Figure 2

HPV 16 E5 enhances growth factor signalling pathways. Activation of EGF-R and the downstream Ras-Raf-MAP kinase pathway or PI3K-Akt pathway leads to altered cell proliferation, angiogenesis, and anti-apoptosis. The last two functions are further enhanced by the E5-induced upregulation of COX-2 expression. COX-2 expression inhibits hydrogen peroxide-induced apoptosis and induces PGE2 secretion that activates EP4 receptor. This, in turn, causes cAMP production, activating PKA; PKA contributes to E5-induced expression of EP4 by enhancing CREB binding to variant CRE of the EP4 promoter. PKA influences also apoptosis through the ubiquitin-proteasome degradation of BAX. Finally, E5 protein enhances cell proliferation through downregulation of tumor suppressor p21/p27 and through up-regulation of G protein-coupled endothelin receptor (ET_A)/ET1 autocrine loop. Dotted arrow shafts indicate uncertain pathways. The possible cross-talking between ETAR and EGFR pathway through Src protein is also indicated.