Activation of Rac1 by paxillin-Crk-DOCK180 signaling complex is antagonized by Rap1 in migrating NBT-II cells.

Abstract	Induction of epithelial cell motility is a fundamental morphogenetic event that is recapitulated during carcinoma metastasis. Random motility of NBT-II carcinoma cells on collagen critically depends on paxillin phosphorylation at Tyr-31 and Tyr-118, the binding sites for the adapter protein CrkII. Two constitutive partners of CrkII are the exchange factors DOCK180 and C3G. CrkII bound to DOCK180 formed a signaling complex with phosphorylated paxillin that was necessary for cell migration as inferred from the inhibition caused by a DOCK180-interfering mutant. DOCK180, which acts predominantly on the Rho family GTPase Rac1, restored cell locomotion in cells expressing Phe-31/118 paxillin mutants deficient in Rac1 GTP-loading, suggesting that formation of paxillin-Crk-DOCK180 signaling complex controls collagen-dependent migration mainly through Rac1 activation. In migrating cells, CrkII constitutive association with C3G was not sufficient to stimulate its GDP/GTP exchange activity toward the Ras family GTPase Rap1. However, when constitutively active RapV12 was overexpressed, it negatively regulated cell motility. Activation of the C3G/Rap1 signaling pathway resulted in down-regulation of the paxillin-Crk-DOCK180 complex and reduction of Rac1-GTP, suggesting that Rap1 activation could suppress the Rac1 signaling pathway in epithelial cells.
Authors	Ana M Vallés, Maud Beuvin, Brigitte Boyer
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 43 Pg. 44490-6 (Oct 22 2004) ISSN: 0021-9258 [Print] United States
PMID	15308668 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Crk protein, rat Cytoskeletal Proteins DOCK180 protein, rat Paxillin Phosphoproteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-crk Pxn protein, rat Tyrosine Collagen GTP Phosphohydrolases rac GTP-Binding Proteins rac1 GTP-Binding Protein
Topics	Animals Binding Sites Blotting, Western Cell Line Cell Line, Tumor Cell Movement Collagen (metabolism) Cytoskeletal Proteins (genetics, metabolism) Down-Regulation Epithelial Cells (metabolism) GTP Phosphohydrolases (metabolism) Immunoprecipitation Mutation Paxillin Phosphoproteins (genetics, metabolism) Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-crk Rats Signal Transduction Time Factors Transfection Tyrosine (chemistry) rac GTP-Binding Proteins (metabolism) rac1 GTP-Binding Protein (physiology)

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