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Helene Paradis, Nhu Ho, Elizabeth Armstrong, Maria Whelan, Kindra Grozinger, Robert L. Gendron; Role of Tubedown in the Signaling Pathways Mediating Retinal Endothelial Cell Permeability. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5950.
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Tubedown (otherwise known as hNat1, NARG1, or NAA15p) is a member of the Nat1 family of proteins which associates with the acetyltransferase Ard1 (otherwise known as NAA10p) and exerts an angiostatic function in adult retinal blood vessel homeostasis by blocking retinal vascular hyperpermeability. Tubedown expression is suppressed in individuals with neovascular retinopathies. Tubedown co-immunopurifies with the actin cytoskeleton binding protein Cortactin and co-localizes with both Cortactin and F-actin in cytoplasmic regions and at the cortex of cultured retinal endothelial cells. Knockdown of Tubedown expression in retinal endothelial cells leads to co-suppression of Ard1 and increase in cellular permeability to Albumin both in vitro and in vivo. Due to the importance of hyperpermeability during retinopathy, the role of Tubedown in endothelial cell permeability now needs in-depth examination at the molecular level. Insights on how Tubedown might regulate endothelial permeability to Albumin come from its interaction with Cortactin, a protein the phosphorylation of which regulates the dynamics of actin-cytoskeleton assembly, cell migration, endocytosis and intracellular movement of vesicles. Moreover, there is evidence that Tubedown and Ard1 complex regulates endocytosis, an intracellular process required for transcellular permeability.
Immunohistochemistry, western blotting, knockdown experiments and in vitro and in vivo model systems were used to explore the role of Tbdn in signaling pathways regulating retinal endothelial permeability.
Here we explored the possible mechanisms underlying the influence of the interaction of Tbdn and Cortactin on retinal endothelial cells. Knockdown of Tbdn expression in retinal endothelial cells was associated with an increase in Cortactin phosphorylation and a redistribution of the Cortactin interacting protein ZO-1.
Tubedown regulation of retinal endothelial cell permeability may be mediated by the regulation of Cortactin phosphorylation.
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