O-Linked N-Acetylglucosamine Is Present on the Extracellular Domain of Notch Receptors

Matsuura, Aiko; Ito, Makiko; Sakaidani, Yuta; Kondo, Toshiyuki; Murakami, Kosuke; Furukawa, Koichi; Nadano, Daita; Matsuda, Tsukasa; Okajima, Tetsuya

doi:10.1074/jbc.m806202200

Cited by 155 publications

(158 citation statements)

References 37 publications

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“…We also identified an O-GlcNAc site on the EGF-like domain of NOTCH2 protein of the Notch signaling pathway, which we infer is on the T residue in the YSCVCSPGFTGQR sequence, consistent with the CXXGXS/ TGXXC motif (Table 3). Our findings suggest that this EOGT (36) has additional substrates. In fact, we determined that 91 mouse proteins, 104 human proteins, and 18 Drosophila proteins contain the CXXGXS/TGXXC motif (Datasets S6, S7, and S8).…”

Section: O-glcnacylation On a Secreted Protein And On The Extracellularmentioning

confidence: 55%

“…The O-GlcNAc transferase that attaches O-β-GlcNAc to NOTCH is a distinct enzyme that is genetically unrelated to OGT (36). It resides in the endoplasmic reticulum (ER) within the secretory pathway and is termed EGF domain-specific O-GlcNAc transferase (EOGT) (36,37).…”

Section: O-glcnacylation On a Secreted Protein And On The Extracellularmentioning

confidence: 99%

“…It resides in the endoplasmic reticulum (ER) within the secretory pathway and is termed EGF domain-specific O-GlcNAc transferase (EOGT) (36,37). EOGT is conserved Proteins are shaded in different colors according to their functional category.…”

Section: O-glcnacylation On a Secreted Protein And On The Extracellularmentioning

confidence: 99%

“…There is no evidence that intracellular forms of OGT or O-GlcNAcase occur in the extracellular or luminal spaces. Four O-GlcNAcylated peptides from these proteins were located within an EGF-like domain, sharing a similar motif sequence CXXGXS/TGXXC to the reported extracellular O-GlcNAcylation on NOTCH and Dumpy in Drosophila and Notch1 in mammals (36)(37)(38). We also identified an O-GlcNAc site on the EGF-like domain of NOTCH2 protein of the Notch signaling pathway, which we infer is on the T residue in the YSCVCSPGFTGQR sequence, consistent with the CXXGXS/ TGXXC motif (Table 3).…”

Section: O-glcnacylation On a Secreted Protein And On The Extracellularmentioning

confidence: 99%

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Tandem mass spectrometry identifies many mouse brain O -GlcNAcylated proteins including EGF domain-specific O -GlcNAc transferase targets

Alfaro

Gong

Monroe

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

264

265

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O -linked N -acetylglucosamine ( O -GlcNAc) is a reversible posttranslational modification of Ser and Thr residues on cytosolic and nuclear proteins of higher eukaryotes catalyzed by O -GlcNAc transferase (OGT). O -GlcNAc has recently been found on Notch1 extracellular domain catalyzed by EGF domain-specific OGT. Aberrant O -GlcNAc modification of brain proteins has been linked to Alzheimer's disease (AD). However, understanding specific functions of O -GlcNAcylation in AD has been impeded by the difficulty in characterization of O -GlcNAc sites on proteins. In this study, we modified a chemical/enzymatic photochemical cleavage approach for enriching O -GlcNAcylated peptides in samples containing ∼100 μg of tryptic peptides from mouse cerebrocortical brain tissue. A total of 274 O -GlcNAcylated proteins were identified. Of these, 168 were not previously known to be modified by O -GlcNAc. Overall, 458 O -GlcNAc sites in 195 proteins were identified. Many of the modified residues are either known phosphorylation sites or located proximal to known phosphorylation sites. These findings support the proposed regulatory cross-talk between O -GlcNAcylation and phosphorylation. This study produced the most comprehensive O -GlcNAc proteome of mammalian brain tissue with both protein identification and O -GlcNAc site assignment. Interestingly, we observed O -β-GlcNAc on EGF-like repeats in the extracellular domains of five membrane proteins, expanding the evidence for extracellular O -GlcNAcylation by the EGF domain-specific OGT. We also report a GlcNAc-β-1,3-Fuc-α-1- O -Thr modification on the EGF-like repeat of the versican core protein, a proposed substrate of Fringe β-1,3- N -acetylglucosaminyltransferases.

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Section: O-glcnacylation On a Secreted Protein And On The Extracellularmentioning

confidence: 55%

Section: O-glcnacylation On a Secreted Protein And On The Extracellularmentioning

confidence: 99%

Section: O-glcnacylation On a Secreted Protein And On The Extracellularmentioning

confidence: 99%

Section: O-glcnacylation On a Secreted Protein And On The Extracellularmentioning

confidence: 99%

See 2 more Smart Citations

Tandem mass spectrometry identifies many mouse brain O -GlcNAcylated proteins including EGF domain-specific O -GlcNAc transferase targets

Alfaro

Gong

Monroe

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

264

265

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“…The EGF-like repeats in the extracellular domain of Notch and other vertebrate proteins are modified by O-fucose and O-glucose glycans (Rampal et al 2007;Stanley and Okajima 2010), as well as O-GlcNAc (Matsuura et al 2008; Fig. 1).…”

Section: O-glycosylationmentioning

confidence: 99%

Golgi Glycosylation

Stanley

2011

Cold Spring Harbor Perspectives in Biology

353

283

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Multiple roles for O‐glycans in Notch signalling

Varshney

Stanley

2018

FEBS Letters

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Notch signalling regulates a plethora of developmental processes and is also essential for the maintenance of tissue homeostasis in adults. Therefore, fine-tuning of Notch signalling strength needs to be tightly regulated. Of key importance for the regulation of Notch signalling are O-fucose, O-GlcNAc and O-glucose glycans attached to the extracellular domain of Notch receptors. The EGF repeats of the Notch receptor extracellular domain harbour consensus sites for addition of the different types of O-glycan to Ser or Thr, which takes place in the endoplasmic reticulum. Studies from Drosophila to mammals have demonstrated the multifaceted roles of O-glycosylation in regulating Notch signalling. O-glycosylation modulates different aspects of Notch signalling including recognition by Notch ligands, the strength of ligand binding, Notch receptor trafficking, stability and activation at the cell surface. Defects in O-glycosylation of Notch receptors give rise to pathologies in humans. This Review summarizes the nature of the O-glycans on Notch receptors and their differential effects on Notch signalling.

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O-Linked N-Acetylglucosamine Is Present on the Extracellular Domain of Notch Receptors

Cited by 155 publications

References 37 publications

Tandem mass spectrometry identifies many mouse brain O -GlcNAcylated proteins including EGF domain-specific O -GlcNAc transferase targets

Tandem mass spectrometry identifies many mouse brain O -GlcNAcylated proteins including EGF domain-specific O -GlcNAc transferase targets

Golgi Glycosylation

Multiple roles for O‐glycans in Notch signalling

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