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Protein-protein interaction analysis focusing on mutational hotspots in cancer genome

Research Project

Project/Area Number 18K19403
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 47:Pharmaceutical sciences and related fields
Research InstitutionOsaka University

Principal Investigator

Hino Nobumasa  大阪大学, 薬学研究科, 助教 (90469916)

Project Period (FY) 2018-06-29 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Keywordsがんゲノム / 遺伝子変異 / タンパク質立体構造 / タンパク質間相互作用 / 光クロスリンク / 人工アミノ酸 / KEAP1 / クロスリンク / プロテオミクス
Outline of Final Research Achievements

We aimed to establish a strategy for identifying protein-protein interactions affected by cancer mutations. By combining datasets of cancer genome mutation and 3D protein structure, we identified structural mutations cluster on the protein surface of KEAP1. We analyzed proteins binding to this surface by in vivo site-specific photo-cross-linking approach and identified Rab8a. Rab8a contributes to cell migration through the recruitment of MT1-MMP to the plasma membrane. Actually, Rab8a gene knockdown reduced cell migration activity, while additional KEAP1 knockdown cancelled this effect, suggesting that KEAP1 negatively regulates Rab8a activity. Furthermore, KEAP1 blocked MT1-MMP transport by tethering Rab8a in the perinuclear region, and the KEAP1 mutation disrupted its interaction with Rab8a, releasing the Rab8a-MT1-MMP complex. These results indicate that the focused analysis on structural mutations cluster can identify protein-protein interactions affected by cancer mutations.

Academic Significance and Societal Importance of the Research Achievements

これまでのがんゲノム創薬研究は既知のがん遺伝子変異をターゲットにしたものがほとんどであり.新規創薬標的の枯渇が問題視されている現状を鑑みると,その研究の方向性を大きくシフトする必要がある.本研究は,これまでほとんど利用されてこなかった低頻度変異情報から新たな創薬標的を見出す戦略を確立することを目指し,実際に,がん変異により異常をきたす新たなタンパク質間相互作用を発見することに成功した.

Report

(3 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (12 results)

All 2020 2019 2018 Other

All Journal Article (5 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 5 results,  Open Access: 2 results) Presentation (6 results) (of which Invited: 1 results) Remarks (1 results)

  • [Journal Article] PRC2 Components Maintain DNA Hypermethylation of the Upstream Promoter and Regulate Robo4 Expression in Endothelial Cells2020

    • Author(s)
      Izawa Kohei、Shirakura Keisuke、Kakiuchi Koji、Funahashi Nobuaki、Maekawa Naoki、Hino Nobumasa、Tanaka Toru、Doi Takefumi、Okada Yoshiaki
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 43 Issue: 4 Pages: 742-746

    • DOI

      10.1248/bpb.b19-01014

    • NAID

      130007825307

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2020-04-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structural Basis for Genetic-Code Expansion with Bulky Lysine Derivatives by an Engineered Pyrrolysyl-tRNA Synthetase2019

    • Author(s)
      Yanagisawa Tatsuo、Kuratani Mitsuo、Seki Eiko、Hino Nobumasa、Sakamoto Kensaku、Yokoyama Shigeyuki
    • Journal Title

      Cell Chemical Biology

      Volume: 26 Issue: 7 Pages: 1-14

    • DOI

      10.1016/j.chembiol.2019.03.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lipin-1 is a novel substrate of protein phosphatase PGAM52019

    • Author(s)
      Okuno Hiroko、Okuzono Haruna、Hayase Ayaka、Kumagai Fumiko、Tanii Shohei、Hino Nobumasa、Okada Yoshiaki、Tachibana Keisuke、Doi Takefumi、Ishimoto Kenji
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 509 Issue: 4 Pages: 886-891

    • DOI

      10.1016/j.bbrc.2019.01.031

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites2019

    • Author(s)
      Noguchi Yu-taro、Nakamura Miki、Hino Nobumasa、Nogami Jumpei、Tsuji Sayaka、Sato Takahiko、Zhang Lidan、Tsujikawa Kazutake、Tanaka Toru、Izawa Kohei、Okada Yoshiaki、Doi Takefumi、Kokubo Hiroki、Harada Akihito、Uezumi Akiyoshi、Gessler Manfred、Ohkawa Yasuyuki、Fukada So-ichiro
    • Journal Title

      Development

      Volume: 146 Issue: 4 Pages: 163618-163618

    • DOI

      10.1242/dev.163618

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation2018

    • Author(s)
      Shirakura Keisuke、Ishiba Ryosuke、Kashio Taito、Funatsu Risa、Tanaka Toru、Fukada So-ichiro、Ishimoto Kenji、Hino Nobumasa、Kondoh Masuo、Ago Yukio、Fujio Yasushi、Yano Kiichiro、Doi Takefumi、Aird William C.、Okada Yoshiaki
    • Journal Title

      Journal of Cell Science

      Volume: 132 Pages: 220228-220228

    • DOI

      10.1242/jcs.220228

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 細胞内光クロスリンク法を用いたがん変異に影響されるタンパク質間相互作用の同定2020

    • Author(s)
      樋野展正
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 変異集積表面への光クロスリンカー導入によるがん特異的蛋白質間相互作用の同定2019

    • Author(s)
      樋野展正,向山樹,鳴海良平,川端猛,山本紘義,重松知沙,山本真実,栗栖 源嗣,足立淳,土井健史_
    • Organizer
      日本ケミカルバイオロジー学会 第14回年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 細胞内光クロスリンク法を利用した新規肺がん治療標的の探索2019

    • Author(s)
      山本紘義,向山樹,鳴海良平,重松知沙,山本真実,足立淳,土井健史 ,樋野展正
    • Organizer
      日本ケミカルバイオロジー学会 第14回年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 細胞内光クロスリンク法によるDNA脱メチル化酵素TET1の活性調節因子の探索2019

    • Author(s)
      和島壮一,喜多絢海,谷口健吾,Jeremia Febrian,齋藤里緒,高島成二,土井健史,樋野展正
    • Organizer
      日本ケミカルバイオロジー学会 第14回年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] DNA脱メチル化関連酵素TET1の活性調節機構の解析2019

    • Author(s)
      Jeremia Febrian, 喜多絢海, 谷口健悟, 和島壮一, 斎藤里緒, 高島成二, 土井健史, 樋野展正
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 細胞内光クロスリンク法を用いたがん特異的タンパク質間相互作用の効率的な解析系の確立2019

    • Author(s)
      向山樹, 廣田康二, 鳴海良平,山本紘義,重松知沙,山本真実,足立淳,土井健史,樋野展正
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Remarks] 大阪大学大学院薬学研究科生命情報解析学分野ホームページ

    • URL

      https://seimeijohokaiseki.wixsite.com/tanpaku

    • Related Report
      2019 Annual Research Report 2018 Research-status Report

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Published: 2018-07-25   Modified: 2021-02-19  

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