Role played by paxillin and paxillin tyrosine phosphorylation in hepatocyte growth factor/sphingosine-1-phosphate-mediated reactive oxygen species generation, lamellipodia formation, and endothelial barrier function

Panfeng Fu, Peter V. Usatyuk, Jeffrey Jacobson, Anne E Cress, Joe GN Garcia, Ravi Salgia, Viswanathan Natarajan

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Paxillin is a multifunctional and multidomain focal adhesion adaptor protein. It serves as an important scaffolding protein at focal adhesions by recruiting and binding to structural and signaling molecules. Paxillin tyrosine phosphorylation at Y31 and Y118 is important for paxillin redistribution to focal adhesions and angiogenesis. Hepatocyte growth factor (HGF) and sphingosine-1-phosphate (S1P) are potent stimulators of lamellipodia formation, a prerequisite for endothelial cell migration. The role played by paxillin and its tyrosine phosphorylated forms in HGF-or S1P-induced lamellipodia formation and barrier function is unclear. HGF or S1P stimulated lamellipodia formation, tyrosine phosphorylation of paxillin at Y31 and Y118, and c-Abl in human lung microvascular endothelial cells (HLMVECs). Knockdown of paxillin with small interfering RNA (siRNA) or transfection with paxillin mutants (Y31F or Y118F) mitigated HGF- or S1P-induced lamellipodia formation, translocation of p47phox to lamellipodia, and reactive oxygen species (ROS) generation in HLMVECs. Furthermore, exposure of HLMVECs to HGF or S1P stimulated c-Abl-mediated tyrosine phosphorylation of paxillin at Y31 and Y118 in a time-dependent fashion, and down-regulation of c-Abl with siRNA attenuated HGF- or S1P-mediated lamellipodia formation, translocation of p47phox to lamellipodia, and endothelial barrier enhancement. In vivo, knockdown of paxillin with siRNA in mouse lungs attenuated ventilator-induced lung injury. Together, these results suggest that c-Abl-mediated tyrosine phosphorylation of paxillin at Y31 and Y118 regulates HGF- or S1Pmediated lamellipodia formation, ROS generation in lamellipodia, and endothelial permeability.

Original languageEnglish (US)
Pages (from-to)619-630
Number of pages12
JournalPulmonary Circulation
Volume5
Issue number4
DOIs
StatePublished - Oct 16 2015

Fingerprint

Paxillin
Pseudopodia
Hepatocyte Growth Factor
Tyrosine
Reactive Oxygen Species
Phosphorylation
Focal Adhesions
Endothelial Cells
Small Interfering RNA
Lung
Ventilator-Induced Lung Injury
sphingosine 1-phosphate
Cell Movement
Transfection
Permeability
Proteins
Down-Regulation

Keywords

  • C-Abl
  • Endothelial barrier
  • Lamellipodia
  • Paxillin
  • Reactive oxygen species
  • Tyrosine phosphorylation of paxillin

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Role played by paxillin and paxillin tyrosine phosphorylation in hepatocyte growth factor/sphingosine-1-phosphate-mediated reactive oxygen species generation, lamellipodia formation, and endothelial barrier function. / Fu, Panfeng; Usatyuk, Peter V.; Jacobson, Jeffrey; Cress, Anne E; Garcia, Joe GN; Salgia, Ravi; Natarajan, Viswanathan.

In: Pulmonary Circulation, Vol. 5, No. 4, 16.10.2015, p. 619-630.

Research output: Contribution to journalArticle

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AU - Usatyuk, Peter V.

AU - Jacobson, Jeffrey

AU - Cress, Anne E

AU - Garcia, Joe GN

AU - Salgia, Ravi

AU - Natarajan, Viswanathan

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AB - Paxillin is a multifunctional and multidomain focal adhesion adaptor protein. It serves as an important scaffolding protein at focal adhesions by recruiting and binding to structural and signaling molecules. Paxillin tyrosine phosphorylation at Y31 and Y118 is important for paxillin redistribution to focal adhesions and angiogenesis. Hepatocyte growth factor (HGF) and sphingosine-1-phosphate (S1P) are potent stimulators of lamellipodia formation, a prerequisite for endothelial cell migration. The role played by paxillin and its tyrosine phosphorylated forms in HGF-or S1P-induced lamellipodia formation and barrier function is unclear. HGF or S1P stimulated lamellipodia formation, tyrosine phosphorylation of paxillin at Y31 and Y118, and c-Abl in human lung microvascular endothelial cells (HLMVECs). Knockdown of paxillin with small interfering RNA (siRNA) or transfection with paxillin mutants (Y31F or Y118F) mitigated HGF- or S1P-induced lamellipodia formation, translocation of p47phox to lamellipodia, and reactive oxygen species (ROS) generation in HLMVECs. Furthermore, exposure of HLMVECs to HGF or S1P stimulated c-Abl-mediated tyrosine phosphorylation of paxillin at Y31 and Y118 in a time-dependent fashion, and down-regulation of c-Abl with siRNA attenuated HGF- or S1P-mediated lamellipodia formation, translocation of p47phox to lamellipodia, and endothelial barrier enhancement. In vivo, knockdown of paxillin with siRNA in mouse lungs attenuated ventilator-induced lung injury. Together, these results suggest that c-Abl-mediated tyrosine phosphorylation of paxillin at Y31 and Y118 regulates HGF- or S1Pmediated lamellipodia formation, ROS generation in lamellipodia, and endothelial permeability.

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