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INHIBITION OF TYROSINE PHOSPHATASE ACTIVITY INITIATES RECEPTOR SIGNALING IN AIRWAY EPITHELIAL CELLS EXPOSED TO DIESEL EXHAUST PARTICLES
Citation:
TAL, T., R. A. SILBAJORIS, J. M. SAMET, AND P. A. BROMBERG. INHIBITION OF TYROSINE PHOSPHATASE ACTIVITY INITIATES RECEPTOR SIGNALING IN AIRWAY EPITHELIAL CELLS EXPOSED TO DIESEL EXHAUST PARTICLES. Presented at Society of Toxicology 47th Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
Therefore, we hypothesize that exposure to DEP impairs PTPase activity resulting in unopposed phosphorylation-dependent signaling.
Description:
Exposure to particulate matter is associated with increased cardiopulmonary morbidity and mortality. Diesel exhaust particles (DEP) are a major component of PM in urban areas and may contribute to PM toxicity through a mechanism involving pulmonary inflammation. Expression of inflammatory cytokines is controlled by phosphorylation-dependent signaling cascades. These signaling pathways involve the opposing activities of tyrosine kinases and protein tyrosine phosphatases (PTPases) which function to maintain signaling quiescence. PTPases contain an invariant catalytic cysteine which is highly susceptible to electrophilic attack. DEP-associated organic compounds can generate reactive oxygen species and form protein cysteine adducts. Therefore, we hypothesize that exposure to DEP impairs PTPase activity resulting in unopposed phosphorylation-dependent signaling. Here we report that exposure to 0-30 µg/cm2 DEP for 4 hrs induces differential activation of kinases in primary cultures of human airway epithelial cells (HAEC). Interestingly, treatment with DEP of low (L-DEP) and high (H-DEP) but not intermediate (I-DEP) organic content induces phosphorylation of the receptor tyrosine kinase EGFR. Experiments showed that EGFR phosphorylation requires EGFR kinase activity but not EGFR dimerization. The same DEP capable of inducing EGFR phosphorylation also impair PTPase activity in HAEC. Moreover, EGFR-directed dephosphorylation is similarly attenuated in HAEC treated with L-DEP and H-DEP. These data show that DEP-induced activation of EGFR-dependent signaling in HAEC is the result of a loss of PTPase activities which normally function to dephosphorylate EGFR in opposition to baseline EGFR kinase activity. These data also suggest that organic content alone is not the sole determinant of the toxicity associated with DEP exposure. THIS ABSTRACT OF A PROPOSED PRESENTATION DOES NOT NECESSARILY REFLECT EPA POLICY.