Received for publication January 26, 2007.
Revised July 18, 2007.
Accepted for publication July 18, 2007.

Lysophosphatidic Acid Decreases Epidermal Growth Factor Receptor Binding in Airway Epithelial Cells

Abstract

We showed previously that treatment of human airway smooth muscle cells and lung fibroblasts with lysophosphatidic acid (LPA) increases the binding of epidermal growth factor (EGF) to its receptors (EGFRs). The purpose of this study was to determine if LPA also regulates EGFR binding in airway epithelial cells. Airway epithelial cells were incubated in the absence or presence of 10 µM LPA for increasing times, and binding of ¹²⁵I-EGF to intact cells on ice was measured. Exposure to LPA for only 15 min caused a 30-70% decrease in EGFR binding in a dose-dependent manner, depending on the cell line. This decrease in binding was sustained to at least 18 hr in BEAS-2B and primary human bronchial epithelial cells. In contrast, the LPA-induced decrease in binding reversed rapidly in two lung cancer epithelial cell lines, H292 and A549, returning to control levels within 3 hr. LPA increased phosphorylation of the EGFR in BEAS-2B cells, and this phosphorylation was inhibited by both AG1478 (EGFR tyrosine kinase inhibitor) and GM6001 (matrix metalloproteinase inhibitor) but not CRM197 (heparin-binding EGF inhibitor). AG1478 and GM6001 also inhibited the LPA-induced decrease in EGFR binding, but only by 50%, suggesting only partial involvement of EGFR transactivation in the decrease in EGFR binding. In summary, LPA stimulates a decrease in EGFR binding in airway epithelial cells that is sustained in normal cells but rapidly reverses in cancer cells. LPA-induced transactivation of EGFRs occurs and contributes to the decrease in EGFR binding, but additional pathway(s) may also be involved.

Key words: EGF receptor, airway epithelial cells, asthma, epidermal growth factor, lung cancer, lysophosphatidic acid

This article has been cited by other articles:

				K. M. Kassel, P. R. Dodmane, N. A. Schulte, and M. L. Toews Lysophosphatidic Acid Induces Rapid and Sustained Decreases in Epidermal Growth Factor Receptor Binding via Different Signaling Pathways in BEAS-2B Airway Epithelial Cells J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 809 - 817. [Abstract] [Full Text] [PDF]