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p18, a novel adaptor protein, regulates pulmonary endothelial barrier function via enhanced endocytic recycling of VE‐cadherin
Author(s) -
Chichger Havovi,
Duong Huetran,
Braza Julie,
Harrington Elizabeth O.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-257212
Subject(s) - endocytic cycle , signal transducing adaptor protein , ve cadherin , microbiology and biotechnology , cadherin , chemistry , function (biology) , biology , endocytosis , signal transduction , biochemistry , cell
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.—Chichger, H., Duong, H., Braza, J., Harrington, E. O., p18, a novel adaptor protein, regulates pulmonary endothelial barrier function via enhanced endocytic recycling of VE‐cadherin. FASEB J. 29, 868–881 (2015). www.fasebj.org