title: O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals.
abstract: The glycosyltransferase EOGT transfers O-GlcNAc to a consensus site in epidermal growth factor-like (EGF) repeats of a limited number of secreted and membrane proteins, including Notch receptors. In EOGT-deficient cells, the binding of DLL1 and DLL4, but not JAG1, canonical Notch ligands was reduced, and ligand-induced Notch signaling was impaired. Mutagenesis of O-GlcNAc sites on NOTCH1 also resulted in decreased binding of DLL4. EOGT functions were investigated in retinal angiogenesis that depends on Notch signaling. Global or endothelial cell-specific deletion ofEogtresulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina. Combined deficiency of differentNotch1mutant alleles exacerbated the abnormalities inEogt-/-retina, and Notch target gene expression was decreased inEogt-/-endothelial cells. Thus, O-GlcNAc on EGF repeats of Notch receptors mediates ligand-induced Notch signaling required in endothelial cells for optimal vascular development.
authors.affiliation: Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Sawaguchi
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, United States.
authors.forename: Shweta
authors.initials: S
authors.lastname: Varshney
authors.affiliation: Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Sakaidani
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Yagi
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.|Institute for Molecular Science and Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, United States.
authors.forename: Subha
authors.initials: S
authors.lastname: Sundaram
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, United States.
authors.forename: Pamela
authors.identifier: 0000-0001-5704-3747
authors.initials: P
authors.lastname: Stanley
authors.affiliation: Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tetsuya
authors.identifier: 0000-0002-3677-648X
authors.initials: T
authors.lastname: Okajima
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D042783:Endothelial Cells / Q000502:physiology; D006031:Glycosylation; D006801:Humans; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D051881:Receptor, Notch1 / Q000378:metabolism*; D012160:Retina / Q000502:physiology; D015398:Signal Transduction
chemical_list: D051881:Receptor, Notch1; C000617979:EOGT protein, human; D017351:N-Acetylglucosaminyltransferases; D000117:Acetylglucosamine
keywords: DLL4; EOGT; Notch signaling; O-GlcNAc; biochemistry; developmental biology; mouse; retinal angiogenesis; stem cells