PMID: 18491227

 

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Title : Unglycosylation at Asn-633 made extracellular domain of E-cadherin folded incorrectly and arrested in endoplasmic reticulum, then sequentially degraded by ERAD

Abstract :

1. The human E-cadherin is a single transmembrane domain protein involved in Ca(2 +)-dependent cell-cell adhesion
2. In a previous study, we demonstrated that all of four potential N-glycosylation sites in E-cadherin are occupied by N-glycans in human breast carcinoma cells in vivo and the elimination of N-glycan at Asn-633 dramatically affected E-cadherin expression and made it degraded
3. In this study we investigated the molecular mechanism of E-cadherin , which lacks N-glycosylation at Asn-633 (M4), degradation and the role of the N-glycan at Asn-633 in E-cadherin folding
4. We treated cells stably expressed M4 E-cadherin with MG123, DMM, respectively
5. Either MG132 or DMM could efficiently block degradation of M4 E-cadherin
6. M4 E-cadherin was recognized as the substrate of ERAD and was retro-translocated from ER lumen to cytoplasm by p97
7. It was observed that the ration of M4 E-cadherin binding to calnexin was significantly increased compared with that of other variants , suggesting that it was a misfolded protein , though cytoplasmic domain of M4 E-cadherin could associate with beta-catenin
8. Furthermore, we found that N-glycans of M4 E-cadherin were modified in immature high mannose type, suggesting that it could not depart to Golgi apparatus
9. In conclusion, this study revealed that N-glycosylation at Asn-633 is essential for E-cadherin expression, folding and trafficking