Epidermal Growth Factor Stimulates Transforming Growth Factor-Beta Receptor Type II Expression In Corneal Epithelial Cells

We previously demonstrated that inhibition of epidermal growth factor receptor (EGFR) slowed corneal epithelial migration. Here we examine the effect of EGF on transforming growth factor-beta receptor II (TGF-βRII) in a corneal wound-healing model and primary human corneal epithelial cells (pHCE). Corneal debridement wounds were made and allowed to heal ± Tyrphostin AG1478 (EGFR inhibitor), and assayed for EGFR activation and EGFR and TGF-βRII localization. Primary HCE were treated with EGF ± U0126 (MEK inhibitor) and assayed for TGF-βRII expression. EGFR activation was maximal 15 minutes after wounding and localized in the migrating epithelial cells. TGF-βRII localization was also observed in the migrating epithelium and was reduced when EGFR was blocked. When pHCE were treated with EGF for 6 hours, the cells produced enhanced levels of TGF-βRII, which was blocked by U0126. Downstream signaling pathways of MEK (p38(MAPK) and ERK1/2(MAPK)) were then examined, and TGF-β1 and EGF were found to have differential effects on the phosphorylation of p38 and ERK1/2, with TGF-β1 upregulating p-p38 but not pERK1/2 and EGF upregulating pERK1/2 but not p-p38. Taken together, these data indicate that EGF stimulates TGF-βRII through ERK1/2 and EGFR signaling, suggesting interplay between EGF- and TGF-β-signaling pathways during corneal wound repair.