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First published online 4 March 2008
doi: 10.1242/jcs.016121

Journal of Cell Science 121, 933-938 (2008)
Published by The Company of Biologists 2008
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Short Report

PAK is required for the disruption of E-cadherin adhesion by the small GTPase Rac

Encarnación Lozano1,2,*, Marieke A. M. Frasa1, Katarzyna Smolarczyk1, Ulla G. Knaus3 and Vania M. M. Braga1,{ddagger}

1 Molecular Medicine Section, NHLI, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK
2 Ecology and Evolution Research Section, Faculty of Life Sciences, Imperial College London, London, SW7 2AZ, UK
3 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA

{ddagger} Author for correspondence (e-mail: v.braga{at}imperial.ac.uk)

Accepted 14 January 2008

Summary

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.

Key words: Rac small GTPase, E-cadherin, PAK, Cell-cell adhesion, Keratinocytes






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