Selective Modulation of Hedgehog/GLI Target Gene Expression by Epidermal Growth Factor Signaling in Human Keratinocytes

The study demonstrated that epidermal growth factor receptor (EGFR) signaling modulated the expression of GLI transcription factor target genes in human keratinocytes, with 19 genes identified as being synergistically induced by GLI1 and EGF treatment. Promoter studies indicated that EGFR and Hedgehog/GLI signaling converged at the promoters of certain GLI target genes. Inhibition of EGFR and MEK/ERK pathways, but not phosphatidylinositol 3-kinase/AKT, disrupted this synergistic activation, suggesting that EGFR signaled through RAF/MEK/ERK to cooperate with GLI proteins. The coexpression of GLI/EGF target IL1R2, EGFR, and activated ERK1/2 in human anagen hair follicles suggested a cooperative role in determining the fate of outer root sheath cells, impacting hair growth and potentially cancer. Additionally, EGF treatment was found to neutralize GLI-mediated induction of epidermal stem cell markers and was essential for GLI-induced cell cycle progression in epidermal cells.