Roles of extracellular O-GlcNAc on Notch signaling and vascular development

• Project/Area Number: 26291020
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Nagoya University
• Principal Investigator: OKAJIMA Tetsuya 名古屋大学, 医学系研究科, 教授 (20420383)
• Co-Investigator(Kenkyū-buntansha): 竹下 享典 名古屋大学, 医学部附属病院, 准教授 (70444403)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: Notch / EOGT / O-GlcNAc / 血管形成 / マウス / NOTCH

Outline of Final Research Achievements

Notch receptors are modified with unique post-translational modifications on epidermal growth (EGF)-like repeats at the extracellular domains. Previous studies revealed that besides O-fucose and O-glucose O-GlcNAc modification occurs on EGF repeats. However, biological function of O-GlcNAc on Notch receptors remained unknown. In this study, EOGT, a glycosyltransferase catalyzing O-GlcNAc modification of EGF domains, is inactivated in mice and phenotypical analyses were performed. Results revealed that specific EGF domains of Notch1 are modified with O-GlcNAc, which regulated DLL4-mediated Notch1 activation and thus Notch-dependent vascular development in the retina.

Research Products

• [Int'l Joint Research] Albert Einstein College of Medicine(米国)
• [Journal Article] O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals (2017)
  • Author(s): *Shogo Sawaguchi, *Shweta Varshney, *Mitsutaka Ogawa, Yuta Sakaidani, Hirokazu Yagi, Kyosuke Takeshita, Toyoaki Murohara, Koichi Kato, Subha Sundaram , Pamela Stanley and Tetsuya Okajima. (*equal contribution)
  • Journal Title: eLife Volume: 6
  • DOI: 10.7554/elife.24419
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Expression of B4GALNT1, an essential glycosyltransferase for the synthesis of complex gangliosides, suppresses BACE1 degradation and modulates APP processing (2016)
  • Author(s): Yamaguchi T, Yamauchi Y, Furukawa K, Ohmi Y, Ohkawa Y, Zhang Q, Okajima T, Furukawa K
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 34505-34505
  • DOI: 10.1038/srep34505
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Ganglioside GD3 enhances invasiveness via Yes activation by forming a complex of GD3/PDGFRα/Yes in gliomas (2015)
  • Author(s): Yuki Ohkawa, Hiroyuki Momota, Akira Kato, Noboru Hashimoto, Yuhsuke Tsuda, Norihiro Kotani, Koichi Honke, Akio Suzumura, Keiko Furukawa, Yuhsuke Ohmi, Atsushi Natsume, Toshihiko Wakabayashi and *Furukawa K
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 32 Pages: 16043-16058
  • DOI: 10.1074/jbc.m115.708834
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Intracellular and extracellular O-linked N-acetylglucosamine in the nervous system. (2015)
  • Author(s): Ogawa M, Sawaguchi S, Kamemura K, Okajima T.
  • Journal Title: Exp Neurol. Volume: 274 Pages: 166-174
  • DOI: 10.1016/j.expneurol.2015.08.009
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] N-acetylglucosamine modification in the lumen of the endoplasmic reticulum. (2015)
  • Author(s): Ogawa M, Sawaguchi S, Furukawa K, Okajima T.
  • Journal Title: Biochim Biophys Acta. Volume: 1850 Issue: 6 Pages: 1319-1324
  • DOI: 10.1016/j.bbagen.2015.03.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] O-fucose monosaccharide of Drosophila Notch has a temperature-sensitive function and cooperates with O-glucose glycan in Notch transport and Notch signaling activation (2015)
  • Author(s): Akira Ishio, Takeshi Sasamura, Tomonori Ayukawa, Junpei Kuroda, Hiroyuki O. Ishikawa, Naoki Aoyama, Kenjiroo Matsumoto, Takuma Gushiken, Tetsuya Okajima, Tomoko Yamakawa and Kenji Matsuno2
  • Journal Title: Jounal of Biochemistry Volume: 290 Issue: 1 Pages: 505-519
  • DOI: 10.1074/jbc.m114.616847
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impaired O-linked N-acetylglucosaminylation in the endoplasmic reticulum by mutated EGF domain-specific O-linked N-acetylglucosamine transferase found in Adams-Oliver syndrome (2015)
  • Author(s): M.Ogawa, S.Sawaguchi, T.Kawai, D.Nadano, T.Matsuda, H.Yagi, K.Kato, K.Furukawa, and T.Okajima
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 4 Pages: 2137-2149
  • DOI: 10.1074/jbc.m114.598821
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular O-linked beta-N-acetylglucosamine: Its biology and relationship to human disease. (2014)
  • Author(s): Ogawa M, Furukawa K, Okajima T.
  • Journal Title: World J Biol Chem Volume: 5 Pages: 224-230
  • Peer Reviewed / Open Access
• [Presentation] 新しい細胞外 O-GlcNAc修飾の分子機能 (2017)
  • Author(s): 小川 光貴、古川 鋼一、岡島 徹也
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
  • Invited
• [Presentation] 脳血管内皮細胞分化におけるNotch受容体O-GlcNAc修飾の役割 (2017)
  • Author(s): 平泉 光佑、澤口 翔伍、岡島 徹也
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] 細胞外O-GlcNAcの修飾に関わるEOGT変異マウスの表現型解析 (2017)
  • Author(s): 澤口 翔伍、小川 光貴、矢木 宏和、加藤 晃一、岡島 徹也
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] ガングリオシドGD3によるグリオーマの腫瘍微小環境の制御機構 (2017)
  • Author(s): 張 璞、大川 裕樹、加藤 彰、小峯 起、百田 洋之、Robiul Bhuiyan、大海 雄介、古川 圭子、若林 俊彦、岡島 徹也、山中 宏二、古川 鋼一
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] Extracellular O-GlcNAc regulates Delta-like 4 mediated Notch signaling and vascular development in mammals (2016)
  • Author(s): 澤口翔伍, 小川光貴, 矢木宏和, 加藤晃一, 岡島徹也
  • Organizer: 第89回日本生化学会大会
• [Presentation] Extracellular O-GlcNAc modification regulates Notch signaling and blood0retina barrier maintenance (2015)
  • Author(s): 小川光貴、澤口翔伍、Bieniasz-krzywiec Pawl, 矢木宏和、加藤晃一、臼倉治郎、古川鋼一、岡島徹也
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Analysis of the biological roles of extracellular O-GlcNAc using EOGT-deficient mice (2015)
  • Author(s): Mitsutaka Ogawa, Pawel Bieniasz-Krzywiec, Hirokazu Yagi, Koichi Kato, Jiro Usukura, Koichi Furukawa, Tetsuya Okajima
  • Organizer: Society for Glycobiology 2015 Annual Meeting
  • Place of Presentation: サンフランシスコ（アメリカ）
  • Year and Date: 2015-12-01
• [Presentation] Phenotypic analysis of mice mutant for EOGT involved in extracellular O-GlcNAc modification. (2015)
  • Author(s): Shogo Sawaguchi, Mitsutaka Ogawa, Hirokazu Yagi, Koichi Kato, Jiro Usukura, Koichi Furukawa, and Tetsuya Okajima
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] 細胞外0-GlcNAc：生物学と疾患との関連 (2015)
  • Author(s): 岡島徹也、澤口翔伍、古川鋼一、小川光貴
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Biological roles of extracellular O-GlcNAc in Notch signaling, vascular development, and blood brain barrier maintenance (2015)
  • Author(s): Mitsutaka Ogawa, Shogo Sawaguchi, Pawel Bieniasz-Krzywiec, Hirokazu Yagi, Koichi Kato, Jiro Usukura, Koichi Furukawa, Tetsuya Okajima
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-07-28
• [Presentation] Biological roles of extracellular O-GlcNAc in Notch signaling, vascular development, and blood retinal barrier maintenance (2015)
  • Author(s): Mitsutaka Ogawa, Shogo Sawaguchi, Pawel Bieniasz-Krzywiec, Hirokazu Yagi, Koichi Kato, Jiro Usukura, Koichi Furukawa, Tetsuya Okajima
  • Organizer: 生化学会中部支部例会シンポジウム
  • Place of Presentation: 信州大学（長野県松本市）
  • Year and Date: 2015-05-25
• [Presentation] アダムズ-オリバー症候群に関連するEOGT遺伝子変異はER型O-GlcNAc修飾の欠損を引き起こす (2014)
  • Author(s): 小川光貴, 河合崇生, 灘野大太, 松田 幹, 矢木宏和, 加藤晃一, 古川鋼一, 岡島徹也
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Impaired O-GlcNAc Modification in the Endoplasmic Reticulum by Mutated EOGT Assosiated with Adams-Oliver Syndrome. (2014)
  • Author(s): Ogawa M, Kawai T, Nadano D, Matsuda T, Yagi H, Kato K, Furukawa K, Okajima T.
  • Organizer: SFG & JSCR 2014 Joint Annual Meeting
  • Place of Presentation: Honolulu, USA
  • Year and Date: 2014-11-16 – 2014-11-19
• [Presentation] Role of extracellular O-GlcNAc in Notch signaling, retinal vascular development, and blood brain barrier function (2014)
  • Author(s): Ogawa M, Bieniasz-Krzywiec P, Yagi H, Kato K, Usukura J. Furukawa K, Okajima T.
  • Organizer: SFG & JSCR 2014 Joint Annual Meeting - Satellite II: Glycans in Neuroscience
  • Place of Presentation: Honolulu, USA
  • Year and Date: 2014-11-16
• [Presentation] O-GlcNAcylation in the endoplasmic reticulum (2014)
  • Author(s): 岡島 徹也、 小川 光貴、 古川 鋼一
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都国際会議場（京都）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Book] 糖鎖の新機能開発・応用ハンドブック―創薬・医療から食品開発まで (2015)
  • Author(s): 谷口直之、顧 建国、中田 博、岡島徹也、古川鋼一、小川光貴、秋元義弘、木下タロウ、北川裕之、菅原一幸、山本一夫、山田修平、宮城妙子 北島 健、木全弘治、松野健治、岡 昌吾、深瀬浩一、門松健治、川島博人、鈴木 匡、加藤晃一 宮本寛子ら
  • Total Pages: 678
  • Publisher: エヌ・ティー・エス