Role of DOCK2 in antigen-specific humoral immunity

• Project/Area Number: 24590586
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Kitasato University (2013-2015); Kyushu University (2012)
• Principal Investigator: Nishikimi Akihiko 北里大学, 理学部, 准教授 (70404019)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: B細胞 / 抗原応答 / シグナル伝達 / 抗体産生 / Rac / 細胞遊走 / 免疫応答 / 分化 / 細胞骨格 / 免疫シナプス / キナーゼ

Outline of Final Research Achievements

The small G protein Rac is known to play important roles in B cell activation by acting downstream of B cell receptor (BCR). We found that DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells, is essential for BCR-mediated Rac activation.DOCK2-deficient B cells failed to form immunological synapse and displayed impaired antigen-stimulated growth in vitro. DOCK2 knock-out mice were shown to have impaired production of antibody in response to antigen immunization, indicating DOCK2 plays a critical role in humoral immunity.

Research Products

• [Journal Article] Dual functions of Rap1 are crucial for T-cell homeostasis and prevention of spontaneous colitis. (2015)
  • Author(s): Ishihara S, Nishikimi A, Umemoto E, Miyasaka M, Saegusa M, Katagiri K
  • Journal Title: Nat Commun. Volume: 6 Pages: 8982-8982
  • DOI: 10.1038/ncomms9982
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Pages: 5660-5607
  • DOI: 10.4049/jimmunol.1400885
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Rab13 acts downstream of the kinase Mst1 to activate the integrin LFA-1 for lymphocyte trafficking. (2014)
  • Author(s): Nishikimi A, Ishihara S, Ozawa M, Etoh K, Fukuda M, Kinashi T and Katagiri K
  • Journal Title: Sci Signal Volume: Vol. 7, Issue 336
  • DOI: 10.1126/scisignal.2005199
  • Peer Reviewed / Acknowledgement Compliant
• [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: The Journal of Experimental Medicine Volume: (In press) Pages: 1407-1419
  • DOI: 10.1084/jem.20131926
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Pages: 386-393
  • DOI: 10.1182/blood-2012-12-475897
  • 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: Developmental Cell Volume: 26 Pages: 292-302
  • DOI: 10.1016/j.devcel.2013.06.008
  • Peer Reviewed
• [Journal Article] Immune regulatory functions of DOCK family proteins in health and disease. (2013)
  • Author(s): Nishikimi A et al.
  • Journal Title: Experimental Cell Research Volume: 319 Pages: 2343-2349
  • DOI: 10.1016/j.yexcr.2013.07.024
  • Peer Reviewed
• [Journal Article] Phosphatidic acid-dependent recruitment and function of the Rat activator DOCK1 during dorsal ruffle formation. (2013)
  • Author(s): Sanematsu F, Nishikimi A, Watanabe M, Hongu T, Tanaka Y, Kanaho Y, Cote JF, Fukui Y
  • Journal Title: J Biol Chem. Volume: 288 Pages: 8092-8100
  • DOI: 10.1074/jbc.m112.410423
  • Peer Reviewed
• [Journal Article] Next-generation sequencing coupled with a cell-free display technology for high-throughput production of reliable interactome data. (2012)
  • Author(s): Fujimori S
  • Journal Title: Scientific Reports Volume: 2 Pages: 1-5
  • DOI: 10.1038/srep00691
  • Peer Reviewed
• [Journal Article] Dimerization of DOCK2 is essential for DOCK2-mediated Racactivation and lymphocyte migration. (2012)
  • Author(s): Terasawa M, Uruno T, Mori S, Kukimoto-Niino M, Nishikimi A, Sanematsu F, Tanaka Y, Yokoyama S, Fukui Y
  • Journal Title: PLoS One Volume: 7
  • DOI: 10.1371/journal.pone.0046277
  • Peer Reviewed
• [Journal Article] DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. (2012)
  • Author(s): Yosuke Harada, Yoshihiko Tanaka, Masao Terasawa, Markus Pieczyk, Katsuyoshi Habiro, Tomoya Katakai, Kyoko Hanawa-Suetsugu, Mutsuko Kukimoto-Niino, Tomoko Nishizaki, Mikako Shirouzu, Xuefeng Duan, Takehito Uruno, Akihiko Nishikimi, Fumiyuki Sanematsu, Shigeyuki Yokoyama, Jens V.Stein, Tatsuo Kinashi, Yoshinori Fukui
  • Journal Title: Blood. Volume: (In press) Pages: 4451-4461
  • DOI: 10.1182/blood-2012-01-407098
  • Peer Reviewed
• [Journal Article] Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2 (2012)
  • Author(s): Nishikimi A, Uruno T, Duan X, Cao Q, Okamura Y, Saitoh T, Saitoh N, Sakaoka S, Du Y, Suenaga A, Kukimoto-Niino M, Miyano K, Gotoh K, Okabe T, Sanematsu F, Tanaka Y, Sumimoto H., Honma T, Yokoyama S, Nagano T, Kohda D, Kanai M, and Fukui Y
  • Journal Title: Chem Biol Volume: 19 Pages: 488-497
  • DOI: 10.1016/j.chembiol.2012.03.008
  • Peer Reviewed
• [Presentation] Rap1とfilaminの相互作用を介したリンパ球の接着制御 (2016)
  • Author(s): 錦見昭彦，石原沙耶花，片桐晃子
  • Organizer: 生体運動合同班会議2016
  • Place of Presentation: キャンパスプラザ京都（京都府京都市）
  • Year and Date: 2016-01-08
• [Presentation] Rab13 is a downstream effector of Mst1 to mediate LFA-1 activation crucial for lymphocyte trafficking. (2015)
  • Author(s): Nishikimi A, Ishiahra S, Katagiri K
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
• [Presentation] Lymphocyte arrest was induced by the binding of active Rap1 to filamins. (2015)
  • Author(s): Ishiahra S, Nishikimi A, Katagiri K
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
• [Presentation] Rab13 is a downstream effector of Mst1 to mediate LFA-1 activation crucial for lymphocyte trafficking. (2014)
  • Author(s): Nishikimi A, Ishihara S, Ozawa M, Kinashi T, Katagiri K.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10
• [Presentation] DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. (2013)
  • Author(s): Nishikimi, A., Harada, Y., Tanaka, Y., Terasawa, M., Stein, J.V., Kinashi, T., Fukui, Y.
  • Organizer: The 23rd CDB Meeting Building Multicellular Systems from Cellular Cross-Talk
  • Place of Presentation: 神戸