title: Scrib regulates PAK activity during the cell migration process.
abstract: 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 betaPIX, 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.
authors: Inserm, U891, Centre de Recherche en Cancérologie de Marseille, Pharmacologie Moléculaire, Marseille, France.
authors: Sébastien
authors: S
authors: Nola
authors: Michael
authors: M
authors: Sebbagh
authors: Sylvie
authors: S
authors: Marchetto
authors: Naël
authors: N
authors: Osmani
authors: Claire
authors: C
authors: Nourry
authors: Stéphane
authors: S
authors: Audebert
authors: Christel
authors: C
authors: Navarro
authors: Rivka
authors: R
authors: Rachel
authors: Mireille
authors: M
authors: Montcouquiol
authors: Nathalie
authors: N
authors: Sans
authors: Sandrine
authors: S
authors: Etienne-Manneville
authors: Jean-Paul
authors: JP
authors: Borg
authors: Marie-Josée
authors: MJ
authors: Santoni
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D002633:Chemotaxis; D005347:Fibroblasts; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D020890:Neuregulin-1 / Q000378:metabolism; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020890:Neuregulin-1; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins; D020764:cdc42 GTP-Binding Protein; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; C576607:Arhgef7 protein, mouse; C480591:SCRIB protein, human; C508433:scrib protein, mouse; C087230:heregulin beta1