Roles of actin cytoskeletal regulation system in tumor cell migrationand invasion

• Project/Area Number: 20013004
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tohoku University
• Principal Investigator: MIZUNO Kensaku Tohoku University, 大学院・生命科学研究科, 教授 (70128396)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥16,000,000 (Direct Cost: ¥16,000,000); Fiscal Year 2009: ¥8,000,000 (Direct Cost: ¥8,000,000); Fiscal Year 2008: ¥8,000,000 (Direct Cost: ¥8,000,000)
• Keywords: 癌 / シグナル伝達 / コフィリン / 細胞運動 / 浸潤・転移 / アクチン骨格 / 浸潤突起 / LIMキナーゼ / 癌浸潤 / 浸潤仮足 / Slinshot / 阻害剤 / Slingshot

Research Abstract

We investigated the roles of actin cytoskeletal regulation in tumor cell migration and invasion and obtained the results, as follows : Cofilin and its regulatory enzymes, LIM-kinase and Slingshot, play critical roles in the invadopodium formation. LIM-kinase is critical for the mesenchymal-to-amoeboid cell morphological transition of tunor cells in 3D matrices. Protein kinase D1 regulates actin reorganization through Slingshot inactivation. We also developed inhibitors for LIM-kinase and found that these inhibitors suppressed tumor cell invasion.

Research Products

• [Journal Article] LIM-kinase is critical for the mesenchymal-to-amoeboid cell morphological transition in 3D matrices. (2010)
  • Author(s): Mishima, T., Naotsuka, M., Horita, Y., Sato, M., Ohashi, K., Mizuno, K
  • Journal Title: Biochem. Biophys. Res. Commum. 392 Pages: 577-581
• [Journal Article] LIM-kinase is critical for the mesenchymal-to-amoeboid cell morphological transition in 3D matrices (2010)
  • Author(s): Mishima, T., et al.
  • Journal Title: Biochem.Biophys.Res.Commum. 392 Pages: 577-581
  • Peer Reviewed
• [Journal Article] Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell motility through Slingshot. (2009)
  • Author(s): Eiseler, T., Doppler, H., Yan, I.K., Kitatani, K., Mizuno, K., Storz, P.
  • Journal Title: Nat. Cell Biol. 11(5) Pages: 545-556
• [Journal Article] MST2- and Furry-mediated activation of NDR1 is critical for precise alignment of mitotic chromosomes. (2009)
  • Author(s): Chiba, S., Ikeda, M., Katsunuma, K., Ohashi, K., Mizuno, K
  • Journal Title: Curr. Biol. 19(8) Pages: 675-681
• [Journal Article] Ca2+/calmodulin-dependent protein kinase IV-mediated LIM-kinase activation is critical for calcium signal-induced neurite outgrowth. (2009)
  • Author(s): Takemura, M., Mishima, T., Wang, Y., Kasahara, J., Fukunaga, K., Ohashi, K., Mizuno, K.
  • Journal Title: J. Biol. Chem. 284 Pages: 28554-28562
• [Journal Article] Requirements for recruitment of a G protein-coupled receptor to clathrin-coated pits in budding yeast. (2009)
  • Author(s): Toshima, J.Y., Nakanishi, J., Mizuno, K., Toshima, J., Drubin, D.G.
  • Journal Title: Mol. Biol. Cell 20(24) Pages: 5039-50
• [Journal Article] Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell motility through Slingshot (2009)
  • Author(s): Eiseler, T., et al.
  • Journal Title: Nat.Cell Biol. 11 Pages: 545-556
  • Peer Reviewed
• [Journal Article] MST2- and Furry-mediated activation of NDR1 is critical for precise alignment of mitotic chromosomes (2009)
  • Author(s): Chiba, S., et al.
  • Journal Title: Curr.Biol. 19 Pages: 675-681
  • Peer Reviewed
• [Journal Article] Ca2+/calmodulin-dependent protein kinase IV-mediated LIM-kinase activation is critical for calcium signal-induced neurite outgrowth (2009)
  • Author(s): Takemura, M., et al.
  • Journal Title: J.Biol.Chem. 284 Pages: 28554-28562
  • Peer Reviewed
• [Journal Article] Requirements for recruitment of a G protein-coupled receptor to clathrin-coated pits in budding yeast (2009)
  • Author(s): Toshima, J.Y., et al.
  • Journal Title: Mol.Biol.Cell 20 Pages: 5039-50
  • Peer Reviewed
• [Journal Article] MST2- and Furry-mediated activation of NDR1 is critical for precise alignment of mitotic chromosonies (2009)
  • Author(s): Chiba, S., et.al.
  • Journal Title: Curr. Biol (印刷中)
  • Peer Reviewed
• [Journal Article] Frotein kmase Dl regulates cofilin activity, F-actin reorganization and cell motility via Slingshot (2009)
  • Author(s): Eiseler, T., et.al.
  • Journal Title: Nat. Cell Biol (印刷中)
  • Peer Reviewed
• [Journal Article] Molecular dissection of the mechanisms of substrate recognition and F-actin-mediated activation of cofilin-phosphatase Slingshot-1. (2008)
  • Author(s): Kurita, S., Watanabe, Y., Gunji, E., Ohashi, K., Mizuno, K
  • Journal Title: J. Biol. Chem. 283 Pages: 32542-32552
• [Journal Article] Critical roles of actin-interacting protein 1 in cytokinesis and chemotactic migration of mammalian cells. (2008)
  • Author(s): Kato, A., Kurita, S., Hayashi, A., Kaji, N., Ohashi, K., Mizuno, K.
  • Journal Title: Biochem. J. 414 Pages: 261-270
• [Journal Article] Cell adhesion-dependent cofilin serine 3 phosphorylation by the integrin-linked kinase/c-Src complex. (2008)
  • Author(s): Kim, Y.B., Choi, S., Choi, M.C., Oh, M.A., Lee, S.A., Cho, M., Mizuno, K., Kim, S.H., Lee, J.W.
  • Journal Title: J. Biol. Chem. 283 Pages: 10089-10096
• [Journal Article] Cell Adhesion-dependent Cofilin Serine 3 Phosphorylation by the Integrin-linked Kinase・c-Src Complex (2008)
  • Author(s): Kim, Y.B., et.al.
  • Journal Title: J. Biol. Chem. 283 Pages: 10089-10096
  • Peer Reviewed
• [Journal Article] Critical roles of actin-interacting protein 1 in cytokinesis and chemotactic migration of mammalian cells (2008)
  • Author(s): Kato, A., et.al.
  • Journal Title: Biochem. J. 414 Pages: 261-270
  • Peer Reviewed
• [Journal Article] Molecular dissection of the mechanisms of substrate recognition and F-actin-mediated activation of cofilin-phosphatase Slingshot-1 (2008)
  • Author(s): Kurita, S., et.al.
  • Journal Title: J. Biol. Chem. 283 Pages: 32542-32552
  • Peer Reviewed
• [Presentation] invadopodia形成におけるコフィリンリン酸化制御の機能 (2009)
  • Author(s): 北谷佳那恵、堀田祐司、大橋一正、水野健作
  • Organizer: 日本生化学会東北支部例会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-09
• [Presentation] Dronpaを用いた細胞内G-アクチン濃度の経時測定によるコフィリンの機能解析 (2009)
  • Author(s): 永井友朗、木内泰、大橋一正、水野健作
  • Organizer: 日本生化学会東北支部例会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-09
• [Presentation] invadopodia 形成におけるコフィリンリン酸化制御の機能 (2009)
  • Author(s): 北谷佳那恵、堀田祐司、大橋一正、水野健作
  • Organizer: 日本生化学会東北支部例会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-09
• [Presentation] Dronpa を用いた細胞G-アクチン濃度の経時測定によるコフィリンの機能解析 (2009)
  • Author(s): 永井友朗、木内泰、大橋一正、水野健作
  • Organizer: 日本生化学会東北支部例会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-09
• [Presentation] Mitotic activation of NDR1 kinase and its role in chromosome alignment (2009)
  • Author(s): 池田真教, 千葉秀平, 大橋一正, 水野健作
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] Identifi cation of filamin A as the Slingshot-binding protein (2009)
  • Author(s): 佐上彩, 太田裕作, 栗田宗一, 大橋一正, 水野健作
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] A critical role of LIM-kinase in Mesenchymal-amoeboid transition of cancer cell migration (2009)
  • Author(s): 三嶋利明, 直塚萌, 堀田祐司, 大橋一正, 水野健作
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] High-throughput screening for low-molecular weight inhibitors of protein-protein interactions using BiFC probes (2009)
  • Author(s): 東海林和康, 大橋一正, 三瓶かおり, 木内泰, 水野健作
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] MST-2and Furry-mediated Activation of NDR1 Kinase Is Critical for Precise Alignment of Mitotic Chromosomes (2009)
  • Author(s): S. Chiba, M. Ikeda, K. Ohashi, K. Mizuno
  • Organizer: 第49回米国細胞生物学会会議
  • Place of Presentation: サンディエゴ(米国)
• [Presentation] Identification of Rho-GEFs that mediate RhoA activation and neurite retraction in the Wnt-PCP pathway (2009)
  • Author(s): 辻拓史, 太田裕作, 菅野祐哉, 大橋一正, 水野健作
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
• [Presentation] Development of FDAP time-lapse imaging for spatiotemporal measurement of cytoplasmic G-actin concentration and important roles of cofilin and G-actin in lamellipodium formation (2009)
  • Author(s): 永井友朗, 木内泰, 大橋一正, 水野健作
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
• [Presentation] :Regulation mechanism of NDR1 kinase and its role in mitotic chromosome alignment. (2009)
  • Author(s): 水野健作, 千葉秀平, 池田真教, 大橋一正
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
• [Presentation] Cofilin phosphatase Slingshot: regulation mechanism and role in polarized cell migration and cytokinesis. (2009)
  • Author(s): 大橋一正, 水野健作
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
• [Presentation] Effects of novel LIM-kinase-specific inhibitors on migration and invasion of tumor cells. (2009)
  • Author(s): Kazumasa Ohashi, Naoto Uchiumi, Kaori Sanpei, Mami Nakagawa, Kensaku Mizuno
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] MST2とFurryによるNDR1の活性化は分裂期染色体の赤道面への整列に必要である (2009)
  • Author(s): 千葉秀平、池田真教、勝沼功吉、大橋一正、水野健作
  • Organizer: 第61回日本細胞生物学会大会ワークショップ
  • Place of Presentation: 名古屋
• [Presentation] 細胞骨格制御とがん細胞の運動 (2009)
  • Author(s): 水野健作
  • Organizer: 分裂がん研究特定領域5領域合同シンポジウム
  • Place of Presentation: 東京
• [Presentation] Effects of novel LIM-kinase-specific inhibitors on migration and invasion of tumor cells (2009)
  • Author(s): Kazumasa Ohashi, Naoto Uchiumi, Kaori Sanpei, Mami Nakagawa, Kensaku Mizuno
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Regulation mechanism of NDR1 kinase and its role in mitotic chromosome alignment (2009)
  • Author(s): 水野健作, 千葉秀平, 池田真教, 大橋一正
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
• [Presentation] Cofilin phosphatase Slingshot : regulation mechanism and role in polarized cell migration and cytokinesis (2009)
  • Author(s): 大橋一正, 水野健作
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
• [Presentation] Identification of filamin A as the Slingshot-binding protein (2009)
  • Author(s): 佐上彩, 太田裕作, 栗田宗一, 大橋一正, 水野健作
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] Wnt-PCP経路による神経突起退縮に関与するRhoA-GEFの同定 (2008)
  • Author(s): 辻拓史、太田裕作、大橋一正、水野健作
  • Organizer: 日本生化学会東北支部例会
  • Place of Presentation: 盛岡
  • Year and Date: 2008-05-17
• [Presentation] Phosphorylation of Slingshot-1 by Polo-like kinase-1. (2008)
  • Author(s): Otsuki, M., Ikebe, C., Ohashi, K., Mizuno, K.
  • Organizer: The 48th Annual Meeting of The American Society for Cell Biology
  • Place of Presentation: San Francisco
• [Presentation] ラメリポディア形成過程における細胞内G-アクチン濃度のタイムラプスイメージングーDronpa-アクチンのFDAP解析を用いてー (2008)
  • Author(s): 永井友朗、木内泰、大橋一正、水野健作
  • Organizer: BMB2008第81回日本生化学会大会・第31回日本分子生物学会年会・合同大会
  • Place of Presentation: 神戸
• [Presentation] 哺乳類細胞の対称分裂における紡錘体位置決定タンパク質の局在とアクチン骨格の関与 (2008)
  • Author(s): 林文、黒沢豪、梶紀子、大橋一正、鎌倉幸子、住本英樹、水野健作
  • Organizer: BMB2008第81回日本生化学会大会・第31回日本分子生物学会年会・合同大会
  • Place of Presentation: 神戸
• [Presentation] MST2, MST3によるNDR1の活性制御と細胞分裂の制御 (2008)
  • Author(s): 池田真教、千葉秀平、勝沼功吉、大橋一正、水野健作
  • Organizer: BMB2008第81回日本生化学会大会・第31回日本分子生物学会年会・合同大会
  • Place of Presentation: 神戸
• [Presentation] Molecular mechanisms of substrate recognition and F-actin-mediated activation of cofilin-phosphatase Slingshot-1 and its roles in cell migration and invasion. (2008)
  • Author(s): Mizuno, K.
  • Organizer: International Phosphatase Conference
  • Place of Presentation: Maebashi
• [Presentation] Cofilin phospho-regulation plays a critical role in tumor cell motility and invasion. (2008)
  • Author(s): Ohashi, K., Horita, Y., Mizuno, K.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Phospho-regulation of cofilin in cell migration and tumor cell invasion (2008)
  • Author(s): 栗田宗一、堀田祐司、大橋一正、水野健作
  • Organizer: がん若手ワークショップ
  • Place of Presentation: 蓼科
• [Presentation] Identification of Rho-GEFs that mediate Dishevelled-induced RhoA activation. (2008)
  • Author(s): Tsuji, T., Ohta, Y., Ohashi, K., Mizuno, K.
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜
• [Presentation] Involvement of cofilin/ADF, Slingshot and LIM-kinase in invadopodium formation of tumor cells. (2008)
  • Author(s): Kitatani, K., Horita, Y., Ohashi, K., Mizuno, K.
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜
• [Presentation] Phosphorylation of Slingshot-1 by Polo-like kinase-1 (2008)
  • Author(s): Otsuki, M., Kaneto, K., Ikebe, C., Ohashi, K., Mizuno, K.
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜
• [Presentation] Roles of cofilin phospho-regulation in tumor cell migration and invasion. (2008)
  • Author(s): Ohashi, K., Horita, Y., Kiuchi, T., Mizuno, K.
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜
• [Presentation] Roles of cofilin phospho-regulation in tumor cell migration and invasion (2008)
  • Author(s): Ohashi, K., Horita, Y., Kiuchi, T., and Mizuno, K
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜
• [Presentation] Involvement of cofilin/ADF, Slingshot and LIM-kinase in invadopodium formation of tumor cells (2008)
  • Author(s): Kitatani, K., Horita, Y., Ohashi, K., and Mizuno, K
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜
• [Presentation] Identification of Rho-GEFs that mediate Dishevelled-induced RhoA activation (2008)
  • Author(s): Tsuji, T., Ohta, Y., Ohashi, K., and Mizuno, K
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜
• [Presentation] Cofilin phospho-regulation plays a critical role in tumor cell motility and invasion (2008)
  • Author(s): Dhashi, K., Horita, Y., and Mizuno, K
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Molecular mechanisms of substrate recognition and F-actin-mediated activation of cofilin-phosphatase Slingshot-1 and its roles in cell migration and invasion (2008)
  • Author(s): Mizuno, K
  • Organizer: International Phosphatase Conference
  • Place of Presentation: Maebashi
• [Presentation] 哺乳類細胞の対称分裂における紡錘体位置決定タンパク質の局在とアクチン壱格の関与 (2008)
  • Author(s): 林文、黒沢豪、梶紀子、大橋一正、鎌倉幸子、住本英樹、水野健作
  • Organizer: BMB2008第81回日本生化学会大会・第31回日本分子生物学会年会・合同大会
  • Place of Presentation: 神戸
• [Presentation] ラメリボディア形成過程における細胞内G-アクチン濃度のタイムラプスイメージングーDronpa-アクチンのFDAP解析を用いて- (2008)
  • Author(s): 永井友朗、木内泰、大橋一正、水野健作
  • Organizer: BMB2008第81回日本生化学会大会・第31回日本分子生物学会年会・合同大会
  • Place of Presentation: 神戸
• [Presentation] Phosphorylation of Slingshot-1 by Polo-like kinase-1 (2008)
  • Author(s): Otsuki, M., Ikebe, C., Ohashi, K., and Mizuno, K
  • Organizer: The 48th Annual Meeting of The American Society for Cell Biology
  • Place of Presentation: San Francisco USA
• [Presentation] Role of cofilin in actin filament assembly and disassembly during lamellipodium formation and extension. (2007)
  • Author(s): Kensaku Mizuno, Tai Kiuchi, Souichi Kurita, Kazumasa Ohashi
  • Organizer: 2nd International Symposium on Bio-nanosystems
  • Place of Presentation: Tokyo
• [Book] 細胞骨格、細胞運動、細胞接着を制御するシグナル伝達機構、生体の科学 (2008)
  • Author(s): 栗田宗一、水野健作
  • Publisher: 医学書院
• [Book] Dronpaを用いたアクチン動態のライブイメージング、実験医学増刊「生命現象の動的理解を目指すライブイメージング」、実験医学 (2008)
  • Author(s): 木内泰、水野健作
  • Publisher: 羊土社
• [Book] 生体の科学(細胞骨格、細胞運動、細胞接着を制御するシグナル伝達機構) (2008)
  • Author(s): 栗田宗一、水野健作(分担)
  • Publisher: 医学書院
• [Book] 実験医学増刊(Dronpaを用いたアクチン動態のライブイメージング) (2008)
  • Author(s): 木内泰、水野健作(分担)
  • Publisher: 羊土社
• [Remarks]
  • URL: http://www.biology.tohoku.ac.jp/lab-www/mizuno_lab/ohashi1234/Top.html