title: Regulation of RhoGEF proteins by G12/13-coupled receptors.
abstract: 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 (G(s), G(i), G(q), G(12)). The G protein coupling pattern links GPCR activation to the specific downstream effector pathways. G(12/13) 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 G(12/13) 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 G(12/13) signalling is involved in multiple pathophysiological conditions such as cancer, cardiovascular diseases, arterial and pulmonary hypertension, and bronchial asthma. Specific targeting of G(12/13) signalling-related diseases of GPCRs hence provides novel therapeutic approaches. Assays to quantitatively measure GPCR-mediated activation of G(12/13) are only emerging, and are required to understand the G(12/13)-linked pharmacology. The review gives an overview of G(12/13) signalling of GPCRs with a focus on RhoGEF proteins as the immediate mediators of G(12/13) activation.
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Center for Proteomic Chemistry, Novartis Pharma AG, Basel, Switzerland. sandra.siehler@novartis.com
authors.forename: Sandra
authors.initials: S
authors.lastname: Siehler
mesh_terms: D000818:Animals; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000737:chemistry / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000502:physiology; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000502:physiology
chemical_list: C576600:ARHGEF1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D043562:Receptors, G-Protein-Coupled; D064067:Rho Guanine Nucleotide Exchange Factors; D044365:GTP-Binding Protein alpha Subunits, G12-G13