Ultraviolet irradiation activates PI 3-kinase/AKT survival pathway via EGFreceptors in human skin in vivo

Growth factors interact with their cell surface receptors and activate the enzyme PI 3-kinase (PI 3-K) resulting in the formation of 3-phosphorylated phosphatidyl-inositols, which in turn activate the serine/threonine kinase AKT/PKB. AKT functions, in part, to promote cell survival by phosphorylatin g the BCL-2 family member BAD and the cell death pathway enzyme, caspase-9. Although induction of apoptosis by ultraviolet (UV) irradiation is well do cumented, little is known about UV activation of cell survival pathways in human skin cells. We have investigated whether UV activates the PI 3-K/AKT pathway in human skin in vivo. UV irradiation (2MED from UVB source) stimul ated PI 3-kinase activity within 15 min. PI 3-K activity was maximal (2.5-f old, n = 6) 30 min post UV and remained elevated for 4 h. UV stimulated AKT activity within 30 min. Maximal activity (4-fold, n = 11) was observed 1 h post UV. UV also stimulated phosphorylation of the downstream AKT effecter s, S6 kinase and BAD. Sb kinase was maximally stimulated 4 h post UV (15-fo ld, n = 6). Increased BAD phosphorylation was observed I h post UV and rema ined elevated for 4 h. Western blot analysis revealed that W-induced phosph orylation of BAD at Ser112, a site known to be phosphorylated by AKT. Inhib itors of EGFR and PI 3-kinase blocked UV-induced phosphorylation of BAD, su ggesting that EGFR mediates UV-activated cell survival pathway. Collectivel y, both positive and negative roles for UV activation of the PI 3-K/AKT pat hway in human skin can be envisioned. The PI 3-K/AKT pathway likely plays a critical role in balancing UV-induced apoptotic signals, thereby preventin g widespread skin cell death. Conversely UV activation of the PI 3-K/AKT pa thway may enhance survival of mutated cells, thereby promoting skin cancer, as has been found in several other types of cancer.