Comprehensive analyses for biological functions and regulatory mechanisms of DOCK family proteins

• Project/Area Number: 25251015
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Kyushu University
• Principal Investigator: Fukui Yoshinori 九州大学, 生体防御医学研究所, 教授 (60243961)
• Co-Investigator(Kenkyū-buntansha): URUNO Takehito 九州大学, 生体防御医学研究所, 准教授 (80532093) ; 田中 芳彦 福岡歯科大学, 歯学部, 教授 (00398083)
• Project Period (FY): 2013-05-31 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥46,150,000 (Direct Cost: ¥35,500,000、Indirect Cost: ¥10,650,000); Fiscal Year 2015: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2014: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2013: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
• Keywords: シグナル伝達 / 生体分子 / 癌 / 免疫学 / 遺伝子改変マウス / がん / 免疫 / 低分子量Gタンパク質

Outline of Final Research Achievements

DOCK family proteins are atypical guanine nucleotide exchange factors that mediate GTP-GDP exchange reaction through their DHR-2 domain. Recent evidence indicates that DOCK family proteins are involved in many cellular functions, yet their regulatory mechanisms are poorly understood. In this study, we have analyzed signaling and functions of DOCK family proteins and obtained the following important findings: 1) DOCK5 acts downstream of FCεRI receptor and critically regulates mast cell degranulation. 2) DOCK1 plays a key role in invasion and metastasis of breast cancer cells. 3) The phosphorylation sites of DOCK2 in response to chemokine stimulation were identified. 4) The critical domain required for membrane localization of DOCK8 was identified. 5) The previously unknown function of DOCK8 and its regulatory mechanism were discovered.

Research Products

• [Journal Article] Parallel regulation of VHL disease by pVHL-mediated degradation of B-Myb and HIF-α. (2016)
  • Author(s): Okumura F, Uematsu K, Byrne S, Hirano M, Joo-Okumura A, Nishikimi A, Shuin T, Fukui Y, Nakatsukasa K, Kamura K.
  • Journal Title: Mol. Cell. Biol. Volume: in press
  • Peer Reviewed
• [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] Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling. (2015)
  • Author(s): Guo X, Shi N, Cui X-B, Wang J-N, Fukui Y, Chen S-Y.
  • Journal Title: Cir. Res. Volume: 116 Issue: 10
  • DOI: 10.1161/circresaha.116.305863
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Axl phosphorylates Elmo scraffold proteins to promote Rac activation and cell invasion. (2015)
  • Author(s): Abu-Thuraia A, Gauthier R, Chidiac R, Fukui Y, Screaton RA, Gratton JP, Cote JF.
  • Journal Title: Mol Cell Biol. Volume: 35 Issue: 1 Pages: 76-87
  • DOI: 10.1128/mcb.00764-14
  • Peer Reviewed
• [Journal Article] Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling. (2015)
  • Author(s): Guo X et al
  • Journal Title: Cir. Res. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Thromboxane A2 acts as tonic immunoregulator by preferentialdisruption of low-avidity CD4+ T cell-dendritic cell interactions. (2014)
  • Author(s): Moalli F, Cupovic J, Thelen F, Halbherr P, Fukui Y, Narumiya S, Ludewig B, Stein JV.
  • Journal Title: J Exp Med. Volume: 211 Issue: 13 Pages: 2507-2517
  • DOI: 10.1084/jem.20140137
  • Peer Reviewed
• [Journal Article] Neutrophils scan for activated platelets to initiate inflammation. (2014)
  • Author(s): Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, Bilbao I, Nacher M, Pitaval C, Radovanovic I, Fukui Y, McEver RP, Filippi M-D, Lizasoain I, Ruiz-Cabello J, Zarbock A, Moro MA, Hidalgo A.
  • Journal Title: Science Volume: 346 Issue: 6214 Pages: 1234-1238
  • DOI: 10.1126/science.1256478
  • Peer Reviewed
• [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] DOCK2 is critical for CD8+TCR- graft facilitating cells to enhance engraftment of hematopoietic stem and progenitor cells. (2014)
  • Author(s): Wen Y, Elliott MJ, Huang Y, Miller TO, Corbin DR, Hussain L-R, Ratajczak MZ, Fukui Y, Ildstad ST.
  • Journal Title: Stem Cells. Volume: 32 Issue: 10 Pages: 2732-2743
  • DOI: 10.1002/stem.1780
  • Peer Reviewed
• [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
• [Journal Article] P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils. (2014)
  • Author(s): Damoulakis G, Gambardella L, Rossman K, Lawson C, Anderson K, Fukui Y, Welch H, Der C, Stephens L, Hawkins P.
  • Journal Title: J Cell Sci. Volume: 127 Pages: 2589-2600
  • DOI: 10.1242/jcs.153049
  • Peer Reviewed
• [Journal Article] The Rac-specific exchange factors Dock1 and Dock5 are dispensable for the establishment of the glomerular filtration barrier in vivo. (2014)
  • Author(s): Laurin M, Dumouchel A, Fukui Y, Cote J-F.
  • Journal Title: Small GTPases Volume: 4 Issue: 4 Pages: 221-230
  • DOI: 10.4161/sgtp.27430
  • Peer Reviewed
• [Journal Article] 免疫抑制剤開発の新しい分子標的としてのDOCK2 (2014)
  • Author(s): 宇留野武人
  • Journal Title: 実験医学増刊 Volume: 32 Pages: 184-189
• [Journal Article] Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse (2013)
  • Author(s): Le Floc'h A, Tanaka Y, Bantilan NS, Voisinne G, Altan-Bonner G, Fukui Y, Huse M.
  • Journal Title: J Exp Med Volume: 210 Issue: 12 Pages: 2721-2737
  • DOI: 10.1084/jem.20131324
  • Peer Reviewed
• [Journal Article] Immune regulatory functions of DOCK family proteins in health and disease (2013)
  • Author(s): Nishikimi A et al.
  • Journal Title: Exp. Cell. Res. Volume: 319 Issue: 15 Pages: 2343-2349
  • DOI: 10.1016/j.yexcr.2013.07.024
  • Peer Reviewed
• [Journal Article] The cell polarity protein mInsc regulates neutrophil chemotaxis via a noncanonical G protein signaling pathway (2013)
  • Author(s): Kamakura S., Nomura M., Hayase J., Iwakiri Y., Nishikimi A., Fukui Y., Takayanagi R., Sumimoto H.
  • Journal Title: Dev Cell Volume: 26 Issue: 3 Pages: 292-302
  • DOI: 10.1016/j.devcel.2013.06.008
  • Peer Reviewed
• [Journal Article] The Rac activator DOCK2 regulates natural killer cell-mediated cytotoxicity in mice through the lytic synapse formation (2013)
  • Author(s): Sakai Y, Tanaka Y, Yanagihara T, Watanabe M, Duan X, Terasawa M, Nishikimi A, Sanematsu F, Fukui Y.
  • Journal Title: Blood Volume: 122 Issue: 3 Pages: 386-393
  • DOI: 10.1182/blood-2012-12-475897
  • Peer Reviewed
• [Journal Article] Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer's disease. (2013)
  • Author(s): Cimino PJ, Yang Y, Li X, Hemingway JF, Cherne MK, Khademi SB, Fukui Y, Montine KS, Montine TJ, Keene CD
  • Journal Title: Exp. Mol. Pathol. Volume: 94 Issue: 2 Pages: 366-371
  • DOI: 10.1016/j.yexmp.2013.01.002
  • Peer Reviewed
• [Journal Article] Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis (2013)
  • Author(s): Laurin M
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 未定 Issue: 18 Pages: 7434-7439
  • DOI: 10.1073/pnas.1213050110
  • Peer Reviewed
• [Presentation] 1.マスト細胞の脱顆粒反応におけるDOCK5の役割とその制御機構 (2015)
  • Author(s): 福井宣規
  • Organizer: 第64回日本アレルギー学会学術大会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2015-05-27
  • Invited
• [Presentation] A novel mechanism controlling Aire protein expression in the thymus. (2015)
  • Author(s): Fukui Y
  • Organizer: The Fourth BIZAN Immunology Symposium
  • Place of Presentation: Tokushima, Japan
  • Year and Date: 2015-01-29 – 2015-01-30
  • Invited
• [Presentation] Critical roles of DOCK family proteins in migration and activation of leukocytes. (2015)
  • Author(s): Fukui Y
  • Organizer: Keystone Symposium
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2015-01-13 – 2015-01-18
  • Invited
• [Presentation] The role of DOCK8 in migration and activation of effector CD4+ T cells during immune responses. (2014)
  • Author(s): Harada Y et at.
  • Organizer: The 43rd Annual Meeting of The Japanese Society for Immunology
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Identification of a novel molecule essential for Aire expression and self-tolerance. (2014)
  • Author(s): Yanagihara T et al
  • Organizer: The 43rd Annual Meeting of The Japanese Society for Immunology
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] DOCK1 as a novel molecular target for controlling cancer invasion and metastasis. (2014)
  • Author(s): Fukui Y
  • Organizer: The 25th Annual Meeting of the Japanese Society for Gastroenterolgical Carcinogeniesis
  • Place of Presentation: 福岡
  • Year and Date: 2014-11-13 – 2014-11-14
  • Invited
• [Presentation] Critical roles of DOCK family proteins in migration and activation of leukocytes. (2014)
  • Author(s): Fukui Y
  • Organizer: The 24th Hot Spring Harbor International Symposium
  • Place of Presentation: 福岡
  • Year and Date: 2014-11-07 – 2014-11-08
• [Presentation] Identification of a molecule critical for degranulation of mast cells and anaphylactic reaction (2013)
  • Author(s): Ogawa K et al.
  • Organizer: Annual Meeting of The Japanese Society for Immunology 2013
  • Place of Presentation: 幕張メッセ，千葉
• [Presentation] Critical roles of DOCK2 and DOCK5 in neutrophil chemotaxis, ROS production, and NETs formation (2013)
  • Author(s): Watanabe M et al
  • Organizer: Annual Meeting of The Japanese Society for Immunology 2013
  • Place of Presentation: 幕張メッセ，千葉
• [Presentation] Immune regulatory functions of DOCK family proteins in health and disease (2013)
  • Author(s): Fukui Y
  • Organizer: Germany-Japan Immunology Seminar
  • Place of Presentation: 日本平ホテル、静岡
  • Invited
• [Presentation] DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses (2013)
  • Author(s): Harada Y et al.
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: MICO Milano Congressi、Milan
• [Presentation] Critical role of DOCK8 in dendritic cell trafficking during T cell immune responses (2013)
  • Author(s): Shiraishi A et al
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: MICO Milano Congressi、Milan
• [Presentation] Critical roles of DOCK2 and DOCK5 in neutrophil chemotaxis, ROS production, and NETs formation (2013)
  • Author(s): Watanabe M et al.
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: MICO Milano Congressi、Milan
• [Presentation] Identification of a molecule critical for degranulation of mast cells and anaphylactic reaction (2013)
  • Author(s): Ogawa K et al.
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: MICO Milano Congressi、Milan
• [Presentation] B cell-intrinsic role of DOCK2 in T cell-dependent humoral immunity (2013)
  • Author(s): Ushijima M et al.
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: MICO Milano Congressi、Milan
• [Presentation] The Rac activator DOCK2 regulates natural killer cell-mediatd cytotoxicity through the lytic synapse formation (2013)
  • Author(s): Yanagihara T et al.
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: MICO Milano Congressi、Milan
• [Presentation] DOCK1 as a key molecule for dorsal ruffle formation and cancer cell metastasis
  • Author(s): Tajiri H et al.
  • Organizer: International Symposium between Kyushu U. Post-Global COE and School of Biomedical Sciences, Monash U.
  • Place of Presentation: Melbourne
• [Presentation] Critical role of DOCK8 in dendritic cell trafficking during T cell immune responses
  • Author(s): Yamamura K et al
  • Organizer: International Symposium between Kyushu U. Post-Global COE and School of Biomedical Sciences, Monash U.
  • Place of Presentation: Melbourne
• [Patent(Industrial Property Rights)] アトピー性皮膚炎モデル非ヒト動物及びその使用 (2016)
  • Inventor(s): 福井宣規、山村和彦、宇留野武人、古江増隆、
  • Industrial Property Rights Holder: 九州大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-034510
  • Filing Date: 2016-02-25