IRP5: FIX proteins as regulators of receptor tyrosine kinase endocytosis and actin dynamics

IRP5：FIX 蛋白作为受体酪氨酸激酶内吞作用和肌动蛋白动力学的调节剂

• 批准号: 45544213
• 负责人: Professorin Dr. Kerstin Kutsche
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/45544213?language=en
• 关键词: IRP5; FIX; proteins; regulators; receptor

Rho GTPases belong to the group of small G proteins and are best known for their function in regulating actin cytoskeletal dynamics in fibroblast and neuronal cells. They act as molecular switches by cycling between an active and inactive form. Proteins modulating the activity of Rho GTPases include guanine nucleotide exchange factors (GEFs), such as α and βPIX, and GTPase-activating proteins (GAPs). Mutations in ARHGEF6/αPIX and other genes encoding regulator and effector proteins of Rho GTPases have been found in patients with X-linked mental retardation indicating that Rho GTPases and associated molecules play a pivotal role in neuronal morphogenesis and structural plasticity. The close homologue of αPIX, βPIX, modulates the activity state of the epidermal growth factor receptor (EGFR) by sequestering the E3 ubiquitin ligase Cbl from EGFR. Cbl proteins are required for monoubiquitylation and subsequent downregulation of EGFR. Since αPIX associates with Cbl, the main objective of our research project is to study the role of αPIX together with Cbl in EGFR ubiquitylation and actin cytoskeletal dynamics mediated by Cdc42 and Rac1 during clathrin-mediated endocytosis. In neurons, βPIX interacts with the postsynaptic scaffold protein Shank. We will analyze the function of the possible ternary Cbl-βPIX-Shank complex at postsynaptic sites. We strongly hope that our data will provide new insight into the concerted regulation of endocytosis and actin cytoskeleton reorganization with αPIX as a key regulatory molecule.

Rho GTP酶属于小G蛋白的组，并且最为人所知的是它们在成纤维细胞和神经元细胞中调节肌动蛋白细胞骨架动力学的功能。它们通过在活性和非活性形式之间循环来充当分子开关。调节Rho GTP酶活性的蛋白质包括鸟嘌呤核苷酸交换因子（GEF），如α和βPIX，以及GTP酶激活蛋白（GAP）。在X连锁智力低下患者中发现了ARHGEF 6/αPIX和其他编码Rho GTP酶调节和效应蛋白的基因的突变，表明Rho GTP酶及其相关分子在神经元形态发生和结构可塑性中起关键作用。αPIX的同源物βPIX通过将E3泛素连接酶Cbl与EGFR隔离来调节表皮生长因子受体（EGFR）的活性状态。Cbl蛋白是EGFR单泛素化和随后下调所需的。由于αPIX与Cbl相关，本研究的主要目的是研究αPIX与Cbl在网格蛋白介导的胞吞过程中Cdc 42和Rac 1介导的EGFR泛素化和肌动蛋白骨架动力学中的作用。在神经元中，βPIX与突触后支架蛋白Shank相互作用。我们将分析可能的三元Cbl-βPIX-Shank复合物在突触后位点的功能。我们强烈希望，我们的数据将提供新的见解，协同调节内吞和肌动蛋白细胞骨架重组与αPIX作为一个关键的调节分子。