P-Rex1 activates RhoG

G-protein-coupled receptors (GPCRs) are a structurally conserved family of plasma membrane receptors that have many functions, including the regulation of cell movement by the activation of the Rac subfamily of Rho GTPases. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 (P-Rex1) is a Rac-specific Rho GTPase guanine-nucleotide-exchange factor (GEF) that acts downstream of GPCRs. Now, using a combination of biochemical and genetic approaches in mouse neutrophils, Phillip Hawkins and colleagues (p. 2589) show that P-Rex1 does not just act on Rac directly but is also a regulator of the Rac-related GTPase RhoG. The authors show that, similar to Rac, the activation of RhoG is a rapid and crucial event in GPCR-driven neutrophil function, but P-Rex1 is required for activation of RhoG stimulated by the formylated peptide fMLP; they also show that P-Rex1 is an efficient GEF for RhoG in vitro. Next, the authors demonstrate that P-Rex1 and RhoG regulate fMLP-driven Rac activity and NADPH oxidase activity. Furthermore, they show that RhoG regulates fMLP-driven translocation of the Rac GEF DOCK2 and the polarisation of F-actin. Taken together, these results show that P-Rex1 acts as a GEF for RhoG downstream of GPCRs in mouse neutrophils, and points to a possible new signalling hierarchy in GTPase signalling in which P-Rex1 regulates a pool of Rac indirectly through RhoG-mediated regulation of DOCK2.