title: Defining functional interactions during biogenesis of epithelial junctions.
abstract: In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell-cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases.
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Erasmus
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: S
authors.initials: S
authors.lastname: Bruche
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.|Computing Department, Imperial College London, London SW7 2AZ, UK.
authors.forename: L
authors.initials: L
authors.lastname: Pizarro
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.|Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK.
authors.forename: N
authors.initials: N
authors.lastname: Maimari
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: T
authors.initials: T
authors.lastname: Pogglioli
authors.affiliation: Department of Surgery &Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: C
authors.initials: C
authors.lastname: Tomlinson
authors.affiliation: Department Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Lees
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: I
authors.initials: I
authors.lastname: Zalivina
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: A
authors.initials: A
authors.lastname: Wheeler
authors.affiliation: Van Andel Institute, Grand Rapids, Michigan 49503, USA.
authors.forename: A
authors.initials: A
authors.lastname: Alberts
authors.affiliation: Computing Department, Imperial College London, London SW7 2AZ, UK.
authors.forename: A
authors.initials: A
authors.lastname: Russo
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: V M M
authors.initials: VM
authors.lastname: Braga
mesh_terms: D001331:Automation; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D009928:Organ Specificity; D020648:Peptide Elongation Factor 1 / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D060066:Protein Interaction Maps; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D034622:RNA Interference; D015203:Reproducibility of Results
chemical_list: D015820:Cadherins; C094814:EEF1A1 protein, human; D008869:Microtubule-Associated Proteins; D015778:Minor Histocompatibility Antigens; D020648:Peptide Elongation Factor 1; D051567:Proto-Oncogene Proteins c-vav; C406285:TRIP10 protein, human; C093651:VAV2 protein, human