Tago, Megumi

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmacy 衛生化学講座 (Shiba-Kyoritsu)

Position

Professor
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Career 【 Display / hide 】

  • 2006.06
    -
    Present

    2003年4月～2006年5月 米国留学 2006年6月 共立薬科大学薬学部生化学講座　助手 (2007年４月より助教） 2008年4月 慶應義塾大学薬学部生化学講座　助教 2009年4月 慶應義塾大学薬学部生化学講座　専任講師 2014年4月 慶應義塾大学薬学部衛生化学講座 准教授

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Academic Background 【 Display / hide 】

  • 1998.03

    共立薬科大学, 薬学部, 薬学科

    University, Graduated

  • 2003.03

    共立薬科大学大学院, 薬学研究科, 分子生物学、生化学

    Graduate School, Completed, Doctoral course

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Academic Degrees 【 Display / hide 】

  • 博士（薬学）, 共立薬科大学, Coursework, 2003.03

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Research Areas 【 Display / hide 】

  • Life Science / Pharmaceutical hygiene and biochemistry (Biological System Pharmaceutical Science)

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Research Keywords 【 Display / hide 】

  • JAK2、STAT、erythropoietin、NF-kappaB

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Research Themes 【 Display / hide 】

  • Analysis of cytokine signaling pathway, 

    2006
    -
    Present

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Books 【 Display / hide 】

  • IL-33レセプターのシグナル伝達.

    笠原 忠、多胡めぐみ., 科学評論社, 2011.03

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Papers 【 Display / hide 】

  • The critical role of the phosphorylation of STAT3 at Y705 in ALCL-associated NPM-ALK-induced transforming activity

    Lin X., Korai A., Nakazawa Y., Tago K., Funakoshi-Tago M.

    Cellular Signalling 136 2025.12

    ISSN  08986568

    　View Summary

    The fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) drives oncogenesis in anaplastic large cell lymphoma (ALCL) by activating signal transducer and activator of transcription 3 (STAT3). NPM-ALK requires its kinase activity to induce STAT3 phosphorylation at tyrosine 705 (Y705) and promotes serine 727 (S727) phosphorylation via JNK activation. However, the role of these modifications in NPM-ALK-driven cellular transformation remains unclear. We herein utilized murine Ba/F3 cells expressing NPM-ALK to investigate the impact of these modifications. STAT3 knockdown, followed by reconstitution with wild-type STAT3 or its mutants (Y705F and S727A) revealed that Y705 phosphorylation was essential for NPM-ALK-mediated transformation. STAT3 knockdown suppressed the expression of NPM-ALK-induced STAT3 target genes (c-Myc, Pim, IL-6, and SOCS3) as well as cell proliferation, tumor formation, and spleen, liver, and lymph node enlargement. These effects were restored upon reconstitution with wild-type STAT3 or the S727A mutant, but not the Y705F mutant, confirming the essential role of Y705 phosphorylation in these biological processes. Additionally, wild-type and mutant STAT3 proteins exhibited differential stability, with Y705F being less stable and S727A being more stable. Lysosomal inhibition by bafilomycin A1 increased the expression of wild-type STAT3 and the Y705F mutant, but had no effect on the S727A mutant. Cycloheximide chase assays further confirmed that S727 phosphorylation regulated STAT3 degradation via the lysosomal pathway. These results identify a novel NPM-ALK-induced oncogenic mechanism mediated by STAT3 phosphorylation, highlighting potential therapeutic targets for ALCL.

  • TRPV1 attenuates epithelial-mesenchymal transition via calpain-protein tyrosine phosphatase pathway in lens epithelial cells

    Nakazawa Y., Nishizawa F., Kawata S., Sugiyama Y., Nagai N., Yamamoto N., Funakoshi-Tago M.

    Experimental Eye Research 258 2025.09

    ISSN  00144835

    　View Summary

    TRPV1, which is widely expressed throughout the body, is a non-selective cation channel activated by capsaicin. We previously reported that TRPV1 activation suppressed TGFβ2-induced epithelial-mesenchymal transition (EMT) by inhibiting Epidermal Growth Factor Receptor (EGFR) phosphorylation in lens epithelial cells (Sugiyama et al., 2021). However, the detailed molecular mechanism remains unclear. In this study, we focused on the calpain–protein tyrosine phosphatase (PTP) pathway to elucidate the detailed mechanism underlying TRPV1-induced EMT suppression. Calpain and PTP inhibitors mitigated the suppressive effect of capsaicin on TGFβ2-induced EMT in vitro and ex vivo. Finally, we shown that CalpainS1 and PTPN9 overexpression abrogated the effect of capsaicin on EMT in lens epithelial cells. Our findings indicate that calpain and PTP proteins are good candidates for preventing EMT after cataract surgery.

  • Development of Keap1-Nrf2 Protein–Protein Interaction Inhibitor Activating Intracellular Nrf2 Based on the Naphthalene-2-acetamide Scaffold, and its Anti-Inflammatory Effects

    Yasuda D., Toyoshima K., Kojima K., Ishida H., Kaitoh K., Imamura R., Kanamitsu K., Kojima H., Funakoshi-Tago M., Osawa M., Ohe T., Hirano T.

    Chemmedchem  2025

    ISSN  18607179

    　View Summary

    Nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) axis is an attractive therapeutic target for various intractable diseases. Although protein–protein interaction inhibitors against Keap1-Nrf2 have been developed over the past decade, more structural expansion is needed to improve efficacy. In this article, several candidate compounds are designed and synthesized as novel Nrf2 activators and their intracellular Nrf2-activating effects are evaluated. Among the synthesized compounds, a novel naphthalene-1,4-(4-ethoxybenzensulfonamide) bearing a tertiary acetamide side chain at the 2-position strongly activated intracellular Nrf2. Particularly, the pyrrolidine-type acetamide compound showed the strongest intracellular Nrf2 activation. X-ray cocrystallography revealed that this compound can bind to the DC domain of Keap1. Additionally, the pyrrolidine-type acetamide compound induced the mRNA expression of the representative Nrf2 target genes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1. Moreover, the compound exhibited anti-inflammatory effects in a lipopolysaccharide-stimulated macrophage cell line. Conclusively, these results suggest that the pyrrolidine-type naphthalene-2-acetamide is a promising compound for the development of Nrf2 activators that can be applied to treat inflammatory diseases.

  • High ambient temperature may induce presbyopia via TRPV1 activation

    Nakazawa Y., Kuno Y., Shimada H., Nagai N., Hiramatsu N., Takeda S., Yamamoto N., Funakoshi-Tago M., Sasaki H.

    Medical Molecular Morphology 57 ( 4 ) 268 - 276 2024.12

    ISSN  18601480

    　View Summary

    The prevalence of presbyopia and nuclear cataracts (NUC) is reported to be higher in tropical areas than that in other regions, suggesting a potential influence of high temperatures on lens health. Transient receptor potential vanilloid (TRPV) channels play a crucial role in detecting ambient temperatures across various species, with TRPV1 and TRPV4 expressed in lens epithelial cells. In this study, we investigated whether ambient temperatures affect TRPV1 and TRPV4 activity in the lens, potentially contributing to the development of presbyopia and NUC. We conducted experiments using cultured human lens epithelial cell lines under different temperature conditions. Our results revealed that the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and p38 pathways, downstream molecules of TRPV1, were activated, while Src family kinase, a downstream molecule of TRPV4, was inhibited at 37.5 °C culture compared to 35.0 °C. Confocal microscope images demonstrated higher expression of TRPV1 in 3D-structured cells under high-temperature culture conditions. Additionally, in organ culture lenses, higher elasticity was observed at elevated temperatures compared to that at lower temperatures. These results suggest that high ambient temperatures may induce lens sclerosis via TRPV1 activation, potentially contributing to the development of presbyopia and NUC.

  • FL118 Is a Potent Therapeutic Agent against Chronic Myeloid Leukemia Resistant to BCR-ABL Inhibitors through Targeting RNA Helicase DDX5

    Takeda K., Ohta S., Nagao M., Kobayashi E., Tago K., Funakoshi-Tago M.

    International Journal of Molecular Sciences 25 ( 7 )  2024.04

    ISSN  16616596

    　View Summary

    Chronic myeloid leukemia (CML) is induced by the expression of the fused tyrosine kinase BCR-ABL, which is caused by a chromosomal translocation. BCR-ABL inhibitors have been used to treat CML; however, the acquisition of resistance by CML cells during treatment is a serious issue. We herein demonstrated that BCR-ABL induced the expression of the RNA helicase DDX5 in K562 cells derived from CML patients in a manner that was dependent on its kinase activity, which resulted in cell proliferation and survival. The knockout of DDX5 decreased the expression of BIRC5 (survivin) and activated caspase 3, leading to apoptosis in K562 cells. Similar results were obtained in cells treated with FL118, an inhibitor of DDX5 and a derivative compound of camptothecin (CPT). Furthermore, FL118 potently induced apoptosis not only in Ba/F3 cells expressing BCR-ABL, but also in those expressing the BCR-ABL T315I mutant, which is resistant to BCR-ABL inhibitors. Collectively, these results revealed that DDX5 is a critical therapeutic target in CML and that FL118 is an effective candidate compound for the treatment of BCR-ABL inhibitor-resistant CML.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • 炎症メディエーターと細胞 IL-1.

    笠原 忠、多胡めぐみ.

    炎症・再生医学事典(松島綱治、西脇徹編) (朝倉書店)  0   52-54 2009.04

    Article, review, commentary, editorial, etc. (scientific journal), Joint Work

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Presentations 【 Display / hide 】

  • Anti-cataract effect of coffee intake on selenite-induced cataract in rat

    TAGO Megumi

    日本薬学会第136年会（横浜）, 

    2016.03
    , 

    Poster presentation

  • Inhibitory effect of ParvifloronE on TNFa signaling pathway

    TAGO Megumi

    日本薬学会第136年会（横浜）, 

    2016.03
    , 

    Poster presentation

  • Anti-inflammatory activity of Coffee extract

    TAGO Megumi

    日本薬学会第136年会（横浜）, 

    2016.03
    , 

    Poster presentation

  • The role of DDX5 in JAK2 V617F mutant – induced transformation.

    TAGO Megumi

    日本薬学会第136年会（横浜）, 

    2016.03
    , 

    Poster presentation

  • Mechanism of NPM-ALK positive cells apoptosis induced by crizotinib

    TAGO Megumi

    日本薬学会第136年会（横浜）, 

    2016.03
    , 

    Poster presentation

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • Elucidation of pathogenesis of anaplastic large cell lymphoma via STAT3 target genes

    2023.04
    -
    2026.03

    基盤研究(C), Principal investigator

  • エリスロポエチン受容体結合分子を介した慢性骨髄増殖性腫瘍の発症機序の解明

    2020.04
    -
    2023.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • エリスロポエチン受容体のリン酸化を介した慢性骨髄増殖性腫瘍の発症機序の解明

    2017.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

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Awards 【 Display / hide 】

  • 柿内三郎記念奨励研究賞第11回（2014年）

    多胡　めぐみ, 2014.10, 日本生化学会, 「定量的リン酸化プロテオミクスによる慢性骨髄増殖性腫瘍の発症機構の解析」

    Type of Award： Award from Japanese society, conference, symposium, etc.

  • 第11回(2014年）柿内三郎記念奨励研究賞

    多胡　めぐみ, 2014.10, 日本生化学会, 定量的リン酸化プロテオミクスによる慢性骨髄増殖性腫瘍の発症機構の解析

  • 平成22年度関東支部奨励賞

    Tago M., 2012.10, 日本薬学会, JAK2 変異体のシグナル伝達解析による真性赤血球増加症発症機構の解明.

  • FEBS Letters Young Group Leader Award 2011

    Tago M., 2012.09, FEBS Letters, FEBS Letters Young Group Leader Award 2012.

  • 2012 FEBS Letters Young Group Leader Award

    TAGO MEGUMI, 2012.09, FEBS, Aurora kinase A critically contributes to the resistance to anti-cancer drug cisplatin in JAK2 V617F mutant-induced transformed cells

    Type of Award： International academic award (Japan or overseas)

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Courses Taught 【 Display / hide 】

  • TOXICOLOGICAL SCIENCES

    2025

  • STUDY OF MAJOR FIELD: (HYGIENIC CHEMISTRY)

    2025

  • SEMINAR: (HYGIENIC CHEMISTRY)

    2025

  • RESEARCH FOR BACHELOR'S THESIS 1

    2025

  • PUBLIC HEALTH

    2025

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Memberships in Academic Societies 【 Display / hide 】

  • 日本薬学会、日本生化学会、日本分子生物学会

    　
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Committee Experiences 【 Display / hide 】

  • 2012.04
    -
    2014.03

    トピックス小委員, 日本薬学会

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