uPAR promotes formation of the p130Cas-Crk complex to activate Rac through DOCK180.
The urokinase-type plasminogen activator receptor (uPAR) drives tumor cell membrane protrusion and motility through activation of Rac; however, the pathway leading from uPAR to Rac activation has not been described. In this study we identify DOCK180 as the guanine nucleotide exchange factor acting downstream of uPAR. We show that uPAR cooperates with integrin complexes containing beta(3) integrin to drive formation of the p130Cas-CrkII signaling complex and activation of Rac, resulting in a Rac-driven elongated-mesenchymal morphology, cell motility, and invasion. Our findings identify a signaling pathway underlying the morphological changes and increased cell motility associated with uPAR expression.
Smith
Harvey W
HW
Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, London, England, UK.
Marra
Pierfrancesco
P
Marshall
Christopher J
CJ
D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000201:enzymology; D050719:Crk-Associated Substrate Protein / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017434:Protein Structure, Tertiary; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; C099818:DOCK1 protein, human; D039661:Integrin beta3; C524898:PLAUR protein, human; D050737:Proto-Oncogene Proteins c-crk; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019000:Phosphotyrosine; D048049:Extracellular Signal-Regulated MAP Kinases; D020744:rac GTP-Binding Proteins