Journal Article

Endoplasmic reticulum quality control: a new mechanism of E-cadherin regulation and its implication in cancer

Joana Simões-Correia, Joana Figueiredo, Carla Oliveira, Jolanda van Hengel, Raquel Seruca, Frans van Roy and Gianpaolo Suriano

in Human Molecular Genetics

Volume 17, issue 22, pages 3566-3576
Published in print November 2008 | ISSN: 0964-6906
Published online September 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn249
Endoplasmic reticulum quality control: a new mechanism of E-cadherin regulation and its implication in cancer

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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.

Journal Article.  6047 words.  Illustrated.

Subjects: Genetics and Genomics

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