhanced Production of Adenosine Triphosphate and Reactive Oxygen Species (2020)
  • 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
  • Peer Reviewed
• [Journal Article] Control of Protein Function Through Oxidation and Reduction of Persulfidated States (2020)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphatase of Regenerating Liver Sensitizes MET to Functional Activation by Hepatocyte Growth Factor (2020)
  • Author(s): Takuya Kojima, Yosuke Funato, Hiroaki Miki
  • Journal Title: Biochem J Volume: 476 Pages: 1419-1431
  • Peer Reviewed
• [Journal Article] Cnnm4 deficiency suppresses Ca2+ signaling and promotes cell proliferation in the colon epithelia (2019)
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphatase of regenerating liver maintains cellular magnesium homeostasis (2018)
  • Author(s): Yoshida A, Funato Y, Miki H
  • Journal Title: Biochem J. Volume: 475 Issue: 6 Pages: 1129-1139
  • DOI: 10.1042/bcj20170756
  • Peer Reviewed
• [Journal Article] CrossTalk proposal: CNNM proteins are Na+/Mg2+exchangers playing a central role in transepithelial Mg2+(re)absorption (2018)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Visualization of long-term Mg2+ dynamics in apoptotic cells using a novel targetable fluorescent probe (2017)
  • 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
  • Peer Reviewed / Open Access
• [Presentation] がん細胞の酸性環境への新規適応機構「acid addiction」の発見 (2020)
  • Author(s): 船戸 洋佑, 橋爪 脩, 吉田 篤, 本田 茉子, 山崎 大輔, 三木 裕明
  • Organizer: 第93回日本生化学会大会
• [Presentation] CNNMによるマグネシウムの輸送とその医学生物学的重要性 (2020)
  • Author(s): 船戸 洋佑, 橋爪 脩, 吉田 篤, 山崎 大輔, 三木 裕明
  • Organizer: 2020年度生理研研究会『上皮膜輸送の多様性・調和機構を基盤とする異分野融合研究の創出』
  • Invited
• [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
• [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
  • 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
  • Invited
• [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
  • Int'l Joint Research / Invited
• [Presentation] CNNM magnesium transporters in health and disease (2017)
  • Author(s): Funato. Y., Yamazaki, D., and Miki, H.
  • Organizer: IUPS 38th world congress
  • Int'l Joint Research / Invited