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

肌动蛋白细胞骨架参与各种动态细胞过程，这些过程允许细胞移动、改变形状或分裂。单体GTdR RhoA已成为肌动蛋白细胞骨架的关键调节因子之一。许多调节肌动蛋白细胞骨架的受体介导的信号传导途径都使用小的GTdR RhoA。RhoA在这些途径中的调节通过特异性鸟嘌呤核苷酸交换因子发生，其促进GTP结合的RhoA的活性形式，其能够调节效应物如Rho激酶或mDia。包括PDZ-RhoGEF和LARG的RhoGEF蛋白亚组已显示将G12/G13偶联受体以及丛蛋白B家族的脑信号蛋白受体与RhoA介导的肌动蛋白细胞骨架调节连接。本研究计划的目的是进一步了解多结构域蛋白PDZ-RhoGEF和LARG的细胞和生物学功能。我们计划使用各种技术来研究蛋白质-蛋白质相互作用，以分析含有PDZ-RhoGEF/LARG的潜在蛋白质复合物。此外，我们希望通过产生具有组成性或条件性PDZ-RhoGEF/LARG缺陷的小鼠系来探索该信号传导途径的生物学作用。最终，这些研究应有助于更好地了解Rho介导的肌动蛋白细胞骨架信号通路的生化机制和生理功能。

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.