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

• Project/Area Number: 17K07339
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Sapporo Medical University
• Principal Investigator: Takahashi Motoko 札幌医科大学, 医学部, 教授 (00303941)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 糖鎖 / 増殖因子受容体 / ErbB / EGFR / N-glycan / シグナル解析 / 結晶構造解析 / 糖鎖生物学 / 受容体

Outline of Final Research Achievements

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.

Academic Significance and Societal Importance of the Research Achievements

ErbBはがん治療のターゲットであり、その制御機構を明らかにすることは社会的にも重要である。研究代表者は糖鎖によるErbBの制御について調べているが、その根本的なメカニズムは「糖鎖による受容体の物性制御」にあると考えている。本研究の結果、特定の糖鎖がErbBの構造変化に関与していることが示唆された。同時に、それらの糖鎖に共通する特徴も見出した。以上の結果は糖鎖の機能の解明につながる可能性がある。

Research Products

• [Journal Article] Insufficient serum L-ficolin is associated with disease presence and extent of pulmonary Mycobacterium avium complex disease (2019)
  • Author(s): Kobayashi Tomofumi、Kuronuma Koji、Saito Atsushi、Ikeda Kimiyuki、Ariki Shigeru、Saitou Atsushi、Otsuka Mitsuo、Chiba Hirofumi、Takahashi Satoshi、Takahashi Motoko、Takahashi Hiroki
  • Journal Title: Respiratory Research Volume: 20 Issue: 1 Pages: 224-224
  • DOI: 10.1186/s12931-019-1185-9
  • Peer Reviewed
• [Journal Article] Impaired diversity of the lung microbiome predicts progression of idiopathic pulmonary fibrosis (2018)
  • Author(s): Takahashi Youhei、Saito Atsushi、Chiba Hirofumi、Kuronuma Koji、Ikeda Kimiyuki、Kobayashi Tomofumi、Ariki Shigeru、Takahashi Motoko、Sasaki Yasushi、Takahashi Hiroki
  • Journal Title: Respir Res Volume: 19 Issue: 1 Pages: 34-34
  • DOI: 10.1186/s12931-018-0736-9
  • Peer Reviewed / Open Access
• [Journal Article] Mice deficient in aldo-keto reductase 1a (Akr1a) are resistant to thioacetamide-induced liver injury. (2018)
  • Author(s): Homma T., Shirato T., Akihara R., Kobayashi S., Lee J., Yamada K., Miyata S., Takahashi M., Fujii J.
  • Journal Title: Toxicol. Lett. Volume: 294 Pages: 37-43
  • DOI: 10.1016/j.toxlet.2018.05.015
  • Peer Reviewed
• [Journal Article] Surfactant protein A down-regulates epidermal growth factor receptor by mechanisms different from those of surfactant protein D (2017)
  • Author(s): Yoshihiro Hasegawa, Motoko Takahashi, Shigeru Ariki, Atsushi Saito, Yasuaki Uehara, Rina Takamiya, Koji Kuronuma, Hirofumi Chiba, Yuji Sakuma, Hiroki Takahashi, Yoshio Kuroki
  • Journal Title: J Bill Chem Volume: 292 Issue: 45 Pages: 18565-18576
  • DOI: 10.1074/jbc.m117.800771
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Disruption of the structural and functional features of surfactant protein A by acrolein in cigarette smoke (2017)
  • Author(s): Takamiya Rina、Uchida Koji、Shibata Takahiro、Maeno Toshitaka、Kato Masaki、Yamaguchi Yoshiki、Ariki Shigeru、Hasegawa Yoshihiro、Saito Atsushi、Miwa Soichi、Takahashi Hiroki、Akaike Takaaki、Kuroki Yoshio、Takahashi Motoko
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 8304-8304
  • DOI: 10.1038/s41598-017-08588-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Surfactant protein D inhibits activation of non-small cell lung cancer-associated mutant EGFR and affects clinical outcomes of patients (2017)
  • Author(s): Umeda Y、Hasegawa Y、Otsuka M、Ariki S、Takamiya R、Saito A、Uehara Y、Saijo H、Kuronuma K、Chiba H、Ohnishi H、Sakuma Y、Takahashi H、Kuroki Y、Takahashi M
  • Journal Title: Oncogene Volume: 36 Issue: 46 Pages: 6432-6445
  • DOI: 10.1038/onc.2017.253
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Surfactant protein A inhibits growth and adherence of uropathogenic Escherichia coli to protect the bladder from infection. (2017)
  • Author(s): Hashimoto J., Takahashi M., Satio A., Murata M., Kurimura Y., Nishitani C., Takamiya R., Uehara Y., Hasegawa Y., Hiyama Y., Sawada N., Takahashi S., Masumori N., Kuroki Y., Ariki S.
  • Journal Title: J. Immunol. Volume: 198 Issue: 7 Pages: 2898-2905
  • DOI: 10.4049/jimmunol.1502626
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Surfactant Protein A (SP-A) and SP-A-derived Peptide Attenuate Chemotaxis of Mast Cells Induced by Human β-defensin 3. (2017)
  • Author(s): Uehara Y., Takahashi M., Murata M., Saito A., Takamiya R., Hasegawa Y., Kuronuma K., Chiba H., Hashimoto J., Sawada N., Takahashi H., Kuroki Y., Ariki S.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 485 Issue: 1 Pages: 107-112
  • DOI: 10.1016/j.bbrc.2017.02.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SP-Dによる変異型EGFR肺がんの制御機構 (2017)
  • Author(s): 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
  • Journal Title: 分子呼吸器病 Volume: 21 Pages: 80-83
• [Presentation] 増殖因子受容体の糖鎖の構造と機能 (2020)
  • Author(s): 高橋素子、藤谷直樹、長谷川喜弘、上原康昭
  • Organizer: 第93回 日本生化学会大会
• [Presentation] ErbB受容体の糖鎖の構造と機能 (2019)
  • Author(s): 高橋素子、藤谷直樹、和田芳直、加藤公児、姚閔
  • Organizer: 第38回日本糖質学会
• [Presentation] ErbB3の糖鎖による物性制御メカニズム (2019)
  • Author(s): 高橋素子、加藤公児、藤谷直樹、齋藤充史、和田芳直、姚閔
  • Organizer: 第92回 日本生化学会大会
• [Presentation] ErbB4のN型糖鎖の機能解析 (2018)
  • Author(s): 高橋素子、和田芳直、浅川大樹、有木茂、齋藤充史
  • Organizer: 第37回日本糖質学会
• [Presentation] ErbB4の糖鎖による機能制御メカニズム (2018)
  • Author(s): 高橋素子、和田芳直、浅川大樹、有木茂、高宮里奈、齋藤充史
  • Organizer: 第91回 日本生化学会大会
• [Presentation] 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 (2017)
  • Author(s): 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
  • Organizer: 第90回日本生化学会大会