Journal
HUMAN MOLECULAR GENETICS
Volume 17, Issue 22, Pages 3566-3576Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddn249
Keywords
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Funding
- Fundacao para a Ciencia e Tecnologia, Portugal [PTDC/SAU-OBD/64319/2006, SFRH/BD/15239/2004]
- National Fund for Scientific Research, Flanders (FWO)
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-OBD/64319/2006, SFRH/BD/15239/2004] Funding Source: FCT
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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.
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