Catching a GEF by its tail

The activation of Rho GTPases is mediated by guanine-nucleotide exchange factors (GEFs), which catalyze the exchange of GDP for GTP. Rho-GEFs are a very diverse family, with >70 members in humans. Bioinformatics analysis of the human Rho-GEFs shows that ∼40% contain a putative PDZ-binding motif at the C-terminus. PDZ domains are protein–protein interaction domains that act as scaffolds to concentrate signaling molecules at specialized regions in the cell. We propose that the interaction between Rho-GEFs and PDZ-domain proteins is a general mechanism that controls Rho-GEF targeting and activation, helping to restrict and concentrate the exchange activity to appropriate subcellular destinations. Here, we summarize recent data that highlight the importance of these interactions in Rho-GEF regulation. The activation of Rho GTPases is mediated by guanine-nucleotide exchange factors (GEFs), which catalyze the exchange of GDP for GTP. Rho-GEFs are a very diverse family, with >70 members in humans. Bioinformatics analysis of the human Rho-GEFs shows that ∼40% contain a putative PDZ-binding motif at the C-terminus. PDZ domains are protein–protein interaction domains that act as scaffolds to concentrate signaling molecules at specialized regions in the cell. We propose that the interaction between Rho-GEFs and PDZ-domain proteins is a general mechanism that controls Rho-GEF targeting and activation, helping to restrict and concentrate the exchange activity to appropriate subcellular destinations. Here, we summarize recent data that highlight the importance of these interactions in Rho-GEF regulation. the ‘breakpoint cluster region’ protein, which functions as an exchange factor for RhoA, Rac and Cdc42. In addition to the DH-PH (GEF) domain it contains a serine/threonine kinase domain, a Rac1-specific Rho-GAP domain and a canonical PDZ-binding C-terminal tail. A fusion between BCR and the Abl kinase formed by genomic translocation is the main cause of chronic myelogenous leukemia (CML). PAK-interacting exchange factor, also called ARHGEF7 or COOL1, which is an exchange factor for Rac1 and Cdc42 that also functions as a scaffold by binding the Rac and Cdc42 effector PAK and also the ARF-GAP GIT. a large multidomain Rho-GEF that activates RhoG, Rac1 and RhoA. It has a role in neurite initiation, axonal growth and dendrite morphogenesis. Kalirin7, an alternative spliced isoform, participates in the regulation of dendritic spine formation. membrane associated guanylate kinases, proteins that contain one to three PDZ domains, an SH3 domain and a guanylate kinase homology domain (GuK). There are 24 MAGUKs encoded in the human genome and they are thought to organize multimolecular signaling complexes through their multiple protein–protein interaction domains. the postsynaptic density, an electron-dense region at the membrane of excitatory postsynaptic neurons. PSDs usually comprise glutamate receptors, molecular scaffolding molecules, cell adhesion molecules and a diverse set of other signaling proteins. Many of the PSD proteins contain PDZ domains. synectin-binding guanine exchange factor, a RhoA-specific exchange factor recently characterized as an interaction partner for the PDZ protein synectin. T-cell lymphoma invasion and metastasis 1. a Rac1-specific Rho-GEF that is expressed highly in the brain, epidermis and testis and at a lower level in other tissues. TIAM1 associates with the Par complex (Par3–Par6–aPKC) and has a role in the establishment of polarity in neuronal and epithelial tissues.