INDUCTION OF MITOGEN-ACTIVATED PROTEIN-KINASE SIGNAL-TRANSDUCTION PATHWAY DURING GASTRIC-ULCER HEALING IN RATS

Background & Aims: Previous studies have shown that gastric ulceration stimulates epithelial cell proliferation and overexpression of epider mal growth factor (EGF) and EGF receptor (EGF-R) in the mucosa borderi ng necrosis. The aim of this study was to investigate whether extracel lular signal-regulated kinase (ERK) cascade is involved in the healing of experimental gastric ulcers. Methods: We studied EGF-R levels, EGF -R phosphorylation levels, and ERK1 and ERK2 activity in normal and ul cerated rat gastric mucosa. We also examined the effect of Tyrphostin A46 (potent inhibitor of EGF-R and EGF-R kinase-dependent proliferatio n) on the above parameters. Results: During the initial stages of heal ing (3 and 7 days), ulcerated mucosa showed significant increase (vs. controls) in protein tyrosine kinase activity, EGF-R levels (510% and 550%), EGF-R phosphorylation levels, ERK1 activity (430% and 880%), an d ERK2 activity (550% and 990%). Tyrphostin A46 treatment significantl y inhibited ulcer healing and reduced EGF-R levels, EGF-R phosphorylat ion, and ERK1 and ERK2 activity. Conclusions: These findings indicate that experimental gastric ulcer healing involves activation of EGF-R-E RK signal transduction pathway.