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. In addition, HGF
treatment stimulates association of GRASP and Dock180. Inhibition of ARF6 trafficking
pathways traps GRASP and Dock180 as a complex in the cell. Finally, we found that the
interaction between GRASP and Dock180 is required for efficient HGF function. These
data elucidate a role for active ARF6 and ARF1 in cytohesin-induced Rac1 activation and
demonstrate the importance of GRASP and Dock180 recycling in the HGF signaling
pathway.
