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

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اقرأ أكثر حفظ في قائمتي
  • معلومة اضافية
    • Contributors:
      Instituto de Investigação e Inovação em Saúde
    • بيانات النشر:
      Nature Publishing Group
    • الموضوع:
      2016
    • Collection:
      Repositório Aberto da Universidade do Porto
    • نبذة مختصرة :
      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. ; IPATIMUP integrates the I3S Research Unit, which is partially supported by FCT, the Portuguese Foundation for Science and Technology. This work is funded by FEDER funds through the Operational Programme for Competitiveness Factors—COMPETE— and National Funds through the FCT—Foundation for Science and Technology, under the projects: PTDC/CVT/111358/2009; EXPL/BIM-MEC/0149/2012; and PTDC/BBB-EBI/0786/2012. SC (SFRH/BD/77386/2011), AMD (SFRH/BI/52380/2013) BiotechHealth Doctoral Programme, and SSP (SFRH/BPD/63094/2009) thank FCT and the Luso-American Foundation ...
    • File Description:
      application/pdf
    • ISSN:
      0950-9232
    • Relation:
      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; Oncogene, vol.35(13), p. 1619-1631; https://www.nature.com/articles/onc2015225; https://repositorio-aberto.up.pt/handle/10216/118212
    • الرقم المعرف:
      10.1038/onc.2015.225
    • Rights:
      info:eu-repo/semantics/openAccess
    • الرقم المعرف:
      edsbas.EB98D5D3