c-Abl mediated tyrosine phosphorylation of paxillin regulates LPS-induced endothelial dysfunction and lung injury.

Titlec-Abl mediated tyrosine phosphorylation of paxillin regulates LPS-induced endothelial dysfunction and lung injury.
Publication TypeJournal Article
Year of Publication2015
AuthorsFu P, Usatyuk PV, Lele A, Harijith A, Gregorio CC, Garcia JGN, Salgia R, Natarajan V
JournalAm J Physiol Lung Cell Mol Physiol
Volume308
Issue10
PaginationL1025-38
Date Published2015 May 15
ISSN Number1522-1504
KeywordsAcute Lung Injury, Animals, Antigens, CD, Cadherins, Capillary Permeability, Cells, Cultured, Endothelium, Vascular, Focal Adhesion Kinase 1, Gene Knockdown Techniques, Humans, Lipopolysaccharides, Male, Mice, Paxillin, Phosphorylation, Proto-Oncogene Proteins c-abl, Tyrphostins
Abstract

<p>Paxillin is phosphorylated at multiple residues; however, the role of tyrosine phosphorylation of paxillin in endothelial barrier dysfunction and acute lung injury (ALI) remains unclear. We used siRNA and site-specific nonphosphorylable mutants of paxillin to abrogate the function of paxillin to determine its role in lung endothelial permeability and ALI. In vitro, lipopolysaccharide (LPS) challenge of human lung microvascular endothelial cells (HLMVECs) resulted in enhanced tyrosine phosphorylation of paxillin at Y31 and Y118 with no significant change in Y181 and significant barrier dysfunction. Knockdown of paxillin with siRNA attenuated LPS-induced endothelial barrier dysfunction and destabilization of VE-cadherin. LPS-induced paxillin phosphorylation at Y31 and Y118 was mediated by c-Abl tyrosine kinase, but not by Src and focal adhesion kinase. c-Abl siRNA significantly reduced LPS-induced endothelial barrier dysfunction. Transfection of HLMVECs with paxillin Y31F, Y118F, and Y31/118F double mutants mitigated LPS-induced barrier dysfunction and VE-cadherin destabilization. In vivo, the c-Abl inhibitor AG957 attenuated LPS-induced pulmonary permeability in mice. Together, these results suggest that c-Abl mediated tyrosine phosphorylation of paxillin at Y31 and Y118 regulates LPS-mediated pulmonary vascular permeability and injury.</p>

DOI10.1152/ajplung.00306.2014
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID25795725
PubMed Central IDPMC4437005
Grant ListP01 HL098050 / HL / NHLBI NIH HHS / United States
P01HL58064 / HL / NHLBI NIH HHS / United States
P01HL98050 / HL / NHLBI NIH HHS / United States