The G12/13-mediated signaling pathway interacts with diverse proteins at various levels. Upon ligand binding, GPCRs catalyze the exchange of GDP for GTP on Gα 13 subunits resulting in activation of the Gα subunit and release of Gβγ. Both Gα-GTP and free Gβγ interact with diverse downstream effectors. LARG is an effector for Gα13, which is a GEF for the monomeric GTPase RhoA. Upon binding of Gα13-GTP to LARG, the DH/PH domains activate RhoA by facilitating the exchange of GDP for GTP. LARG, in turn, stimulates the intrinsic GTPase activity of Gα13 through its N-terminal RH domain. Gα-GDP dissociates from effectors and reassociates with Gβγ to terminate the signal. Thus, regulation of the G protein cycle of activation and deactivation profoundly affects the cellular response. The amplitude and duration of the signal response are determined by the amount of GTPbound Gα subunit. A dotted line indicates evidence for direct activation of LARG without activated Gα13. Domains: RH = RGS (regulator of G protein signaling) homology; DH = Dbl homology; PH = pleckstrin homology; PDZ = PSD-95/SA90-Discs-large-ZO-1. See the text for details.

A schematic representation of domain structures of RHRhoGEFs. LARG, PDZ-RhoGEF and p115RhoGEF are the three known human RH-RhoGEFs. All RH-RhoGEFs contain RH domains followed by tandem DH/PH domains. The N-terminal region of PDZ-RhoGEF and LARG each contain a PDZ domain. For comparison, CeRhoGEF and DRhoGEF2, RGS-RhoGEFs from C. elegans and D. melanogaster, respectively, are depicted as well. Unlike human RGS-RhoGEFs, CeRhoGEF and DRhoGEF2 each contain one C1 homology domain. Domains: RH = RGS homology domain; DH = Dbl homology; PH = pleckstrin homology; PDZ = PSD-95/SA90-Discs-large-ZO-1; C = C1 homology domain.