Regulation of the actin cytoskeleton via the RhoGEF proteins PDZ-RhoGEF/LARG

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The actin cytoskeleton is involved in a variety of dynamic cellular processes which allow cells to move, to change shape or to divide. The monomeric GTPase RhoA has emerged as one of the key regulators of the actin cytoskeleton. Many receptor-mediated signaling pathways which regulate the actin cytoskeleton employ the small GTPase RhoA. Regulation of RhoA in these pathways occurs via specific guanine nucleotide exchange factors, which promote the GTP-bound, active form of RhoA which is able to regulate effectors like Rho-kinase or mDia. A subgroup of RhoGEF proteins including PDZ-RhoGEF and LARG has been shown to link G12/G13-coupled receptors as well as the semaphorin receptors of the plexin-B family to the RhoA-mediated regulation of the actin cytoskeleton. The aim of this research proposal is to gain further insight into the cellular and biological function of the multi-domain-proteins PDZ-RhoGEF and LARG. We plan to use various techniques for studying protein-protein interactions to analyze potential protein complexes containing PDZ-RhoGEF/LARG. Furthermore, we would like to explore the biological role of this signaling pathway by generating mouse lines with constitutive or conditional PDZ-RhoGEF/LARG deficiency. Eventually, these studies should contribute to a better understanding of the biochemical mechanisms and physiological functions of Rho-mediated signalling pathways to the actin cytoskeleton.