title: E-cadherin regulates MAL-SRF-mediated transcription in epithelial cells.
abstract: Epithelial junctions are dynamically and functionally linked to the actin cytoskeleton, and their disassembly is a key event during physiological and pathological processes. We recently showed that epithelial disintegration facilitates transcriptional activation via Rac, G-actin, MAL (also known as MRTF) and serum response factor (SRF). Here, we investigate which specific component of the epithelial junction is essential for this MAL-SRF-mediated transcription. The Ca(2+)-dependent dissociation of polarised epithelial cells depleted of ZO proteins - which form adherens junctions (AJs) but completely lack tight junctions (TJs) - fully activated SRF. By contrast, AGS gastric adenocarcinoma epithelial cells, which form TJs but are deficient in E-cadherin, and therefore also in AJs, failed to activate SRF. The introduction of wild-type E-cadherin in AGS cells restored AJ formation and MAL-SRF inducibility. To gain further insight into the membrane-proximal signalling, AGS cells were stably transfected with E-cadherin-alpha-catenin fusions. Despite restored formation of cell-cell contacts containing the nectin-afadin complex and p120-catenin, these cells did not activate SRF upon junction dissociation, suggesting that signal transmission depends on the C-terminal tail of E-cadherin. We conclude that the dissociation of intercellular E-cadherin interactions from AJs, and signals originating from the C-terminal region covering the beta-catenin-binding site of E-cadherin, are essential for transcriptional activation via Rac, MAL and SRF, whereas TJs are not involved.
authors.affiliation: Department of Molecular Biology, AG Regulation of Gene Expression, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Busche
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Guido
authors.initials: G
authors.lastname: Posern
mesh_terms: D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D051379:Mice; D015514:Oncogene Proteins, Fusion; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D051178:alpha Catenin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D004268:DNA-Binding Proteins; C431575:MRTFA protein, human; C511173:Mrtfa protein, mouse; D015514:Oncogene Proteins, Fusion; D026362:Serum Response Factor; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin