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

Hum Mol Genet. 2008 Nov 15;17(22):3566-76. doi: 10.1093/hmg/ddn249. Epub 2008 Sep 4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Collagen
  • Cricetinae
  • Cricetulus
  • Drug Combinations
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Immunoprecipitation
  • Laminin
  • Molecular Chaperones / metabolism
  • Mutation, Missense
  • Neoplasms / metabolism*
  • Proteoglycans
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ubiquitination

Substances

  • Cadherins
  • Drug Combinations
  • Laminin
  • Molecular Chaperones
  • Proteoglycans
  • matrigel
  • Collagen