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Yoshinori Fukui Last modified date:2018.07.10

Graduate School
Administration Post
Director of the Research Center for Advanced Immunology

Academic Degree
Doctor of Medical Science
Field of Specialization
Immunogenetics, Molecular Immunology, Cell Biology
Outline Activities
Remodeling of the actin cytoskeleton is a fundamental biological response that regulates various cellular functions in the immune system. The aim of my research is to elucidate the mechanism by which remodeling of the actin cytoskeleton is induced in lymphoid and myeloid cells downstream of various receptors, and to define its relevance to cellular functions. This accomplishment will lead to the development of new therapeutics for intractable diseases such as autoimmune diseases, graft rejection and infectious diseases.
Research Interests
  • Remodeling of the actin cytoskeleton in the immune system
    keyword : cytoskeleton, cell migration, antigen recognition, development of the immune system, G proteins
    2001.01Remodeling of the actin cytoskeleton is a fundamental biological response that regulates various cellular functions in the immune system. The aim of this study is to elucidate the mechanism by which remodeling of the actin cytoskeleton is induced in lymphoid and myeloid cells following the stimulation of various receptors, and to define its relevance to cellular functions. This accomplishment will lead to the development of new therapeutics for intractable diseases such as autoimmune diseases, graft rejection and infectious diseases..
Academic Activities
1. Toyoshi Yanagihara, Takahiro Tomino, Takehito Uruno, Yoshinori Fukui, Thymic epithelial cell–specific deletion of Jmjd6 reduces Aire protein expression and exacerbates disease development in a mouse model of autoimmune diabetes, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.05.113, 489, 1, 8-13, 2017.07, Thymic epithelial cells (TECs) establish spatially distinct microenvironments in which developing T cells are selected to mature or die. A unique property of medullary TECs is their expression of thousands of tissue-restricted self-antigens that is largely under the control of the transcriptional regulator Aire. We previously showed that Jmjd6, a lysyl hydroxylase for splicing regulatory proteins, is important for Aire protein expression and that transplantation of Jmjd6-deficient thymic stroma into athymic nude mice resulted in multiorgan autoimmunity. Here we report that TEC-specific deletion of Jmjd6 exacerbates development of autoimmune diabetes in a mouse model, which express both ovalbumin (OVA) under the control of the rat insulin gene promoter and OT-I T cell receptor specific for OVA peptide bound to major histocompatibility complex class I Kb molecules. We found that Aire protein expression in mTECs was reduced in the absence of Jmjd6, with retention of intron 2 in Aire transcripts. Our results thus demonstrate the importance of Jmjd6 in establishment of immunological tolerance in a more physiological setting..
2. Lauren A. Peters, Jacqueline Perrigoue, Arthur Mortha, Alina Iuga, Won Min Song, Eric M. Neiman, Sean R. Llewellyn, Antonio Di Narzo, Brian A. Kidd, Shannon E. Telesco, Yongzhong Zhao, Aleksandar Stojmirovic, Jocelyn Sendecki, Khader Shameer, Riccardo Miotto, Bojan Losic, Hardik Shah, Eunjee Lee, Minghui Wang, Jeremiah J. Faith, Andrew Kasarskis, Carrie Brodmerkel, Mark Curran, Anuk Das, Joshua R. Friedman, Yoshinori Fukui, Mary Beth Humphrey, Brian M. Iritani, Nicholas Sibinga, Teresa K. Tarrant, Carmen Argmann, Ke Hao, Panos Roussos, Jun Zhu, Bin Zhang, Radu Dobrin, Lloyd F. Mayer, Eric E. Schadt, A functional genomics predictive network model identifies regulators of inflammatory bowel disease, Nature Genetics, 10.1038/ng.3947, 49, 10, 1437-1449, 2017.10, A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD..
3. Tomino T, Tajiri H, Tatsuguchi T, Shirai T, Oisaki K, Matsunaga S, Sanematsu F, Sakata D, Yoshizumi T, Maehara Y, Kanai M, Côté JF, Fukui Y, Uruno T, DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1P29S mutation.
, Biochem. Biophys. Res. Commun. , 497, 298-304, 2018.03.
4. Masutaka Furue, K. Yamamura, Makiko Nakahara, Takeshi Nakahara, Yoshinori Fukui, Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis, Allergy: European Journal of Allergy and Clinical Immunology, 10.1111/all.13239, 73, 1, 29-36, 2018.01, Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (TH2)-deviated immune reactions. Interleukin-31 (IL-31), preferentially produced from TH2 cells, is a potent pruritogenic cytokine, and its systemic and local administration induces scratching behavior in rodents, dogs and monkeys. Recent clinical trials have revealed that administration of an anti-IL-31 receptor antibody significantly alleviates pruritus in patients with AD. In this review, we summarize recent topics related to IL-31 and its receptor with special references to atopic itch..
5. Ushijima M, Uruno T, Nishikimi A, Sanematsu F, Kamikaseda Y, Kunimura K, Sakata D, Okada T, Fukui Y, The Rac activator DOCK2 mediates plasma cell differentiation and IgG antibody production., Front. Immunol. , 9, 243, 2018.03.
6. Hirotada Tajiri H, Takehito Uruno, Takahiro Shirai, Daisuke Takaya, Shigeki Matsunaga, Daiki Setoyama, Mayuki Watanabe, Mutsuko Kukimoto-Niino, Kounosuke Oisaki, Miho Ushijima, Fumiyuki Sanematsu, Teruki Honma, Eiji Oki, Senji Shirasawa, Yoshihiko Maehara, Dongchon Kang, Jean-Francosis Cote, Shigeyuki Yokoyama S, Motomu Kanai, Yoshinori Fukui, Targeting Ras-Driven cancer cell survival and invasion through selective inhibition of DOCK1., Cell Rep., 19, 969-980, 2017.05, がん遺伝子Rasは、癌の発生において重要な役割を果たすのみならず、栄養源となる細胞外タンパク質の取り込みを促進し、細胞外基質への浸潤応答を誘導することで、がんの悪性形質転換に関わっている。これらの細胞応答はいずれもRacを介したアクチン細胞骨格の再構成が必要であることから、Racの活性化に関与する分子は、癌治療のための新たな創薬標的となる可能性がある。今回私達は、変異Rasによって形質転換した細胞において、Rac特異的グアニンヌクレオチド交換因子であるDOCK1を遺伝的に欠損させると、マクロピノサイトーシスに依存した栄養源の取り込みや浸潤応答が、抑制されることを見いだした。そこで、20万を超える化合物ライブラリーをスクリーニングし、構造最適化を行うことで、1-(2-(3 '-(トリフルオロメチル)-[1,1'-ビフェニル]-4-イル-2-オキソエチル)-5-ピロリジニルスルホニル-2(1H)-ピリドン(TBOPP)というDOCK1選択的阻害剤を開発した。TBOPPは、DOCK1と構造的に類似したDOCK2およびDOCK5タンパク質の機能を損なうことなく、DOCK1を介したがん細胞の浸潤応答やマクロピノサイトーシス、グルタミン欠乏条件下での生存を抑制した。さらに、TBOPPを投与することで、マウス個体における癌の生着や転移が顕著に抑制された。以上の結果は、DOCK1選択的阻害剤が、癌の生存や浸潤を標的とした新たな治療薬になりうることを実証するものである。.
7. Kazuhiro Yamamura, Takehito Uruno, Akira Shiraishi, Yoshihiko Tanaka, Miho Ushijima, Takeshi Nakahara, Mayuki Watanabe, Makiko Kido-Nakahara, Ikuya Tsuge, Masutaka Furue, Yoshinori Fukui, The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction., Nat. Commun., 8, 13946, 2017.01, ヒトにおけるDOCK8の変異は、血清IgE高値を伴うアトピー性皮膚炎を特徴とする複合免疫不全を引き起こす。しかしながら、DOCK8欠損がどのようなメカニズムでアトピー性皮膚炎を惹起するのか良く分かっていない。今回我々は、DOCK8欠損マウスのCD4+ T細胞が刺激に伴い、アトピー性皮膚炎の重要な起痒物質であるIL-31を大量に産生することを示す。IL-31の産生誘導は転写因子EPAS1に依存しており、CD4+ T細胞においてEPAS1の発現を欠失させると、DOCK8欠損マウスにおける皮膚炎の発症がキャンセルされた。EPAS1は芳香族炭化水素受容体核内輸送体(ARNT)と複合体を形成して、低酸素応答を制御することが知られているが、EPAS1によるIl31のプロモーター活性化には、ARNTではなく、SP1という別の転写因子が関与していた。一方でDOCK8はアダプター分子として機能し、EPAS1の核移行を負に制御していた。従って、DOCK8を欠損したCD4+ T細胞では、EPAS1を介してIL-31の産生が誘導され、その結果アトピー性皮膚炎が発症することが示された。.
8. Shiraishi A, Takehito Uruno, Fumiyuki Sanematsu, 牛島 美保, Daiji Sakata, Hara T, Yoshinori Fukui, DOCK8 Protein Regulates Macrophage Migration through Cdc42 Activation and LRAP35a Interaction., J. Biol. Chem., 292, 2191-2202, 2016.12.
9. Uematsu K, Okumura F, Tonogai S, Joo-Okumura A, Alemayehu DH, Akihiko Nishikimi, Yoshinori Fukui, Nakatsukasa K, Kamura T, ASB7 regulates spindle dynamics and genome integrity by targeting DDA3 for proteasomal degradation., J. Cell. Biol., 215, 95-106, 2016.10.
10. Liu Z, Man SM, Zhu Q, Vogel P, Frase S, Yoshinori Fukui, Kanneganti TD, DOCK2 confers immunity and intestinal colonization resistance to Citrobacter rodentium infection., Sci. Rep., 6, 27814, 2016.06.
11. Okumura F, Uematsu K, Byrne SD, Hirano M, Joo-Okumura A, Akihiko Nishikimi, Shuin T, Yoshinori Fukui, Nakatsukasa K, Kamura T, Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α., Mol. Cell Biol., 36, 1803-1817, 2016.06.
12. Toyoshi Yanagihara, Fumiyuki Sanematsu, Sato T, Takehito Uruno, DUAN XUEFENG, Takahiro Tomino, Yosuke Harada, Mayuki Watanabe, YUQING WANG, Yoshihiko Tanaka, Yoichi Nakanishi, M. Suyama, Yoshinori Fukui, Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus, Nature Commun., 6, 8820, 2015.11.
13. Guo X, Shi N, Cui X-B, Wang J-N, Yoshinori Fukui, Chen S-Y, Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling, Cir. Res. , 116, e71-e80, 2015.05.
14. Moalli F, Cupovic J, Thelen F, Halbherr P, Yoshinori Fukui, Narumiya S, Ludewig B, Stein JV, Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell-dendritic cell interactions, J. Exp. Med., 211, 2507-2517, 2014.12.
15. Sreeramkumar V, Drover JM, Ballesteros I, Cuartero MI, Rossaint R, Bilbao I, Nacher M, Pitaval C, Radovanovic I, Yoshinori Fukui, McEver RP, Filippi M-D, Lizasoain I, Ruiz-Cabello J, Zarbock A, Moro MA, Hidalgo A, Neutrophils scan for activated platelets to initiate inflammation, Science, 346, 1234-1238, 2014.12.
16. Mayuki Watanabe, 寺澤 公男, Miyano K, Yanagihara T, Takehito Uruno, Fumiyuki Sanematsu, Akihiko Nishikimi, Cote JF, Hideki Sumimoto, Yoshinori Fukui, DOCK2 and DOCK5 act additively in neutrophils to regulate chemotaxis, superoxide production, and extracellular trap formation, J. Immunol., 193, 5660-5667, 2014.12.
17. Abu-Thuraia A, Gauthier R, Chidiac R, Yoshinori Fukui, Screaton RA, Gratton JP, Cote JF, Axl phosphorylates Elmo scraffold proteins to promote Rac activation and cell invasion, Mol. Cell. Biol., 35, 76-87, 2015.01.
18. Watanabe M, Terasawa M, Miyano K, Yanagihara T, 宇留野 武人, Fumiyuki Sanematsu, Cote JF, Hideki Sumimoto, Yoshinori Fukui, DOCK2 and DOCK5 act additively in neutrophils to regulate chemotaxis, superoxide production, and extracellular trap formation, J. Immunol., 193, 5660-5667, 2014.12.
19. Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, Bilbao I, Nacher M, Pitaval C, Radovanovic I, Yoshinori Fukui, McEver RP, Filippi M-D, Lizasoain I, Ruiz-Cabello J, Zarbock A, Moro MA, Hidalgo A, Neutrophils scan for activated platelets to initiate inflammation, Science, 346, 1234-1238, 2014.12.
20. Moalli F, Cupovic J, Thelen F, Halbherr P, Yoshinori Fukui, Narumiya S, Ludewig B, Stein JV, Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell-dendritic cell interactions, J. Exp. Med., 211, 2507-2517, 2014.12.
21. Wen Y, Elliott MJ, Huang Y, Miller TO, Corbin DR, Hussain L-R, Ratajczak MZ, Yoshinori Fukui, Ilsars ST, DOCK2 is critical for CD8+TCR- graft facilitating cells to enhance engraftment of hematopoietic stem and progenitor cells, Stem Cells, 32, 2732-2734, 2014.10.
22. Kana Ogawa, Yoshihiko Tanaka, Takehito Uruno, DUAN XUEFENG, Yosuke Harada, Fumiyuki Sanematsu, Kazuhiko Yamamura, 寺澤 公男, Akihiko Nishikimi, JF Côté, Yoshinori Fukui, DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation, J. Exp.Med., 211, 1407-1419, 2014.07, マスト細胞は、細胞内に分泌顆粒を有しており、これに含まれるケミカルメディエーターを細胞外部に放出することで、アナフィラキシーと呼ばれる重篤なアレルギー反応を惹起する。マスト細胞はその表面にIgE抗体の高親和性受容体であるFcεRIを発現しており、これが抗原およびIgE抗体で架橋されると微小管のダイナミックな再構築が誘導され、脱顆粒反応がおこる。しかしながらこれまで、FcεRI近位のシグナル伝達機構に関してよく解析されているものの、微小管動態を制御する遠位のシグナル経路については依然として不明な点が多い。本研究において私達は、Racのグアニンヌクレオチド交換因子 (GEF)であるDOCK5が、マスト細胞の脱顆粒反応を重要な役割を演じていることを示す。私達は、DOCK5欠損マウスが全身性および皮膚アナフィラキシーショックに抵抗性を示すことを見いだした。驚いたことに、DOCK5が持つRac GEFとしての活性は、マスト細胞の脱顆粒反応に必要ではなかった。代わり、DOCK5はNck2やAktと会合し、GSK3βのリン酸化と不活性化を制御することで、微小管動態をコントロールしており、これらの分子との会合をブロックすると、微小管形成や脱顆粒反応が著しく障害された。以上より、DOCK5はアダプターとして機能し、マスト細胞の脱顆粒反応に重要な微小管動態を制御していることを明らかにした。.
23. Damoulakis G, Gambardella L, Rossman K, Lawson C, Anderson K, Yoshinori Fukui, Welch H, Der C, Stephens L, Hawkins P, P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils., J. Cell Sci., 127, 2589-2600, 2014.06.
24. Laurin M, Dumouchel A, Yoshinori Fukui, Côté JF, The Rac-specific exchange factors Dock1 and Dock5 are dispensable for the establishment of the glomerular filtration barrier in vivo., Small GTPases , 4, 4, 2013.12.
25. Le Floc’h A, Yoshihiko Tanaka, Bantilan BS, Voisinne G, Altan-Bonnet G, Yoshinori Fukui, Huse M, Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse. , J. Exp. Med., 210, 2721-2737, 2013.11.
26. Akihiko Nishikimi, M Kukimoto-Niino, S Yokoyama, Yoshinori Fukui, Immune regulatory functions DOCK family proteins in health and disease., Exp.Cell.Res., 319, 15, 2343-2349, 2013.09.
27. Sachiko Kamakura, Masatoshi Nomura, Jyunya Hayase, Y Iwakiri, Akihiko Nishikimi, Ryoichi Takayanagi, Yoshinori Fukui, Hideki Sumimoto, The cell polarity protein mlnsc regulates neutrophil chemotaxis via a noncanonical G protein signaling pathway., Dev. Cell., 26, 3, 292-302, 2013.08.
28. Yusuke Sakai, Yoshihiko Tanaka, Tohoshi Yanagihara, Mayuki Watanabe, DUAN XUEFENG, 寺澤 公男, Akihiko Nishikimi, Fumiyuki Sanematsu, Yoshinori Fukui, The Rac activator DOCK2 regulates natural killer cell-mediated cytotoxicity in mice through the lytic synapse formation., Blood, 122, 3, 386-393, 2013.05.
29. M Laurin, J Huber, A Pelletier, T Houalla, M Park, Yoshinori Fukui, B Haibe-Kains, WJ Muller, JF Côté, Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis., Proc.Natl.Acad.Sci.USA, 110, 18, 7434-7439, 2013.03.
30. Cimino PJ, Yang Y, Li X, Hemingway JF, Cherne MK, Khademi SB, Fukui Y, Montine KS, Montine TJ, Keene CD, Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of alzheimer's disease, Exp. Mol. Pathol., 10.1016/j.yexmp.2013.01.002., in press, 1-5, 2013.01.
31. Unoki M, Masuda A, Dohmae N, Arita K, Yoshimatsu M, Iwai Y, Fukui Y, Ueda K, Hamamoto R, Shirakawa M, Sasaki H, Nakamura Y, Lysyl 5-Hydroxylation, a novel histone modification, by jumonji domain containing 6(JMJD6), J. Biol. Chem., in press, 1-5, 2013.01.
32. Fumiyuki Sanematsu, Akihiko Nishikimi, Mayuki Watanabe, T Hongu, Yoshihiko Tanaka, Y Kanaho, JF Côté, Yoshinori Fukui, Phosphatidic acid-dependent recruitment and function of the Rat activator DOCK1 during dorsal ruffle formation, J. Biol. Chem., 288, 8092-8100, 2013.01.
33. Shigeo Fujimori, Naoya Hirai, Hiroyuki Ohashi, Kazuyo Masuoka, Akihiko Nishikimi, Yoshinori Fukui, Takanori Washio, Tomohiro Oshikubo, Tatsuhiro Yamashita, Etsuko Miyamoto-Sato, Next-generation sequencing coupled with a cell-free display technology for high-throughput production of reliable interactome data, Scientific Reports, 10.1038/srep00691, 2:691, 1-5, 2012.10.
34. Masao Terasawa, Takehito Uruno, Sayako Mori, Mutsuko Kukimoto-Niino, Akihiko Nishikimi, Fumiyuki Sanematsu, Yoshihiko Tanaka, Shigeyuki Yokoyama, Yoshinori Fukui, Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration, PLoS One, 2012.09.
35. Nishikimi A, Uruno T, Duan X, Cao Q, Okamura Y, Saitoh N, Sakaoka S, Du Y, Suenaga A, Kukimoto-NIino M, Miyano K, Okabe T, Sanematsu F, Tanaka Y, Sumimoto H, Honma T, Yokoyama S, Nagano T, Kohda D, Kanai M, Fukui Y, Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2., Chem. Biol., 19, 488-497, 2012.04.
36. Harada Y, Tanaka Y, Terasawa M, Pieczyk M, Habiro K, Katakai T, Hanawa-Suetsugu K, Kukimoto-Niino M, Nishizaki T, Shirousu M, Duan X, Uruno T, Nishikimi A, Sanematsu F, Yokoyama S, Stein JV, Kinashi T, Fukui Y , DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses, Blood, 119, 4451-4461, 2012.03, 樹状細胞は、抗原に暴露されると輸入リンパ管を介してリンパ節に移動し、T 細胞に抗原を提示することで免疫応答を惹起する。樹状細胞は、三次元微小環境下では、二次元環境と異なり、インテグリン非依存的に細胞外マトリックスの隙間を形を変えながら進んでいくが、このアメーバ様運動を制御するシグナル伝達機構やスペースを感知するメカニズムは明らかではない。私達は、ヒト免疫不全症の責任分子として近年注目を集めているDOCK8の機能を、ノックアウトマウスを作製することで解析した。その結果、DOCK8欠損樹状細胞ではリンパ節へのホーミングが障害されており、T細胞を効率よく活性化できないことを見いだした。DOCK8欠損樹状細胞は二次元環境では正常に運動できるにも関わらず、三次元微小環境下での運動が顕著に障害されていた。DOCK8はCdc42特異的なGEFとして機能しており、その複合体の構造を決定すると共に、FRETを用いて、DOCK8がCdc42活性化の場の制御に重要な役割を演じることを明らかにした。.
37. Hanawa-Suetugu K, Kukimoto-Niino M, Mishima-Tsumagari C, Akasaka R, Ohsawa N, Sekine S, Ito T, Tochio N, Koshiba S, Kigawa T, Terada T, Shirouzu M, Nishikimi A, Uruno T, Katakai T, Kinishi T, Kohda D, Fukui Y, Yokoyama S, Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms., Proc. Natl. Acad. Sci. USA, 109, 9, 3305-3310, 2012.02.
38. Ippagunta SK, Subbarao Malireddi RK, Shaw PJ, Neal GA, Walle LV, Green DR, Fukui Y, Lamkanfi M, Kanneganti T-D, The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization., Nature Immunology, 2011.09.
39. Sanematsu F, Hirashima M, Laurin M, Takii R, Nishikimi A, Kitajima K, Ding G, Noda M, Murata Y, Tanaka Y, Masuko S, Suda T, Meno C, Côté JF, Nagasawa T, Fukui Y, DOCK180 is a Rac activator that regulates cardiovascular development by acting downstream of CXCR4., Circ. Res., 107:1102-1105, 2010.10.
40. Gotoh K, Tanaka Y, Nishikimi A, Nakamura R, Yamada H, Maeda N, Ishikawa T, Hoshino K, Uruno T, Cao Q, Higashi S, Kawaguchi Y, Enjoji M, Takayanagi R, Kaisho T, Yoshikai Y, Fukui Y, Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation, J. Exp. Med., 207: 721-730, 2010.04, 形質細胞様樹状細胞(pDC)は、微生物由来の核酸を細胞内に存在するTLR7/TLR9を介して認識することで、炎症性サイトカインのみならず、大量のI型インターフェロン(IFN)を産生することから、近年脚光を集めている細胞である。pDC活性化におけるDOCK2の役割を解析する目的で、種々のTLRリガンドでpDCを刺激したところ、DOCK2欠損pDCではIL-12p40、IL-6といった炎症性サイトカインは正常に産生されるにも関わらず、I型IFNの産生が著しく低下することを見出した。このメカニズムを詳細に解析することで、TLRによる抗原認識とは独立してDOCK2-Racシグナル伝達系が作動し、IKK-alphaの活性化を介して、I型IFN産生を選択的に制御するという、新しい制御機構の存在を明らかにした。.
41. Nishikimi A, Fukuhara H, Su W, Hongu T, Takasuga S, Mihara H, Cao Q, Sanematsu F, Kanai M, Hasegawa H, Tanaka Y, Shibasaki M, Kanaho Y, Sasaki T, Frohman MA, Fukui Y, , Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis, Science, 324:384-387, 2009.04.
42. Gollmer K, Asperti-Boursin F, Tanaka Y, Okkenhaug K, Vanhaesebroeck B, Peterson JR, Fukui Y, Donnadieu E, Stein JV, CCL21 mediates CD4+ T cell costimulation via a DOCK2/Rac-dependent pathway, Blood, 114(3) : 580-588, 2009.03.
43. Gotoh K, Tanaka Y, Nishikimi A, Inayoshi A, Enjoji M, Takayanagi R, Sasazuki T, Fukui Y, Differential requirement for DOCK2 in migration of plasmacytoid dendritic cells versus myeloid dendritic cells, Blood, 111(6), 2973-2976, 2008.03.
44. Tanaka Y, Hamano S, Gotoh K, Murata Y, Kunisaki Y, Nishikimi A, Takii R, Kawaguchi M, Inayoshi A, Masuko S, Himeno K, Sasazuki T, Fukui Y, T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-α subunit controlled by the Rac activator Dock2., Nature Immunol., 8,1067-1075, 2007.09.
45. Nombela-Arrieta C, Mempel TR, Soriano SF, Mazo I, Wymann MP, Hirsch E, Martínez-A C, Fukui Y, von Andrian UH, Stein JV, A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediatsd egress, J. Exp. Med., 9: 121-128, 2007.03.
46. Handa Y, Suzuki M, Ohya K, Iwai H, Ishijima N, Koleske AJ, Fukui Y, Sasakawa C, Shignella IpgB1 promotes bacterial entry through the ELMO-Dock180 machinery., Nature Cell Biology, 9: 121-128, 2007.01.
47. García-Bernal D, Sotillo-Mallo E, Nombela-Arrieta C, Samaniego R, Fukui Y, Stein JV, Teixidó J, DOCK2 is required for chemokine-promoted human T lymphocyte adhesion under shear stress mediated by the integrin alpha4beta1., J. Immunol., 177: 5215-5225, 2006.10.
48. Kunisaki Y, Nishikimi A, Tanaka Y, Takii R, Noda M, Inayoshi A, Watanabe K, Sanematsu F, Sasazuki T, Sasaki T, Fukui Y, DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis., J. Cell Biol., 174: 647-652, 2006.04.
49. Kunisaki Y, Tanaka Y, Sanui T, Inayoshi A, Noda M, Nakayama T, Harada M, Taniguchi M, Sasazuki T, Fukui Y, DOCK2 is required in T cell precursors for development of Valpha14 natural killer T (NKT) cells., J. Immunol., 176: 4640-4645, 2006.04.
50. Shulman Z, Pasvolsky R, Woolf E, Grabovsky V, Feigelson SW, Erez N, Fukui Y, Alon R, DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration., Blood, 108: 2150-2158, 2006.04.
51. Jiang H, Pan F, Erickson LM, Jang MS, Sanui T, Kunisaki Y, Sasazuki T, Fukui Y, Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection, J. Exp. Med, 10.1084/jem.20050911, 202, 8, 1121-1130, 202: 1121-1130, 2005.10.
52. Nombela-Arrieta C, Lacalle RA, Montoya M, Kunisaki Y, Megilas D, Marques M, Carrera AC, Manes S, Fukui Y, Martines-A C, Stein JV, Differential requirements of DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing, Immunity, 10.1016/j.immuni.2004.07.012, 21, 3, 429-441, 21: 429-441, 2004.09.
53. Kunisaki T, Masuko S, Noda M, Inayoshi A, Sanui T, Harada M, Sasazuki T, Fukui Y., Defective fetal liver erythropoiesis and T-lymphopoiesis in mice lacking phosphatidylserine receptor, Blood, 10.1182/blood-2003-09-3245, 103, 9, 3362-3364, 103:119-129, 2004.05.
54. Sanui T, Inayoshi A, Noda M, Iwata E, Oike M, Sasazuki T, Fukui Y, DOCK2 is essential for antigen-induced translocation of TCR and lipid rafts, but not PKC-q and LFA-1, in T cells, Immunity, 10.1016/S1074-7613(03)00169-9, 19, 1, 119-129, 19:119-129, 2003.01.
55. Sanui T, Inayoshi A, Noda M, Iwata E, Stein JV, Sasazuki T, Fukui Y, DOCK2 regulates Rac activation and cytoskeletal reorganization through the interaction with ELMO1, Blood, 10.1182/blood-2003-01-0173, 102, 8, 2948-2950, 102: 2948-2950, 2003.01.
56. Fukui Y, Hashimoto O, Sanui T, Oono T, Koga H, Abe M, Inayoshi A, Noda M, Oike M, Shirai T, Sasazuki T, Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration, Nature, 10.1038/35090591, 412, 6849, 826-831, 412: 826-831, 2001.01.
57. Oono T, Fukui Y, Masuko S, Hashimoto O, Ueno T, Sanui T, Inayoshi A, Noda M, Sata M, Sasazuki T, Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide., J. Clin. Invest, 10.1172/JCI13256, 108, 11, 1589-1596, 108: 1589-1596, 2001.01.
58. Fukui Y, Oono T, Cabaniols JP, Nakao K, Hirokawa K, Inayoshi A, Sanui T, Kanellopoulos J, Iwata E, Noda M, Katsuki M, Kourilsky P, Sasazuki T, Diversity of T cell repertoire shaped by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor-contact., Proc. Natl. Acad. Sci. USA, 10.1073/pnas.250470797, 97, 25, 13760-13765, 97:13760-13765, 2000.01.
59. Fukui Y, Hashimoto O, Inayoshi A, Gyotoku T, Sano T, Koga T, Gushima T, Sasazuki T, Highly restricted T cell repertoire shaped by a single major histocompatibility complex-peptide ligand in the presence of a single rearranged T cell receptor b chain., J. Exp. Med., 10.1084/jem.188.5.897, 188, 5, 897-907, 188:897-907, 1998.01.
60. Gapin L, Fukui Y, Kanellopoulos J, Sano T, Casrouge A, Malier V, Beaudoing E, Gautheret D, Claverie JM, Sasazuki T, Kourilsky P, Quantitative analysis of the T-cell repertoire by a single peptide/MHC complex, J. Exp. Med., 187: 1871-1883, 1998.01.
61. Fukui Y, Ishimoto T, Utsuyama M, Gyotoku T, Koga T, Nakao K, Hirokawa K, Katsuki M, Sasazuki,, Positive and negative CD4+ thymocyte selection by a single MHC class II/peptide ligand affected by its expression level in the thymus, Immunity, 10.1016/S1074-7613(00)80283-6, 6, 4, 401-410, 6: 401-410, 1997.01.
62. Yamamoto K, Fukui Y, Esaki Y, Inamitsu T, Sudo T, Yamane K, Kamikawaji N, Kimura A, Sasazuki T, Functional interaction between human histocompatibility leukocyte antigen (HLA) class II and mouse CD4 molecule in antigen recognition by T cells in HLA-DR and DQ transgenic mice., J. Exp. Med., 10.1084/jem.180.1.165, 180, 1, 165-171, 180: 165-171, 1994.01.
63. Todd JA, Fukui Y, Kitagawa T, Sasazuki T, The A3 allele of the HLA-DQA1 locus in associated with susceptibility to type 1 diabetes in Japanese. , Proc.Natl. Acad. Sci., 10.1073/pnas.87.3.1094, 87, 3, 1094-1098, 87:1094-1098, 1990.01.
Educational Activities
Classes: Genetics, Immunology