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.

The Arf Family GTPase Arl4A Complexes with ELMO Proteins to Promote Actin Cytoskeleton Remodeling and Reveals a Versatile Ras-binding Domain in the ELMO Proteins Family

“…The Arf family member, Arf6, is heavily implicated in cytoskeletal reorganization via numerous signaling events (8, 24, 29 -31). One such pathway places Arf6 upstream of DOCK180 and ELMO and ensuing Rac activation and signaling (8). However, the exact mechanism by which Arf6 controls ELMO-DOCK180-mediated Rac signaling is unclear.…”

ADP Ribosylation Factor 6 (Arf6) Acts through FilGAP Protein to Down-regulate Rac Protein and Regulates Plasma Membrane Blebbing

“…Previous studies have demonstrated that Arf6 can activate Rac by activating RacGEFs such as DOCK180 and Karilin (9,10). This study demonstrated that Arf6 could not only stimulate Rac activity but also down-regulate Rac through recruitment of RacGAP.…”

Dock3 regulates BDNF‐TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG

“…It has been reported that a Dock family member Dock1 binds to Elmo, leading to activation of Rac1 at the cell front (Gumienny et al 2001;Santy et al 2005). In addition to migration, Elmo proteins are important mediators of engulfment of apoptotic cells and bacterial invasion (Gumienny et al 2001;Katoh & Negishi 2003;Handa et al 2007).…”