Epidermal Growth Factor Receptor-dependent Control of Keratinocyte Survival and Bcl-xL Expression through a MEK-dependent Pathway

Abstract

Previous work has shown that the epidermal growth factor receptor (EGFR) tyrosine kinase moiety provides protection to normal human keratinocytes against apoptosis. This protection is, at least in part, due to EGFR-dependent expression of the antiapoptotic Bcl-2 family member, Bcl-xL. Here we focused on intracellular signaling pathways relevant to keratinocyte survival and/or Bcl-xL expression. By using pharmacological inhibitors and dominant negative expression constructs, we observed that phosphatidylinositol 3-kinase/AKT and phospholipase Cγ/protein kinase Cα activation were required for keratinocyte survival independently of EGFR activation or Bcl-xL expression. By contrast, MEK activity required EGFR activation and, as shown by use of the MEK inhibitor PD98059 and a dominant negative MEK construct, was necessary for Bcl-xL expression and survival. Consistent with an earlier study, blocking SRC kinase activities similarly led to down-regulation of Bcl-xL protein expression and impaired keratinocyte survival. In conclusion, our results demonstrate that EGFR-dependent MEK activity contributes to both Bcl-xL expression and survival of normal keratinocytes. Other signaling pathways (i.e. phosphatidylinositol 3-kinase/AKT and phospholipase Cγ/protein kinase Cα) are obligatory to keratinocyte survival but not to Bcl-xL expression, and control of these pathways by EGFR activation is not rate-limiting to normal keratinocyte survival.