O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals

Shogo Sawaguchi, Shweta Varshney, Mitsutaka Ogawa, Yuta Sakaidani, Hirokazu Yagi, Kyosuke Takeshita, Toyoaki Murohara, Koichi Kato, Subha Sundaram, Pamela Stanley, Tetsuya Okajima

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 of Eogt resulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina. Combined deficiency of different Notch1 mutant alleles exacerbated the abnormalities in Eogt/ retina, and Notch target gene expression was decreased in Eogt/ endothelial cells. Thus, O-GlcNAc on EGF repeats of Notch receptors mediates ligand-induced Notch signaling required in endothelial cells for optimal vascular development.

Original languageEnglish (US)
Article numbere24419
JournaleLife
Volume6
DOIs
StatePublished - Apr 11 2017

Fingerprint

Mammals
Epidermal Growth Factor
Notch Receptors
Blood Vessels
Endothelial cells
Endothelial Cells
Ligands
Retina
Glycosyltransferases
Mutagenesis
Membrane Proteins
Alleles
Gene expression
Phenotype
Gene Expression

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Sawaguchi, S., Varshney, S., Ogawa, M., Sakaidani, Y., Yagi, H., Takeshita, K., ... Okajima, T. (2017). O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals. eLife, 6, [e24419]. https://doi.org/10.7554/eLife.24419

O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals. / Sawaguchi, Shogo; Varshney, Shweta; Ogawa, Mitsutaka; Sakaidani, Yuta; Yagi, Hirokazu; Takeshita, Kyosuke; Murohara, Toyoaki; Kato, Koichi; Sundaram, Subha; Stanley, Pamela; Okajima, Tetsuya.

In: eLife, Vol. 6, e24419, 11.04.2017.

Research output: Contribution to journalArticle

Sawaguchi, S, Varshney, S, Ogawa, M, Sakaidani, Y, Yagi, H, Takeshita, K, Murohara, T, Kato, K, Sundaram, S, Stanley, P & Okajima, T 2017, 'O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals', eLife, vol. 6, e24419. https://doi.org/10.7554/eLife.24419
Sawaguchi S, Varshney S, Ogawa M, Sakaidani Y, Yagi H, Takeshita K et al. O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals. eLife. 2017 Apr 11;6. e24419. https://doi.org/10.7554/eLife.24419
Sawaguchi, Shogo ; Varshney, Shweta ; Ogawa, Mitsutaka ; Sakaidani, Yuta ; Yagi, Hirokazu ; Takeshita, Kyosuke ; Murohara, Toyoaki ; Kato, Koichi ; Sundaram, Subha ; Stanley, Pamela ; Okajima, Tetsuya. / O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals. In: eLife. 2017 ; Vol. 6.
@article{219b1b09b0084b39ac33c42e10ddd0eb,
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 of Eogt resulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina. Combined deficiency of different Notch1 mutant alleles exacerbated the abnormalities in Eogt/ retina, and Notch target gene expression was decreased in Eogt/ endothelial cells. Thus, O-GlcNAc on EGF repeats of Notch receptors mediates ligand-induced Notch signaling required in endothelial cells for optimal vascular development.",
author = "Shogo Sawaguchi and Shweta Varshney and Mitsutaka Ogawa and Yuta Sakaidani and Hirokazu Yagi and Kyosuke Takeshita and Toyoaki Murohara and Koichi Kato and Subha Sundaram and Pamela Stanley and Tetsuya Okajima",
year = "2017",
month = "4",
day = "11",
doi = "10.7554/eLife.24419",
language = "English (US)",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals

AU - Sawaguchi, Shogo

AU - Varshney, Shweta

AU - Ogawa, Mitsutaka

AU - Sakaidani, Yuta

AU - Yagi, Hirokazu

AU - Takeshita, Kyosuke

AU - Murohara, Toyoaki

AU - Kato, Koichi

AU - Sundaram, Subha

AU - Stanley, Pamela

AU - Okajima, Tetsuya

PY - 2017/4/11

Y1 - 2017/4/11

N2 - 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 of Eogt resulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina. Combined deficiency of different Notch1 mutant alleles exacerbated the abnormalities in Eogt/ retina, and Notch target gene expression was decreased in Eogt/ endothelial cells. Thus, O-GlcNAc on EGF repeats of Notch receptors mediates ligand-induced Notch signaling required in endothelial cells for optimal vascular development.

AB - 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 of Eogt resulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina. Combined deficiency of different Notch1 mutant alleles exacerbated the abnormalities in Eogt/ retina, and Notch target gene expression was decreased in Eogt/ endothelial cells. Thus, O-GlcNAc on EGF repeats of Notch receptors mediates ligand-induced Notch signaling required in endothelial cells for optimal vascular development.

UR - http://www.scopus.com/inward/record.url?scp=85017556517&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017556517&partnerID=8YFLogxK

U2 - 10.7554/eLife.24419

DO - 10.7554/eLife.24419

M3 - Article

C2 - 28395734

AN - SCOPUS:85017556517

VL - 6

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e24419

ER -