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名古屋大学・医学系研究科・教授

科学研究費助成事業  研究成果報告書

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

２０４２０３８３ 研究者番号： 岡島 徹也（OKAJIMA, Tetsuya） 研究期間： ２６２９１０２０ 平成 ３０ 年 ５ 月 ２４ 日現在 円 12,800,000 研究成果の概要（和文）：Notch受容体の細胞外領域に存在する上皮成長因子（EGF）様リピートには特徴的な翻 訳後修飾が存在している。これまでの研究で、O-フコースとO-グルコースに加えて、O-GlcNAc修飾が存在するこ とを報告した。しかしながら、O-GlcNAc修飾のNotch受容体における役割は不明であった。本研究では、 O-GlcNAc修飾に関わる糖転移酵素EOGTの遺伝子欠損マウスを作製し、表現型解析を行なった。その結果、Notch1 の特定のEGFドメインのO-GlcNAc修飾が、Delta-like 4リガンドを介したNotch1の活性化を制御することで、網 膜の血管形成に関与することが明らかになった。

研究成果の概要（英文）：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.

研究分野： 生化学

キーワード： Notch EOGT O-GlcNAc 血管形成 マウス

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1) Sawaguchi S, Ogawa M, Okajima T. Protocol for Notch-ligand Binding Assays Using Dynabeads. Bio-protocol 7: e2582(2017) doi: 10.21769/BioProtoc.2582

2) Sawaguchi S, Varshney S, Ogawa M,

Sakaidani Y, Yagi H, Takeshita K, Murohara T, Kato K, Sundaram S, Stanley P and Okajima T. O-GlcNAc on NOTCH1 EGF Repeats Regulates Ligand-Induced Notch Signaling and Vascular Development in Mammals. eLife 6: e24419. (2017) doi: 10.7554/eLife.24419

3) Kaneko K, Ohkawa Y, Hashimoto N, Ohmi Y, Kotani N, Honke K, Ogawa M, Okajima T, Furukawa K, Furukawa K. Neogenin defined as a GD3-associated molecule by enzyme-mediated activation of radical sources confers malignant properties via intra-cytoplasmic domain in melanoma cells. J Biol Chem. 291, 16630-16643 (2016)

4) Ogawa M, Sawaguchi S, Kamemura K, Okajima T. Intracellular and extracellular O-linked N-acetylglucosamine in the nervous system. Exp. Neurol. 274:166-174 (2015)

5) Ogawa M, Sawaguchi S, Furukawa K, Okajima T. N-acetylglucosamine modification in the lumen of the endoplasmic reticulum. Biochim. Biophys. Acta. Gen. Subj. 1850:1319-1324 (2015)

6) Ogawa M, Furukawa K, Okajima T. Extracellular O-linked

beta-N-acetylglucosamine: Its biology and relationship to human disease. World J Biol Chem 5:224-230 (2014) h i 15 0 2 4 6 *** *** 0 2 4 ** DLL4 JAG1

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