title: E-cadherin missense mutations, associated with hereditary diffuse gastric cancer (HDGC) syndrome, display distinct invasive behaviors and genetic interactions with the Wnt and Notch pathways in Drosophila epithelia.
abstract: Germline mutations in the human E-cadherin (hEcad) gene, CDH1, are initiating events in cases of human hereditary diffuse gastric cancer (HDGC) indicating that hEcad is a tumor suppressor. Among the hEcad mutations identified so far, some are missense, but the pathological relevance of these missense mutants is still unclear. In vitro assays show that missense mutations result in full-length hEcad molecules that retain some distinct biological activity, but in vivo functional studies in animal models are still lacking. Here we verify the potential of a Drosophila model to in vivo characterize the functional consequences of HDGC-associated germline missense mutations and to identify signaling pathways affected by these mutations. To this end, we have generated transgenic fly strains expressing the wild-type hEcad gene or its missense mutations. Similar to the fly Ecad, expression of wild-type hEcad and missense forms in fly epithelia resulted in their localization to the subapical region. In addition, we verify a genotype-phenotype correlation associated to the specific domain affected by the mutations, because cells expressing normal or missense mutant hEcad display different migratory and invasive behaviors in fly epithelia. We show that some of these effects might be mediated through hEcad interacting with the endogenous fly ss-catenin, Armadillo, thus interfering with the Wnt signaling pathway. Therefore, the use of this simple in vivo system will contribute to characterize the effects that missense hEcad have on cell behavior in a tissue environment, and might help to understand their significance in gastric cancer onset.
authors.affiliation: Instituto de Biologia Molecular e Celular, IBMC, Universidade do Porto, Porto 4150-180, Portugal.
authors.forename: Paulo S
authors.initials: PS
authors.lastname: Pereira
authors.forename: Alexandra
authors.initials: A
authors.lastname: Teixeira
authors.forename: Sofia
authors.initials: S
authors.lastname: Pinho
authors.forename: Paulo
authors.initials: P
authors.lastname: Ferreira
authors.forename: Joana
authors.initials: J
authors.lastname: Fernandes
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Suriano
authors.forename: Fernando
authors.initials: F
authors.lastname: Casares
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051186:Armadillo Domain Proteins / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics*; D014921:Wings, Animal / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051186:Armadillo Domain Proteins; D015820:Cadherins; D051880:Receptors, Notch; D051153:Wnt Proteins; D051176:beta Catenin