The role of N-acetylglucosaminyltransferase III and V in the post-transcriptional modifications of E-cadherin

• Published in: Human molecular genetics 2009-07, Vol.18 (14), p.2599-2608
• Main Authors: Pinho, Salomé S., Reis, Celso A., Paredes, Joana, Magalhães, Ana Maria, Ferreira, António Carlos, Figueiredo, Joana, Xiaogang, Wen, Carneiro, Fátima, Gärtner, Fátima, Seruca, Raquel
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cadherins - genetics; Cadherins - metabolism; Carcinoma - genetics; Carcinoma - metabolism; Cell Line, Tumor; Fundamental and applied biological sciences. Psychology; Gene Expression; Genetics of eukaryotes. Biological and molecular evolution; Glycosylation; Humans; Molecular and cellular biology; Molecular genetics; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; Protein Processing, Post-Translational; Protein Transport; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Transcription. Transcription factor. Splicing. Rna processing
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddp194

It has long been recognized that E-cadherin dysfunction is a major cause of epithelial cell invasion. However, very little is known about the post-transcriptional modifications of E-cadherin and its role in E-cadherin mediated tumor progression. N-acetylglucosaminyltransferase III (GnT-III) catalyzes the formation of a bisecting GlcNAc structure in N-glycans, and has been pointed as a metastasis suppressor. N-acetylglucosaminyltransferase V (GnT-V) catalyzes the addition of β1,6 GlcNAc branching of N-glycans, and has been associated to increase metastasis. The regulatory mechanism between E-cadherin expression and the remodeling of its oligosaccharides structures by GnT-III and GnT-V were explored in this study. We have demonstrated that wild-type E-cadherin regulates MGAT3 gene transcription resulting in increased GnT-III expression. We also showed that GnT-III and GnT-V competitively modified E-cadherin N-glycans. The GnT-III knockdown cells revealed a membrane de-localization of E-cadherin leading to its cytoplasmic accumulation. Further, the GnT-III knockdown cells also caused modifications of E-cadherin N-glycans catalyzed by GnT-III and GnT-V. Altogether our results have clarified the existence of a bidirectional crosstalk between E-cadherin and GnT-III/GnT-V that was, for the first time, reproduced in an in vivo model. This study opens new insights into the post-transcriptional modifications of E-cadherin in its biological function, in a tumor context.