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

Rho GTP酶属于小G蛋白的一组，以其调节成纤维细胞和神经细胞的肌动蛋白细胞骨架动力学而闻名。它们充当分子开关，在活跃和不活跃的形式之间循环。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编码Rho GTP酶调节蛋白和效应蛋白的ARHGEF6/αPIX等基因的突变，表明Rho GTP酶及其相关分子在神经元的形态发生和结构可塑性中起着关键作用。αPIX的同源物βPIX通过将E3泛素连接酶Cb1从表皮生长因子受体中隔离出来，调节表皮生长因子受体的活性状态。CBL蛋白是EGFR的单素化和随后下调所必需的。由于αPIX与Cb1相关，我们的研究项目的主要目的是研究αPIx和Cb1在分子筛蛋白介导的细胞吞噬过程中的泛素化和CDC42和Rac1介导的肌动蛋白细胞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Cbl-βPIX-Shank复合体在突触后部位的功能。我们强烈希望，我们的数据将为以αPIX为关键调控分子的内吞作用和肌动蛋白细胞骨架重组的协同调控提供新的见解。

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.