Emerging role of FGF receptors in papillomavirus replication

Human papillomaviruses (HPV) are small DNA tumor viruses infecting cervix, mouth and throat tissues leading to cervical, oropharyngeal and anogenital cancers [1]. The HPV being an intra-epithelial pathogen, the long-term survival and replication of the virus inside the cell necessitates a two-pronged approach. First, the virus should evade the host immune response. Second, the epithelia are subject to growth factor-dependent proliferation and differentiation programming where the virus has to adapt to the dynamic cellular microenvironment. The replicative lifecycle of the virus is linked to the epithelial differentiation program [2,3]. The initial infection occurs in the basal cells in which the viral genome replicates but persists as low copy-number episomes. During this stage, the virus must undergo replication but not over-replicate as to not permit lytic infection. Next, the viral genome is maintained as a stable multicopy episome in dividing basal and suprabasal cells in a cell cycle dependent manner. During this maintenance mode, it is assumed that the viral genomes replicate once per cell cycle during S-phase of cellular division. Monolayer cultures harboring viral episomes mimic this stage. The E2 and E1 proteins are the initially expressed viral proteins encoded by all HPVs and it is believed that basal levels of E2 are required for the initiation of viral replication and transcription. Structurally, E2 consists of an Nterminal transactivation domain (TAD), a nonconserved hinge region and a DNA-binding domain. Functionally, E2 is a sequence-specific DNA-binding protein, binding to E2binding sites ACCGN4CGGT in the upstream regulatory region and recruiting the viral E1 helicase [4]. The E2 activates transcription of the early promoter and tethers viral genomes to host mitotic chromosomes in basal cells. As infected cells migrate into the upper epithelial strata, the differentiation program is triggered, viral genomes are amplified to hundreds of copies and packaged within the nucleus into virions requiring robust E2 activity. The molecular mechanisms by which the viral genome switches from the initial latent maintenance mode of replication to amplification mode during epithelial differentiation is unclear. An increased E2 expression may explain this phenomenon. However, we and others have identified E2 post-translational modifications that are regulatory in nature [5–8]. Among these PTMs, tyrosine phosphorylations are of particular interest since our data suggest that these contribute to switching mechanism from once per cell cycle genome replication to genome amplification. We recently discovered a phosphorylation of BPV E2 at tyrosine 102 in the TAD. The phosphomimetic tyrosineto-glutamate E2 mutation was unable to bind to the viral helicase E1 and the transcription activator protein Brd4 and was defective for replication and transcription [6]. Growth factor receptors play a major role in cellular reprogramming during viral infection hence, we hypothesized that any of these receptor tyrosine kinases may be responsible for Y102 phosphorylation. Paolini et al. observed an interaction between HPV-16 E2 and the ubiquitin ligase Nrdp-1, which is necessary for regulating the ErbB-3 (HER-3), EGFR family and viral integration [9]. We did not observe an association between E2 and the EGFR or the EphB2, but discovered that FGFRs modulate E2 activity [10,11].