Journal
ONCOGENE
Volume 35, Issue 13, Pages 1619-1631Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2015.225
Keywords
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Funding
- FCT, the Portuguese Foundation for Science and Technology
- FEDER funds through the Operational Programme for Competitiveness Factors-COMPETE-
- National Funds through the FCT-Foundation for Science and Technology [PTDC/CVT/111358/2009, EXPL/BIM-MEC/0149/2012, PTDC/BBB-EBI/0786/2012]
- FCT [SFRH/BD/77386/2011, SFRH/BI/52380/2013, SFRH/BPD/63094/2009]
- Luso-American Foundation (FLAD) [SFRH/BD/77386/2011, SFRH/BI/52380/2013, SFRH/BPD/63094/2009]
- Max Planck Society
- European Union [PCIG09-GA-2011-293847, 316929]
- Grants-in-Aid for Scientific Research [15H04700] Funding Source: KAKEN
- Fundação para a Ciência e a Tecnologia [PTDC/CVT/111358/2009, UID/EEA/50009/2013, SFRH/BD/77386/2011, PTDC/BBB-EBI/0786/2012, EXPL/BIM-MEC/0149/2012] Funding Source: FCT
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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 beta 1,6 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.
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