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Regulatory mechanism of ubiquitin-proteasome system-mediated ciliogenesis

Research Project

Project/Area Number 17K08269
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionMie University

Principal Investigator

Kasahara Kousuke  三重大学, 医学系研究科, 准教授 (90455535)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords一次線毛 / 細胞増殖 / ユビキチン / プロテアソーム / 癌 / 脱ユビキチン化酵素 / 一次繊毛 / プロテアゾーム / 受容体型チロシンキナーゼ / 中心体 / リン酸化 / EGF受容体 / 細胞周期 / ユビキチン・プロテアソーム
Outline of Final Research Achievements

Ciliogenesis is generally inhibited in dividing cells, however, it has been unclear which signaling cascades regulate the phenomenon. Here, we report that EGFR kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 in RPE1 cells. The phosphorylations elevate the deubiquitinase activity, which then stabilizes the trichoplein-Aurora A pathway, an inhibitory mechanism of ciliogenesis. EGFR knockdown and serum starvation result in ciliogenesis through down-regulation of the USP8-trichoplein-Aurora A signal. Moreover, primary cilia abrogation, which is induced upon IFT20 or Cep164 depletion, ameliorates the cell cycle arrest of EGFR knockdown cells. The present data reveal that the EGFR-USP8-trichoplein-Aurora A axis is a critical signaling cascade that restricts ciliogenesis in dividing cells, and functions to facilitate cell proliferation.

Academic Significance and Societal Importance of the Research Achievements

本研究により、一次線毛の形成メカニズムの一端が明らかになり、且つ、一次線毛の形成動態を介して細胞増殖の制御が可能であることを示した。本研究成果により、一次線毛の異常に起因する種々の疾患の病態メカニズム解明や、一次線毛の形成動態を制御する分子群を標的とする新たな癌治療戦略の開発に繋がることが期待できる。

Report

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

    (9 results)

All 2019 2018 2017

All Journal Article (6 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 6 results,  Open Access: 5 results) Presentation (2 results) (of which Invited: 1 results) Book (1 results)

  • [Journal Article] Intermediate filaments and IF-associated proteins: from cell architecture to cell proliferation2019

    • Author(s)
      Yuhei Nishimura, Kousuke Kasahara, Masaki Inagaki
    • Journal Title

      Proceedings of the Japan Academy, Series B

      Volume: 95 Issue: 8 Pages: 479-493

    • DOI

      10.2183/pjab.95.034

    • NAID

      130007728178

    • ISSN
      0386-2208, 1349-2896
    • Year and Date
      2019-10-11
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Primary Cilia as Signaling Hubs in Health and Disease2018

    • Author(s)
      Nishimura Yuhei、Kasahara Kousuke、Shiromizu Takashi、Watanabe Masatoshi、Inagaki Masaki
    • Journal Title

      Advanced Science

      Volume: 6 Issue: 1 Pages: 1801138-1801138

    • DOI

      10.1002/advs.201801138

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tetraploidy in cancer and its possible link to aging.2018

    • Author(s)
      Tanaka K, Goto H, Nishimura Y, Kasahara K, Mizoguchi A, Inagaki M.
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 9 Pages: 2632-2640

    • DOI

      10.1111/cas.13717

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] EGF receptor kinase suppresses ciliogenesis through activation of USP8 deubiquitinase2018

    • Author(s)
      Kasahara K, Aoki H, Kiyono T, Wang S, Kagiwada H, Yuge M, Tanaka T, Nishimura Y, Mizoguchi A, Goshima N, Inagaki M
    • Journal Title

      Nat Commun

      Volume: 9 Issue: 1 Pages: 758-758

    • DOI

      10.1038/s41467-018-03117-y

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Regulation of keratin 5/14 intermediate filaments by CDK1, Aurora-B, and Rho-kinase2018

    • Author(s)
      Inaba H, Yamakawa D, Tomono Y, Enomoto A, Mii S, Kasahara K, Goto H, Inagaki M
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 498 Issue: 3 Pages: 544-550

    • DOI

      10.1016/j.bbrc.2018.03.016

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression2017

    • Author(s)
      Andrieu G, Ledoux A, Branka S, Bocquet M, Gilhodes J, Walzer T, Kasahara K, Inagaki M, Sabbadini RA, Cuvillier O, Hatzoglou A
    • Journal Title

      Sci Signal

      Volume: - Issue: 472

    • DOI

      10.1126/scisignal.aah4007

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 一次線毛の形成動態によるがん細胞増殖制御機構の解明2018

    • Author(s)
      笠原広介, 稲垣昌樹
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 増殖因子による一次繊毛の形成抑制メカニズム2017

    • Author(s)
      笠原広介、青木啓将、清野透、山川大史、稲垣昌樹
    • Organizer
      第69回日本細胞生物学会大会
    • Related Report
      2017 Research-status Report
  • [Book] メディカル・サイエンス・ダイジェスト4月号2019

    • Author(s)
      笠原広介、稲垣昌樹
    • Total Pages
      244
    • Publisher
      ニューサイエンス社
    • Related Report
      2019 Annual Research Report 2018 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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