title: PAK is required for the disruption of E-cadherin adhesion by the small GTPase Rac.
abstract: E-cadherin cell-cell adhesion plays a major role in the maintenance of the morphology and function of epithelial tissues. Modulation of E-cadherin function is an important process in morphogenesis and tumour de-differentiation. We have previously shown that constitutively active Rac1 induces the disassembly of E-cadherin complexes from junctions in human keratinocytes. Here, we compare this activity in three members of the Rac subfamily (Rac1, Rac3 and Rac1b) and investigate the molecular mechanisms underlying Rac1-induced destabilization of junctions. We demonstrate that Rac3 shares with Rac1 the ability to interfere with cadherin-mediated adhesion. Rac1b is an alternative splice variant of Rac1 but, surprisingly, Rac1b cannot induce junction disassembly. Thus, Rac family members differ on their potential to perturb keratinocyte cell-cell contacts. The mechanism through which Rac promotes disassembly of cadherin-dependent adhesion does not involve an increase in contractility. Instead, activation of the Rac target PAK1 is necessary for destabilization of cell-cell contacts. Inhibition of PAK1 by dominant-negative constructs or depletion of endogenous PAK1 by RNA interference efficiently blocked Rac1-induced perturbation of junctions. Interestingly, PAK1 cannot be activated by Rac1b, suggesting that this may contribute to the inability of Rac1b to disrupt cell-cell contacts in keratinocytes. As PAK1 also plays a crucial role in lamellipodia formation, our data indicate that PAK1 is at the interface between junction destabilization and increased motility during morphogenetic events.
authors.affiliation: Molecular Medicine Section, NHLI, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK. v.braga@imperial.ac.uk
authors.forename: Encarnación
authors.initials: E
authors.lastname: Lozano
authors.forename: Marieke A M
authors.initials: MA
authors.lastname: Frasa
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Smolarczyk
authors.forename: Ulla G
authors.initials: UG
authors.lastname: Knaus
authors.forename: Vania M M
authors.initials: VM
authors.lastname: Braga
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008845:Microinjections; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D018076:DNA, Complementary; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein