Kalirin: A Dual Rho Guanine Nucleotide Exchange Factor That Is So Much More Than the Sum of Its Many Parts

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Abstract
A large number of Rho guanine nucleotide exchange factors (GEFs) and Rho GTPase activating proteins (GAPs) are used in the CNS to activate specific Rho GTPase family members, thereby inducing various signaling mechanisms that regulate neuronal shape, growth, and plasticity, in part through their effects on the actin cytoskeleton. Kalirin is a large neuronal dual Rho GEF that activates Rac1, RhoA, and RhoG via its two Rho GEF domains. This activation, which is spatially and temporally regulated, allows Kalirin to influence neurite initiation, axonal growth, and dendritic morphogenesis. In addition, this alternatively spliced gene generates developmentally regulated transcripts that yield proteins localized to the postsynaptic density (PSD). Kalirin-7, which interacts with PSD-95, is necessary for dendritic spine formation. In addition, Kalirins have the ability to regulate and influence other aspects of neuronal morphogenesis via protein-protein interactions with their other domains, including many spectrins, other protein and lipid interaction domains, and a potential kinase. These interactions have implications not only for neuronal morphogenesis but also for vesicle trafficking, secretion, neuronal maintenance, and neurodegenerative disease.