Human Molecular Genetics Advance Access published online on September 4, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn249
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Endoplasmic Reticulum Quality Control: a new mechanism of E-cadherin regulation and its implication in cancer
1 IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal 2 Medical Faculty of the University of Porto, 4200-319 Porto, Portugal 3 Molecular Cell Biology Unit, Department for Molecular Biomedical Research, VIB, B-9052 Ghent, Belgium 4 Department of Molecular Biology, Ghent University, Ghent, Belgium
Corresponding Author: Gianpaolo Suriano, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal; Tel: +351225570700; FAX: +351225570799; E-mail: gsuriano{at}ipatimup.pt
Received July 7, 2008; Revised August 8, 2008; Accepted August 16, 2008
E-cadherin is critical for the maintenance of tissue architecture and is a major component of adherens junctions. Its role in tumour development is well established, with many human carcinomas exhibiting E-cadherin loss at the invasive front. In many invasive carcinomas the mechanisms leading to E-cadherin loss remain elusive. Here, we hypothesise that mechanisms of protein quality control play a key role in E-cadherin regulation. As a cell model system, we used CHO cells stably expressing E-cadherin germline missense mutations R749W and E757K, which are associated with hereditary diffuse gastric cancer. An abnormal pattern of E-cadherin expression was observed, with protein accumulating mainly in the ER. We demonstrated that E-cadherin missense mutants are subjected to Endoplasmic Reticulum Quality Control (ERQC) and that their loss is due to ER-associated degradation (ERAD). Treatment of these mutant cells with specific chemical chaperones restored E-cadherin to the cell membrane and rescued its function. We show that ERQC plays a major role in E-cadherin regulation and propose that overcoming this regulation may represent an approach to rescue E-cadherin expression and functionality in cancer.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. S. Pinho, C. A. Reis, J. Paredes, A. M. Magalhaes, A. C. Ferreira, J. Figueiredo, W. Xiaogang, F. Carneiro, F. Gartner, and R. Seruca The role of N-acetylglucosaminyltransferase III and V in the post-transcriptional modifications of E-cadherin Hum. Mol. Genet., July 15, 2009; 18(14): 2599 - 2608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Oliveira, J. Senz, P. Kaurah, H. Pinheiro, R. Sanges, A. Haegert, G. Corso, J. Schouten, R. Fitzgerald, H. Vogelsang, et al. Germline CDH1 deletions in hereditary diffuse gastric cancer families Hum. Mol. Genet., May 1, 2009; 18(9): 1545 - 1555. [Abstract] [Full Text] [PDF]
|
|