Analysis of Kinesin family proteins as the downstream of Src-p130Cas axis in osteoclastic bone resorption

• Project/Area Number: 18K09509
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57010:Oral biological science-related
• Research Institution: Kyushu Dental College
• Principal Investigator: Matsubara Takuma 九州歯科大学, 歯学部, 准教授 (00423137)
• Co-Investigator(Kenkyū-buntansha): 中富 満城 九州歯科大学, 歯学部, 講師 (10571771) ; 古株 彰一郎 九州歯科大学, 歯学部, 教授 (30448899) ; 自見 英治郎 九州大学, 歯学研究院, 教授 (40276598)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 破骨細胞 / Src / p130Cas / 骨吸収 / 骨代謝

Outline of Final Research Achievements

Actin ring formation in osteoclasts is essential structure for bone resorption. Osteoclasts lacking Src or its downstream proteins p130Cas could not form actin ring. We investigated the mechanism how regulates Src-p130Cas signaling regulates actin ring formation. First, we explore the target protein of Src-p130Cas with microarray analysis using Src deficient osteoclasts and p130Cas deficient osteoclasts. Then, we identified Kif1c that is less expressed in Src and p130Cas. We found the potential of Kif1c to regulate actin ring because of Kif1c localization in actin ring by immunostaining. To examine the function of Kif1c, we suppressed Kif1c expression by shRNA in osteoclasts. Osteoclasts lost actin ring formation by kif1c knock down. Interestingly, overexpression of Kif1c accelerates actin ring formation in p130Cas deficient osteoclasts. These results suggest that Kif1c works under the Src-p130Cas signaling.

Academic Significance and Societal Importance of the Research Achievements

近年の研究により破骨細胞を喪失させずに骨吸収機能を制御できれば有害事象の少ない代謝性骨疾患の治療法につながると考えられている。そこで申請者らは破骨細胞の生存とは関係なく骨吸収機能を強力に活性化するSrc-p130Casシグナル分子に着目した。Srcとp130Casは様々な生命現象にも重要であるため、治療標的とはなりにくい。そこで、本研究ではSrc-p130Casシグナルの下流分子を探索し、破骨細胞の骨吸収機能を担う新たな分子としてKif1cを同定した。これによりSrc-p130Casシグナルの解明による代謝性骨疾患治療法の開発の一助になると期待される。

Research Products

• [Journal Article] Plectin stabilizes microtubules during osteoclastic bone resorption by acting as a scaffold for Src and Pyk2 (2020)
  • Author(s): Matsubara T, Yaginuma T, Addison WN. Fujita Y, Watanabe K, Yoshioka I, Hikiji H, Maki K, Baron R, Kokabu S
  • Journal Title: Bone Volume: 132 Pages: 15209-15209
  • DOI: 10.1016/j.bone.2019.115209
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] p130Cas induces bone invasion by oral squamous cell carcinoma by regulating tumor epithelial?mesenchymal transition and cell proliferation (2020)
  • Author(s): Yaginuma Tatsuki、Gao Jing、Nagata Kengo、Muroya Ryusuke、Fei Huang、Nagano Haruki、Chishaki Sakura、Matsubara Takuma、Kokabu Shoichiro、Matsuo Kou、Kiyoshima Tamotsu、Yoshioka Izumi、Jimi Eijiro
  • Journal Title: Carcinogenesis Volume: - Issue: 8 Pages: 1038-1048
  • DOI: 10.1093/carcin/bgaa007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bif‐1/Endophilin B1/SH3GLB1 regulates bone homeostasis (2019)
  • Author(s): Touyama Kenya、Khan Masud、Aoki Kazuhiro、Matsuda Miho、Hiura Fumitaka、Takakura Nana、Matsubara Takuma、Harada Yui、Hirohashi Yuna、Tamura Yukihiko、Gao Jing、Mori Kayo、Kokabu Shoichiro、Yasuda Hisataka、Fujita Yuko、Watanabe Koji、Takahashi Yoshinori、Maki Kenshi、Jimi Eijiro
  • Journal Title: Journal of Cellular Biochemistry Volume: 120 Issue: 11 Pages: 18793-18804
  • DOI: 10.1002/jcb.29193
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Kif1c regulates osteoclastic bone resorption as a downstream molecule of p130Cas (2019)
  • Author(s): Kobayakawa Miki、Matsubara Takuma、Mizokami Akiko、Hiura Fumitaka、Takakura Nana、Kokabu Shoichiro、Matsuda Miho、Yasuda Hisataka、Nakamura Ichiro、Takei Yosuke、Honda Hiroaki、Hosokawa Ryuji、Jimi Eijiro
  • Journal Title: Cell Biochemistry and Function Volume: 2019 Issue: 3 Pages: 1-9
  • DOI: 10.1002/cbf.3476
  • Peer Reviewed / Open Access
• [Presentation] A phosphatase regulatory protein PPP1r18 inhibits osteoclast differentiation via NFATc1 regulation (2020)
  • Author(s): Yasuda, K., Matsubara, T., Shirakawa, T., Gunjigake, K., Kuroishi, K., Kawamoto, T., Kokabu, S
  • Organizer: The 9th International Orthodontic Congress
  • Int'l Joint Research
• [Presentation] PPP1r18はNFATc1の発現を調節し破骨細胞分化に関与する (2020)
  • Author(s): 安田和真、松原琢磨、William Addison、川元龍夫、古株彰一郎
  • Organizer: 第38回日本骨代謝学会学術集会
• [Presentation] 中間径フィラメント関連タンパク質Plectin1による破骨細胞の細胞骨格制御 (2019)
  • Author(s): 松原 琢磨、浦田真梨子、William N Addison、古株彰一郎
  • Organizer: 第79回九州歯科学会総会・学術大会
• [Presentation] 中間径フィラメント関連タンパク質Plectin による骨吸収制御機構 (2019)
  • Author(s): 松原 琢磨，Addison William，古株彰一郎
  • Organizer: 第37回日本骨代謝学会学術集会
• [Presentation] The Role of Motor Protein Kif1c in Osteoclast Actin Ring Formation (2018)
  • Author(s): Miki Kobayakawa, Takuma Matsubara, Shoichiro Kokabu, Ryuji Hosokawa, Eijiro Jimi
  • Organizer: Asia-Pacific Conference in Fukuoka
  • Int'l Joint Research
• [Presentation] 破骨細胞のアクチンリング形成におけるKif1c の役割 (2018)
  • Author(s): 小早川美輝，松原琢磨，古株彰一郎，細川隆司，自見英治郎
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] 破骨細胞のアクチンリング形成におけるSrc とHck の重複した役割 (2018)
  • Author(s): 松原 琢磨，古株彰一郎
  • Organizer: 第36回日本骨代謝学会学術集会