Education 【 display / non-display 】

Education 【 display / non-display 】

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  2006

  九州大学大学院   理学府   生物科学  

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  2003

  九州大学大学院   理学府   生物科学  

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  2001

  Kyushu University   School of Sciences   生物  

Degree 【 display / non-display 】

Degree 【 display / non-display 】

• 九州大学   博士（理学）

• Kyushu University   Master(Science)

Research Experience 【 display / non-display 】

Research Experience 【 display / non-display 】

• 2015.04

  -

  Now

  札幌医科大学医療人育成センター   教養教育研究部門   准教授

• 2012.08

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  2015.03

  札幌医科大学医学部   医化学講座   講師

• 2007.08

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  2012.07

  札幌医科大学医学部   医化学講座   助教

• 2007.04

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  2007.07

  九州大学大学院理学研究院   学術研究員

• 2005.04

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  2007.03

  日本学術振興会特別研究員  

Professional Memberships 【 display / non-display 】

Professional Memberships 【 display / non-display 】

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  The Japanese Biochemical Society

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  生化学会

Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Functional biochemistry  

• Life sciences   Medical biochemistry  

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• Sapporo Medical University   Center for Medical Education Department of Liberal Arts and Sciences   Graduate Student  

Research Interests 【 display / non-display 】

Research Interests 【 display / non-display 】

• innate immunity

• 自然免疫

Papers 【 display / non-display 】

Papers 【 display / non-display 】

• N-glycosylation regulates MET processing and signaling.

  Atsushi Saitou, Yoshihiro Hasegawa, Naoki Fujitani, Shigeru Ariki, Yasuaki Uehara, Ukichiro Hashimoto, Atsushi Saito, Koji Kuronuma, Kunio Matsumoto, Hirofumi Chiba, Motoko Takahashi

  Cancer science   113 ( 4 ) 1292 - 1304  2022.04  [Refereed]  [International journal]

  　View Summary

  MET, the receptor for the hepatocyte growth factor (HGF), is strongly associated with resistance to tyrosine kinase inhibitors, key drugs that are used in the therapy of non-small cell lung cancer. MET contains 11 potential N-glycosylation sites, but the site-specific roles of these N-glycans have not been elucidated. We report herein that these N-glycans regulate the proteolytic processing of MET and HGF-induced MET signaling, and that this regulation is site specific. Inhibitors of N-glycosylation were found to suppress the processing and trafficking of endogenous MET in H1975 and EBC-1 lung cancer cells and exogenous MET in CHO-K1 cells. We purified the recombinant extracellular domain of human MET and determined the site-specific N-glycan structures and occupancy using mass spectrometry. The results indicated that most sites were fully glycosylated and that the dominant population was the complex type. To examine the effects of the deletion of N-glycans of MET, we prepared endogenous MET knockout Flp-In CHO cells and transfected them with a series of N-glycan-deletion mutants of MET. The results showed that several N-glycans are implicated in the processing of MET. The findings also suggested that the N-glycans of the SEMA domain of MET positively regulate HGF signaling, and the N-glycans of the region other than the SEMA domain negatively regulate HGF signaling. Processing, cell surface expression, and signaling were significantly suppressed in the case of the all-N-glycan-deletion mutant. The overall findings suggest that N-glycans of MET affect the status and the function of the receptor in a site-specific manner.

  DOI PubMed

• Integrated Structural Analysis of N-Glycans and Free Oligosaccharides Allows for a Quantitative Evaluation of ER Stress.

  Naoki Fujitani, Shigeru Ariki, Yoshihiro Hasegawa, Yasuaki Uehara, Atsushi Saito, Motoko Takahashi

  Biochemistry   60 ( 21 ) 1708 - 1721  2021.06  [Refereed]  [International journal]

  　View Summary

  Endoplasmic reticulum (ER) stress has been reported in a variety of diseases. Although ER stress can be detected using specific markers, it is still difficult to quantitatively evaluate the degree of stress and to identify the cause of the stress. The ER is the primary site for folding of secretory or transmembrane proteins as well as the site where glycosylation is initiated. This study therefore postulates that tracing the biosynthetic pathway of asparagine-linked glycans (N-glycans) would be a reporter for reflecting the state of the ER and serve as a quantitative descriptor of ER stress. Glycoblotting-assisted mass spectrometric analysis of the HeLa cell line enabled quantitative determination of the changes in the structures of N-glycans and degraded free oligosaccharides (fOSs) in response to tunicamycin- or thapsigargin-induced ER stress. The integrated analysis of neutral and sialylated N-glycans and fOSs showed the potential to elucidate the cause of ER stress, which cannot be readily done by protein markers alone. Changes in the total amount of glycans, increase in the ratio of high-mannose type N-glycans, increase in fOSs, and changes in the ratio of sialylated N-glycans in response to ER stress were shown to be potential descriptors of ER stress. Additionally, drastic clearance of accumulated N-glycans was observed in thapsigargin-treated cells, which may suggest the observation of ER stress-mediated autophagy or ER-phagy in terms of glycomics. Quantitative analysis of N-glycoforms composed of N-glycans and fOSs provides the dynamic indicators reflecting the ER status and the promising strategies for quantitative evaluation of ER stress.

  DOI PubMed

• Acrolein in cigarette smoke attenuates the innate immune responses mediated by surfactant protein D.

  Rina Takamiya, Motoko Takahashi, Toshitaka Maeno, Atsushi Saito, Masaki Kato, Takahiro Shibata, Koji Uchida, Shigeru Ariki, Miyako Nakano

  Biochimica et biophysica acta. General subjects   1864 ( 11 ) 129699 - 129699  2020.11  [Refereed]  [International journal]

  　View Summary

  BACKGROUND: Surfactant proteins (SP) A and D belong to collectin family proteins, which play important roles in innate immune response in the lung. We previously demonstrated that cigarette smoke (CS) increases the acrolein modification of SP-A, thereby impairing the innate immune abilities of this protein. In this study, we focused on the effects of CS and its component, acrolein, on the innate immunity role of another collectin, SP-D. METHODS: To determine whether aldehyde directly affects SP-D, we examined the lungs of mice exposed to CS for 1 week and detected aldehyde-modified SP-D using an aldehyde reactive probe. The structural changes in CS extract (CSE) or acrolein-exposed recombinant human (h)SP-D were determined by western blot, liquid chromatography-electrospray ionization tandem mass spectrometry, and blue native-polyacrylamide gel electrophoresis analyses. Innate immune functions of SP-D were determined by bacteria growth and macrophage phagocytosis. RESULTS: Aldehyde-modified SP-D as well as SP-A was detected in the lungs of mice exposed to CS for 1 week. Exposure of hSP-D to CSE or acrolein induced an increased higher-molecular -weight of hSP-D and acrolein induced modification of five lysine residues in hSP-D. These modifications led to disruption of the multimer structure of SP-D and attenuated its ability to inhibit bacterial growth and activate macrophage phagocytosis. CONCLUSION: CS induced acrolein modification in SP-D, which in turn induced structural and functional defects in SP-D. GENERAL SIGNIFICANCE: These results suggest that CS-induced structural and functional defects in SP-D contribute to the dysfunction of innate immune responses in the lung following CS exposure.

  DOI PubMed

• Insufficient serum L-ficolin is associated with disease presence and extent of pulmonary Mycobacterium avium complex disease.

  Kobayashi T, Kuronuma K, Saito A, Ikeda K, Ariki S, Saitou A, Otsuka M, Chiba H, Takahashi S, Takahashi M, Takahashi H

  Respiratory research   20 ( 1 ) 224 - 224  2019.10  [Refereed]  [International journal]

  　View Summary

  BACKGROUND: The incidence of infectious disease caused by nontuberculous mycobacteria is increasing worldwide. Pulmonary Mycobacterium avium complex (MAC) disease is difficult to treat with chemotherapy, and its mechanism of infection, infection route, disease onset, and severity remain unknown. Ficolins are oligomeric defense lectins. L-ficolin plays an important role in innate immunity. This study's aim was to identify L-ficolin's role in patients with pulmonary MAC disease. METHODS: Between April 2011 and September 2017, 61 Japanese patients with pulmonary MAC disease were seen at our hospital. A control group, comprising 30 healthy individuals, without respiratory disease were enrolled in our study. The relationship between serum L-ficolin levels and disease severity was assessed, and L-ficolin's antibacterial role was examined. RESULTS: Serum L-ficolin levels were significantly lower in patients with pulmonary MAC disease than in healthy subjects (1.69 ± 1.27 μg/ml vs. 3.96 ± 1.42 μg/ml; p < 0.001). The cut-off value, based on receiver operating characteristic (ROC) analysis results, was 2.48 μg/ml (area under the curve (AUC) 0.90, sensitivity and specificity 83.6 and 86.7%, respectively). Serum L-ficolin levels were significantly lower in the patients with nodular bronchiectatic type disease compared with the patients with fibrocavitary type disease and were lower in the high-resolution computed tomography high-scoring group compared with low-scoring group. An in vitro analysis showed that purified recombinant L-ficolin bound to M. avium and its major cell wall component, lipoarabinomannan, in a concentration-dependent manner. In addition, recombinant L-ficolin suppressed M. avium growth in a concentration-dependent manner. CONCLUSIONS: Insufficient serum L-ficolin is associated with disease progression in pulmonary MAC disease, and the level of serum L-ficolin is a possible biomarker. TRIAL REGISTRATION: This study is registered with UMIN ( UMIN000022392 ).

  DOI PubMed

• Impaired diversity of the lung microbiome predicts progression of idiopathic pulmonary fibrosis.

  Youhei Takahashi, Atsushi Saito, Hirofumi Chiba, Koji Kuronuma, Kimiyuki Ikeda, Tomofumi Kobayashi, Shigeru Ariki, Motoko Takahashi, Yasushi Sasaki, Hiroki Takahashi

  Respiratory research   19 ( 1 ) 34 - 34  2018.02  [Refereed]  [International journal]

  　View Summary

  BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe form of idiopathic interstitial pneumonias. Although IPF has not been thought to be associated with bacterial communities, recent papers reported the possible role of microbiome composition in IPF. The roles of microbiomes in respiratory functions and as clinical biomarkers for IPF remain unknown. In this study, we aim to identify the relationship between the microbial environment in the lung and clinical findings. METHODS: Thirty-four subjects diagnosed with IPF were included in this analysis. The 16S rDNA was purified from bronchoalveolar lavage fluid obtained at the time of diagnosis and analyzed using next-generation sequencing techniques to characterize the bacterial communities. Furthermore, microbiomes from mice with bleomycin-induced lung fibrosis were analyzed. RESULTS: The most prevalent lung phyla were Firmicutes, Proteobacteria and Bacteroidetes. Decreased microbial diversity was found in patients with low forced vital capacity (FVC) and early mortality. Additionally, the diversity and relative abundance of Firmicutes, Streptococcaceae, and Veillonellaceae were significantly associated with FVC, 6-min walk distance, and serum surfactant protein D. Bleomycin-induced lung fibrosis resulted in decrease of diversity and alteration of microbiota in PCoA analysis. These results support the observations in human specimens. CONCLUSIONS: This study identified relationships between specific taxa in BALF and clinical findings, which were also supported by experiments in a mouse model. Our data suggest the possibility that loss of microbial diversity is associated with disease activities of IPF.

  DOI PubMed

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• 肺サーファクタントタンパク質Dは変異型EGFRの活性化を阻害し、肺腺がんの進展を抑制する

  長谷川 喜弘, 梅田 泰淳, 大塚 満雄, 有木 茂, 高宮 里奈, 齋藤 充史, 高橋 弘毅, 黒木 由夫, 高橋 素子

  生命科学系学会合同年次大会 ( 生命科学系学会合同年次大会運営事務局 )  2017年度   [1P - 0948]  2017.12

• タバコ煙中のアクロレインが肺サーファクタントタンパク質A(SP‐A)に及ぼす影響

  高宮里奈, 内田浩二, 内田浩二, 柴田貴広, 前野敏孝, 加藤雅樹, 山口芳樹, 有木茂, 長谷川喜弘, 齋藤充史, 高橋素子, 黒木由夫

  日本糖質学会年会要旨集   36th   84  2017.07

  J-GLOBAL

• SP-Dによる変異型EGFR肺がんの制御機構

  長谷川 喜弘, 梅田 泰淳, 大塚 満雄, 有木 茂, 高宮 里奈, 齋藤 充史, 黒沼 幸治, 千葉 弘文, 高橋 弘毅, 黒木 由夫, 高橋 素子

  分子呼吸器病 ( (株)先端医学社 )  21 ( 1 ) 80 - 83  2017.03

• SP-Dによる変異型EGFR肺がんの制御機構

  長谷川 喜弘, 梅田 泰淳, 大塚 満雄, 有木 茂, 高宮 里奈, 齋藤 充史, 黒沼 幸治, 千葉 弘文, 高橋 弘毅, 黒木 由夫, 高橋 素子

  分子呼吸器病 ( (株)先端医学社 )  21 ( 1 ) 80 - 83  2017.03

• 糖鎖改変・可溶型EGFRによるEGFシグナル抑制作用のメカニズム

  高橋素子, 長谷川喜弘, 加藤公児, 姚閔, 和田芳直, 有木茂, 高宮里奈, 齋藤充史, 黒木由夫

  日本生化学会大会(Web) ( (公社)日本生化学会 )  89th   ROMBUNNO.1T08‐01(1P‐042) (WEB ONLY) - 01(1P  2016.09

  J-GLOBAL

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Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• 尿路病原性大腸菌に対する異所性肺コレクチンの生体防御機能の分子基盤解明

  基盤研究(C)

  Project Year :

  2017.04

  -

  2020.03

   

  有木 茂

  Authorship： Principal investigator

  　View Summary

  今年度は、肺コレクチン（SP-AおよびSP-D）の大腸菌に対する増殖抑制活性が、異なる種類の緩衝液中でどのように変化するのかを詳細に解析した。また、SP-Aのコラーゲン様ドメインとSP-Dの糖鎖認識ドメインを組み合わせたキメラタンパク質を用いて、増殖抑制活性と構造の機能相関を解析した。その結果、カルシウムイオンを含む緩衝液中では、コレクチンが十字架様構造をとっていることが増殖抑制活性に必須であることが明らかとなった。一方、カルシウムイオンを含まない緩衝液中では、コレクチンが花束様構造をとっていることが必須であった。いずれの緩衝液中でも、コレクチンの糖鎖認識ドメインの種類は結果に影響しなかった。これらの結果は、緩衝液の組成が異なることでコレクチンが大腸菌へ結合できなくなることに起因する可能性がある。そこで、大腸菌とコレクチンをそれぞれの緩衝液中で混合した後、大腸菌を遠心により回収して、結合したコレクチンをウエスタンブロッティングにより検出した。その結果、SP-A、SP-D、キメラタンパク質の全てが、いずれの緩衝液中でも大腸菌に結合していた。 ここまでの結果から、コレクチンの大腸菌に対する増殖抑制活性には、コレクチンの結合特異性よりもオリゴマー構造が重要であると考えられる。そこで、SP-A（花束構造）、SP-D（十字架構造）、キメラタンパク質（花束構造）を混合した場合にどのような効果が得られるのかを解析してみると、予想通り、キメラタンパク質はSP-Aと相加的にはたらいたが、SP-Dの効果は抑制した。 今年度の解析から、大腸菌に対するコレクチンの構造機能相関をこれまでよりも詳細に明らかにできた。

• Regulation of ErbB receptors by N-glycans

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2014.04

  -

  2017.03

   

  TAKAHASHI MOTOKO, ARIKI Shigeru, WADA Yoshinao

  　View Summary

  The fundamental role of the glycan chain is to modify the physicochemical properties of target molecules. The aim of this study is to determine the mechanisms by which N-glycans regulate the function and structure of ErbB. First, we improved the purification efficiency of recombinant soluble ErbB (sErbB) over 100-fold. It was observed that the sEGFR N418Q N-glycan deletion mutant suppressed EGF signaling more effectively than the wild type. The crystal structure of the sErbB3 N418Q N-glycan deletion mutant revealed that the static structure of sErbB3 is not altered by the deletion of the N-glycan. In contrast, the thermostability of sErbB3 N418Q was reduced compared to the wild type. These results indicate that the N-glycan on N418 of ErbB3 is involved in the conformational stability of sErbB3, and the deletion of the N-glycan would increase the flexibility of the molecule.

• 肺コレクチンによるレジオネラ菌の細胞内増殖抑制の分子機構解明

  Project Year :

  2014

  　

  　

   

  Authorship： Principal investigator

• 抗菌ペプチドによる組織傷害をSP-Aが抑制する分子機構の解明

  Project Year :

  2014

  　

  　

   

• Studies of pulmonary surfactant proteins on new aspects of host defense functions: anti-tumor activity and defensive activity against disease development.

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2013.04

  -

  2016.03

   

  Kuroki Yoshio, TAKAHASHI MOTOKO, ARIKI SHIGERU, HASEGAWA YOSHIHIRO, TAKAMIYA RINA, UEHARA YASUAKI, SAITO ATSUSHI, TAKAHASHI HIROKI

  　View Summary

  Pulmonary surfactant proteins, SP-A and SP-D, suppress the growth and progression of lung cancer cells by attenuating the EGF signaling of EGFR phosphorylation and its downstream. SP-D interferes with the EGF binding to EGFR by binding to the high mannose type-sugar moieties of EGFR. SP-A binds to EGFR in a Ca2+-independent manner, indicating the different mechanism from that of SP-D. SP-A and its peptide (SAP01:Tyr161-Lys201) attenuate mast cell migration stimulated with hBD3 and weakened the accumulation of mast cells in the tracheas of asthma model rats. SP-A protein was modified by cigarette smoke extract (CSE) and acrolein containing in the cigarette smoke. The reduction of reactive thiol in the SP-A molecule and the addition of acrolein was observed. The modified SP-A exhibited the decreased ability to attenuate the E. coli growth.

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Teaching Experience 【 display / non-display 】

Teaching Experience 【 display / non-display 】

• 自然科学実験  

  札幌医科大学保健医療学部  

  2017

  -

  Now

   

• 化学２  

  札幌医科大学保健医療学部  

  2017

  -

  Now

   

• 化学１  

  札幌医科大学保健医療学部  

  2017

  -

  Now

   

• 自然科学実験  

  札幌医科大学医学部  

  2015

  -

  Now

   

• 基礎生化学  

  札幌医科大学医学部  

  2014

  -

  Now

   

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