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Signaling pathways for lysophosphatidic acid (LPA) inhibition of epidermal growth factor receptor (EGFR) binding in lung epithelial cells
Author(s) -
Toews Myron Lee,
Parker Stacey M,
Kassel Karen M
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a695
Subject(s) - lysophosphatidic acid , egfr inhibitors , a549 cell , pertussis toxin , epidermal growth factor receptor , cancer research , chemistry , epidermal growth factor , microbiology and biotechnology , signal transduction , receptor , cell , medicine , biology , g protein , biochemistry
The EGFR is implicated in airway remodeling in asthma and is a therapeutic target in lung cancer. We reported that LPA decreases cell surface EGFR binding within15 min in the normal airway epithelial cell line BEAS‐2B and in H292 and A549 lung cancer cells; this decrease was sustained to 18 hr in BEAS‐2B cells but reversed within a few hours in the cancer cells ( FASEB J . 19:A527). The signaling pathways for these changes in EGFR binding were investigated. Cells were treated for 15 min or 18 hrs and then incubated with 125 I‐EGF on ice to measure cell surface EGFR binding. The EC 50 for LPA was 3 nM for 15‐min treatments of BEAS‐2B cells but 1 μM for 18‐hr treatments. Sphingosine‐1‐phosphate and thrombin caused changes in EGFR binding similar to those with LPA. PMA also mimicked the rapid LPA‐induced decrease in binding in all cell types, implicating a role for PKC; the PMA effect was sustained in BEAS‐2B and H292 cells but transient in A549 cells. None of the effects of LPA on EGFR binding were inhibited by pertussis toxin or the Rho kinase inhibitor Y‐27632. The MEK inhibitor U0126 blocked the rapid but not the sustained decrease induced by LPA; the rapid decrease by PMA was also blocked by U0126, suggesting PKC involvement upstream of MEK. These studies define key elements of the multiple LPA signaling pathways regulating EGFR binding in different lung epithelial cells. Supported by an AHA predoctoral fellowship to KMK and by Nebraska DHHS.