Endoplasmic reticulum quality control: a new mechanism of E-cadherin regulation and its implication in cancer.
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.
Simões-Correia
Joana
J
IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
Figueiredo
Joana
J
Oliveira
Carla
C
van Hengel
Jolanda
J
Seruca
Raquel
R
van Roy
Frans
F
Suriano
Gianpaolo
G
D000818:Animals; D016466:CHO Cells; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D003094:Collagen; D006224:Cricetinae; D003412:Cricetulus; D004338:Drug Combinations; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007797:Laminin; D018832:Molecular Chaperones / Q000378:metabolism; D020125:Mutation, Missense; D009369:Neoplasms / Q000378:metabolism*; D011509:Proteoglycans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054875:Ubiquitination
D015820:Cadherins; D004338:Drug Combinations; D007797:Laminin; D018832:Molecular Chaperones; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen