Role of DOCK family proteins in malignant transformation by human oncogenic Rac

• Project/Area Number: 26430115
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kyushu University
• Principal Investigator: Uruno Takehito 九州大学, 生体防御医学研究所, 准教授 (80532093)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: がん / 浸潤・転移 / 阻害剤 / Rac / Ras / DOCK1 / 浸潤転移 / マクロピノサイトーシス / 細胞骨格 / 浸潤 / 転移 / 阻害化合物 / 抗がん剤

Outline of Final Research Achievements

Oncogenic mutations in the small G proteins Rac and Ras are frequently found in a variety of human cancers. In this study, we found that genetic ablation of the Rac specific guanine nucleotide exchange factor DOCK1 or its pharmacological inhibition by its selective inhibitor TBOPP suppressed the survival and invasion of Rac/Ras-driven cancer cells. Moreover, the growth and invasion of these cancer cells transplanted in mice were effectively suppressed by treatment with TBOPP. Thus, DOCK1 plays critical roles in malignant transformation by oncogenic Rac and Ras, and may be a good therapeutic target for Rac/Ras-driven cancers.

Research Products

• [Journal Article] Targeting Ras-driven cancer cell survival and invasion through selective inhibition of DOCK1 (2017)
  • Author(s): Tajiri H, Uruno T, Shirai T, Takaya D, Matsunaga S, Setoyama D, Watanabe M, Kukimoto-Niino M, Oisaki K, Ushijima M, Sanematsu F, Honma T, Terada T, Oki E, Shirasawa S, Maehara Y, Kang D, Cote J-F, Yokoyama S, Kanai M, Fukui Y
  • Journal Title: Cell Reports Volume: 19 Issue: 5 Pages: 969-980
  • DOI: 10.1016/j.celrep.2017.04.016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction. (2017)
  • Author(s): Yamamura K, Uruno T, Shiraishi A, Tanaka Y, Ushijima M, Nakahara T, Watanabe M, Kido-Nakahara M, Tsuge I, Furue M, Fukui Y.
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 13946-13946
  • DOI: 10.1038/ncomms13946
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DOCK8 Regulates Macrophage Migration through Cdc42 Activation and LRAP35a Interaction. (2017)
  • Author(s): Shiraishi A, Uruno T, Sanematsu F, Ushijima M, Sakata D, Hara T, Fukui Y.
  • Journal Title: J Biol Chem Volume: 292 Issue: 6 Pages: 2191-2202
  • DOI: 10.1074/jbc.m116.736306
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus. (2015)
  • Author(s): Yanagihara T, Sanematsu F, Sato T, Uruno T, Duan X, Tomino T, Harada Y, Watanabe M, Wang Y, Tanaka Y, Nakanishi Y, Suyama M, Yoshinori F.
  • Journal Title: Nature Communications Volume: 6 Issue: 1 Pages: 8820-8820
  • DOI: 10.1038/ncomms9820
  • Peer Reviewed / Open Access
• [Journal Article] DOCK2 and DOCK5 act additively in neutrophils to regulate chemotaxis, superoxide production, and extracellular trap formation. (2014)
  • Author(s): Watanabe M, Terasawa M, Miyano K, Yanagihara T, Uruno T, Sanematsu F, Nishikimi A, Cote JF, Sumimoto H, Fukui Y.
  • Journal Title: J Immunol. Volume: 193 Issue: 11 Pages: 5660-5667
  • DOI: 10.4049/jimmunol.1400885
  • Peer Reviewed / Open Access
• [Journal Article] DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation. (2014)
  • Author(s): Ogawa K, Tanaka Y, Uruno T, Duan X, Harada Y, et al.
  • Journal Title: J. Exp. Med. Volume: (In press) Issue: 7 Pages: 1407-1419
  • DOI: 10.1084/jem.20131926
  • Peer Reviewed / Open Access
• [Presentation] DOCK1 as a novel molecular target for controlling cancer invasion and metastasis (2015)
  • Author(s): Tajiri H, Uruno T, Watanabe M, Maehara Y, Fukui Y.
  • Organizer: 第26回日本消化器癌発生学会
  • Place of Presentation: 鳥取
  • Year and Date: 2015-11-20
• [Patent(Industrial Property Rights)] ピリジノン化合物およびその用途 (2016)
  • Inventor(s): 福井宣規、宇留野武人、他
  • Industrial Property Rights Holder: 九州大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-02-26
  • Overseas
• [Patent(Industrial Property Rights)] ピリジノン化合物及びその用途 (2015)
  • Inventor(s): 福井宣規、宇留野武人、他
  • Industrial Property Rights Holder: 福井宣規、宇留野武人、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-02-27