Epidermal growth factor receptor transactivation and decreased binding in response to lysophosphatidic acid treatment of airway epithelial cells

Abstract

Exposure of BEAS‐2B airway epithelial cells to lysophosphatidic acid (LPA) induces biphasic decreases in epidermal growth factor receptor (EGFR) binding measured with intact cells on ice. A rapid decrease occurs within 15 min and is blocked by the MEK inhibitor U0126. The decrease is sustained to 18 hr, and the protein kinase C (PKC) inhibitor BisI prevents this sustained decrease. We hypothesized that EGFR transactivation by LPA mediates the decreases in EGFR binding. LPA rapidly induced a 2‐fold increase in EGFR tyrosine phosphorylation. The EGFR tyrosine kinase inhibitor AG1478 and the MMP inhibitor GM6001 completely inhibited EGFR phosphorylation but only partially inhibited ERK1/2 phosphorylation and the rapid decrease in EGFR binding, and they had no effect on the sustained decrease. The HB‐EGF inhibitor CRM197 had no effect on the LPA‐induced EGFR phosphorylation or the decrease in binding. U0126 partially inhibited LPA‐induced EGFR phosphorylation but BisI had no effect. These results indicate that the rapid decrease in EGFR binding induced by LPA is partially due to MMP‐mediated EGFR transactivation but that mechanisms other than transactivation also contribute. PKC does not contribute to EGFR phosphorylation, and PKC‐mediated mechanisms other than EGFR transactivation mediate the sustained phase of decreased binding. Supported by funds from GlaxoSmithKline and Nebraska DHHS.