title: ARF1 and ARF6 regulate recycling of GRASP/Tamalin and the Rac1-GEF Dock180 during HGF-induced Rac1 activation.
abstract: Hepatocyte growth factor (HGF) is a potent signaling factor that acts on epithelial cells, causing them to dissociate and scatter. This migration is coordinated by a number of small GTPases, such as ARF6 and Rac1. Active ARF6 is required for HGF-stimulated migration and intracellular levels of ARF6-GTP and Rac1-GTP increase following HGF treatment. During migration, cross talk between ARF6 and Rac1 occurs through formation of a multi-protein complex containing the ARF-GEF cytohesin-2, the scaffolding protein GRASP/Tamalin, and the Rac1-GEF Dock180. Previously, the role of ARF6 in this process was unclear. We have now found that ARF6 and ARF1 regulate trafficking of GRASP and Dock180 to the plasma membrane following HGF treatment. Trafficking of GRASP and Dock180 is impaired by blocking ARF6-mediated recycling pathways and is required for HGF-stimulated Rac1 activation. Finally, HGF treatment stimulates association of GRASP and Dock180. Inhibition of ARF6 trafficking pathways traps GRASP and Dock180 as a complex in the cell.
authors: a Department of Biochemistry and Molecular Biology , The Pennsylvania State University , University Park , PA , USA.
authors: Emily J
authors: EJ
authors: Koubek
authors: a Department of Biochemistry and Molecular Biology , The Pennsylvania State University , University Park , PA , USA.
authors: Lorraine C
authors: LC
authors: Santy
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D002352:Carrier Proteins; C099818:DOCK1 protein, human; D008565:Membrane Proteins; C410230:tamalin protein, human; D017228:Hepatocyte Growth Factor; D020823:ADP-Ribosylation Factor 1; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
keywords: ARF1; ARF6; Cytohesin-2; Dock180; HGF; Rac1; epithelial migration