Function and regulation of the novel Ras-subfamily guanine nucleotide-releasing factor very-KIND

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Ras GTPases are activated by guanine nucleotide exchange factors (GEFs), which catalyze the transfer of the proteins into the active GTP bound form. We recently have discovered the novel RasGEF very-KIND, which encodes two kinase non-catalytical C-lobe domains (KIND) in its N-terminal part and RasGEFN and RasGEF domains in the C-terminal part. The KIND domain has structural similarities to the C-terminal protein kinase fold. It potentially evolved from the catalytic protein kinase domain into a protein interaction domain. The mouse very-KIND gene is exclusively expressed in the developing and adult nervous system. Its limited expression in vertebrates points towards a very specified function of the gene in the sophisticated nervous systems of higher organisms. Here we propose experiments to analyse the function and regulation of the RasGEF very-KIND. We plan to determine, which Ras GTPases are activated by very- KIND and the signals regulating the activity of the exchange factor. We are specifically interested in the function of the KIND motifs, which might regulate the activity of the exchange factor by the attraction of signalling proteins. The generation of very-KIND deficient mice should help to understand role of the gene in the mouse nervous system and will also be essential for the understanding of the cell biological function of the protein.