Significance of glycosylation in Notch signaling

Takeuchi, Hideyuki; Haltiwanger, Robert S.

doi:10.1016/j.bbrc.2014.05.115

Cited by 143 publications

(137 citation statements)

References 109 publications

(165 reference statements)

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“…The role of O-glycosylation on the EGF repeats of Notch has been studied intensely in recent years, especially the mechanisms of how Fringe modulates Notch-ligand binding (16,43). However, to gain additional insight into how these essential modifications impart functionality to the receptor, it is critical to first establish whether the predicted sites of O-glycosylation are modified as well as to determine the relative amounts of the various glycoforms of O-glycosylation at each of those sites.…”

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Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

Harvey

Rana

Moss

et al. 2016

Journal of Biological Chemistry

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Glycosylation of the Notch receptor is essential for its activity and serves as an important modulator of signaling. Three major forms of O-glycosylation are predicted to occur at consensus sites within the epidermal growth factor-like repeats in the extracellular domain of the receptor: O-fucosylation, O-glucosylation, and O-GlcNAcylation. We have performed comprehensive mass spectral analyses of these three types of O-glycosylation on Drosophila Notch produced in S2 cells and identified peptides containing all 22 predicted O-fucose sites, all 18 predicted O-glucose sites, and all 18 putative O-GlcNAc sites. Using semiquantitative mass spectral methods, we have evaluated the occupancy and relative amounts of glycans at each site. The majority of the O-fucose sites were modified to high stoichiometries. Upon expression of the ␤3-N-acetylglucosaminyltransferase Fringe with Notch, we observed varying degrees of elongation beyond O-fucose monosaccharide, indicating that Fringe preferentially modifies certain sites more than others. Rumi modified O-glucose sites to high stoichiometries, although elongation of the O-glucose was site-specific. Although the current putative consensus sequence for O-GlcNAcylation predicts 18 O-GlcNAc sites on Notch, we only observed apparent O-GlcNAc modification at five sites. In addition, we performed mass spectral analysis on endogenous Notch purified from Drosophila embryos and found that the glycosylation states were similar to those found on Notch from S2 cells. These data provide foundational information for future studies investigating the mechanisms of how O-glycosylation regulates Notch activity.

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Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

Harvey

Rana

Moss

et al. 2016

Journal of Biological Chemistry

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“…However, only a subset of these contain the conserved C2-X(3-5)-S/T-C3 site that is the described substrate of O-fucosyltransferases (see Fig. 3C, Table S1) (Takeuchi and Haltiwanger, 2014). Interestingly, the list of putative protein substrates contains mostly receptor-like kinases, suggesting a role in signaling.…”

Section: Results and Discussion A Cell Adhesion Defect Suppressor Screenmentioning

confidence: 99%

Cell adhesion in plants is under the control of putative O-fucosyltransferases

Verger¹,

Chabout²,

Gineau³

et al. 2016

Journal of Cell Science

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Cell-to-cell adhesion in plants is mediated by the cell wall and the presence of a pectin-rich middle lamella. However, we know very little about how the plant actually controls and maintains cell adhesion during growth and development and how it deals with the dynamic cell wall remodeling that takes place. Here we investigate the molecular mechanisms that control cell adhesion in plants. We carried out a genetic suppressor screen and a genetic analysis of cell adhesion-defective Arabidopsis thaliana mutants. We identified a genetic suppressor of a cell adhesion defect affecting a putative O-fucosyltransferase. Furthermore, we show that the state of cell adhesion is not directly linked with pectin content in the cell wall but instead is associated with altered pectin-related signaling. Our results suggest that cell adhesion is under the control of a feedback signal from the state of the pectin in the cell wall. Such a mechanism could be necessary for the control and maintenance of cell adhesion during growth and development.

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“…Glycosylation is one of the most abundant protein modifications (12,13). Although N-glycosylation occurs at predictable sites (-Asn-Xaa-Ser/Thr-, where Xaa is not Pro) and must be initiated in the endoplasmic reticulum, O-glycosylation sites cannot be predicted based on primary sequence (14,15).…”

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“…These O-linked oligosaccharides are generally short, often containing only one to four sugar residues; the O-linked oligosaccharides identified in PAM-1 share these properties (3). O-Glycosylation governs many aspects of cellular homeostasis, including vascular integrity (17), notch signaling (12), and intestinal homeostasis (18). Many congenital diseases have been attributed to deficits in O-glycosylation (19,20), including autoimmune disorders (21), heterotaxy (22), hyperphosphatemia (23,24), nephropathy, and breast adenocarcinoma (25).…”

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