title: Cooperation of distinct Rac-dependent pathways to stabilise E-cadherin adhesion.
abstract: The precise mechanisms via which Rac1 is activated by cadherin junctions are not fully known. In keratinocytes Rac1 activation by cadherin junctions requires EGFR signalling, but how EGFR does so is unclear. To address which activator could mediate E-cadherin signalling to Rac1, we investigated EGFR and two Rac1 GEFs, SOS1 and DOCK180. EGFR RNAi prevented junction-induced Rac1 activation and led to fragmented localization of E-cadherin at cadherin contacts. In contrast, depletion of another EGFR family member, ErbB3, did not interfere with either process. DOCK180 RNAi, but not SOS1, prevented E-cadherin-induced Rac1 activation. However, in a strong divergence from EGFR RNAi phenotype, DOCK180 depletion did not perturb actin recruitment or cadherin localisation at junctions. Rather, reduced DOCK180 levels impaired the resistance to mechanical stress of pre-formed cell aggregates. Thus, within the same cell type, EGFR and DOCK180 regulate Rac1 activation by newly-formed contacts, but control separate cellular events that cooperate to stabilise junctions.
authors.affiliation: Molecular Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, SW7 2AZ London, UK.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Erasmus
authors.affiliation: Molecular Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, SW7 2AZ London, UK.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Welsh
authors.affiliation: Molecular Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, SW7 2AZ London, UK. Electronic address: v.braga@imperial.ac.uk.
authors.forename: Vania M M
authors.initials: VM
authors.lastname: Braga
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; C099818:DOCK1 protein, human; C107953:RAC1 protein, human; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
keywords: Cadherin; DOCK180; EGFR; GEF; Rac