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p18, a novel adaptor protein, regulates pulmonary endothelial barrier function via enhanced endocytic recycling of VE-cadherin

journal contribution
posted on 2023-07-26, 13:47 authored by Havovi Chichger, Huetran Duong, Julie Braza, Elizabeth O. Harrington
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.

History

Refereed

  • Yes

Volume

29

Issue number

3

Page range

868-881

Publication title

FASEB Journal

ISSN

1530-6860

Publisher

Federation of American Society of Experimental Biology

Language

  • other

Legacy posted date

2016-06-01

Legacy Faculty/School/Department

ARCHIVED Faculty of Science & Technology (until September 2018)

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