title: p18, a novel adaptor protein, regulates pulmonary endothelial barrier function via enhanced endocytic recycling of VE-cadherin.
abstract: Vascular permeability is a hallmark of several disease states including acute lung injury (ALI). Endocytosis of VE-cadherin, away from the interendothelial junction (IEJ), causes acute endothelial barrier permeability. A novel protein, p18, anchors to the endosome membrane and plays a role in late endosomal signaling via MAPK and mammalian target of rapamycin. However, the fate of the VE-cadherin-positive endosome has yet to be elucidated. We sought to elucidate a role for p18 in VE-cadherin trafficking and thus endothelial barrier function, in settings of ALI. Endothelial cell (EC) resistance, whole-cell ELISA, and filtration coefficient were studied in mice or lung ECs overexpressing wild-type or nonendosomal-binding mutant p18, using green fluorescent protein as a control. We demonstrate a protective role for the endocytic protein p18 in endothelial barrier function in settings of ALI in vitro and in vivo, through enhanced recycling of VE-cadherin-positive early endosomes to the IEJ. In settings of LPS-induced ALI, we show that Src tethered to the endosome tyrosine phosphorylates p18 concomitantly with VE-cadherin internalization and pulmonary edema formation. We conclude that p18 regulates pulmonary endothelial barrier function in vitro and in vivo, by enhancing recycling of VE-cadherin-positive endosomes to the IEJ.
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island, USA; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, USA havovi_chichger@brown.edu.
authors.forename: Havovi
authors.initials: H
authors.lastname: Chichger
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island, USA; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Huetran
authors.initials: H
authors.lastname: Duong
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island, USA; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Braza
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island, USA; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Harrington
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D022005:Adherens Junctions; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects*; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D008070:Lipopolysaccharides; D054778:NM23 Nucleoside Diphosphate Kinases; D014443:Tyrosine; D019061:src-Family Kinases; D000099152:Cadherin 5; C517941:Nme2 protein, mouse
keywords: adherensjunction; endocytosis; endosome; lunginjury