Human Molecular Genetics Advance Access originally published online on August 20, 2008
Human Molecular Genetics 2008 17(22):3552-3565; doi:10.1093/hmg/ddn248
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Scrib regulates PAK activity during the cell migration process
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,*1 Inserm, U891, Centre de Recherche en Cancérologie de Marseille, Pharmacologie Moléculaire, Marseille F-13009, France 2 Institut Paoli-Calmettes, Marseille F-13009, France 3 Univ Méditerranée F-13007, Marseille, France 4 Institut Pasteur, 25 Rue du Dr Roux 75724, Paris, cedex 15, France 5 National Eye Institute Neurobiology, Neurodegeneration & Repair Laboratory, Bethesda, MD 20892-2510, USA 6 Avenir U862 Equipe 6 7 Avenir U862 Equipe 7, Institut François Magendie, 146 rue Léo Saignat, 33077 Bordeaux, France
* To whom correspondence should be addressed at: Centre de Recherche en Cancérologie de Marseille, UMR891 Inserm-Institut Paoli-Calmettes-Université de la Méditerranée, 27 boulevard Leï Roure 13009 Marseille, France. Tel: +33 491758403; Fax: +33 491260364; Email: jean-paul.borg{at}inserm.fr
Received June 5, 2008; Accepted August 15, 2008
Genetic studies have highlighted the key role of Scrib in the development of Metazoans. Deficiency in Scrib impairs many aspects of cell polarity and cell movement although the mechanisms involved remain unclear. In mammals, Scrib belongs to a protein complex containing βPIX, an exchange factor for Rac/Cdc42, and GIT1, a GTPase activating protein for ARF6 implicated in receptor recycling and exocytosis. Here we show that the Scrib complex associates with PAK, a serine–threonine kinase family crucial for cell migration. PAK colocalizes with members of the Scrib complex at the leading edge of heregulin-treated T47D breast cancer cells. We demonstrate that the Scrib complex is required for epithelial cells and primary mouse embryonic fibroblasts to efficiently respond to chemoattractant cues. In Scrib-deficient cells, the pool of cortical PAK is decreased, thereby precluding its proper activation by Rac. Loss of Scrib also impairs the polarized distribution of active Rac at the leading edge and compromises the regulated activation of the GTPase in T47D cells and mouse embryonic fibroblasts. These data underscore the role of Scrib in cell migration and show the strong impact of Scrib in the function of PAK and Rac, two key molecules implicated in this process.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors and the last two authors should be regarded as joint Last Authors.
Present address: Molecular Medicine National Heart and Lung Institute, Faculty of Medicine Imperial College London, London SW7 2AZ, UK.
Present address: Randall Division of Cell & Molecular Biophysics, King’s College, London SE1 1UL, UK.
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