Human Molecular Genetics Advance Access originally published online on September 4, 2008
Human Molecular Genetics 2008 17(22):3566-3576; doi:10.1093/hmg/ddn249
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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, Rua Dr. Roberto Frias, s/n, Porto 4200-465, Portugal 2 Medical Faculty of the University of Porto, Porto 4200-319, Portugal 3 Molecular Cell Biology Unit, Department for Molecular Biomedical Research, VIB, Ghent B-9052, Belgium 4 Department of Molecular Biology, Ghent University, Ghent, Belgium
* To whom correspondence should be addressed. Tel: +351 225570700; Fax: +351 225570799; Email: 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 the loss of E-cadherin remains elusive. Here, we hypothesize 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 endoplasmic reticulum (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. 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.
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