Acute irreparable UV-induced DNA damage leads to apoptosis of epidermal 
keratinocytes (KC) and the formation of sunburn cells, whereas less severely 
damaged cells survive but harbor the potential of tumor formation. Here we 
report that hepatocyte growth factor/scatter factor (HGF/SF) prevents 
UVB-induced apoptosis in primary KC cultured in vitro. When we analyzed the 
signaling pathways initiated by the HGF/SF receptor c-met, we found that the 
phosphatidylinositol (PI) 3-kinase and its downstream-element AKT and the 
mitogen-activated protein (MAP) kinase were activated. Inhibition of PI 3-kinase 
led to a complete abrogation of the anti-apoptotic effect of HGF/SF, whereas 
blockade of the MAP kinase pathway had no effect. In contrast to the observation 
with primary KC, HGF/SF could not enhance survival after UVB irradiation of 
HaCaT and A431 cell lines, despite the fact that in these cells the PI 3-kinase 
and MAP kinase pathways were also activated by HGF/SF. Cell cycle analysis of KC 
revealed a G(2)/M arrest after UVB irradiation and a complete loss of 
proliferating cells. Because HGF/SF in the skin is produced by dermal 
fibroblasts, our findings suggest that the HGF/SF-mediated rescue of KC from 
apoptosis represents an important paracrine loop by which UVB-damaged KC can be 
kept alive to maintain the epidermal barrier function but cannot further 
proliferate, thereby preventing the induction of epithelial skin tumors.