Scrib regulates PAK activity during the cell migration process.
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.
Nola
Sébastien
S
Inserm, U891, Centre de Recherche en Cancérologie de Marseille, Pharmacologie Moléculaire, Marseille, France.
Sebbagh
Michael
M
Marchetto
Sylvie
S
Osmani
Naël
N
Nourry
Claire
C
Audebert
Stéphane
S
Navarro
Christel
C
Rachel
Rivka
R
Montcouquiol
Mireille
M
Sans
Nathalie
N
Etienne-Manneville
Sandrine
S
Borg
Jean-Paul
JP
Santoni
Marie-Josée
MJ
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
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