<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "A Role for ATP1A1 in Unconventional Secretion of Fibroblast Growth Factor 2"^^ . "Fibroblast growth factor 2 (FGF2) is a potent mitogen involved in many physiological\r\nprocesses such as cell proliferation, differentiation as well as angiogenesis and, therefore,\r\nhas a prominent function in tumor growth. FGF2 is secreted via an unconventional pathway\r\nusing a route that is independent from the endoplasmic reticulum and the Golgi apparatus.\r\nSecretion of FGF2 occurs by direct translocation across the plasma membrane in a folded\r\nstate, which is initiated by binding to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) at the\r\ninner leaflet of the plasma membrane. In the extracellular space, membrane proximal\r\nheparan sulfate proteoglycans (HSPGs) are required to complete translocation as well as to\r\nstore and protect FGF2 on cell surfaces. The interaction with PI(4,5)P2 was shown to\r\nfacilitate oligomerization of FGF2 leading to the formation of a lipidic membrane pore that\r\nhas been interpreted as an intermediate structure in FGF2 membrane translocation. In\r\naddition, Tec kinase was discovered as a factor regulating FGF2 secretion by\r\nphosphorylating tyrosine 82 in FGF2. Recent evidence suggests that phosphorylation\r\nstabilizes the formation of FGF2 oligomers, which favors the arrangement of a transient\r\nhydrophilic pore constituted by FGF2 molecules in the plasma membrane.\r\nBased on a genome-wide ribonucleic acid interference (RNAi) screen this study aimed for\r\nthe identification of further proteinaceous components that regulate or facilitate FGF2\r\nsecretion. Pharmacological studies previously implicated the sodium potassium pump\r\n(Na+/K+-ATPase) as a potential factor involved in FGF2 secretion, which indeed was a major\r\nhit in the genome-wide RNAi screen described in this thesis. Therefore, the main goal of this\r\nstudy was to validate these findings and to obtain mechanistic insight into the role of the\r\nNa+/K+-ATPase in the overall process of FGF2 secretion.\r\nSince the Na+/K+-ATPase is formed of a heterodimeric complex that consists of the α- and\r\nβ-subunit, cell-based secretion experiments identified the α1-subunit (ATP1A1) as the\r\ncomponent involved in FGF2 secretion. Furthermore, a direct interaction between the\r\ncytoplasmic domains of ATP1A1 with FGF2 could be demonstrated. In addition, both\r\nproteins were shown to co-localize at the plasma membrane in HeLa cells. Therefore, it is\r\nhighly likely that a direct interaction of FGF2 and ATP1A1 occurs at the cytoplasmic leaflet\r\nfacilitating export of FGF2 from cells.\r\nBased on an alpha screening setup analyzing a large library of small molecules, compounds\r\nwere identified that block the interaction between FGF2 and ATP1A1. Therefore, this study\r\nprovides new tools for future investigations on the mechanism of FGF2 secretion as well as\r\nlead compounds with a high potential for the development of novel anti-angiogenic drugs."^^ . "2014" . . . . . . . "Sonja"^^ . "Zacherl"^^ . "Sonja Zacherl"^^ . . . . . . "A Role for ATP1A1 in Unconventional Secretion of Fibroblast Growth Factor 2 (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "A Role for ATP1A1 in Unconventional Secretion of Fibroblast Growth Factor 2 (PDF)"^^ . . . "Thesis_Sonja_final.pdf"^^ . . . "A Role for ATP1A1 in Unconventional Secretion of Fibroblast Growth Factor 2 (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "A Role for ATP1A1 in Unconventional Secretion of Fibroblast Growth Factor 2 (Other)"^^ . . . . . . "preview.jpg"^^ . . . "A Role for ATP1A1 in Unconventional Secretion of Fibroblast Growth Factor 2 (Other)"^^ . . . . . . "medium.jpg"^^ . . . "A Role for ATP1A1 in Unconventional Secretion of Fibroblast Growth Factor 2 (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #16581 \n\nA Role for ATP1A1 in Unconventional Secretion of Fibroblast Growth Factor 2\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .