Regulation of retrograde transport mediated by LRRK1-Dynein complex

• Project/Area Number: 15H04697
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Nagoya University
• Principal Investigator: Hanafusa Hiroshi 名古屋大学, 理学研究科, 准教授 (00345844)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2015: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: LRRK1 / EGFR / CLIP170 / Rab7 / 細胞内トラフィック / Dynein / オートファゴソーム / エンドソーム

Outline of Final Research Achievements

From this study, we revealed that (1) LRRK1 functions to initiate the transport of EGFR-containing endosom along microtubules through the phosphorylation of a microtubule plus end-binding factor CLIP-170 and the promotion of its binding to p150Glued. Furthermore, we revealed that (2) LRRK1 phosphorylates Ser-72 located in the SwitchII region of Rab7 and selectively promotes the binding between Rab7 and RILP. In addition, we revealed that (3) LRRK1 was activated in the M-phase centrosome and phosphorylates the centrosome component CDK5RAP2. This functions in the regulation of spindle orientation by promoting g-tubulin-dependent microtubule nucleation.

Academic Significance and Societal Importance of the Research Achievements

ある種の癌細胞では、EGFRシグナルが過剰になっている。我々はLRRK1が、EGFRの細胞内トラフィックを制御することで、EGFRシグナルを負に制御することを明らかにした。このことは、過剰なEGFRシグナルが引き起こす細胞癌化に対し、それを防ぐ手立てを開発するのに役立つ可能性がある。さらにLRRK1のファミリー分子LRRK2は、家族性パーキンソン病原因遺伝子（Park8）であるが、その作用機序や生理的役割・パーキンソン病発症機構は依然として不明なままである。LRRK1とLRRK2は一部共通の機構で機能しており、LRRK1の機能解析はLRRK2の作用機構解明に繋がる可能性がある。

Research Products

• [Journal Article] LRRK1 phosphorylation of Rab7 at Ser-72 links trafficking of EGFR-containing endosomes to its effector RILP (2019)
  • Author(s): Hiroshi Hanafusa, Takuya Yagi, Haruka Ikeda, Naoki Hisamoto, Tomoki Nishioka, Kozo Kaibuchi, Kyoko Shirakabe, & Kunihiro Matsumoto
  • Journal Title: Journal of Cell Science Volume: 印刷中
  • Peer Reviewed
• [Journal Article] LRRK1-phosphorylated CLIP-170 regulates EGFR trafficking by recruiting p150Glued to microtubule plus ends (2015)
  • Author(s): Shin Kedashiro, Strahil I. Pastuhov, Tomoki Nishioka, Takashi Watanabe, Kozo Kaibuchi, Kunihiro Matsumoto, Hiroshi Hanafusa
  • Journal Title: Journal of Cell Science Volume: 128 Pages: 385-96
  • DOI: 10.1242/jcs.161547
  • Peer Reviewed / Open Access
• [Presentation] LRRK1によるエンドソームから発信されるEGFRシグナルの制御 (2018)
  • Author(s): 花房洋
  • Organizer: 日本生化学会
• [Presentation] ROCO family kinase LRRK1 regulates the transport and maturation of EGFR-containing endosomes (2018)
  • Author(s): 花房洋
  • Organizer: Annual Congress of Molecular & Cell Biology-2018
• [Presentation] LRRK1による細胞内トラフィックを介したEGFRシグナル制御 (2017)
  • Author(s): 花房洋
  • Organizer: 分子生物学会
  • Invited
• [Presentation] ROCOファミリーキナーゼLRRK1による シリア退縮制御 (2016)
  • Author(s): 花房洋
  • Organizer: 日本分子生物学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] ROCO family kinase LRRK1 regulates the transport and maturation of autophagosomes through Rab7 phosphorylation (2016)
  • Author(s): 花房洋
  • Organizer: 日本細胞生物学会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-15
  • Invited