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Human Molecular Genetics Advance Access originally published online on September 18, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 22 3007-3016
DOI: 10.1093/hmg/ddg316
© 2003 Oxford University Press

E-cadherin germline missense mutations and cell phenotype: evidence for the independence of cell invasion on the motile capabilities of the cells

Gianpaolo Suriano1, Maria José Oliveira2, David Huntsman3, Ana Rita Mateus1, Paulo Ferreira1, Fernando Casares4, Carla Oliveira1, Fátima Carneiro1,5,6, José Carlos Machado1,5, Marc Mareel2 and Raquel Seruca1,5,*

1Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-465 Porto,Portugal, 2Laboratory of Experimental Cancerology, Ghent University Hospital, B-9000 Ghent, Belgium, 3Department of Pathology and Laboratory Medicine, University of British Columbia Vancouver, Canada, 4Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4150-180, Porto, Portugal, 5Faculdade de Medicina, 4200-465 Porto, Portugal and 6Serviço de Anatomia Patológica, Hospital S. João,4200-465 Porto, Portugal

Received August 1, 2003; Revised August 22, 2003; Accepted September 10, 2003

In Hereditary Diffuse Gastric Cancer syndrome, E-cadherin germline mutations of the missense type harbour significant functional consequences. In this study, we have characterised the effect of T340A, A617T, A634V and V832M E-cadherin germline missense mutations on cell morphology, motility and proliferation. Wild-type E-cadherin and A617T expressing cells have an epithelial-like morphology, with polarised cells migrating unidirectionally. T340A and A634V expressing cells, fibroblast-like, have a high motile phenotype. We show that this phenotype is dependent on an increased level of active RhoA. V832M expressing cells grow in piled-up structure of round cells, as an effect of the disturbance of the binding between {alpha}-catenin and ß-catenin. The destabilisation of the adhesion complex is shown to hamper the motile capabilities of these cells. We did not observe any effect of the E-cadherin mutations on cell proliferation. We show the existence of a genotype–phenotype correlation between different E-cadherin mutations and cell behaviour. However, we demonstrate that the ability of cells expressing the different E-cadherin mutations to invade is independent on their motile capabilities, providing evidence that motility is neither necessary nor sufficient for cells to invade. Our data give new insights into the understanding of the mechanisms linking invasion and E-cadherin mutations in diffuse gastric cancer.

* To whom correspondence should be addressed at: IPATIMUP, Rua Dr Roberto Frias s/n, 4200-465 Porto, Potugal. Tel: +351 225570764; Fax: +351 225570799; Email: rseruca{at}ipatimup.pt


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