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

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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.