Please use this identifier to cite or link to this item: https://repositorio-aberto.up.pt/handle/10216/118212
Author(s): Carvalho, S
Catarino, TA
Dias, A
Kato, M
Almeida, A
Hessling, B
Figueiredo, J
Gärtner, F
Sanches, J
Ruppert, T
Miyoshi, E
Pierce, M
Carneiro, F
Kolarich, D
Seruca, R
Yamaguchi, Y
Taniguchi, N
Reis, CA
Pinho, SS
Title: Preventing E-cadherin aberrant N-glycosylation at Asn-554 improves its critical function in gastric cancer
Publisher: Nature Publishing Group
Issue Date: 2016
Abstract: E-cadherin is a central molecule in the process of gastric carcinogenesis and its posttranslational modifications by N-glycosylation have been described to induce a deleterious effect on cell adhesion associated with tumor cell invasion. However, the role that site-specific glycosylation of E-cadherin has in its defective function in gastric cancer cells needs to be determined. Using transgenic mice models and human clinical samples, we demonstrated that N-acetylglucosaminyltransferase V (GnT-V)-mediated glycosylation causes an abnormal pattern of E-cadherin expression in the gastric mucosa. In vitro models further indicated that, among the four potential N-glycosylation sites of E-cadherin, Asn-554 is the key site that is selectively modified with ß1,6 GlcNAc-branched N-glycans catalyzed by GnT-V. This aberrant glycan modification on this specific asparagine site of E-cadherin was demonstrated to affect its critical functions in gastric cancer cells by affecting E-cadherin cellular localization, cis-dimer formation, molecular assembly and stability of the adherens junctions and cell-cell aggregation, which was further observed in human gastric carcinomas. Interestingly, manipulating this site-specific glycosylation, by preventing Asn-554 from receiving the deleterious branched structures, either by a mutation or by silencing GnT-V, resulted in a protective effect on E-cadherin, precluding its functional dysregulation and contributing to tumor suppression.
Subject: Amino Acid Sequence
Animals
Asparagine/genetics
Cadherins/chemistry
Cadherins/genetics
Cadherins/metabolism
Cadherins/physiology
Catalytic Domain/genetics
Cell Line, Tumor
Dogs
Gastric Mucosa/metabolism
Gastric Mucosa/pathology
Glycosylation
HT29 Cells
Humans
Madin Darby Canine Kidney Cells
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Sequence Data
Mutagenesis, Site-Directed
N-Acetylglucosaminyltransferases/antagonists & inhibitors
N-Acetylglucosaminyltransferases/genetics
N-Acetylglucosaminyltransferases/metabolism
Sequence Homology, Amino Acid
Stomach Neoplasms/genetics
Stomach Neoplasms/metabolism
Stomach Neoplasms/pathology
URI: https://repositorio-aberto.up.pt/handle/10216/118212
Source: Oncogene, vol.35(13), p. 1619-1631
Related Information: info:eu-repo/grantAgreement/FCT/5876-PPCDTI/111358/PT
info:eu-repo/grantAgreement/FCT/5876-PPCDTI/124445/PT
info:eu-repo/grantAgreement/FCT/COMPETE/125428/PT
info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F77386%2F2011/PT
info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F63094%2F2009/PT
info:eu-repo/grantAgreement/FCT/5876/147329/PT
Document Type: Artigo em Revista Científica Internacional
Rights: openAccess
Appears in Collections:I3S - Artigo em Revista Científica Internacional

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