Correlation between EGFR Y1068 tyrosine phosphorylation and AP-1 activation by tumor promoter 12-O-tetradecanoylphorbol-13-acetate in mouse skin

The mouse skin carcinogenesis is unique model for our understating of molecular events leading to tumor development. The tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) activates a variety of signaling pathways, including MAPK/AP-1. In this study, we examined the time course of EGFR phosphorylation and AP-1 activation in mouse epidermis after topical application of a single 10 nmol dose of TPA. Remarkable differences in the phosphorylation kinetics of EGFR tyrosine residues were observed. While the maximal level of Y1068 tyrosine phosphorylation occurred 4 h after TPA treatment, the Y1173 residue phosphorylation was initially down-regulated, and reached the highest level after 24 h. Phosphorylation of Y1068 tyrosine was correlated with AP-1 activation and c-Jun N-terminal kinase (JNK) activity. These results indicate that the stimulation of AP-1 in mouse epidermis by TPA may be the effect of EGFR activation, but not all tyrosine residues forming its catalytic center are equally involved in this process.