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

通过 RhoGEF 蛋白 PDZ-RhoGEF/LARG 调节肌动蛋白细胞骨架

• 批准号: 5408694
• 负责人: Professor Dr. Stefan Offermanns
• 金额: --
• 依托单位: Abteilung II: Pharmakologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2003
• 资助国家: 德国
• 起止时间: 2002-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5408694?language=en
• 关键词: Regulation; actin; cytoskeleton; via; RhoGEF

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.

肌动蛋白细胞骨架参与了允许细胞移动、改变形状或分裂的各种动态细胞过程。单体GTP酶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通路都使用小GTP酶RhoA。在这些途径中，RhoA的调节是通过特定的鸟核苷酸交换因子进行的，这些因子促进GTP结合的活性形式的RhoA，从而能够调节Rho-Kinase或MDIA等效应器。包括PDZ-Rhogef和LARG在内的一组Rhogef蛋白已被证明将G12/G13偶联受体以及Plexin-B家族的信号素受体与RhoA介导的肌动蛋白细胞骨架调节联系起来。这项研究计划的目的是进一步深入了解多结构域蛋白PDZ-Rhogef和LARG的细胞和生物学功能。我们计划使用各种研究蛋白质相互作用的技术来分析含有PDZ-Rhogef/LARG的潜在蛋白质复合体。此外，我们希望通过建立具有结构性或条件性PDZ-Rhogef/LARG缺陷的小鼠株系来探索这一信号通路的生物学作用。最终，这些研究将有助于更好地理解Rho介导的通往肌动蛋白细胞骨架的信号通路的生化机制和生理功能。