Regulation of Notch signaling by glycosylation

Stanley, Pamela

doi:10.1016/j.sbi.2007.09.007

Cited by 122 publications

(90 citation statements)

References 50 publications

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“…Specific types of glycosyl residues modulate particular signaling pathways and regulate cell phenotypes. For example, GM3 inhibits epithelial growth factor receptor (EGFR) activation (3,4); GM2 associated with tetraspanine CD82 inhibits the activation of the hepatocyte growth factor receptor cMet (5); and O-Fucose glycans modulate Notch signaling, which controls the fate of many cell types (6)(7)(8).…”

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confidence: 99%

Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process

Freire-de-Lima

Gelfenbeyn

Ding

et al. 2011

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

113

130

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The process termed "epithelial-mesenchymal transition" (EMT) was originally discovered in ontogenic development, and has been shown to be one of the key steps in tumor cell progression and metastasis. Recently, we showed that the expression of some glycosphingolipids (GSLs) is down-regulated during EMT in human and mouse cell lines. Here, we demonstrate the involvement of GalNAc-type (or mucintype) O-glycosylation in EMT process, induced with transforming growth factor β (TGF-β) in human prostate epithelial cell lines. We found that: (i) TGF-β treatment caused up-regulation of oncofetal fibronectin (onfFN), which is defined by mAb FDC6, and expressed in cancer or fetal cells/tissues, but not in normal adult cells/tissues. The reactivity of mAb FDC6 requires the addition of an O-glycan at a specific threonine, inside the type III homology connective segment (IIICS) domain of FN. (ii) This change is associated with typical EMT characteristics; i.e., change from epithelial to fibroblastic morphology, enhanced cell motility, decreased expression of a typical epithelial cell marker, E-cadherin, and enhanced expression of mesenchymal markers. (iii) TGF-β treatment up-regulated mRNA level of FN containing the IIICS domain and GalNAc-T activity for the IIICS domain peptide substrate containing the FDC6 onfFN epitope. (iv) Knockdown of GalNAc-T6 and T3 inhibited TGF-β-induced up-regulation of onfFN and EMT process. (v) Involvement of GSLs was not detectable with the EMT process in these cell lines. These findings indicate the important functional role of expression of onfFN, defined by sitespecific O-glycosylation at IIICS domain, in the EMT process.O-glycosylated fibronectin | siRNA G lycoconjugates, such as glycosphingolipids (GSLs) and N-and O-linked glycoproteins, have been shown to play important roles in embryogenesis (1), tumorigenesis, and cancer progression (2). Specific types of glycosyl residues modulate particular signaling pathways and regulate cell phenotypes. For example, GM3 inhibits epithelial growth factor receptor (EGFR) activation (3, 4); GM2 associated with tetraspanine CD82 inhibits the activation of the hepatocyte growth factor receptor cMet (5); and O-Fucose glycans modulate Notch signaling, which controls the fate of many cell types (6-8).Epithelial-mesenchymal transition (EMT) was initially observed during early embryonic development and organ formation (9-11). Accumulating evidence has shown that the EMT process plays a key role in disease development, particularly in cancer progression to metastasis (10-14) and fibrosis (15). During EMT, cells lose their apical-basal polarity, change morphology to fibroblastic, display reduced expression of epithelial cell marker molecules such as E-cadherin (Ecad), and enhance expression of mesenchymal cell marker molecules such as fibronectin (FN), N-cadherin (Ncad), vimentin, and matrix-metalloproteinases (MMPs). When combined, these effects result in increased cell motility (10-15).Our recent studies found a reduction in specific GSLs (Gg4 and/ or GM2) in ...

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confidence: 99%

Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process

Freire-de-Lima

Gelfenbeyn

Ding

et al. 2011

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

113

130

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“…Post-translational modification of proteins can also play a role in Notch regulation. For example, Notch itself can be modified by O-fucosyl transferase (a glycosyltransferase and chaperone), Fringe (a glycosyltransferase), and proteases such as Furin (Nichols et al 2007b;Stanley 2007;Irvine 2008). Drosophila wing, eye, and bristle development are excellent contexts in which to study mechanisms of Notch-mediated development and uncover additional components in the pathway.…”

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confidence: 99%

A Screen for Modifiers of Notch Signaling Uncovers Amun, a Protein With a Critical Role in Sensory Organ Development

et al. 2009

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Notch signaling is an evolutionarily conserved pathway essential for many cell fate specification events during metazoan development. We conducted a large-scale transposon-based screen in the developing Drosophila eye to identify genes involved in Notch signaling. We screened 10,447 transposon lines from the Exelixis collection for modifiers of cell fate alterations caused by overexpression of the Notch ligand Delta and identified 170 distinct modifier lines that may affect up to 274 genes. These include genes known to function in Notch signaling, as well as a large group of characterized and uncharacterized genes that have not been implicated in Notch pathway function. We further analyze a gene that we have named Amun and show that it encodes a protein that localizes to the nucleus and contains a putative DNA glycosylase domain. Genetic and molecular analyses of Amun show that altered levels of Amun function interfere with cell fate specification during eye and sensory organ development. Overexpression of Amun decreases expression of the proneural transcription factor Achaete, and sensory organ loss caused by Amun overexpression can be rescued by coexpression of Achaete. Taken together, our data suggest that Amun acts as a transcriptional regulator that can affect cell fate specification by controlling Achaete levels.

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“…The mild detergents used in BN-PAGE, which was developed for the analysis of mitochondrial protein complexes, appear well suited to the study of endocytic trafficking (62); at steady state, most of the PAM-1 in cell lysates is located in endocytic compartments (5,63). Aberrant O-glycosylation is known to alter early steps in the endocytic trafficking of MUC1, a type 1 transmembrane protein with multiple mucin-type O-linked glycans (64), and Notch 1 (65). In addition, lectins are well recognized contributors to the endocytic trafficking so essential to immune cell functioning.…”

Section: Discussionmentioning

confidence: 99%

O-Glycosylation of a Secretory Granule Membrane Enzyme Is Essential for Its Endocytic Trafficking

Vishwanatha

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Lam

et al. 2016

Journal of Biological Chemistry

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Regulation of Notch signaling by glycosylation

Cited by 122 publications

References 50 publications

Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process

Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process

A Screen for Modifiers of Notch Signaling Uncovers Amun, a Protein With a Critical Role in Sensory Organ Development

O-Glycosylation of a Secretory Granule Membrane Enzyme Is Essential for Its Endocytic Trafficking

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