Exploring the molecular mechanism of GTP-driven stress response system

2023 Fiscal Year Annual Research Report

• Project/Area Number: 20H03165
• Research Institution: Keio University
• Principal Investigator: 佐々木 敦朗 慶應義塾大学, 政策・メディア研究科(藤沢), 特任教授 (80620385)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: GTP / 恒常性 / ストレス応答 / イノシトールリン脂質

Outline of Annual Research Achievements

PI5P4Kβはイノシトール脂質キナーゼの分野で初期メンバーとして同定されたものの、その機能や制御機構は未だ謎が多い。PI5P4Kβはイノシトール脂質キナーゼの分野において重要なメンバーであり、GTPエネルギーセンサーとして哺乳類の細胞で機能することを見出してきた（Mol Cell, 2016）。しかしながら、その制御するセカンドメッセンジャーPI5Pへの結合因子の同定が遅れていることが大きな問題となっている。
本研究では、これまでに同定した候補分子について生化学的解析および細胞生物学的解析を行い、PI5Pシグナルの仲介因子かどうかを検証するRNAとプロテオームの多層的オミックス解析を、GTP濃度を変化させつつ、時系列にサンプリングし、ビッグデータの解析を行った。その中でGTP制御に関した幾つかの進展があり報告してきた(e.g., Structure, 2020; Nat Metab, 2022; FEBS J, 2023)。PI5P4Kのシグナル経路として、細胞の同化と異化作用に関した新たなメカニズムや、細胞が増殖ストレス耐性を発揮するための新たなメカニズムを示す候補分子を得た。PI5P4Kの阻害により起こる様々な細胞機能変化と増殖ストレスへの関与への理解が分子レベルで深まり、この新たな分野の発展に重要な知見が得られた。

Research Progress Status

令和5年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和5年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Homogeneous luminescent quantitation of cellular guanosine and adenosine triphosphates (GTP and ATP) using QT-LucGTP&ATP assay (2023)
  • Author(s): Kopra Kari、Mahran Randa、Yli-Hollo Titta、Tabata Sho、Vuorinen Emmiliisa、Fujii Yuki、Vuorinen Iida、Ogawa-Iio Aki、Hirayama Akiyoshi、Soga Tomoyoshi、Sasaki Atsuo T.、Harma Harri
  • Journal Title: Analytical and Bioanalytical Chemistry Volume: 415 Pages: 6689～6700
  • DOI: 10.1007/s00216-023-04944-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells (2023)
  • Author(s): Ikeda Yoshiki、Davis Mindy I.、Sumita Kazutaka、Zheng Yuxiang、Kofuji Satoshi、Sasaki Mika、Hirota Yoshihisa、Pragani Rajan、Shen Min、Boxer Matthew B.、Takeuchi Koh、Senda Toshiya、Simeonov Anton、Sasaki Atsuo T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 679 Pages: 116～121
  • DOI: 10.1016/j.bbrc.2023.08.050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional molecular evolution of a GTP sensing kinase: PI5P4Kβ (2023)
  • Author(s): Takeuchi Koh、Senda Miki、Ikeda Yoshiki、Okuwaki Koji、Fukuzawa Kaori、Nakagawa So、Sasaki Mika、Sasaki Atsuo T.、Senda Toshiya
  • Journal Title: The FEBS Journal Volume: 290 Pages: 4419～4428
  • DOI: 10.1111/febs.16763
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Fueling the Way-The Role of Localized GTP Synthesis in Renal Cell Carcinoma Metastasis. (Posters). (2024)
  • Author(s): Aki Ogawa-Iio.(Mentor: Atsuo Sasaki).
  • Organizer: 13TH ANNUAL RESEARCH SYMPOSIUM DEPARTMENT OF INTERNAL MEDICINE
  • Int'l Joint Research
• [Presentation] Targeting the GTP sensing kinase PI5P4Kβ to sensitize oxidative and nutrient stresses to suppress the metastatic potential of invasive cancer cells. (Posters). (2024)
  • Author(s): Fujii Yuki. (Mentor: Atsuo Sasaki).
  • Organizer: 13TH ANNUAL RESEARCH SYMPOSIUM DEPARTMENT OF INTERNAL MEDICINE
  • Int'l Joint Research
• [Presentation] Identification of DNA damage response-related genes as biomarkers for castrationresistant prostate cancer. (Posters). (2024)
  • Author(s): Oshima Masashi. (Mentor: Atsuo Sasaki).
  • Organizer: 13TH ANNUAL RESEARCH SYMPOSIUM DEPARTMENT OF INTERNAL MEDICINE
  • Int'l Joint Research
• [Presentation] GTP-sensor PI5P4Kβ counteracts anabolic stresses by lysosomal acidification.(Poster). (2024)
  • Author(s): Yoshiki Ikeda, Risa Kawaguchi, Yoshihisa Hirota, Shun Kageyama, Akiyoshi Hirayama, Kazutaka Sumita,Mikako Warren, Yuki Fujii, Mika Sasaki, Kensuke Tateishi, Manabu Natsumeda, Tomoyoshi Soga, Takahisa Nakamura, Diego Perez-Tilve, Koh Takeuchi, Toshiya Senda, Atsuo T. Sasaki.
  • Organizer: KEYSTONE SYMPOSIA on Molecular and Cellular Biology Tumor Metabolism (B3)
  • Int'l Joint Research
• [Presentation] Fueling the Way-The Role of Localized GTP Synthesis in Renal Cell Carcinoma Metastasis.(Poster) . (2024)
  • Author(s): Aki OGAWA-IIO, Kari Kopra, Harri H, Satoshi Ogasawara, Ryo Kamata, Atsuo T Sasaki.
  • Organizer: KEYSTONE SYMPOSIA on Molecular and Cellular Biology Tumor Metabolism (B3)
  • Int'l Joint Research
• [Presentation] Workshop 2: Metabolic Targets and Vulnerabilities. Fueling the Way-The Role of Localized GTP Synthesis in Renal Cell Carcinoma Metastasis.(Presentation). (2024)
  • Author(s): Aki Ogawa-Iio, Ryo Kamata, Hirofumi Yoshino, Kara Wolfe, Satoshi Kofuji, Harri H, Kari Kopra, Titta Yli-Hollo, Osamu Ogawa, Eijiro Nakamura, Takeshi Kobayashi,Satoshi Ogasawara, Takeshi Murata, Koh Takeuchi, Toshiya Senda, Tomoyoshi Soga, Akiyoshi Hirayama, Laura M Machesky, Atsuo T Sasaki.
  • Organizer: KEYSTONE SYMPOSIA on Molecular and Cellular Biology Tumor Metabolism (B3)
  • Int'l Joint Research
• [Presentation] G-SHINE プローブによる細胞内GTP 局在可視化法とその応用(口頭発表). (2023)
  • Author(s): 飯尾 亜樹、Kari Kopra、Harri H、小笠原 諭、鎌田 諒、佐々木 敦朗.
  • Organizer: 第46回日本分子生物学会
• [Presentation] 時空間マルチスケール分析が照らすGTPエネルギー代謝の未踏領域（口頭発表） (2023)
  • Author(s): 佐々木敦朗
  • Organizer: 第46回日本分子生物学会
  • Invited
• [Presentation] プロドラッグ・ミコフェノール酸モフェチルは非肝臓細胞でも活性化されるのか？(口頭発表) (2023)
  • Author(s): 大田祐誠,佐々木敦朗
  • Organizer: 第46回日本分子生物学会
• [Presentation] Targeting the GTP sensing kinase PI5P4Kβ to sensitize oxidative and nutrient stresses to suppress the metastatic potential of invasive cancer cells. (2023)
  • Author(s): Yuki Fujii, Aki Iio (Ogawa), Shun Kageyama, Sho Tabata, Kazutaka Sumita, Mika Sasaki, Ko Takeuchi, Toshiya Senda, Atsuo T. Sasaki.
  • Organizer: CANCER METASTASIS RESEARCH SYMPOSIUM.
  • Int'l Joint Research
• [Presentation] At the Front of Cancer Metastasis -A Dynamic Role of Energy Metabolism(Presentations). (2023)
  • Author(s): Atsuo T Sasaki.
  • Organizer: CANCER METASTASIS RESEARCH SYMPOSIUM.
  • Int'l Joint Research / Invited
• [Presentation] Fueling the way-The Role of Localized GTP Synthesis in Cancer Metastasis(Presentations). (2023)
  • Author(s): Atsuo T Sasaki.
  • Organizer: CANCER METASTASIS RESEARCH SYMPOSIUM.
  • Int'l Joint Research / Invited
• [Presentation] Targeting the GTP sensing kinase PI5P4Kβ to sensitize oxidative and nutrient stresses to suppress the metastatic potential of invasive cancer cells. (Posters). (2023)
  • Author(s): Yuki Fujii, Aki Ogawa-lio, Shun Kageyama, Sho Tabata, Kazutaka Sumita, Mika Sasaki, Ko Takeuchi, Toshiya Senda, Atsuo Sasaki.
  • Organizer: CANCER METASTASIS RESEARCH SYMPOSIUM.
  • Int'l Joint Research
• [Presentation] Inosine monophosphate dehydrogenase drives "leadership" in collective cell migration of glioblastoma.(Posters) (2023)
  • Author(s): Aki Ogawa-lio, Satoshi Kofuji, Kari Kopra, Harri H, Satoshi Ogasawara,Atsuo Sasaki.
  • Organizer: CANCER METASTASIS RESEARCH SYMPOSIUM.
  • Int'l Joint Research