Education 【 display / non-display 】

Education 【 display / non-display 】

• 1991

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  1995

  大阪大学大学院   医学系研究科  

• 1985

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  1991

  Hokkaido University   School of Medicine  

Degree 【 display / non-display 】

Degree 【 display / non-display 】

• 大阪大学   医学博士

Research Experience 【 display / non-display 】

Research Experience 【 display / non-display 】

• 2017.09

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  Now

  Sapporo Medical University School of Medicine   Department of Biochemistry   Professor

  Professor

• 2007.01

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  2017.08

  Sapporo Medical University   School of Medicine, Department of Biochemistry   准教授

  准教授

• 2005.01

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  2006.12

  Saga University   Faculty of Medicine   助教授

  助教授

• 1998.03

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  2004.12

  Osaka University   Faculty of Medicine   助手

  助手

Professional Memberships 【 display / non-display 】

Professional Memberships 【 display / non-display 】

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  SOCIETY FOR FREE RADICAL RESEARCH JAPAN

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  THE JAPANESE CANCER ASSOCIATION

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  THE JAPANESE SOCIETY OF CARBOHYDRATE RESEARCH

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  THE JAPANESE BIOCHEMICAL SOCIETY

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  Japan Maillard Reaction Society

Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Medical biochemistry  

• Life sciences   Pathobiochemistry  

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• Sapporo Medical University   School of Medicine, Medicalchemistry   Professorr  

Research Interests 【 display / non-display 】

Research Interests 【 display / non-display 】

• 糖鎖生物学 酸化還元酵素 タンパク質糖化反応

Papers 【 display / non-display 】

Papers 【 display / non-display 】

• Site-specific glycosylation analysis of epidermal growth factor receptor 2 (ErbB2): exploring structure and function toward therapeutic targeting.

  Naoki Fujitani, Yasuaki Uehara, Shigeru Ariki, Ukichiro Hashimoto, Jo Mukai, Yoshihiro Hasegawa, Motoko Takahashi

  Glycobiology   34 ( 3 )  2024.04  [International journal]

  　View Summary

  Glycans found on receptor tyrosine kinases (RTKs) have emerged as promising targets for cancer chemotherapy, aiming to address issues such as drug resistance. However, to effectively select the target glycans, it is crucial to define the structure and function of candidate glycans in advance. Through mass spectrometric analysis, this study presents a "glycoform atlas" of epidermal growth factor receptor 2 (ErbB2), an RTK targeted for the treatment of ErbB2-positive cancers. Our analysis provides an in-depth and site-specific glycosylation profile, including both asparagine- and serine/threonine-linked glycosylation. Molecular dynamics simulations of N-glycosylated ErbB2 incorporating the identified glycan structures suggested that the N-glycan at N124 on the long flexible loop in the N-terminal region plays a role in stabilizing the ErbB2 structure. Based on the model structures obtained from the simulations, analysis employing an ErbB2 mutant deficient in N-glycosylation at N124 exhibited a significantly shorter intracellular half-life and suppressed autophosphorylation compared to wild-type ErbB2. Moreover, a structural comparison between the N-glycosylated forms of ErbB2 and its structurally homologous receptor, epidermal growth factor receptor (EGFR), demonstrated distinct variations in the distribution and density of N-glycans across these two molecules. These findings provide valuable insights into the structural and functional implications of ErbB2 glycosylation and will contribute to facilitating the establishment of glycan-targeted therapeutic strategies for ErbB2-positive cancers.

  DOI PubMed

• N-glycan on N262 of FGFR3 regulates the intracellular localization and phosphorylation of the receptor.

  Ukichiro Hashimoto, Naoki Fujitani, Yasuaki Uehara, Hiromi Okamoto, Atsushi Saitou, Fumie Ito, Shigeru Ariki, Akiko Shiratsuchi, Yoshihiro Hasegawa, Motoko Takahashi

  Biochimica et biophysica acta. General subjects   1868 ( 4 ) 130565 - 130565  2024.04  [International journal]

  　View Summary

  N-glycosylation and proper processing of N-glycans are required for the function of membrane proteins including cell surface receptors. Fibroblast growth factor receptor (FGFR) is involved in a wide variety of biological processes including embryonic development, osteogenesis, angiogenesis, and cell proliferation. Human FGFR3 contains six potential N-glycosylation sites, however, the roles of glycosylation have not been elucidated. The site-specific profiles of N-glycans of the FGFR3 extracellular domain expressed and secreted by CHO-K1 cells were examined, and glycan occupancies and structures of four sites were determined. The results indicated that most sites were fully occupied by glycans, and the dominant populations were the complex type. By examining single N-glycan deletion mutants of FGFR3, it was found that N262Q mutation significantly increased the population with oligomannose-type N-glycans, which was localized in the endoplasmic reticulum. Protein stability assay suggested that fraction with oligomannose-type N-glycans in the N262Q mutant is more stable than those in the wild type and other mutants. Furthermore, it was found that ligand-independent phosphorylation was significantly upregulated in N262Q mutants with complex type N-glycans. The findings suggest that N-glycans on N262 of FGFR3 affect the intracellular localization and phosphorylation status of the receptor.

  DOI PubMed

• RANK C175R変異はERストレスを誘導し大理石骨病を引き起こす

  上原 康昭, 藤谷 直樹, 長谷川 喜弘, 有木 茂, 橋本 宇吉郎, 高橋 素子

  日本生化学会大会プログラム・講演要旨集 ( (公社)日本生化学会 )  96回   [1P - 137]  2023.10

• FGFR3のN型糖鎖は細胞膜への発現と活性を制御する

  橋本 宇吉郎, 藤谷 直樹, 上原 康昭, 長谷川 喜弘, 有木 茂, 高橋 素子

  日本生化学会大会プログラム・講演要旨集 ( (公社)日本生化学会 )  96回   [1P - 009]  2023.10

• FGFR1のN型糖鎖はレセプターの細胞内輸送と自己リン酸化を制御する

  岡本 弘美, 藤谷 直樹, 上原 康昭, 長谷川 喜弘, 橋本 宇吉郎, 有木 茂, 白土 明子, 高橋 素子

  日本生化学会大会プログラム・講演要旨集 ( (公社)日本生化学会 )  96回   [1P - 044]  2023.10

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• CINC-2 and miR-199a-5p in exosomes secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration

  Norihisa Ichinohe, Naoki Tanimizu, Keisuke Ishigami, Yusuke Yoshioka, Naoki Fujitani, Takahiro Ochiya, Motoko Takahashi, Toshihiro Mitaka

  Research Square ( Research Square Platform LLC )   2023.01

  Internal/External technical report, pre-print, etc.  

  　View Summary

  Abstract Background Small hepatocyte-like progenitor cells (SHPCs) are hepatocytic progenitor cells that transiently form clusters in rat livers treated with retrorsine and with 70% partial hepatectomy (PH). We previously reported that transplantation of Thy1⁺ cells derived from d-galactosamine-treated livers promotes SHPC expansion, resulting in the acceleration of liver regeneration. Extracellular vesicles (EVs) produced by Thy1⁺ cells act on sinusoidal endothelial cells (SECs) and Kupffer cells to secrete IL17B and IL25, respectively, resulting in SHPC activation through IL17 receptor B (RB) signaling. Our aim is to identify factors in Thy1-EVs that activate IL17RB signaling.Methods Thy1⁺ cells isolated from rats with d-galactosamine-induced liver injury were cultured for one week. Although some liver stem/progenitor cells proliferated into colonies, others maintained as mesenchymal cells (MCs). Thy1-MCs or Thy1-liver stem/progenitor cells were transplanted into retrorsine/PH-treated livers to examine their effects on SHPCs. SHs isolated from adult rat livers were used to validate factors regulating growth induction.Results The number and size of SHPCs remarkably increased in livers transplanted with Thy1-MCs. Comprehensive analysis of Thy1-MC-EVs revealed that miR-199a-5p, CINC-2, and MCP-1 are candidates for stimulating SHPC growth. Administration of the miR-199a-5p mimic, and not CINC-2, promoted SH growth. SECs treated with CINC-2 induced IL17b expression and their conditioned medium promoted SH growth.Conclusion Thy1-MC transplantation may accelerate liver regeneration due to SHPCs expansion, which is stimulated by CINC-2/IL17RB signaling and miR-199a-5p.

  DOI

• Site-specific Analysis of N-glycans of Receptor Tyrosine Kinases

  高橋素子, 藤谷直樹, 上原康昭, 長谷川喜弘

  Trends in Glycoscience and Glycotechnology (Web)   35 ( 206 )  2023

  J-GLOBAL

• Structural and functional analysis of N-glycans of growth factor receptors

  高橋素子, 岡本弘美, 藤谷直樹, 上原康昭, 橋本宇吉郎, 長谷川喜弘

  日本糖質学会年会要旨集   42nd  2023

  J-GLOBAL

• Structural and functional analysis of N-glycans of hepatocyte growth factor receptor MET

  高橋素子, 齋藤淳, 長谷川喜弘, 藤谷直樹, 有木茂, 上原康昭, 松本邦夫

  日本糖質学会年会要旨集   41st  2022

  J-GLOBAL

• 細胞グライコミクスから部位特異的グライコミクスへ:生物学的機能を明らかにするための部位特異的なN結合型糖鎖の構造解析

  藤谷直樹, 高橋素子

  日本分子生物学会年会プログラム・要旨集(Web)   42nd  2019

  J-GLOBAL

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Awards 【 display / non-display 】

Awards 【 display / non-display 】

• Postdoctoral Fellowship Award of Juvenile Diabetes Foundation International›

Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• ErbB4の部位特異的糖鎖解析による糖鎖機能の解明

  基盤研究(C)

  Project Year :

  2021.04

  -

  2024.03

   

  高橋 素子, 藤谷 直樹, 上原 康昭, 長谷川 喜弘

  　View Summary

  ErbBファミリーは、EGFR、ErbB2、ErbB3、ErbB4の４つの分子からなる増殖因子受容体ファミリーである。いずれもがんの発症・進展に深く関与していると考えられている。研究代表者はこれまでにEGFRとErbB3の糖鎖解析を行い、特定の糖鎖構造が機能に関係している可能性を見出した。本研究では、ErbB4の部位特異的糖鎖構造解析を行い、糖鎖によるシグナル制御機構を明らかにすることを目的とする。令和3年度の研究では、以下の結果が得られた。 １）ErbB4の部位特異的糖鎖付加率および糖鎖構造：CHOK1細胞で発現させたErbB4細胞外ドメインを精製し、LC-ESI-MS/MSを用いて11か所の糖鎖付加部位における糖鎖付加率と糖鎖構造を解析した。N113、N333、N523の３か所はほぼ100%の糖鎖付加率を示した。また、N113、N228、N523の３か所は高マンノース型糖鎖、それ以外の８か所は複合型糖鎖が付加することがわかった。N333上の糖鎖は、他の複合型糖鎖と比較してフコース付加が少ないという特徴がみられた。 ２）ErbB4の機能に重要な糖鎖の同定：CHOK1細胞を用いてErbBの野生型および糖鎖欠損変異体の安定発現細胞を樹立した。ヘレグリン刺激に対するシグナルを比較する予定である。 ３）ErbB4細胞外ドメインの糖鎖欠損変異体の性質の評価：ErbB4の細胞外ドメインの野生型および糖鎖欠損変異体の大量調製を行った。ErbB4の細胞外ドメインはEGFシグナルとヘレグリンシグナルの両方を抑制することを確認した。野生型と糖鎖欠損変異体の比較を行う予定である。

• 高性能イミュノトキシンを用いた小細胞肺がんの標的化治療法の開発

  基盤研究(C)

  Project Year :

  2021.04

  -

  2024.03

   

  山口 美樹, 高橋 素子, 佐久間 裕司, 藤谷 直樹, 内田 宏昭

  　View Summary

  本研究は小細胞肺がんに対する抗体薬物複合体（antibody drug conjugate: ADC）型抗体薬の開発を目的としたモノクローナル抗体の樹立と新規標的の探索である。初年度は、これまでに私たちが樹立したモノクローナル抗体（免疫原：膵臓癌、前立腺癌、肺腺癌、悪性中皮腫、悪性黒色腫、骨髄性白血病、その他の難治性腫瘍、抗原数：68個、抗体数：1200クローン以上）について小細胞肺がん治療における有効性を調査した。小細胞肺がん細胞株であるSBC3、SBC5、NCI-H1092、NCI-H1439、STC1、Lu134AH、MS1L、Lu135、KHM3SおよびNCI-H69について網羅的にフローサイトメトリー（FCM）解析を行った。公共データベースから正常組織および血液系細胞で発現が認められる標的（抗原）について除外した。その結果、調査した全てで強陽性を示したCD#05、CD#55、A#AM10およびJ#M3の4つの抗原が小細胞肺がんに対するADC型抗体薬開発における有望な標的と考えられた。これらの標的に対する内在化能を有するモノクローナル抗体の樹立を現在進めADC型抗体薬の開発に結びつけたい。また、同時に小細胞肺がん細胞株であるSBC5を免疫原とするモノクローナル抗体の樹立も進行中であり、こちらは現時点で内在化能を有する抗体を50個以上樹立出来ており、現在抗原同定を進めているところである。

• Development of a selective culture method for pulmonary epithelial stem cells using high-performance immunotoxin

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2018.04

  -

  2021.03

   

  Yamaguchi Miki

  　View Summary

  In the respiratory field, idiopathic pulmonary fibrosis or chronic obstructive pulmonary disease is a chronic progressive disease with a poor prognosis for which no cure has been established. We thought that if the lung epithelial stem cells that make up the lung could be transplanted, it could be a new therapeutic method, and devised a selective culture using immunotoxin. By adding CD90-DT3C (immunotoxin), lung epithelial precursors / stem cells could be selectively cultured. In addition, the culture efficiency was further improved by culturing with the addition of A83-01 and Y27632. From the above, selective culture using immunotoxin was completed. We will proceed with the development of a treatment method for chronic obstructive pulmonary disease using this culture system.

• The mechanisms of conformational regulation of ErbB receptors by N-glycans

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2017.04

  -

  2020.03

   

  Takahashi Motoko

  　View Summary

  The functional regulation and conformational regulation of growth factor receptors ErbB by N-glycans were examined. N-glycans on EGFR N420, ErbB3 N418, ErbB4 N333 were involved in receptor activation. We examined the site-specific glycosylation status and glycan structures of ErbBs and found that their glycan occupancies were 100% and they were a complex type with little fucose. The signaling inhibitory effects were increased in sEGFR N420Q and sErbB3 N418Q mutants. Although the crystal structure of sErbB3 was not altered by the deletion of N-glycan on N418 by N418Q mutation, the melting temperature of sErbB3 N418Q decreased compared to the wild type, suggesting that this N-glycan contributes to the conformational stability of sErbB3. Taken together, our results suggested that N-glycan on N418 of sErbB3 is involved in the stabilization of structure and that deletion of this glycan increases the structural flexibility which results in facilitation of dimer formation.

• Pulmonary fibrosis treatment with pulmonary surfactant as a TLR regulatory molecule and HSP47 inhibition

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2017.04

  -

  2020.03

   

  Takahashi Hiroki

  　View Summary

  Objective: To develop a new therapeutic method for idiopathic pulmonary fibrosis under the hypothesis that surfactant protein (SP) -A supplementation and HSP47 siRNA suppress lung inflammation and fibrosis. Method: BLM was intratracheally administered to SP-A (-/-) and wild-type mice to prepare a lung injury / fibrosis model, and siRNA HSP47 was intravenously administered. Results: Inflammation and fibrosis were enhanced in SP-A deficient mice compared to wild type. In addition, siRNA HSP47 reduced lung injury and suppressed BLM-induced airway inflammation. Conclusion: SP-A supplementation and siRNA HSP47 suppressed the formation of lung injury / fibrotic lesions, and it was shown that the combination of both could be one of the new treatments for pulmonary fibrosis.

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Committee Memberships 【 display / non-display 】

Committee Memberships 【 display / non-display 】

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    評議員

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    評議員

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    世話人