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Preventing E-cadherin aberrant N -glycosylation at Asn-554 improves its critical function in gastric cancer

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-cadher...

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Main Authors: Carvalho, Silvia L. (Author) , Catarino, T. A. (Author) , Dias, A. M. (Author) , Kato, M. (Author) , Almeida, A. (Author) , Heßling, Bernd (Author) , Figueiredo, J. (Author) , Gärtner, F. (Author) , Sanches, J. M. (Author) , Ruppert, Thorsten (Author) , Miyoshi, E. (Author) , Pierce, M. (Author) , Carneiro, F. (Author) , Kolarich, D. (Author) , Seruca, R. (Author) , Yamaguchi, Y. (Author) , Taniguchi, N. (Author) , Reis, C. A. (Author) , Pinho, S. S. (Author)
Format: Article (Journal)
Language:English
Published: 2016
In: Oncogene
Year: 2015, Volume: 35, Issue: 13, Pages: 1619-1631
ISSN:1476-5594
DOI:10.1038/onc.2015.225
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/onc.2015.225
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/onc2015225
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Author Notes:S. Carvalho, T.A. Catarino, A.M. Dias, M. Kato, A. Almeida, B. Hessling, J. Figueiredo, F. Gärtner, J.M. Sanches, T. Ruppert, E. Miyoshi, M. Pierce, F. Carneiro, D. Kolarich, R. Seruca, Y. Yamaguchi, N. Taniguchi, C.A. Reis and S.S. Pinho
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Summary: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 β1,6 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.
Item Description:Published 20 July 2015
Gesehen am 29.04.2020
Physical Description:Online Resource
ISSN:1476-5594
DOI:10.1038/onc.2015.225

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