2024/12/03 更新

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写真a

ウルノ タケヒト
宇留野 武人
URUNO TAKEHITO
所属
生体防御医学研究所 個体機能制御学部門 准教授
医学系学府 医学専攻(併任)
医学系学府 医科学専攻(併任)
職名
准教授
電話番号
0926426830
ホームページ
  • https://loop.frontiersin.org/people/479156/overview

    Loop: A guest review for Frontiers in Immunology

  • https://casiozaidan.org/naiyou/index.html

    公益財団法人 カシオ科学振興財団 「第42回(令和6年度) 研究助成」(基本テーマ2)に採択されました。貴重なご支援を賜り、心より御礼申し上げます。新しい学術領域の開拓を目指す挑戦的研究プロジェクトです。ご期待に添えますよう、誠心誠意努めてまいります。

  • https://www.terumozaidan.or.jp/support/doc/research/pdf_poster_2024.pdf

    公益財団法人 テルモ生命科学振興財団 「2024年度研究開発助成:"生命科学の発展と科学技術の振興への寄与を目指して" 」(III-4 研究助成)に採択されました。貴重なご支援を賜り大変嬉しく存じますと共に、心より御礼申し上げます。ご期待に添えますよう、誠心誠意努めてまいります。

  • https://www.amed.go.jp/koubo/15/01/1501C_00108.html

    国立研究開発法人日本医療研究開発機構(AMED)「令和6年度 新興・再興感染症研究基盤創生事業(多分野融合研究領域)」に、長崎大学 見市文香教授(研究開発代表者)らとの共同研究プロジェクトが採択されました

  • https://www.suzukenzaidan.or.jp/jisseki/index.php

    公益財団法人 鈴木謙三記念医科学応用研究財団より、令和5年度調査研究助成に採択されました。貴重なご支援を賜り心より御礼申し上げます。

  • https://tks.keystonesymposia.org/index.cfm?e=Web.Meeting.Program&Meetingid=1958

    Keystone Symposia "Cancer Immunotherapy: Mechanisms of Response versus Resistance" に招待され、あらゆるがん免疫療法に対して治療抵抗性を付与する 「がん性メタボライト」 に関する最新の研究成果を発表しました。(カナダ・アルバータ州、バンフ、2023.3.5-3.9)

  • https://doi.org/10.1093/intimm/dxac002

    がんの微小環境で働く新しい免疫制御メタボライトの同定:
    免疫チェックポイント阻害やCAR-T療法など、既存の腫瘍免疫療法の弱点を克服出来る可能性を示しています

  • https://doi.org/10.1016/j.bbrc.2022.04.035

    画期的な抗がん免疫賦活化剤の開発につながる研究成果です

  • https://www.amed.go.jp/news/release_20180801.html

    白血球の動きを制御する内因性の脂質成分を同定:
    コレステロール硫酸が白血球の動きを抑え、炎症制御に関わることを発見しました

  • http://www.amed.go.jp/news/release_20170503.html

    変異Rasを有するがん細胞の生存・浸潤・転移に重要なタンパク質を同定:
    新しいタイプの抗がん剤の開発につながる発見です

  • https://www.life-science-alliance.org/content/4/4/e202000873

    複合型免疫不全症の原因遺伝子DOCK8の細胞内局在を制御するリン脂質相互作用を同定:
    白血球の動きを制御する大事なメカニズムを解明しました

  • http://unmet.phar.kyushu-u.ac.jp/document/uruno.pdf

    創薬等支援技術基盤プラットフォーム事業「大型創薬研究基盤を活用した創薬オープンイノベーションの推進(九州大学拠点推進事業)」
    研究班員

  • http://www.bioreg.kyushu-u.ac.jp/iden/

    生医研 免疫遺伝学分野 ホームページ

研究分野

  • ライフサイエンス / 機能生物化学

  • ライフサイエンス / 医化学

学位

  • 平成6年3月  東京大学大学院 薬学系研究科  薬学博士

経歴

  • 通産省工業技術院生命工学工業技術研究所(1994~1999)、アメリカ赤十字社ホランド研究所(1999~2004)、アメリカ国立衛生研究所/NIH(2004~2008)、理化学研究所CDB(2008~2009)、九州大学生体防御医学研究所免疫遺伝学分野(特任講師、2009~2013)、九州大学生体防御医学研究所免疫遺伝学分野(助教、2013~2014)、2014年2月〜現職 「細胞生理応答研究から新しい創薬につながる研究を目指します」 「次世代の若い研究者に、世界基準の研究価値観を期待します」   

    通産省工業技術院生命工学工業技術研究所(1994~1999)、アメリカ赤十字社ホランド研究所(1999~2004)、アメリカ国立衛生研究所/NIH(2004~2008)、理化学研究所CDB(2008~2009)、九州大学生体防御医学研究所免疫遺伝学分野(特任講師、2009~2013)、九州大学生体防御医学研究所免疫遺伝学分野(助教、2013~2014)、2014年2月〜現職 「細胞生理応答研究から、新しい創薬につながる研究を目指しています」 「次世代の日本の若い研究者に、世界基準の研究価値観を期待しています」

  • なし   

研究テーマ・研究キーワード

  • 研究テーマ: 疾患免疫制御

    研究キーワード: 疾患免疫制御

    研究期間: 2024年

  • 研究テーマ: 生化学

    研究キーワード: 生化学

    研究期間: 2024年

  • 研究テーマ: メタボライト、生理活性物質

    研究キーワード: メタボライト、生理活性物質

    研究期間: 2024年

  • 研究テーマ: 疾患免疫代謝制御学: DOCKファミリー分子、SULTファミリーの構造と生体機能/がん・免疫・アレルギー疾患に関わる新規分子標的の同定とその創薬応用/メタボライト生物学

    研究キーワード: がん、免疫、シグナル伝達、細胞骨格制御、創薬研究

    研究期間: 2009年5月 - 2033年3月

受賞

  • 内藤記念科学奨励金・研究助成

    2017年9月   公益財団法人 内藤記念科学振興財団  

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    膵臓がんにおけるRac活性化因子DOCK1の機能解析とその選択的阻害による治療

論文

  • Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells 査読 国際誌

    Tatsuguchi, T; Uruno, T; Sugiura, Y; Sakata, D; Izumi, Y; Sakurai, T; Hattori, Y; Oki, E; Kubota, N; Nishimoto, K; Oyama, M; Kunimura, K; Ohki, T; Bamba, T; Tahara, H; Sakamoto, M; Nakamura, M; Suematsu, M; Fukui, Y

    INTERNATIONAL IMMUNOLOGY   34 ( 5 )   277 - 289   2022年4月   ISSN:0953-8178 eISSN:1460-2377

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Immunology  

    本研究は、大腸癌臨床検体及びマウスの移植がんモデルを用いて、がん細胞によって産生されるコレステロール硫酸がリンパ球の腫瘍内浸潤を抑制してがんの免疫回避に寄与していることを明らかにした。

    DOI: 10.1093/intimm/dxac002

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  • Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye 査読 国際誌

    Tetsuya Sakurai, Takehito Uruno, Yuki Sugiura, Takaaki Tatsuguchi, Kazuhiko Yamamura, Miho Ushijima, Yuko Hattori, Mutsuko Kukimoto-Niino, Chiemi Mishima-Tsumagari, Mayuki Watanabe, Makoto Suematsu, Yoshinori Fukui

    Science Signaling   11 ( 541 )   2018年7月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although immune responses are essential to protect the body from infection, they can also harm tissues. Certain tissues and organs, including the eye, constitute specialized microenvironments that locally inhibit immune reactivity. Dedicator of cytokinesis protein 2 (DOCK2) is a Rac-specific guanine nucleotide exchange factor (GEF) that is predominantly found in hematopoietic cells. DOCK2 plays a key role in immune surveillance because it is essential for the activation and migration of leukocytes. DOCK2 mutations cause severe immunodeficiency in humans. We found that DOCK2-mediated Rac activation and leukocyte migration were effectively inhibited by cholesterol sulfate (CS), but not by cholesterol or other sulfated steroids. CS bound to the catalytic domain of DOCK2 and suppressed its GEF activity. Mass spectrometric quantification revealed that CS was most abundantly produced in the Harderian gland, which provides the lipids that form the oily layer of the tear film. Sulfation of cholesterol is mediated by the sulfotransferases SULT2B1b and, to a lesser extent, SULT2B1a, which are produced from the same gene through alternative splicing. By genetically inactivating Sult2b1, we showed that the lack of CS in mice augmented ultraviolet- and antigen-induced ocular surface inflammation, which was suppressed by administration of eye drops containing CS. Thus, CS is a naturally occurring DOCK2 inhibitor and contributes to the generation of the immunosuppressive microenvironment in the eye.

    DOI: 10.1126/scisignal.aao4874

  • A conserved PI(4,5)P2–binding domain is critical for immune regulatory function of DOCK8 査読 国際誌

    Tetsuya Sakurai, Mutsuko Kukimoto-Niino, Kazufumi Kunimura, Nana Yamane, Daiji Sakata, Ryosuke Aihara, Tomoharu Yasuda, Shigeyuki Yokoyama, Mikako Shirouzu, Yoshinori Fukui, Takehito Uruno*

    Life Science Alliance   4 ( 4 )   e202000873 - e202000873   2021年2月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOCK8 is a Cdc42-specific guanine-nucleotide exchange factor that is essential for development and functions of various subsets of leukocytes in innate and acquired immune responses. Although DOCK8 plays a critical role in spatial control of Cdc42 activity during interstitial leukocyte migration, the mechanism remains unclear. We show that the DOCK homology region (DHR)-1 domain of DOCK8 binds specifically to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and is required for its recruitment to the plasma membrane. Structural and biochemical analyses reveal that DOCK8 DHR-1 domain consists of a C2 domain-like core with loops creating the upper surface pocket, where three basic residues are located for stereospecific recognition of phosphoinositides. Substitution of the two basic residues, K576 and R581, with alanine abolished PI(4,5)P2 binding in vitro, ablated the ability of DOCK8 to activate Cdc42 and support leukocyte migration in three-dimensional collagen gels. Dendritic cells carrying the mutation exhibited defective interstitial migration in vivo. Thus, our study uncovers a critical role of DOCK8 in coupling PI(4,5)P2 signaling with Cdc42 activation for immune regulation.

    DOI: 10.26508/lsa.202000873

  • Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1. 査読

    Takehito Uruno

    Cell reports   2017年5月

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    担当区分:筆頭著者   記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells. By screening chemical libraries, we have identified 1-(2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl-2(1H)-pyridone (TBOPP) as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion.

    DOI: 10.1016/j.celrep.2017.04.016

  • The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction. 査読

    Takehito Uruno

    Nature communications   2017年1月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells.

    DOI: 10.1038/ncomms13946

  • Activation of Arp2/3 complex-mediated actin polymerization by cortactin 査読

    URUNO T

    Nat. Cell Biol.   3   259 - 266   2001年3月

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    担当区分:筆頭著者   記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Activation of Arp2/3 complex-mediated actin polymerization by cortactin.
    Cortactin, a filamentous actin (F-actin)-associated protein and prominent substrate of Src, is implicated in progression of breast tumours through gene amplification at chromosome 11q13. However, the function of cortactin remains obscure. Here we show that cortactin co-localizes with the Arp2/3 complex, a de novo actin nucleator, at dynamic particulate structures enriched with actin filaments. Cortactin binds directly to the Arp2/3 complex and activates it to promote nucleation of actin filaments. The interaction of cortactin with the Arp2/3 complex occurs at an amino-terminal domain that is rich in acidic amino acids. Mutations in a conserved amino-acid sequence of DDW abolish both the interaction with the Arp2/3 complex and complex activation. The N-terminal domain is not only essential but also sufficient to target cortactin to actin-enriched patches within cells. Interestingly, the ability of cortactin to activate the Arp2/3 complex depends on an activity for F-actin binding, which is almost 20-fold higher than that of the Arp2/3 complex. Our data indicate a new mechanism for activation of actin polymerization involving an enhanced interaction between the Arp2/3 complex and actin filaments.

    DOI: 10.1038/35060051

  • DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis 査読

    Kunimura, K; Akiyoshi, S; Uruno, T; Matsubara, K; Sakata, D; Morino, K; Hirotani, K; Fukui, Y

    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY   151 ( 6 )   1585 - 1594.e9   2023年6月   ISSN:0091-6749 eISSN:1097-6825

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Allergy and Clinical Immunology  

    Background: Drug-induced anaphylaxis is triggered by the direct stimulation of mast cells (MCs) via Mas-related G protein–coupled receptor X2 (MRGPRX2; mouse ortholog MRGPRB2). However, the precise mechanism that links MRGPRX2/B2 to MC degranulation is poorly understood. Dedicator of cytokinesis 2 (DOCK2) is a Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 regulates migration and activation of leukocytes, its role in MCs remains unknown. Objective: We aimed to elucidate whether—and if so, how—DOCK2 is involved in MRGPRX2/B2-mediated MC degranulation and anaphylaxis. Methods: Induction of drug-induced systemic and cutaneous anaphylaxis was compared between wild-type and DOCK2-deficient mice. In addition, genetic or pharmacologic inactivation of DOCK2 in human and murine MCs was used to reveal its role in MRGPRX2/B2-mediated signal transduction and degranulation. Results: Induction of MC degranulation and anaphylaxis by compound 48/80 and ciprofloxacin was severely attenuated in the absence of DOCK2. Although calcium influx and phosphorylation of several signaling molecules were unaffected, MRGPRB2-mediated Rac activation and phosphorylation of p21-activated kinase 1 (PAK1) were impaired in DOCK2-deficient MCs. Similar results were obtained when mice or MCs were treated with small-molecule inhibitors that bind to the catalytic domain of DOCK2 and inhibit Rac activation. Conclusion: DOCK2 regulates MRGPRX2/B2-mediated MC degranulation through Rac activation and PAK1 phosphorylation, thereby indicating that the DOCK2-Rac-PAK1 axis could be a target for preventing drug-induced anaphylaxis.

    DOI: 10.1016/j.jaci.2023.01.029

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  • がん免疫療法に対する抵抗性を付与する腫瘍メタボライト 査読

    宇留野 武人, 竜口 崇明, 杉浦 悠毅, 福井 宣規

    日本がん免疫学会総会プログラム・抄録集   27回   173 - 173   2023年6月

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    担当区分:筆頭著者, 責任著者   記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury 査読 国際誌

    Morino, K; Kunimura, K; Sugiura, Y; Izumi, Y; Matsubara, K; Akiyoshi, S; Maeda, R; Hirotani, K; Sakata, D; Mizuno, S; Takahashi, S; Bamba, T; Uruno, T; Fukui, Y

    FRONTIERS IN IMMUNOLOGY   14   1131146 - 1131146   2023年3月   ISSN:1664-3224

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers in Immunology  

    During mucosal injury, intestinal immune cells play a crucial role in eliminating invading bacteria. However, as the excessive accumulation of immune cells promotes inflammation and delays tissue repair, it is essential to identify the mechanism that limits the infiltration of immune cells to the mucosal-luminal interface. Cholesterol sulfate (CS) is the lipid product of the sulfotransferase SULT2B1 and suppresses immune reactions by inhibiting DOCK2-mediated Rac activation. In this study, we aimed to elucidate the physiological role of CS in the intestinal tract. We found that, in the small intestine and colon, CS is predominantly produced in the epithelial cells close to the lumen. While dextran sodium sulfate (DSS)-induced colitis was exacerbated in Sult2b1-deficient mice with increased prevalence of neutrophils, the elimination of either neutrophils or intestinal bacteria in Sult2b1-deficient mice attenuated disease development. Similar results were obtained when the Dock2 was genetically deleted in Sult2b1-deficient mice. In addition, we also show that indomethacin-induced ulcer formation in the small intestine was exacerbated in Sult2b1-deficient mice and was ameliorated by CS administration. Thus, our results uncover that CS acts on inflammatory neutrophils, and prevents excessive gut inflammation by inhibiting the Rac activator DOCK2. The administration of CS may be a novel therapeutic strategy for inflammatory bowel disease and non-steroidal anti-inflammatory drug-induced ulcers.

    DOI: 10.3389/fimmu.2023.1131146

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  • コレステロール関連代謝産物と疾患制御 コレステロール硫酸は白血球の遊走制御を介して眼の免疫特権環境の形成に寄与する 招待 査読

    國村 和史, 宇留野 武人, 杉浦 悠毅, 福井 宣規

    日本生化学会大会プログラム・講演要旨集   95回   2S01e - 04   2022年11月

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    記述言語:日本語   出版者・発行元:(公社)日本生化学会  

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  • Identification of a functional <i>DOCK8</i> gene polymorphism associated with atopic dermatitis 査読 国際誌

    Kunimura, K; Yamamura, K; Nakahara, T; Kido-Nakahara, M; Uruno, T; Fukui, Y

    ALLERGY   77 ( 12 )   3670 - 3672   2022年7月   ISSN:0105-4538 eISSN:1398-9995

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Allergy: European Journal of Allergy and Clinical Immunology  

    DOI: 10.1111/all.15429

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  • 癌由来のコレステロール硫酸はエフェクターT細胞の腫瘍浸潤を防ぐ重要なメディエーターである(Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells) 査読

    Tatsuguchi Takaaki, Uruno Takehito, Sugiura Yuki, Sakata Daiji, Izumi Yoshihiro, Sakurai Tetsuya, Hattori Yuko, Oki Eiji, Kubota Naoto, Nishimoto Koshiro, Oyama Masafumi, Kunimura Kazufumi, Ohki Takuto, Bamba Takeshi, Tahara Hideaki, Sakamoto Michiie, Nakamura Masafumi, Suematsu Makoto, Fukui Yoshinori

    International Immunology   34 ( 5 )   277 - 289   2022年5月   ISSN:0953-8178

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    担当区分:筆頭著者, 責任著者   記述言語:英語   出版者・発行元:Oxford University Press  

    腫瘍微小環境へのエフェクターT細胞の浸潤を排除するメカニズムの解明を試みた。硫酸基転移酵素SULT2B1bによって生成される癌由来のコレステロール硫酸(CS)がRac活性化因子DOCK2を阻害し、エフェクターT細胞の腫瘍浸潤を阻害することが明らかになった。臨床サンプルを用いて、CSが大腸癌などの特定の種類のヒト癌で豊富に産生されていることを見出した。機能的には、CSを産生する癌細胞は、癌特異的T細胞移植や免疫チェックポイント阻害に対して抵抗性を示した。SULT2B1bはオキシステロールを硫酸化し、その腫瘍促進活性を不活性化することが知られているが、SULT2B1bを発現する癌ではオキシステロール産生を媒介するコレステロール水酸化酵素の発現量が低かった。したがって、SULT2B1bの阻害は、オキシステロール非産生癌の腫瘍免疫回避を妨害する治療戦略となる可能性があった。以上より、新たな腫瘍の免疫回避のメカニズムを明らかになり、効果的な免疫療法の開発に新たな知見が得られた。

  • Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity 査読 国際誌

    Tatsuguchi, T; Uruno, T; Sugiura, Y; Oisaki, K; Takaya, D; Sakata, D; Izumi, Y; Togo, T; Hattori, Y; Kunimura, K; Sakurai, T; Honma, T; Bamba, T; Nakamura, M; Kanai, M; Suematsu, M; Fukui, Y

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   609   183 - 188   2022年4月   ISSN:0006-291X eISSN:1090-2104

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    担当区分:筆頭著者, 責任著者   記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochemical and Biophysical Research Communications  

    Effective cancer immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute special microenvironments that exclude T cells and resist immunotherapy. Cholesterol sulfate (CS) is a product of sulfotransferase SULT2B1b and acts as an endogenous inhibitor of DOCK2, a Rac activator essential for migration and activation of lymphocytes. We have recently shown that cancer-derived CS prevents tumor infiltration by effector T cells. Therefore, SULT2B1b may be a therapeutic target to dampen CS-mediated immune evasion. Here, we identified 3β-hydroxy-5-cholenoic acid (3β-OH-5-Chln) as a cell-active inhibitor of SULT2B1b. 3β-OH-5-Chln inhibited the cholesterol sulfotransferase activity of SULT2B1b in vitro and suppressed CS production from cancer cells expressing SULT2B1b. In vivo administration of 3β-OH-5-Chln locally reduced CS level in murine CS-producing tumors and increased infiltration of CD8+ T cells. When combined with immune checkpoint blockade or antigen-specific T cell transfer, 3β-OH-5-Chln suppressed the growth of CS-producing tumors. These results demonstrate that pharmacological inhibition of SULT2B1b can promote antitumor immunity through suppressing CS-mediated T cell exclusion.

    DOI: 10.1016/j.bbrc.2022.04.035

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  • DOCK8 deficiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells 査読 国際誌

    Matsubara K, Kunimura K, Yamane N, Aihara R, Sakurai T, Sakata D, Uruno T, Fukui Y.

    Biochem Biophys Res Commun.   559   135 - 140   2021年6月

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    記述言語:英語  

    DOI: 10.1016/j.bbrc.2021.04.094.

  • Targeted inhibition of EPAS1–driven IL-31 production by a small-molecule compound 査読

    Yasuhisa Kamikaseda, Takehito Uruno, Kazufumi Kunimura, Akihito Harada, Kuniko Saiki, Kounosuke Oisaki, Daiji Sakata, Takeshi Nakahara, Makiko Kido-Nakahara, Motomu Kanai, Seiji Nakamura, Yasuyuki Ohkawa, Masutaka Furue, Yoshinori Fukui

    Journal of Allergy and Clinical Immunology   2021年4月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jaci.2021.03.029

  • DOCK8 controls survival of group 3 innate lymphoid cells in the gut through Cdc42 activation 査読 国際誌

    Ryosuke Aihara, Kazufumi Kunimura, Mayuki Watanabe, Takehito Uruno, Nana Yamane, Tetsuya Sakurai, Daiji Sakata, Fusanori Nishimura, Yoshinori Fukui

    International Immunology   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    <jats:title>Abstract</jats:title>
    <jats:p>Innate lymphoid cells (ILCs) are a family of developmentally related leukocytes that rapidly secrete polarized sets of cytokines to combat infection and promote tissue repair at mucosal barriers. Among them, group 3 ILCs (ILC3s) play an important role in maintenance of the gut homeostasis by producing IL-22, and their development and function critically depend on the transcription factor RORγt. Although recent evidence indicates that RORγt+ ILC3s are reduced in the gut in the absence of the Cdc42 activator DOCK8 (dedicator of cytokinesis 8), the underlying mechanism remains unclear. We found that genetic deletion of Dock8 in RORγt+-lineage cells markedly reduced ILC3s in the lamina propria of the small intestine. By analyzing BrdU incorporation, it was revealed that DOCK8 deficiency did not affect the cell proliferation. Furthermore, when lineage marker-negative (Lin–) α4β7+ CD127+ RORγt– fetal liver cells were cultured with OP9 stromal cells in the presence of stem cell factor (SCF) and IL-7 in vitro, RORγt+ ILC3s normally developed irrespective of DOCK8 expression. However, DOCK8-deficient ILC3s exhibited a severe defect in survival of ILC3s under the condition with or without IL-7. Similar defects were observed when we analyzed Dock8VAGR mice having mutations in the catalytic center of DOCK8, thereby failing to activate Cdc42. Thus, DOCK8 acts in cell-autonomous manner to control survival of ILC3s in the gut through Cdc42 activation.</jats:p>

    DOI: 10.1093/intimm/dxaa066

  • S100A4 Protein Is Essential for the Development of Mature Microfold Cells in Peyer’s Patches 査読 国際誌

    Takehito Uruno

    Cell Reports   29 ( 9 )   2823 - 2834   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Intestinal microfold cells (M cells) in Peyer's patches are a special subset of epithelial cells that initiate mucosal immune responses through uptake of luminal antigens. Although the cytokine receptor activator of nuclear factor-κB ligand (RANKL) expressed on mesenchymal cells triggers differentiation into M cells, other environmental cues remain unknown. Here, we show that the metastasis-promoting protein S100A4 is required for development of mature M cells. S100A4-producing cells are a heterogenous cell population including lysozyme-expressing dendritic cells and group 3 innate lymphoid cells. We found that in the absence of DOCK8, a Cdc42 activator critical for interstitial leukocyte migration, S100A4-producing cells are reduced in the subepithelial dome, resulting in a maturation defect of M cells. While S100A4 promotes differentiation into mature M cells in organoid culture, genetic inactivation of S100a4 prevents the development of mature M cells in mice. Thus, S100A4 is a key environmental cue that regulates M cell differentiation in collaboration with RANKL.

    DOI: 10.1016/j.celrep.2019.10.091

  • Selective role of neurokinin B in IL-31-induced itch response in mice. 査読

    Takehito Uruno

    The Journal of allergy and clinical immunology   144 ( 4 )   1130 - 1133.e8   2019年8月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jaci.2019.06.031

  • The Rac Activator DOCK2 Mediates Plasma Cell Differentiation and IgG Antibody Production. 査読 国際誌

    Takehito Uruno

    Frontiers in immunology   9   243 - 243   2018年2月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A hallmark of humoral immune responses is the production of antibodies. This process involves a complex cascade of molecular and cellular interactions, including recognition of specific antigen by the B cell receptor (BCR), which triggers activation of B cells and differentiation into plasma cells (PCs). Although activation of the small GTPase Rac has been implicated in BCR-mediated antigen recognition, its precise role in humoral immunity and the upstream regulator remain elusive. DOCK2 is a Rac-specific guanine nucleotide exchange factor predominantly expressed in hematopoietic cells. We found that BCR-mediated Rac activation was almost completely lost in DOCK2-deficient B cells, resulting in defects in B cell spreading over the target cell-membrane and sustained growth of BCR microclusters at the interface. When wild-type B cells were stimulated in vitro with anti-IgM F(ab')2 antibody in the presence of IL-4 and IL-5, they differentiated efficiently into PCs. However, BCR-mediated PC differentiation was severely impaired in the case of DOCK2-deficient B cells. Similar results were obtained in vivo when DOCK2-deficient B cells expressing a defined BCR specificity were adoptively transferred into mice and challenged with the cognate antigen. In addition, by generating the conditional knockout mice, we found that DOCK2 expression in B-cell lineage is required to mount antigen-specific IgG antibody. These results highlight important role of the DOCK2-Rac axis in PC differentiation and IgG antibody responses.

    DOI: 10.3389/fimmu.2018.00243

  • DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1P29S mutation. 査読

    Takehito Uruno

    Biochemical and biophysical research communications   2018年2月

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    担当区分:最終著者, 責任著者   記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Rac1 is a member of the Rho family of small GTPases that regulates cytoskeletal reorganization, membrane polarization, cell migration and proliferation. Recently, a self-activating mutation of Rac1, Rac1P29S, has been identified as a recurrent somatic mutation frequently found in sun-exposed melanomas, which possesses increased inherent GDP/GTP exchange activity and cell transforming ability. However, the role of cellular Rac1-interacting proteins in the transforming potential of Rac1P29S remains unclear. We found that the catalytic domain of DOCK1, a Rac-specific guanine nucleotide exchange factor (GEF) implicated in malignancy of a variety of cancers, can greatly accelerate the GDP/GTP exchange of Rac1P29S. Enforced expression of Rac1P29S induced matrix invasion and macropinocytosis in wild-type (WT) mouse embryonic fibroblasts (MEFs), but not in DOCK1-deficient MEFs. Consistently, a selective inhibitor of DOCK1 that blocks its GEF function suppressed the invasion and macropinocytosis in WT MEFs expressing Rac1P29S. Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1P29S mutation and express DOCK1 endogenously. Genetic inactivation and pharmacological inhibition of DOCK1 suppressed their invasion and macropinocytosis. Taken together, these results indicate that DOCK1 is a critical regulator of the malignant phenotypes induced by Rac1P29S, and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1P29S mutation.

    DOI: 10.1016/j.bbrc.2018.02.073

  • Thymic epithelial cell-specific deletion of Jmjd6 reduces Aire protein expression and exacerbates disease development in a mouse model of autoimmune diabetes. 査読

    Takehito Uruno

    Biochemical and biophysical research communications   2017年5月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    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.

    DOI: 10.1016/j.bbrc.2017.05.113

  • DOCK8 Protein Regulates Macrophage Migration through Cdc42 Protein Activation and LRAP35a Protein Interaction. 査読

    Takehito Uruno

    The Journal of biological chemistry   2016年12月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOCK8 is an atypical guanine nucleotide exchange factor for Cdc42, and its mutations cause combined immunodeficiency in humans. Accumulating evidence indicates that DOCK8 regulates the migration and activation of various subsets of leukocytes, but its regulatory mechanism is poorly understood. We here report that DOCK8-deficient macrophages exhibit a migration defect in a 2D setting. Although DOCK8 deficiency in macrophages did not affect the global Cdc42 activation induced by chemokine stimulation, rescue experiments revealed that the guanine nucleotide exchange factor activity of DOCK8 was required for macrophage migration. We found that DOCK8 associated with LRAP35a, an adaptor molecule that binds to the Cdc42 effector myotonic dystrophy kinase-related Cdc42-binding kinase, and facilitated its activity to phosphorylate myosin II regulatory light chain. When this interaction was disrupted in WT macrophages, they showed a migration defect, as seen in DOCK8-deficient macrophages. These results suggest that, during macrophage migration, DOCK8 links Cdc42 activation to actomyosin dynamics through the association with LRAP35a.

    DOI: 10.1074/jbc.M116.736306

  • Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus. 査読

    Takehito Uruno

    Nature communications   2015年11月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    The thymus has spatially distinct microenvironments, the cortex and the medulla, where the developing T-cells are selected to mature or die through the interaction with thymic stromal cells. To establish the immunological self in the thymus, medullary thymic epithelial cells (mTECs) express diverse sets of tissue-specific self-antigens (TSAs). This ectopic expression of TSAs largely depends on the transcriptional regulator Aire, yet the mechanism controlling Aire expression itself remains unknown. Here, we show that Jmjd6, a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins, is critical for Aire expression. Although Jmjd6 deficiency does not affect abundance of Aire transcript, the intron 2 of Aire gene is not effectively spliced out in the absence of Jmjd6, resulting in marked reduction of mature Aire protein in mTECs and spontaneous development of multi-organ autoimmunity in mice. These results highlight the importance of intronic regulation in controlling Aire protein expression.

    DOI: 10.1038/ncomms9820

  • DOCK2 and DOCK5 Act Additively in Neutrophils To Regulate Chemotaxis, Superoxide Production, and Extracellular Trap Formation 査読 国際誌

    Mayuki Watanabe, Masao Terasawa, Kei Miyano, Toyoshi Yanagihara, Takehito Uruno, Fumiyuki Sanematsu, Akihiko Nishikimi, Jean Francois Cote, Hideki Sumimoto, Yoshinori Fukui

    JOURNAL OF IMMUNOLOGY   193 ( 11 )   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.4049/jimmunol.1400885

  • DOCK5 functions as a key signaling adaptor that links Fc epsilon RI signals to microtubule dynamics during mast cell degranulation 査読 国際誌

    Kana Ogawa, Yoshihiko Tanaka, Takehito Uruno, Duan Xuefeng, Yosuke Harada, Fumiki Sanematsu, Kazuhiko Yamamura, Masao Terasawa, Akihiko Nishikimi, Jena Francois Cote, Yoshinori Fukui

    JOURNAL OF EXPERIMENTAL MEDICINE   211 ( 7 )   2014年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1084/jem.20131926

  • Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration. 査読

    Takehito Uruno

    PloS one   2012年9月

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    担当区分:筆頭著者   記述言語:その他   掲載種別:研究論文(学術雑誌)  

    The migratory properties of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain the Dbl homology domain typically found in guanine nucleotide exchange factors (GEFs), DOCK2 mediates the GTP-GDP exchange reaction for Rac via its DOCK homology region (DHR)-2 (also known as CZH2 or Docker) domain. DOCK2 DHR-2 domain is composed of three lobes, and Rac binding site and catalytic center are generated entirely from lobes B and C. On the other hand, lobe A has been implicated in dimer formation, yet its physiological significance remains unknown. Here, we report that lobe A-mediated DOCK2 dimerization is crucial for Rac activation and lymphocyte migration. We found that unlike wild-type DOCK2, DOCK2 mutant lacking lobe A failed to restore motility and polarity when expressed in thymoma cells and primary T cells lacking endogenous expression of DOCK2. Similar results were obtained with the DOCK2 point mutant having a defect in dimerization. Deletion of lobe A from the DHR-2 domain did not affect Rac GEF activity in vitro. However, fluorescence resonance energy transfer analyses revealed that lobe A is required for DOCK2 to activate Rac effectively during cell migration. Our results thus indicate that DOCK2 dimerization is functionally important under the physiological condition where only limited amounts of DOCK2 and Rac are localized to the plasma membrane.

    DOI: 10.1371/journal.pone.0046277

  • Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2. 査読 国際誌

    Takehito Uruno

    Chemistry & biology   19 ( 4 )   488 - 97   2012年4月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tissue infiltration of activated lymphocytes is a hallmark of transplant rejection and organ-specific autoimmune diseases. Migration and activation of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain Dbl homology domain typically found in guanine nucleotide exchange factors, DOCK2 mediates the GTP-GDP exchange reaction for Rac through its DHR-2 domain. Here, we have identified 4-[3'-(2″-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) as a small-molecule inhibitor of DOCK2. CPYPP bound to DOCK2 DHR-2 domain in a reversible manner and inhibited its catalytic activity in vitro. When lymphocytes were treated with CPYPP, both chemokine receptor- and antigen receptor-mediated Rac activation were blocked, resulting in marked reduction of chemotactic response and T cell activation. These results provide a rational of and a chemical scaffold for development of the DOCK2-targeting immunosuppressant.

    DOI: 10.1016/j.chembiol.2012.03.008

  • DOCK8は免疫反応時の間質樹状細胞遊走に重要なCdc42アクチベータである 査読

    TANAKA Yoshihiko, TANAKA Yoshihiko, HARADA Yosuke, HARADA Yosuke, TERASAWA Masao, TERASAWA Masao, NISHIKIMI Akihiko, NISHIKIMI Akihiko, KINASHI Tatsuo, KINASHI Tatsuo, FUKUI Yoshinori, FUKUI Yoshinori

    日本免疫学会総会・学術集会記録   41   2012年3月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses.
    To migrate efficiently through the interstitium, dendritic cells (DCs) constantly adapt their shape to the given structure of the extracellular matrix and follow the path of least resistance. It is known that this amoeboid migration of DCs requires Cdc42, yet the upstream regulators critical for localization and activation of Cdc42 remain to be determined. Mutations of DOCK8, a member of the atypical guanine nucleotide exchange factor family, causes combined immunodeficiency in humans. In the present study, we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration. By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming. Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor. This function of DOCK8 depended on the DHR-2 domain mediating Cdc42 activation. DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration. Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially.

    DOI: 10.1182/blood-2012-01-407098

  • Racグアニンヌクレオチド交換因子DOCK2及びそのパートナーELMO1のそれらの自己阻害化形からの相互排除のための構造的基盤 査読

    HANAWA-SUETSUGU Kyoko, KUKIMOTO-NIINO Mutsuko, KUKIMOTO-NIINO Mutsuko, MISHIMA-TSUMAGARI Chiemi, AKASAKA Ryogo, OHSAWA Noboru, SEKINE Shun-ichi, SEKINE Shun-ichi, ITO Takuhiro, ITO Takuhiro, TOCHIO Naoya, KOSHIBA Seizo, KIGAWA Takanori, KIGAWA Takanori, TERADA Takaho, TERADA Takaho, SHIROUZU Mikako, NISHIKIMI Akihiko, NISHIKIMI Akihiko, URUNO Takehito, KATAKAI Tomoya, KINASHI Tatsuo, KOHDA Daisuke, FUKUI Yoshinori, FUKUI Yoshinori, YOKOYAMA Shigeyuki, YOKOYAMA Shigeyuki, YOKOYAMA Shigeyuki

    Proceedings of the National Academy of Sciences of the United States of America   109 ( 9 )   2012年2月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms.
    DOCK2, a hematopoietic cell-specific, atypical guanine nucleotide exchange factor, controls lymphocyte migration through ras-related C3 botulinum toxin substrate (Rac) activation. Dedicator of cytokinesis 2-engulfment and cell motility protein 1 (DOCK2•ELMO1) complex formation is required for DOCK2-mediated Rac signaling. In this study, we identified the N-terminal 177-residue fragment and the C-terminal 196-residue fragment of human DOCK2 and ELMO1, respectively, as the mutual binding regions, and solved the crystal structure of their complex at 2.1-Å resolution. The C-terminal Pro-rich tail of ELMO1 winds around the Src-homology 3 domain of DOCK2, and an intermolecular five-helix bundle is formed. Overall, the entire regions of both DOCK2 and ELMO1 assemble to create a rigid structure, which is required for the DOCK2•ELMO1 binding, as revealed by mutagenesis. Intriguingly, the DOCK2•ELMO1 interface hydrophobically buries a residue which, when mutated, reportedly relieves DOCK180 from autoinhibition. We demonstrated that the ELMO-interacting region and the DOCK-homology region 2 guanine nucleotide exchange factor domain of DOCK2 associate with each other for the autoinhibition, and that the assembly with ELMO1 weakens the interaction, relieving DOCK2 from the autoinhibition. The interactions between the N- and C-terminal regions of ELMO1 reportedly cause its autoinhibition, and binding with a DOCK protein relieves the autoinhibition for ras homolog gene family, member G binding and membrane localization. In fact, the DOCK2•ELMO1 interface also buries the ELMO1 residues required for the autoinhibition within the hydrophobic core of the helix bundle. Therefore, the present complex structure reveals the structural basis by which DOCK2 and ELMO1 mutually relieve their autoinhibition for the activation of Rac1 for lymphocyte chemotaxis.

    DOI: 10.1073/pnas.1113512109

  • Molecular basis for barbed end uncapping by CARMIL homology domain 3 of mouse CARMIL-1. 査読

    Takehito Uruno

    The Journal of biological chemistry   2010年7月

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    担当区分:筆頭著者   記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Capping protein (CP) is a ubiquitously expressed, 62-kDa heterodimer that binds the barbed end of the actin filament with approximately 0.1 nm affinity to prevent further monomer addition. CARMIL is a multidomain protein, present from protozoa to mammals, that binds CP and is important for normal actin dynamics in vivo. The CARMIL CP binding site resides in its CAH3 domain (CARMIL homology domain 3) located at or near the protein's C terminus. CAH3 binds CP with approximately 1 nm affinity, resulting in a complex with weak capping activity (30-200 nm). Solution assays and single-molecule imaging show that CAH3 binds CP already present on the barbed end, causing a 300-fold increase in the dissociation rate of CP from the end (i.e. uncapping). Here we used nuclear magnetic resonance (NMR) to define the molecular interaction between the minimal CAH3 domain (CAH3a/b) of mouse CARMIL-1 and CP. Specifically, we show that the highly basic CAH3a subdomain is required for the high affinity interaction of CAH3 with a complementary "acidic groove" on CP opposite its actin-binding surface. This CAH3a-CP interaction orients the CAH3b subdomain, which we show is also required for potent anti-CP activity, directly adjacent to the basic patch of CP, shown previously to be required for CP association to and high affinity interaction with the barbed end. The importance of specific residue interactions between CP and CAH3a/b was confirmed by site-directed mutagenesis of both proteins. Together, these results offer a mechanistic explanation for the barbed end uncapping activity of CARMIL, and they identify the basic patch on CP as a crucial regulatory site.

    DOI: 10.1074/jbc.M110.134221

  • Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation. 査読 国際誌

    Takehito Uruno

    The Journal of experimental medicine   207 ( 4 )   721 - 30   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity, but also contribute to the pathogenesis of certain autoimmune diseases, by producing large amounts of type I IFNs. Although activation of pDCs is triggered by engagement of nucleotide-sensing toll-like receptors (TLR) 7 and 9, type I IFN induction additionally requires IkappaB kinase (IKK) alpha-dependent activation of IFN regulatory factor (IRF) 7. However, the signaling pathway mediating IKK-alpha activation is poorly defined. We show that DOCK2, an atypical Rac activator, is essential for TLR7- and TLR9-mediated IFN-alpha induction in pDCs. We found that the exposure of pDCs to nucleic acid ligands induces Rac activation through a TLR-independent and DOCK2-dependent mechanism. Although this Rac activation was dispensable for induction of inflammatory cytokines, phosphorylation of IKK-alpha and nuclear translocation of IRF-7 were impaired in Dock2-deficient pDCs, resulting in selective loss of IFN-alpha induction. Similar results were obtained when a dominant-negative Rac mutant was expressed in wild-type pDCs. Thus, the DOCK2-Rac signaling pathway acts in parallel with TLR engagement to control IKK-alpha activation for type I IFN induction. Owing to its hematopoietic cell-specific expression, DOCK2 may serve as a therapeutic target for type I IFN-related autoimmune diseases.

    DOI: 10.1084/jem.20091776

  • Purification of capping protein using the capping protein binding site of CARMIL as an affinity matrix. 査読

    Takehito Uruno

    Protein expression and purification   2009年5月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Capping protein (CP) is a ubiquitously expressed, heterodimeric actin binding protein that is essential for normal actin dynamics in cells. The existing methods for purifying native CP from tissues and recombinant CP from bacteria are time-consuming processes that involve numerous conventional chromatographic steps and functional assays to achieve a homogeneous preparation of the protein. Here, we report the rapid purification of Acanthamoeba CP from amoeba extracts and recombinant mouse CP from E. coli extracts using as an affinity matrix GST-fusion proteins containing the CP binding site from Acanthamoeba CARMIL and mouse CARMIL-1, respectively. This improved method for CP purification should facilitate the in vitro analysis of CP structure, function, and regulation.

    DOI: 10.1016/j.pep.2009.05.002

  • CARMIL is a potent capping protein antagonist: identification of a conserved CARMIL domain that inhibits the activity of capping protein and uncaps capped actin filaments. 査読

    Takehito Uruno

    The Journal of biological chemistry   2006年1月

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    担当区分:筆頭著者   記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Acanthamoeba CARMIL was previously shown to co-purify with capping protein (CP) and to bind pure CP. Here we show that this interaction inhibits the barbed end-capping activity of CP. Even more strikingly, this interaction drives the uncapping of actin filaments previously capped with CP. These activities are CP-specific; CARMIL does not inhibit the capping activities of either gelsolin or CapG and does not uncap gelsolin-capped filaments. Although full-length (FL) CARMIL (residues 1-1121) possesses both anti-CP activities, C-terminal fragments like glutathione S-transferase (GST)-P (940-1121) that contain the CARMIL CP binding site are at least 10 times more active. We localized the full activities of GST-P to its C-terminal 51 residues (1071-1121). This sequence contains a stretch of 25 residues that is highly conserved in CARMIL proteins from protozoa, flies, worms, and vertebrates (CARMIL Homology domain 3; CAH3). Point mutations showed that the majority of the most highly conserved residues within CAH3 are critical for the anti-CP activity of GST-AP (862-1121). Finally, we found that GST-AP binds CP approximately 20-fold more tightly than does FL-CARMIL. This observation together with the elevated activities of C-terminal fragments relative to FL-CARMIL suggests that FL-CARMIL might exist primarily in an autoinhibited state. Consistent with this idea, proteolytic cleavage of FL-CARMIL with thrombin generated an approximately 14-kDa C-terminal fragment that expresses full anti-CP activities. We propose that, after some type of physiological activation event, FL-CARMIL could function in vivo as a potent CP antagonist. Given the pivotal role that CP plays in determining the global actin phenotype of cells, our results suggest that CARMIL may play an important role in the physiological regulation of actin assembly.

    DOI: 10.1074/jbc.m513186200, 10.1074/jbc.M513186200

  • Interaction of cortactin and Arp2/3 complex is required for sphingosine-1-phosphate-induced endothelial cell remodeling. 査読

    Takehito Uruno

    Experimental cell research   2004年8月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Sphingosine-1-phosphate (S1P) induces capillary formation of endothelial cells on Matrigel in accompany with actin assembly and accumulation of cortactin and Arp2/3 complex at the cell-leading edge. Suppression of cortactin expression with a cortactin antisense oligo significantly impaired S1P-induced capillary formation, migration of endothelial cells, and actin assembly at the cell periphery. Overexpression of wild-type cortactin tagged by green fluorescent protein (GFP) increased the S1P-induced tube formation and cell motility, whereas the cells overexpressing the mutant formed poorly capillary network and became less motile in response to S1P. Analysis of distribution in Triton X-100 insoluble fractions demonstrated that the cortactin mutant inhibited the association of wild-type cortactin and Arp2/3 complex with the actin-enriched complex. Furthermore, actin polymerization at and distribution of Arp2/3 complex as well as endogenous cortactin into the cell-leading edge mediated by S1P was disturbed. These data suggest that the interaction between cortactin and Arp2/3 complex plays an important role in S1P-mediated remodeling of endothelial cells.

    DOI: 10.1016/j.yexcr.2004.03.023

  • Sequential interaction of actin-related proteins 2 and 3 (Arp2/3) complex with neural Wiscott-Aldrich syndrome protein (N-WASP) and cortactin during branched actin filament network formation. 査読

    Takehito Uruno

    The Journal of biological chemistry   2003年5月

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    担当区分:筆頭著者   記述言語:その他   掲載種別:研究論文(学術雑誌)  

    The WASP and cortactin families constitute two distinct classes of Arp2/3 modulators in mammalian cells. Physical and functional interactions among the Arp2/3 complex, VCA (a functional domain of N-WASP), and cortactin were examined under conditions that were with or without actin polymerization. In the absence of actin, cortactin binds significantly weaker to the Arp2/3 complex than VCA. At concentrations of VCA 20-fold lower than cortactin, the association of cortactin with the Arp2/3 complex was nearly abolished. Analysis of the cells infected with Shigella demonstrated that N-WASP located at the tip of the bacterium, whereas cortactin accumulated in the comet tail. Interestingly, cortactin promotes Arp2/3 complex-mediated actin polymerization and actin branching in the presence of VCA at a saturating concentration, and cortactin acquired 20 nm affinity for the Arp2/3 complex during actin polymerization. The interaction of VCA with the Arp2/3 complex was reduced in the presence of both cortactin and actin. Moreover, VCA reduced its affinity for Arp2/3 complex at branching sites that were stabilized by phalloidin. These data imply a novel mechanism for the de novo assembly of a branched actin network that involves a coordinated sequential interaction of N-WASP and cortactin with the Arp2/3 complex.

    DOI: 10.1074/jbc.m301997200, 10.1074/jbc.M301997200

  • Haematopoietic lineage cell-specific protein 1 (HS1) promotes actin-related protein (Arp) 2/3 complex-mediated actin polymerization. 査読

    Takehito Uruno

    The Biochemical journal   2003年4月

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    担当区分:筆頭著者   記述言語:その他   掲載種別:研究論文(学術雑誌)  

    HS1 (haematopoietic lineage cell-specific gene protein 1), a prominent substrate of intracellular protein tyrosine kinases in haematopoietic cells, is implicated in the immune response to extracellular stimuli and in cell differentiation induced by cytokines. Although HS1 contains a 37-amino acid tandem repeat motif and a C-terminal Src homology 3 domain and is closely related to the cortical-actin-associated protein cortactin, it lacks the fourth repeat that has been shown to be essential for cortactin binding to filamentous actin (F-actin). In this study, we examined the possible role of HS1 in the regulation of the actin cytoskeleton. Immunofluorescent staining demonstrated that HS1 co-localizes in the cytoplasm of cells with actin-related protein (Arp) 2/3 complex, the primary component of the cellular machinery responsible for de novo actin assembly. Furthermore, recombinant HS1 binds directly to Arp2/3 complex with an equilibrium dissociation constant (K(d)) of 880 nM. Although HS1 is a modest F-actin-binding protein with a K(d) of 400 nM, it increases the rate of the actin assembly mediated by Arp2/3 complex, and promotes the formation of branched actin filaments induced by Arp2/3 complex and a constitutively activated peptide of N-WASP (neural Wiskott-Aldrich syndrome protein). Our data suggest that HS1, like cortactin, plays an important role in the modulation of actin assembly.

    DOI: 10.1042/BJ20021791

  • Osmotic stress-induced remodeling of the cortical cytoskeleton. 査読

    Takehito Uruno

    American journal of physiology. Cell physiology   2002年9月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Osmotic stress is known to affect the cytoskeleton; however, this adaptive response has remained poorly characterized, and the underlying signaling pathways are unexplored. Here we show that hypertonicity induces submembranous de novo F-actin assembly concomitant with the peripheral translocation and colocalization of cortactin and the actin-related protein 2/3 (Arp2/3) complex, which are key components of the actin nucleation machinery. Additionally, hyperosmolarity promotes the association of cortactin with Arp2/3 as revealed by coimmunoprecipitation. Using various truncation or phosphorylation-incompetent mutants, we show that cortactin translocation requires the Arp2/3- or the F-actin binding domain, but the process is independent of the shrinkage-induced tyrosine phosphorylation of cortactin. Looking for an alternative signaling mechanism, we found that hypertonicity stimulates Rac and Cdc42. This appears to be a key event in the osmotically triggered cytoskeletal reorganization, because 1) constitutively active small GTPases translocate cortactin, 2) Rac and cortactin colocalize at the periphery of hypertonically challenged cells, and 3) dominant-negative Rac and Cdc42 inhibit the hypertonicity-provoked cortactin and Arp3 translocation. The Rho family-dependent cytoskeleton remodeling may be an important osmoprotective response that reinforces the cell cortex.

    DOI: 10.1152/ajpcell.00018.2002

  • Fibroblast growth factor-1 interacts with the glucose-regulated protein GRP75/mortalin. 査読

    Takehito Uruno

    The Biochemical journal   1999年10月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Fibroblast growth factor-1 (FGF-1), which lacks a signal peptide and is intracellularly localized as a result of endogenous expression or endocytosis, is thought to be involved in regulating cell growth and differentiation. In the study reported here, we purified proteins that bind intracellular FGF-1. Affinity adsorption was used to purify FGF-1-binding proteins from rat L6 cells expressing FGF-1. One of the isolated proteins was identified as the glucose-regulated protein GRP75/mortalin/PBP-74/mthsp70, a member of the hsp70 family of heat-shock proteins known to be involved in regulating glucose responses, antigen processing and cell mortality. The interaction of FGF-1 and GRP75/mortalin in vivo was confirmed by co-immunoprecipitation, immunohistochemical co-localization in Rat-1 fibroblasts and by using the yeast two-hybrid system. Moreover, a binding assay in vitro with the use of recombinant FGF-1 and mortalin demonstrated a direct physical interaction between the two proteins. These results reveal that GRP75/mortalin is an intracellular FGF-1-binding protein in cells and suggest that GRP75/mortalin is involved in the trafficking of and/or signalling by FGF-1.

    DOI: 10.1042/bj3430461

  • Distinct regulation of myoblast differentiation by intracellular and extracellular fibroblast growth factor-1. 査読

    Takehito Uruno

    Growth factors (Chur, Switzerland)   1999年1月

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    担当区分:筆頭著者   記述言語:その他   掲載種別:研究論文(学術雑誌)  

    We studied the role of fibroblast growth factor (FGF)-1 in the physiology of myoblast differentiation. We found that, while endogenous FGF-1 in L6-10 rat myoblasts did not suppress the progress of differentiation, the addition of FGF-1 to the culture medium suppressed it. Moreover, L6-10 cells stably transfected with full length FGF-1 undergo enhanced differentiation. The latter was well correlated with myogenin expression and myotube formation. Constitutive expression of a mutant FGF-1 (FGF-1U) that lacked a nuclear localization signal, promoted the differentiation of the myoblasts even more strongly. Furthermore, the expression of FGF-1U in an inducible expression system enhanced myogenin expression promptly. In L6-10 transfectants expressing a dominant-negative mutant of FGF receptor, stable transfection of FGF-1 promoted differentiation as it did in parent cells. Studies with FGF receptors and MAP kinase suggest that both are involved in the effect of FGF-1 when it is supplemented to culture medium but not during the effect of endogenous FGF-1 synthesized in cells. We conclude that intracellular (endogenous) and extracellular (exogenous) FGF-1 have differential effects on the regulation of myogenic differentiation of L6-10 cells.

    DOI: 10.3109/08977199909103519

  • The C-terminal region of fibroblast growth factor-1 is crucial for its biological activity and high level protein expression in mammalian cells. 査読

    Takehito Uruno

    Growth factors (Chur, Switzerland)   1999年1月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    We have studied the role of the carboxyl(C)-terminus of fibroblast growth factor(FGF)-1 using prokaryotic and eukaryotic expression systems. The full-length FGF-1 protein and its mutants lacking 6- and 9-amino acids at the C-terminus IFGF-1 (Cdel6) and FGF-1 (Cdel9), respectively] could be expressed in E. coli cells at the similar levels. The deletion mutants bound very weakly to FGF receptor and to heparin, and did not stimulate DNA synthesis in BALB/c3T3 cells. In contrast to E. coli cells, in NIH3T3 transfectants and L6 transfectants, the protein expression level of FGF-1 (Cdel6) was significantly lower than that of FGF-1, and longer C-terminal deletions further decreased the protein expression levels. However, the level of transcripts in the transfectants and the level of translates in in vitro system were equivalent for all the FGF-1 constructs. Treatment with proteasome inhibitors of the NIH3T3 transfectants expressing FGF-1(Cdel6) increased the protein level six-fold. The results indicate that the C-terminus of FGF-I is crucial for its biological activity and high-level expression in mammalian cells and suggest that deletion of the C-terminus of FGF-1 induces its post-translational degradation by proteasome system.

    DOI: 10.3109/08977199909002129

  • Expression of the fibroblast growth factor family and their receptor family genes during mouse brain development. 査読

    Takehito Uruno

    Brain research. Molecular brain research   1996年9月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    The fibroblast growth factor (FGF) family is composed of nine members and four genes encode protein tyrosine kinase receptors for them. To gain insight into the involvement of FGFs and their receptors in the development of nervous system, their expression in brains of perinatal and adult mice was examined by semi-quantitative reverse transcription-linked polymerase chain reactions and in situ hybridization. Although all the genes, with the exception of FGF-4, were found to be expressed, FGF-3, FGF-6, FGF-7 and FGF-8 genes demonstrated higher expression in the late embryonic stages than in postnatal stages, suggesting that these members are involved in the late stages of brain development. In contrast, expression of FGF-1 and FGF-5 increased after birth. Interestingly, FGF-6 expression in perinatal mice was restricted to the central nervous system and skeltal muscles, with intense signals in the developing cerebrum in embryos but in cerebellum in 5-day-old neonates. Furthermore, FGF-receptor (FGFR)-4, a cognate receptor for FGF-6, demonstrated similar spatiotemporal expression, suggesting that FGF-6 and FGFR-4 plays significant roles in the maturation of nervous system as a ligand-receptor system. The results indicate that individual member of the fibroblast growth factor and their receptor family are expressed either sequentially or simultaneously in brain development, strongly suggesting their involvement in the regulation of a variety of developmental processes of brain, i.e., proliferation and migration of neuronal progenitor cells, neuron and glia differentiation, neurite extensions, and synapse formations.

    DOI: 10.1016/0169-328x(96)00108-8, 10.1016/0169-328X(96)00108-8

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講演・口頭発表等

  • A tumor metabolite impacting immunotherapy efficacy: Cholesterol sulfate regulates tumor-immune interactions 招待 国際会議

    Takehito Uruo, Takaaki Tatsuguchi, Yuki Sugiura, Yoshinori Fukui

    Keystone Symposia on "Cancer Immunotherapy: Mechanisms of Response versus Resistance"  2023年3月 

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    開催年月日: 2023年3月

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    開催地:Banff, Alberta, Canada   国名:日本国  

    Tumors constitute an ecosystem of heterogeneous metabolic environments where a variety of metabolites function as intra- and intercellular mediators that affect tumor development. We previously identified that cholesterol sulfate (CS) is an endogenous inhibitor of DOCK2, a Rac activator essential for leukocyte migration and activation. Thereby, local CS production creates immune-evasive/immunosuppressive microenvironments. Many types of human cancers express the SULT2B1 gene, encoding the steroid sulfotransferase SULT2B1b responsible for CS production, and in certain cancers, the gene expression associates with poor prognosis. In colon cancers, level of CS is higher in tumor tissues, and tumor regions with high CS were poorly infiltrated with CD8+ T cells. In syngeneic mouse models, CS-producing cancer cells formed larger tumors in a host-immunity-dependent manner, and exhibited resistance to immunotherapies via antigen-specific T cell transfer and immune-checkpoint blockade. A novel SULT2B1b inhibitor we identified counteracted the above phenotypes. Thus, cancer-derived CS is a key mediator of tumor-immune interactions, and CS/SULT2B1b may be a potential target for enhancing the efficacy of immunotherapies.

  • コレステロール代謝と疾患制御の新たな展開

    宇留野武人(オーガナイザー)、大石由美子(オーガナイザー) 講演者リスト: 佐藤 隆一郎(東京大学大学院 農学生命科学研究科) Esperanza Perucha(Centre for Inflammation Biology and Cancer Immunology;Centre for Rheumatic Diseases, King’s College London) 高橋 勇人(慶應義塾大学医学部) 大石 由美子(日本医科大学 大学院医学研究科) 小黒 秀行(University of Connecticut Health Center) 國村 和史(九州大学 生体防御医学研究所) 宇留野 武人(九州大学 生体防御医学研究所)

    第95回日本生化学大会  2022年11月 

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    開催年月日: 2022年11月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    開催地:名古屋国際会議場   国名:日本国  

    コレステロールは、細胞膜の主要構成成分の一つであると共に、各種ステロイドホルモン生合成の起点となり、生命活動の維持に不可欠の役割を果たす。社会の長寿高齢化が進む中で、コレステロールと生活習慣病や慢性疾患の関係に大きな関心が寄せられているが、依然として不明な点が多く残されている。最近、その代謝過程で生じる様々なコレステロール代謝産物が、免疫応答やがん、炎症制御において重要な役割を担うことが次々と明らかにされ、トランスレーショナル・リサーチの観点からも大きな注目を集めている。そこで、本シンポジウムでは、これら最新の知見を紹介し、コレステロール代謝と生体機能・疾患制御の関係性を新たな視点から俯瞰することで、コレステロール・バイオロジーの更なる進化と発展を促す機会としたい。

  • ホスファチジン酸産生酵素PLD1は好中球細胞外トラップの形成に必須である

    @宇留野 武人、@相原 良亮

    第101回日本生理学会大会  2024年3月 

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    開催年月日: 2024年3月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:福岡県北九州市小倉   国名:日本国  

  • がん免疫療法に対する抵抗性を付与する腫瘍メタボライト

    @宇留野 武人、#竜口 崇明、@杉浦 悠毅、@福井 宣規

    第27回日本がん免疫学会総会  2023年7月 

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    開催年月日: 2023年7月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:三重県津市   国名:日本国  

  • マウスハーダー腺の加齢に伴うトランスクリプトーム・リピドーム変化

    宇留野武人、高橋政友

    日本生理学会 第100回記念大会  2023年3月 

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    開催年月日: 2023年3月

    記述言語:日本語  

    開催地:国立京都国際会館   国名:日本国  

  • A tumor metabolite impacting immunotherapy efficacy: Cholesterol sulfate regulates tumor-immune interactions 招待

    Takehito Uruno, Takaaki Tatsuguchi, Yuki Sugiura, Yoshinori Fukui

    Keystone Symposia "Cancer Immunotherapy: Mechanisms of Response versus Resistance"  2023年3月 

     詳細を見る

    開催年月日: 2023年3月

    記述言語:その他  

    国名:その他  

  • A tumor metabolite impacting immunotherapy efficacy: Cholesterol sulfate regulates tumor-immune interactions 招待

    Takehito Uruno, Takaaki Tatsuguchi, Yuki Sugiura, Yoshinori Fukui

    Keystone Symposia "Cancer Immunotherapy: Mechanisms of Response versus Resistance"  2023年3月 

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    開催年月日: 2023年3月

    会議種別:口頭発表(招待・特別)  

    researchmap

  • RAS変異を有する難治性がんの新規分子標的治療薬の開発

    宇留野武人、坂田大治、福井宣規、生長幸之助

    第94回日本生化学会大会  2021年11月 

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    開催年月日: 2021年11月 - 2022年6月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:京都   国名:日本国  

  • DOCK1 as a novel molecular target for controlling cancer cell survival and invasion 国際会議

    Tatsuguchi T, Uruno T, Fukui Y

    25th Biennial Congress on the European Association for Cancer Research  2018年7月 

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    開催年月日: 2018年7月

    記述言語:英語  

    開催地:Amsterdam   国名:オランダ王国  

  • 細胞骨格制御とシグナル伝達におけるDOCKファミリー分子の多彩な機能と構造基盤~DOCK GEF発見から20年を経て~ DOCK2/DOCK8分子を介した多彩な免疫制御メカニズム

    國村 和史, 宇留野 武人, 福井 宣規

    日本生化学会大会プログラム・講演要旨集  2023年10月  (公社)日本生化学会

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    記述言語:日本語  

  • マウスハーダー腺の加齢に伴うトランスクリプトーム・リピドーム変化(Transcriptome and lipidome analyses of mouse Harderian glands in aging)

    Uruno Takehito, Takahashi Masatomo

    The Journal of Physiological Sciences  2023年5月  (一社)日本生理学会

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    記述言語:英語  

  • コレステロール関連代謝産物と疾患制御 コレステロール硫酸を介した腫瘍の免疫回避と創薬応用

    宇留野 武人

    日本生化学会大会プログラム・講演要旨集  2022年11月  (公社)日本生化学会

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    記述言語:日本語  

  • コレステロール関連代謝産物と疾患制御 コレステロール硫酸は白血球の遊走制御を介して眼の免疫特権環境の形成に寄与する

    國村 和史, 宇留野 武人, 杉浦 悠毅, 福井 宣規

    日本生化学会大会プログラム・講演要旨集  2022年11月  (公社)日本生化学会

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    記述言語:日本語  

  • がん免疫療法に対する抵抗性を付与する腫瘍メタボライト

    宇留野 武人, 竜口 崇明, 杉浦 悠毅, 福井 宣規

    日本がん免疫学会総会プログラム・抄録集  2023年6月  日本がん免疫学会

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    記述言語:日本語  

  • PLD1欠損がNeutrophil extracellular traps(NETs)産生に及ぼす影響

    相原 良亮, 宇留野 武人, 北村 知昭

    特定非営利活動法人日本歯科保存学会学術大会プログラムおよび講演抄録集  2024年4月  (NPO)日本歯科保存学会

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    記述言語:日本語  

  • Phospholipase D1は好中球細胞外トラップの形成に必須である(Phospholipase D1 is essential for neutrophil extracellular trap formation)

    Uruno Takehito, Aihara Ryosuke

    The Journal of Physiological Sciences  2024年5月  (一社)日本生理学会

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    記述言語:英語  

  • Phospholipase D1は好中球細胞外トラップの形成に必須である(Phospholipase D1 is essential for neutrophil extracellular trap formation)

    Uruno Takehito, Aihara Ryosuke

    The Journal of Physiological Sciences  2024年5月  (一社)日本生理学会

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    記述言語:英語  

  • Phospholipase D1は好中球細胞外トラップの形成に必須である(Phospholipase D1 is essential for neutrophil extracellular trap formation)

    Uruno Takehito, Aihara Ryosuke

    The Journal of Physiological Sciences  2024年5月  (一社)日本生理学会

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    記述言語:英語  

▼全件表示

MISC

  • DOCK-family proteins: key players in immune surveillance mechanisms 査読

    Takehito Uruno

    International Immunology   2019年10月

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    記述言語:英語  

    <jats:title>Abstract</jats:title>
    <jats:p>Dedicator of cytokinesis (DOCK) proteins constitute a family of evolutionarily conserved guanine nucleotide exchange factors (GEFs) for the Rho family of GTPases. Although DOCK-family proteins do not contain the Dbl homology domain typically found in other GEFs, they mediate the GTP–GDP exchange reaction through the DHR-2 domain. In mammals, this family consists of 11 members, each of which has unique functions depending on the expression pattern and the substrate specificity. For example, DOCK2 is a Rac activator critical for migration and activation of leukocytes, whereas DOCK8 is a Cdc42-specific GEF that regulates interstitial migration of dendritic cells. Identification of DOCK2 and DOCK8 as causative genes for severe combined immunodeficiency syndromes in humans has highlighted their roles in immune surveillance. In addition, the recent discovery of a naturally occurring DOCK2-inhibitory metabolite has uncovered an unexpected mechanism of tissue-specific immune evasion. On the other hand, GEF-independent functions have been shown for DOCK8 in antigen-induced IL-31 production in helper T cells. This review summarizes multifaced functions of DOCK-family proteins in the immune system.</jats:p>

    DOI: 10.1093/intimm/dxz067

所属学協会

  • 日本がん免疫学会

    2023年4月 - 現在

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  • 日本生理学会

    2020年2月 - 現在

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  • 日本生化学会

    - 現在

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  • 日本生化学会

  • 日本生理学会

  • 日本がん免疫学会

  • 日本がん免疫学会

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学術貢献活動

  • 学術論文等の審査

    役割:査読

    2023年

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    種別:査読等 

    外国語雑誌 査読論文数:2

  • 事前準備、運営全般 国際学術貢献

    The 24th Hot Spring Harbor International Symposium 'Recent Advances in Immunology and Inflammtion'  ( 九州大学病院キャンパス ) 2014年11月

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    種別:大会・シンポジウム等 

    参加者数:300

共同研究・競争的資金等の研究課題

  • 令和5年度 鈴木謙三記念医科学応用研究財団 研究助成

    2024年

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    資金種別:寄附金

  • 基盤研究(B) 腫瘍の免疫特権環境形成における硫酸化コレステロールの役割と創薬応用

    2021年4月 - 2024年3月

    九州大学(日本) 

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    担当区分:研究代表者 

    腫瘍の免疫特権環境形成における硫酸化コレステロールの役割と創薬応用、機能生物化学関連分野

  • AMED革新的がん医療実用化研究事業、「RAS変異を有する難治性がんの新規分子標的治療薬の非臨床評価」

    2019年7月 - 2022年3月

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    担当区分:研究代表者 

  • RAS変異を有する難治性がんの新規分子標的治療薬の非臨床評価

    2019年 - 2021年

    AMED 革新的がん医療実用化研究事業

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    担当区分:研究代表者  資金種別:受託研究

  • 基盤研究(B) 腫瘍の免疫回避機構におけるRac活性化因子DOCK1の機能

    2018年4月 - 2021年3月

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    担当区分:研究代表者 

  • リジン水酸化酵素Jmjd6を介したAire発現制御の分子基盤とその進化学的考察

    2016年4月 - 2019年3月

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    担当区分:研究分担者 

  • 革新的先端研究開発支援事業インキュベートタイプ(LEAP) DOCKファミリー分子の生体機能と動作原理の理解に基づく革新的医薬品の創出

    2015年11月 - 2020年3月

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    担当区分:研究分担者 

  • 基盤研究(C) ヒト変異型Racによる細胞癌化におけるDOCKファミリー分子の役割

    2014年4月 - 2017年3月

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    担当区分:研究代表者 

  • 創薬等支援技術基盤プラットフォーム事業「大型創薬研究基盤を活用した創薬オープンイノベーションの推進(九州大学拠点推進事業)」

    2014年4月 - 2016年3月

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    担当区分:研究分担者 

  • 次世代がん研究戦略推進プロジェクト

    2014年4月 - 2015年3月

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    担当区分:研究分担者 

  • 橋渡し研究・新規開発シーズA

    2014年4月 - 2015年3月

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    担当区分:連携研究者 

  • 基盤研究(A) DOCKファミリー分子の生体機能と動作原理の統合的理解

    2014年1月 - 2016年3月

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    担当区分:研究分担者 

  • 硫酸基転移酵素SULT2B1bの発現制御機構と生体機能の統合的理解

    研究課題/領域番号:19H00983 

    福井 宣規, 宇留野 武人

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    資金種別:科研費

    研究代表者は、SULT2B1bによって生成されるコレステロール硫酸(CS)が、免疫細胞の遊走や活性化に重要なRac活性化因子であるDOCK2の触媒ドメインに会合し、その機能を阻害することを見出した。本研究では、SULT2B1bの遺伝子発現制御機構を解明し、その発現を個体レベルでモニターできるレポーターマウスを開発すると共に、妊娠時の胎盤や子宮、がん組織等を対象に、SULT2B1bを介したCS産生の免疫回避における機能的重要性を実証する。

    CiNii Research

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教育活動概要

  • 研究室配属の大学院生(博士・修士課程)および卒研生の研究指導・学部生実習補助

担当授業科目

  • 免疫学

    2023年4月 - 2023年9月   前期

  • 医学研究特論 I

    2023年4月 - 2023年9月   前期

  • 医学研究特論 I

    2021年10月 - 2022年3月   後期

FD参加状況

  • 2019年10月   役割:パネリスト   名称:馬出地区4部局合同男女共同参画FD

    主催組織:部局

  • 2017年10月   役割:参加   名称:「無意識のバイアスからの開放:ダイバーシティのススメ」

    主催組織:全学

  • 2016年10月   役割:参加   名称:「なぜ今『女性活躍推進法』か?    —男女共同参画の必要性と九州大学における取組み—」

    主催組織:全学

その他教育活動及び特記事項

  • 2023年  クラス担任  学部

  • 2021年  その他特記事項  医学研究特論 I (免疫遺伝学分野担当)、90分1コマ、教育目標: 基礎医学研究の最新の実験手法を理解し知識を深める。

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    医学研究特論 I (免疫遺伝学分野担当)、90分1コマ、教育目標: 基礎医学研究の最新の実験手法を理解し知識を深める。

  • 2017年  その他特記事項  医学研究特論 I (免疫遺伝学分野担当)、90分1コマ

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    医学研究特論 I (免疫遺伝学分野担当)、90分1コマ

メディア報道

  • がん抑える新化合物 九大など、副作用少ない薬開発に期待 テレビ・ラジオ番組

    2017年5月

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    がん抑える新化合物 九大など、副作用少ない薬開発に期待

  • 九州大・研究グループ がん抑える新たな化合物を開発 新聞・雑誌

    2017年5月

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    九州大・研究グループ がん抑える新たな化合物を開発

学内運営に関わる各種委員・役職等

  • 2024年3月 - 2025年3月   全学 男女共同参画推進委員会 委員 & 男女共同参画推進室 室員

  • 2016年12月 - 2019年12月   全学 ガンマ線照射施設運営委員会

  • 2014年4月 - 2028年3月   研究所 生体防御医学研究所 動物実験委員会委員