Regulatory mechanism of ubiquitin-proteasome system-mediated ciliogenesis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08269
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Mie 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
• Keywords: 一次線毛 / 細胞増殖 / ユビキチン / プロテアソーム / 癌

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.

Free Research Field

細胞生物学

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。