Fig. 1

EGF-R and TGF-β signaling pathways interfered by E5. EGF-R and TGF-β share several signal transduction pathways, so that the inteference of hrHPV E5 on any of these receptors have effects on each other. TGF-β is an important immunosuppressive cytokine, which activates different transduction pathways interposed by E5 activity. In a natural condition (without any infection), TGF-β prioritizes SMAD pathway, which results in expression of several tumor suppressive proteins. In the HPV infection, SMAD pathway is hampered by HPV oncoproteins, whereas other alternative pathways are stimulated. (1) E5 is capable of increasing the EGF-R levels (by preventing the activities of c-Cbl and V-ATPase) and activating MAPK-ERK, NF-κB and PI3K pathways. (2 and 3) These pathways interact each other in an intricate regulation way. Ras protein stabilizes TGIF [75], a co-inhibitor of SMAD pathway. Moreover, ERK activation inhibits the SMAD activity through phosphorylation [77] and activates PI3K and NF-κB pathways [78]. In turn, activation of NF-κB and PI3K pathways by EGF-R cause a negative feedback on SMAD pathway. (4) E5 also inhibits TGF-βRII expression, (5) SMAD2 phosphorylation and (6) SMAD2-SMAD4 complex translocation to the nucleus [68]. (7) The activation of non-SMAD pathways leads to cell proliferation and disruption of cytokines synthesis, which stimulate tumor progression. (8) E5 can also can stimulates VEGF through EGF-R-PI3K-Akt signaling inducing angiogenesis [144]