Induction of EGFR-dependent and EGFR-independent signaling pathways by ultraviolet a irradiation

Most of the signal pathways involved in ultraviolet (UV)-induced skin carcinogenesis are thought to originate at plasma membrane receptors. However, UVA-induced signal transduction to downstream ribosomal protein S6 kinases, p70^S6Kand p90^RSKis not well understood. In this report, we show that UVA stimulation of the epidermal growth factor receptor (EGFR) may lead to activation of p70^S6K/p90^RSKthrough phosphatidyl isositol (PI)-3 kinase and extracellular receptor-activated kinases (ERKs). Evidence is provided that phosphorylation and activation of p70^S6K/p90^RSKinduced by UVA were prevented in Egfr^-/-cells and were also markedly inhibited by the EGFR-specific tyrosine kinase inhibitors AG1478 and PD153035. Furthermore, EGFR tyrosine kinase inhibitors and EGFR deficiency significantly suppressed activation of PI-3 kinase and ERKs in regulating activation of p90^RSK/p70^S6Kbut had no effect on activation of c-Jun NH₂-terminal kinases (JNKs) and p38 kinase in response to UVA. Thus, our results suggest that UVA-induced EGFR signaling may be required for activation of p90^RSK/p70^S6KPI-3 kinase, and ERKs but not JNKs or p38 kinase.