title: Occludin S490 Phosphorylation Regulates Vascular Endothelial Growth Factor-Induced Retinal Neovascularization.
abstract: Occludin is a transmembrane tight junction protein that contributes to diverse cellular functions, including control of barrier properties, cell migration, and proliferation. Vascular endothelial growth factor (VEGF) induces phosphorylation of occludin at S490, which is required for VEGF-induced endothelial permeability. Herein, we demonstrate that occludin S490 phosphorylation also regulates VEGF-induced retinal endothelial cell proliferation and neovascularization. Using a specific antibody, phospho-occludin was located in centrosomes in endothelial cell cultures, animal models, and human surgical samples of retinal neovessels. Occludin S490 phosphorylation was found to increase with endothelial tube formation in vitro and in vivo during retinal neovascularization after induction of VEGF expression. More important, expression of occludin mutated at S490 to Ala, completely inhibited angiogenesis in cell culture models and in vivo. Collectively, these data suggest a novel role for occludin in regulation of endothelial proliferation and angiogenesis in a phosphorylation-dependent manner. These findings may lead to methods of regulating pathological neovascularization by specifically targeting endothelial cell proliferation.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan.
authors.forename: Xuwen
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Dreffs
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan.
authors.forename: Monica
authors.initials: M
authors.lastname: Díaz-Coránguez
authors.affiliation: Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: E Aaron
authors.initials: EA
authors.lastname: Runkle
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gardner
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, Florida.
authors.forename: Vince A
authors.initials: VA
authors.lastname: Chiodo
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, Florida.
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan. Electronic address: dantonet@umich.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Antonetti
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier / Q000378:metabolism; D015153:Blotting, Western; D002417:Cattle; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D062793:Occludin / Q000378:metabolism*; D010766:Phosphorylation; D015861:Retinal Neovascularization / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D062793:Occludin; D042461:Vascular Endothelial Growth Factor A