title: The DOCK180/Elmo complex couples ARNO-mediated Arf6 activation to the downstream activation of Rac1.
abstract: Cell motility requires extensions of the plasma membrane driven by reorganization of the actin cytoskeleton. Small GTPases, particularly the Rho family, are key regulators of this process. A second class of GTPases, the ADP-ribosylation factors (ARFs), have also been implicated in the regulation of the actin cytoskeleton and motility. ARF6 is intimately involved in the regulation of Rac activity; however, the mechanisms by which ARF activation leads to activation of Rac remain poorly understood. We have previously shown that expression of the ARF-GEF ARNO in MDCK cells induces robust activation of Rac, the formation of large lamellipodia, and the onset of motility. We report here that ARNO-dependent activation of Rac is mediated by a bipartite Rac GEF, the Dock180/Elmo complex. Both DOCK180 and Elmo colocalize extensively with ARNO in migrating MDCK cells. Importantly, both a catalytically inactive Dock180 mutant and an Elmo mutant that fails to couple to Dock180 block ARNO-induced Rac activation and motility. In contrast, a similar mutant of the Rac GEF beta-PIX fails to inhibit ARNO-induced Rac activation or motility. Together, these data suggest that ARNO and ARF6 coordinate with the Dock180/Elmo complex to promote Rac activation at the leading edge of migrating cells.
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, Virginia 22908, USA. lcsanty@psu.edu
authors.forename: Lorraine C
authors.initials: LC
authors.lastname: Santy
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
authors.forename: James E
authors.initials: JE
authors.lastname: Casanova
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D004285:Dogs; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D048868:Adaptor Proteins, Signal Transducing; C099818:DOCK1 protein, human; C465214:ELMO1 protein, human; D020690:GTPase-Activating Proteins; C102474:cytohesin-2; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein