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Comprehensive analysis of O-linked glycans on Notch receptors using mass spectrometry

ABSTRACT: Notch signaling is essential for the development and homeostasis of multicellular organisms. Dysregulation of Notch signaling leads to several human diseases. Genetic and biochemical studies have shown that O-linked glycosylation on Notch receptors is essential for the transduction of Notch signaling. However, how O-linked glycans regulate the activity of Notch signaling is still unknown. To pursue this, we need to know the whole aspect of glycan modification on Notch. We performed mass spectrometric analysis of Notch1 and 3 to reveal O-glycosylation on each EGF repeat.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Hideyuki Takeuchi

PROVIDER: PXD048533 | JPOST Repository | Tue Jan 14 00:00:00 GMT 2025

REPOSITORIES: jPOST

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			Action	DRS
	B4GALT2%20KO%20%232.raw	Raw
	B4GALT3%20KO%20%231.raw	Raw
	B4GALT3%20KO%20%232.raw	Raw
	B4GALT4%20KO%20%231.raw	Raw
	B4GALT4%20KO%20%232.raw	Raw

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NRARP-TAP/MS, Sanchez et. al., Science Signaling 2019

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Glyco-gene expression in DP thymic T cells from control and mutant mice that carry a mutation in the ligand binding domain of Notch1

Project description:Dr. Stanley's laboratory is interested in determining how O-fucose glycans function in Notch receptor signaling and in modulating the interactions of Notch receptors with their ligands. We have generated mice carrying a point mutation in the ligand binding domain of Notch1 that reduces Notch ligand binding to mutant T cells. We wish to identify Notch target genes including glycosylation genes with altered expression in DP thymic T cells from mutant and control mice. DP cells were prepared from the thymus of 3 control and 3 mutant mice at ~8 weeks of age and RNA extracted from each prep will be analysed. RNA preparations from CD4+CD8+ double positive (DP) T cells from F+2323, F+2324, F+2329 (control) and FF2330, FF2332, FF2333 (Notch1 with a point mutation to prevent fucosylation in EGF12) mice of ~8 weeks were sent to the Microarray Core (E). The RNA was amplified, labeled, and hybridized to the GLYCOv3 microarrays.

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Cancer-associated Notch receptor variants lead to O-fucosylation defects that can deregulate Notch signaling

Project description:NOTCH1 is a transmembrane receptor that initiates the Notch signaling pathway involved in embryonic development and maintenance of adult tissue homeostasis. The extracellular part of NOTCH1 is composed largely of EGF-like domains (EGFs) many of which can be O-fucosylated by protein O-fucosyltransferase 1 (POFUT1). O-fucosylation of NOTCH1 is necessary for its function. The Notch pathway is deregulated in many cancers, and alteration of POFUT1 has been reported in some cancers. Using the Biomuta and COSMIC databases, we selected 9 NOTCH1 variants that could cause a change in O-fucosylation of key EGFs. Cell-based N1 signaling assays, Notch ligand-binding assays and cell surface N1 analysis were used to determine the effect of each mutation on Notch activation. Then mass spectral glycoproteomic site mapping was used to identify alterations in the O-fucosylation of EGFs containing the selected mutation. One of the variants had few effects, two lead to a gain of function (GOF) and six to a loss of function (LOF). Most GOF and LOF could be associated with a change in O-fucosylation. Finally, by comparing our results with known NOTCH1 alterations in cancers from which our mutations originated, we were able to establish a correlation between our results and the known GOF or LOF of NOTCH1 in these cancers. This study shows that point mutations in NOTCH1 can lead to alterations in O-fucosylation that deregulate the Notch pathway and be associated with cancer processes.

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