E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer
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- dc.contributor.author Simões Correia, Joanaca
- dc.contributor.author Figueiredo, Joanaca
- dc.contributor.author Lopes, Ruica
- dc.contributor.author Stricher, Françoisca
- dc.contributor.author Oliveira, Carlaca
- dc.contributor.author Serrano Pubull, Luis, 1982-ca
- dc.contributor.author Seruca, Raquelca
- dc.date.accessioned 2014-04-29T09:46:17Z
- dc.date.available 2014-04-29T09:46:17Z
- dc.date.issued 2012ca
- dc.description.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.
- dc.description.sponsorship 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)
- dc.format.mimetype application/pdfca
- dc.identifier.citation Simões-Correia J, Figueiredo J, Lopes R, Stricher F, Oliveira C, Serrano L et al. E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer. PLoS One. 2012; 7(3): e33783. DOI: 10.1371/journal.pone.0033783ca
- dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0033783
- dc.identifier.issn 1932-6203ca
- dc.identifier.uri http://hdl.handle.net/10230/22232
- dc.language.iso engca
- dc.publisher Public Library of Science (PLoS)ca
- dc.relation.ispartof PLoS ONE. 2012;7(3):e33783
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/201648
- dc.rights © 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 creditedca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.rights.uri http://creativecommons.org/licenses/by/2.5/
- dc.subject.other Cadherines
- dc.subject.other Estómac -- Càncer
- dc.subject.other Mutació (Biologia)
- dc.title E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancerca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersion