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

Panfeng Fu, Peter V. Usatyuk, Abhishek Lele, Anantha Harijith, Carol C. Gregorio, Joe G.N. Garcia, Ravi Salgia, Viswanathan Natarajan

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)L1025-L1038
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume308
Issue number10
DOIs
StatePublished - May 15 2015

Keywords

  • C-Abl
  • Cytoskeleton
  • Endothelial dysfunction
  • Lipopolysaccharide
  • Paxillin
  • Permeability
  • Tyrosine kinase

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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