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

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

doi:10.7554/elife.24419

Cited by 82 publications

(73 citation statements)

References 81 publications

(123 reference statements)

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“…We observed a similar reduction in arterial smooth muscle coverage in Lamc3 2/2 and Dag1 DEC retinae, phenocopying Eogt 2/2 retinae in which Dll4 binding to Notch1 receptor is disrupted (39). The arterial dysgenesis, detectable in the Lamc3 2/2 retina as early as P5, persisted even after retinal arteries were fully specified and arterial morphology is established (P12).…”

Section: Laminin-g3-dg Signaling Regulates Arterial Morphogenesis In supporting

confidence: 59%

Laminin‐dystroglycan signaling regulates retinal arteriogenesis

et al. 2018

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Proper arteriovenous morphogenesis is crucial for maintaining normal tissue perfusion. However, our understanding of how arterial morphogenesis is regulated in the CNS is incomplete. In this study, we asked whether vascular basement membrane (BM) laminins, specifically the γ3-containing isoforms, regulate retinal arterial morphogenesis. We provide evidence that Laminin-γ3 is deposited at both arterial and venous BMs during arteriogenesis. Vascular BM Laminin-γ3 bound dystroglycan (DG), a laminin receptor preferentially expressed by arterial endothelial cells (ECs) during arteriogenesis. Blockade of laminin-DG binding in vitro led to decreased Delta-like ligand (DLL)-4 expression in ECs. Moreover, genetic deletion of the Laminin-γ3- and EC-specific deletion of DG led to similar defects in retinal arteriogenesis, including reduced Dll4 expression, hyperbranching and reduced smooth muscle coverage. These results implicate a newly identified Laminin-γ3-DG signaling cascade that regulates arterial Dll4/Notch signaling to specify and stabilize retinal arteries.-Biswas, S., Watters, J., Bachay, G., Varshney, S., Hunter, D. D., Hu, H., Brunken, W. J. Laminin-dystroglycan signaling regulates retinal arteriogenesis.

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Section: Laminin-g3-dg Signaling Regulates Arterial Morphogenesis In supporting

confidence: 59%

Laminin‐dystroglycan signaling regulates retinal arteriogenesis

et al. 2018

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“…Three O-glycans are added at specific sites on EGF repeats by three separate enzymes: protein O-glucosyltransferase 1 (POGLUT1) adds O-glucose to serine residues within the sequence C 1 XSX(P/A)C 2 (where C 1 and C 2 are the first and second conserved cysteine of the EGF repeat); POFUT1 adds O-fucose to serine/threonine residues within the sequence C 2 XXXX(S/T)C 3 ; and EGF-specific O-GlcNAc transferase (EOGT) adds O-GlcNAc to serine/threonine residues within the sequence C 5 XXGX(T/S)GXXC 6 (10,11). All three enzymes modify multiple EGF repeats in the extracellular domain of the Notch receptor (12)(13)(14), and these modifications are essential for optimal Notch activity (15)(16)(17). Human diseases result from inactivating mutations in these enzymes and appear to be mediated by reduced Notch function (17)(18)(19)(20).…”

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confidence: 99%

“…Similarly, elimination of the Drosophila form of POGLUT1 (Rumi) caused some Notch trafficking defects, whereas knockdown of Poglut1 in mouse cell lines did not reduce cell-surface Notch (8,16). Elimination of EOGT in mammalian cells does not appear to have any effect on Notch trafficking (17).…”

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confidence: 99%

O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking

Takeuchi

Hao

et al. 2017

Journal of Biological Chemistry

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Glycosylation in the endoplasmic reticulum (ER) is closely associated with protein folding and quality control. We recently described a non-canonical ER quality control mechanism for folding of thrombospondin type 1 repeats by protein O-fucosyltransferase 2 (POFUT2). Epidermal growth factor-like (EGF) repeats are also small cysteine-rich protein motifs that can be O-glycosylated by several ER-localized enzymes, including protein O-glucosyltransferase 1 (POGLUT1) and POFUT1. Both POGLUT1 and POFUT1 modify the Notch receptor on multiple EGF repeats and are essential for full Notch function. The fact that POGLUT1 and POFUT1 can distinguish between folded and unfolded EGF repeats raised the possibility that they participate in a quality control pathway for folding of EGF repeats in proteins such as Notch. Here, we demonstrate that cell-surface expression of endogenous Notch1 in HEK293T cells is dependent on the presence of POGLUT1 and POFUT1 in an additive manner. In vitro unfolding assays reveal that addition of O-glucose or O-fucose stabilizes a single EGF repeat and that addition of both O-glucose and O-fucose enhances stability in an additive manner. Finally, we solved the crystal structure of a single EGF repeat covalently modified by a full O-glucose trisaccharide at 2.2 Å resolution. The structure reveals that the glycan fills up a surface groove of the EGF with multiple contacts with the protein, providing a chemical basis for the stabilizing effects of the glycans. Taken together, this work suggests that O-fucose and O-glucose glycans cooperatively stabilize individual EGF repeats through intramolecular interactions, thereby regulating Notch trafficking in cells.

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“…Notch binding to DLL1 or DLL4, whereas Notch binding to JAG1 was not affected (Sawaguchi et al, 2017). In mammals, O-GlcNAc glycans can be elongated with a galactose and a sialic acid (Kakuda & Haltiwanger, 2017;Ogawa et al, 2018).…”

Section: ) Mechanistically Eogt-deficient Cells Exhibited Decrementioning

confidence: 97%

Effects of Notch glycosylation on health and diseases

Urata

Takeuchi

2019

Dev Growth Differ

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Notch signaling is an evolutionarily conserved signaling pathway and is essential for cell-fate specification in metazoans. Dysregulation of Notch signaling results in various human diseases, including cardiovascular defects and cancer. In 2000, Fringe, a known regulator of Notch signaling, was discovered as a Notch-modifying glycosyltransferase. Since then, glycosylation-a post-translational modification involving literal sugars-on the Notch extracellular domain has been noted as a critical mechanism for the regulation of Notch signaling. Additionally, the presence of diverse Oglycans decorating Notch receptors has been revealed in the extracellular domain epidermal growth factor-like (EGF) repeats. Here, we concisely summarize the recent studies in the human diseases associated with aberrant Notch glycosylation. K E Y W O R D S

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

Cited by 82 publications

References 81 publications

Laminin‐dystroglycan signaling regulates retinal arteriogenesis

Laminin‐dystroglycan signaling regulates retinal arteriogenesis

O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking

Effects of Notch glycosylation on health and diseases

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