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Title: E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer
Authors: Simões-Correia, Joana 
Figueiredo, Joana
Lopes, Rui
Stricher, François
Oliveira, Carla
Serrano, Luís 
Seruca, Raquel 
Issue Date: 2012
Publisher: Public Library of Science
Project: This work was supported by Fundac¸a˜o para a Cieˆncia e Tecnologia, Portugal (PTDC/SAU-OBD/64319/2006, PTDC/SAU-OBD/104017/2008, SFRH/BPD/ 48765/2008), EMBO (short-term fellowship ASTF 60-2009) and EU grant Prospects (HEALTH-F4-2008-201648). 
Serial title, monograph or event: PLoS ONE
Volume: 7
Issue: 3
Abstract: E-cadherin is critical for the maintenance of tissue architecture due to its role in cell-cell adhesion. E-cadherin mutations are the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to loss-of-function, although the causal factor is unknown for the majority. We hypothesized that destabilization could account for the pathogenicity of E-cadherin missense mutations in HDGC, and tested our hypothesis using in silico and in vitro tools. FoldX algorithm was used to calculate the impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by SIFT. Interestingly, HDGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death, suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V, S232C and L583R), of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by stabilization with the artificial mutation L583I (structurally tolerated). Herein we report E-cadherin structural models suitable to predict the impact of the majority of cancer-associated missense mutations and we show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo.
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0033783
Rights: openAccess
Appears in Collections:I&D IBILI - Artigos em Revistas Internacionais

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