Investigating Tyrosine Phosphatases as Targets of Air Pollutants

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  • March 19, 2019
Creator
  • Tal, Tamara
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Exposure to ambient particulate matter (PM) is associated with elevated rates of morbidity and mortality. Inflammation is thought to be a central mechanism by which PM exposure induces adverse health effects. In lung epithelial cells, a principle target of inhaled PM, proinflammatory signaling is mediated by phosphorylation-dependent signaling pathways whose activation is opposed by the activity of protein tyrosine phosphatases (PTPases), which thereby function to maintain signaling quiescence. PTPases contain an invariant catalytic cysteine that is susceptible to electrophilic attack. Therefore, we hypothesized that exposure to oxidative, electrophilic or metal cation components of ambient PM would impair PTPase activity allowing for unopposed basal tyrosine kinase activity. Here we report that exposure to the ubiquitous PM components Zn2+ or diesel exhaust particles (DEP) induce activation of the receptor tyrosine kinase Epidermal Growth Factor Receptor (EGFR) in primary human airway epithelial cells. This phosphorylation event occurs by a ligand-independent mechanism that requires EGFR kinase activity. We also show that exposure to Zn or DEP impair the activity of PTPases, which function to dephosphorylate the EGFR. These data provide a mechanism by which disparate components of ambient PM can similarly activate proinflammatory signaling in human lung cells. In summary, these data show that PM-induced EGFR-phosphorylation in human airway epithelial cells is the result of a loss of PTPase activities that normally function to dephosphorylate EGFR in opposition to baseline EGFR kinase activity.
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  • In Copyright
Advisor
  • Samet, James
  • Singleton, Scott
  • Graves, Lee
  • Cordeiro-Stone, Marila
  • Jaspers, Ilona
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2008
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  • This item is restricted from public view for 2 years after publication.
Date uploaded
  • April 26, 2017

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