E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer

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 vitr...

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Autores: Simões Correia, Joana, Figueiredo, Joana, Lopes, Rui, Stricher, François, Oliveira, Carla, Serrano Pubull, Luis, 1982-, Seruca, Raquel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2012
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/22232
Acceso en línea:http://hdl.handle.net/10230/22232
http://dx.doi.org/10.1371/journal.pone.0033783
Access Level:acceso abierto
Palabra clave:Cadherines
Estómac -- Càncer
Mutació (Biologia)
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spelling E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancerSimões Correia, JoanaFigueiredo, JoanaLopes, RuiStricher, FrançoisOliveira, CarlaSerrano Pubull, Luis, 1982-Seruca, RaquelCadherinesEstómac -- CàncerMutació (Biologia)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.This work was supported by Fundação para a Ciência 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)Public Library of Science (PLoS)201420142012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/22232http://dx.doi.org/10.1371/journal.pone.0033783reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésPLoS ONE. 2012;7(3):e33783info:eu-repo/grantAgreement/EC/FP7/201648© 2012 Simões-Correia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits/nunrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedhttp://creativecommons.org/licenses/by/2.5/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/222322026-05-29T05:05:01Z
dc.title.none.fl_str_mv E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer
title E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer
spellingShingle E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer
Simões Correia, Joana
Cadherines
Estómac -- Càncer
Mutació (Biologia)
title_short E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer
title_full E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer
title_fullStr E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer
title_full_unstemmed E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer
title_sort E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer
dc.creator.none.fl_str_mv Simões Correia, Joana
Figueiredo, Joana
Lopes, Rui
Stricher, François
Oliveira, Carla
Serrano Pubull, Luis, 1982-
Seruca, Raquel
author Simões Correia, Joana
author_facet Simões Correia, Joana
Figueiredo, Joana
Lopes, Rui
Stricher, François
Oliveira, Carla
Serrano Pubull, Luis, 1982-
Seruca, Raquel
author_role author
author2 Figueiredo, Joana
Lopes, Rui
Stricher, François
Oliveira, Carla
Serrano Pubull, Luis, 1982-
Seruca, Raquel
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Cadherines
Estómac -- Càncer
Mutació (Biologia)
topic Cadherines
Estómac -- Càncer
Mutació (Biologia)
description 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.
publishDate 2012
dc.date.none.fl_str_mv 2012
2014
2014
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/22232
http://dx.doi.org/10.1371/journal.pone.0033783
url http://hdl.handle.net/10230/22232
http://dx.doi.org/10.1371/journal.pone.0033783
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv PLoS ONE. 2012;7(3):e33783
info:eu-repo/grantAgreement/EC/FP7/201648
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/2.5/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/2.5/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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