ARF1 and ARF6 regulate recycling of GRASP/Tamalin and the Rac1-GEF Dock180 during HGF-induced Rac1 activation.
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.
['Koubek|Emily J|EJ|', 'Santy|Lorraine C|LC|']
D020823:ADP-Ribosylation Factor 1 D000089982:ADP-Ribosylation Factor 6 D020727:ADP-Ribosylation Factors D000818:Animals D002352:Carrier Proteins D002462:Cell Membrane D004285:Dogs D011992:Endosomes D004789:Enzyme Activation D055785:Gene Knockdown Techniques D017228:Hepatocyte Growth Factor D006801:Humans D061985:Madin Darby Canine Kidney Cells D008565:Membrane Proteins D021381:Protein Transport D020744:rac GTP-Binding Proteins D020830:rac1 GTP-Binding Protein
ARF1 ARF6 Dock180 Rac1 HGF Cytohesin-2 epithelial migration