KEIO RESEARCHERS INFORMATION SYSTEM

Career 【 Display / hide 】

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

Academic Background 【 Display / hide 】

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

Academic Degrees 【 Display / hide 】

Academic Degrees 【 Display / hide 】

• 博士（薬学）, 共立薬科大学, Coursework, 2003.03

Research Areas 【 Display / hide 】

Research Areas 【 Display / hide 】

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

Research Keywords 【 Display / hide 】

Research Keywords 【 Display / hide 】

• JAK2、STAT、erythropoietin、NF-kappaB

Research Themes 【 Display / hide 】

Research Themes 【 Display / hide 】

• Analysis of cytokine signaling pathway, 

  2006

  -

  Present

Books 【 Display / hide 】

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

Papers 【 Display / hide 】

Papers 【 Display / hide 】

• Targeting DDX5 using FL118 suppresses mTOR signaling and tumorigenicity in JAK2V617F-driven myeloproliferative neoplasms

  Takeda K., Tago K., Ohta S., Nakazawa Y., Funakoshi-Tago M.

  International Immunopharmacology 173 2026.03

  　View Summary

  The constitutively active mutant of the tyrosine kinase Janus kinase 2 (JAK2V617F) is a major driver of myeloproliferative neoplasms (MPNs). We previously demonstrated that JAK2V617F activates the transcription factor signal transducer and activator of transcription 5 (STAT5), which upregulates the expression of the RNA helicase DDX5. DDX5 promotes activation of the mTOR pathway and is essential for the proliferation and tumorigenicity of JAK2V617F-positive hematopoietic cell models, even though its RNA helicase activity is dispensable for JAK2V617F-induced transformation. In the present study, we investigated the therapeutic potential of targeting DDX5 using FL118, a camptothecin (CPT) derivative known to induce the proteasomal degradation of DDX5. In Ba/F3 cells expressing JAK2V617F and the erythropoietin receptor (EpoR), as well as in human erythroleukemia (HEL) cells harboring JAK2V617F, FL118, but not CPT, successfully induced DDX5 degradation. Consist with this, FL118, but not CPT, suppressed mTOR pathway activation and triggered apoptosis in both Ba/F3 cells expressing JAK2V617F and EpoR and HEL cells. In a subcutaneous tumor model, in which Ba/F3 cells expressing JAK2V617F and EpoR were transplanted into nude mice, oral administration of FL118 significantly reduced tumor growth and hepatosplenomegaly. Collectively, these findings establish DDX5 as a promising therapeutic target in MPNs and underscore the potential of FL118 as a treatment strategy for JAK2V617F-driven disease.

  • Access to Document (DOI)

• DDX5 is required for JAK2V617F-induced cell proliferation and tumorigenesis independent of its RNA helicase activity

  Takeda K., Tago K., Ohta S., Nakazawa Y., Funakoshi-Tago M.

  Cellular Signalling 138 2026.02

  Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  08986568

  　View Summary

  The constitutively active Janus kinase 2 mutant (JAK2V617F) is a major driver of myeloproliferative neoplasms (MPNs). Our previous studies demonstrated that JAK2V617F upregulates the expression of the RNA helicase DDX5 via activation of the transcription factor, signal transducer and activator of transcription 5 (STAT5). Furthermore, DDX5 facilitates mechanistic target of rapamycin (mTOR) signaling, thereby promoting the proliferation and tumorigenic potential of MPN cells. However, whether the RNA helicase activity of DDX5 is essential for JAK2V617F-driven oncogenesis remained unclear. In this study, we investigated the role of DDX5 in JAK2V617F-induced transformation by knocking down DDX5 in Ba/F3 cells expressing JAK2V617F and the erythropoietin receptor (V617F/EpoR cells), followed by reconstitution with either wild-type DDX5 or the helicase-deficient mutant K144N. DDX5 knockdown suppressed activation of the mTOR pathway, resulting in reduced proliferation and increased apoptosis in V617F/EpoR cells. In contrast, reconstitution with either wild-type DDX5 or the K144N mutant restored mTOR pathway activation, enhanced proliferation, and suppressed apoptosis. Furthermore, transplantation experiments using nude mice showed that DDX5 knockdown inhibited JAK2V617F-mediated tumor formation and hepatosplenomegaly, whereas reconstitution with DDX5 or the K144N mutant reversed these effects. These findings demonstrate that the RNA helicase activity of DDX5 is dispensable for JAK2V617F-induced transformation. These findings suggest that DDX5 promotes oncogenesis through helicase-independent mechanisms and represents a potential therapeutic target in JAK2V617F-driven malignancies.

  • Access to Document (DOI)

• KMN003 activates Nrf2 via disruption of the Keap1-Nrf2 interaction and p38-dependent transcriptional regulation

  Komeda K., Toyoshima K., Yasuda D., Ishida H., Kojima K., Osawa M., Hirano T., Ohe T., Tago K., Funakoshi-Tago M.

  Cellular Signalling 137 2026.01

  Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  08986568

  　View Summary

  Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a crucial role in cellular defenses against oxidative stress and inflammation. Under normal conditions, Kelch-like ECH-associated protein 1 (Keap1), a ubiquitin ligase adaptor, binds to Nrf2, facilitating its ubiquitination and subsequent degradation via the proteasome. In this study, we investigated the properties of KMN003, a novel Nrf2 activator specifically designed to stabilize Nrf2 by disrupting its interaction with Keap1. X-ray crystallographic analysis revealed that KMN003 binds to the DGR-Cul3 (DC) domain of Keap1, occupying the Nrf2 interaction site. An AlphaScreen assay further showed that KMN003 effectively inhibits the binding between the Keap1 DC domain and the DLG motif of Nrf2 (IC₅₀ = 300 nM). We also investigated the mechanism of Nrf2 activation by KMN003 and its anti-inflammatory properties using murine macrophage-like RAW264.7 cells. KMN003 significantly reduced the lipopolysaccharide (LPS)-induced production of nitric oxide, CCL2, and tumor necrosis factor-alpha (TNFα) as well as the mRNA expression of inducible nitric oxide synthase, CCL2, and TNFα, which are essential inflammatory markers. KMN003 strongly inhibited nuclear translocation and transcriptional activation of nuclear factor-kappa B (NF-κB), a central regulator of inflammatory gene expression. KMN003 did not affect the LPS-induced phosphorylation of ERK or JNK, but strongly induced p38 phosphorylation in the absence of the LPS stimulation. The inhibition of p38 with SB203580 blocked KMN003-induced Nrf2 transcriptional activation despite promoting Nrf2 accumulation. These results highlight KMN003 as a promising anti-inflammatory drug that selectively stabilizes and activates Nrf2 via the p38 pathway.

  • Access to Document (DOI)

• 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   112128 2025.12

  Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted,  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.

  • Access to Document (DOI)

• 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

  Research paper (scientific journal), Last author,  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.

  • Access to Document (DOI)

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

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

• Elucidation of the mechanism of drug resistance acquired through STAT3 activation by BCR-ABL inhibitors and development of methods to overcome it

  Tago, Megumi

  福澤諭吉記念慶應義塾学事振興基金事業報告集 (福澤基金運営委員会)  2023

• Elucidation of pathogenesis of chronic myeloproliferative neoplasms via erythropoietin receptor-binding molecules

  Tago, Megumi

  科学研究費補助金研究成果報告書 2022

• Elucidation of tumor formation mechanism mediated by a transcription factor STAT3 in anaplastic large cell lymphoma

  Tago, Megumi

  学事振興資金研究成果実績報告書 (慶應義塾大学)  2021

• Elucidation of the physiological significance of twin molecules STAT5A and STAT5B in the onset of chronic myeloproliferative neoplasms

  Tago, Megumi

  福澤諭吉記念慶應義塾学事振興基金事業報告集 (福澤基金運営委員会)  2021

• Molecular analysis of preventive effects of coffee constituents on life-style-related diseases via protein degradations

  Tago, Megumi

  科学研究費補助金研究成果報告書 2020

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Reviews, Commentaries, etc. 【 Display / hide 】

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

Presentations 【 Display / hide 】

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 】

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

Awards 【 Display / hide 】

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 】

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 】

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

  　

Committee Experiences 【 Display / hide 】

Committee Experiences 【 Display / hide 】

• 2012.04

  -

  2014.03

  トピックス小委員, 日本薬学会