Regulation of RhoGEF proteins by G12/13-coupled receptors


Sandra Siehler, Novartis Institutes for BioMedical Research Basel, WSJ-88.2.05, Novartis Pharma AG, 4002 Basel, Switzerland. E-mail:


G protein-coupled receptors (GPCRs) represent a large family of seven transmembrane receptors, which communicate extracellular signals into the cellular lumen. The human genome contains 720–800 GPCRs, and their diverse signal characteristics are determined by their specific tissue and subcellular expression profiles, as well as their coupling profile to the various G protein families (Gs, Gi, Gq, G12). The G protein coupling pattern links GPCR activation to the specific downstream effector pathways. G12/13 signalling of GPCRs has been studied only recently in more detail, and involves activation of RhoGTPase nucleotide exchange factors (RhoGEFs). Four mammalian RhoGEFs regulated by G12/13 proteins are known: p115-RhoGEF, PSD-95/Disc-large/ZO-1 homology-RhoGEF, leukemia-associated RhoGEF and lymphoid blast crisis-RhoGEF. These link GPCRs to activation of the small monomeric GTPase RhoA, and other downstream effectors. Misregulated G12/13 signalling is involved in multiple pathophysiological conditions such as cancer, cardiovascular diseases, arterial and pulmonary hypertension, and bronchial asthma. Specific targeting of G12/13 signalling-related diseases of GPCRs hence provides novel therapeutic approaches. Assays to quantitatively measure GPCR-mediated activation of G12/13 are only emerging, and are required to understand the G12/13-linked pharmacology. The review gives an overview of G12/13 signalling of GPCRs with a focus on RhoGEF proteins as the immediate mediators of G12/13 activation.