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HPV16 E5 protein disrupts the c-Cbl-EGFR interaction and EGFR ubiquitination in human foreskin keratinocytes

Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202-5120, USA.
Oncogene (Impact Factor: 8.56). 05/2005; 24(15):2585-8. DOI: 10.1038/sj.onc.1208453
Source: PubMed

ABSTRACT The E5 protein of human papillomavirus type 16 (HPV16) is a small hydrophobic protein, which localizes to the cell membrane, Golgi apparatus and endosomes. HPV16 E5 enhances the activation of the epidermal growth factor (EGFR). The activated EGFR is downregulated through the endocytic pathway, where E5 has been shown to inhibit endosomal acidification and trafficking. Ubiquitination of the activated EGFR plays a role in this downregulation. c-Cbl is a ubiquitin ligase that associates with the activated EGFR and targets it for degradation. Since E5 has been shown to form a complex with the EGFR, we tested the hypothesis that E5 affects the interaction of c-Cbl with the EGFR. We found a significant decrease of c-Cbl bound to the EGFR and of ubiquitinated EGFR in the presence of E5. E5 did not affect c-Cbl steady-state level, phosphorylation or translocation to the membrane. This novel result suggests that HPV16 E5 may, at least in part, upregulate EGFR-mediated signal transduction by inhibiting the interaction of c-Cbl with the EGFR, thereby decreasing c-Cbl-mediated degradation of the EGFR.

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    • "High-risk HPV E5 binds the 16 kDa component of the vacuolar ATPase, decreases the acidity of endosomes, decreases trafficking through the endocytic pathway and increases ligand-dependent signaling through the EGF receptor (Conrad et al., 1993; Hwang et al., 1995; Straight et al., 1995; Thomsen et al., 2000). While this latter may be due to the decreased degradation of the EGFR in the endosomes or to decreased trafficking through the endosome pathway, it may also be due to E5-mediated disruption of the interaction of c-Cbl, an ubiquitin ligase, with the EGFR (Straight et al., 1995; Thomsen et al., 2000; Zhang et al., 2005a). Alternatively, the increased signaling may be due to E5-mediated upregulation of surface gangliosides (Suprynowicz et al., 2008). "
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    • "The diverse functions proposed for E5 include protecting the cell against apoptosis (Kabsch and Alonso, 2002; Zhang, Spandau, and Roman, 2002), interfering with cell-cell communication (Oelze et al., 1995), and inhibition of antigen presentation in infected cells (Zhang et al., 2003). The most commonly accepted model is that the E5 gene product potentiates the signaling of the epidermal growth factor receptor (EGFR) by slowing EGFR endocytic trafficking and degradation (Straight, Herman, and McCance, 1995; Straight et al., 1993; Zhang et al., 2005). "
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    • "The mechanism driving EGFR overexpression in adenosquamous carcinomas remains to be determined. Previous studies have shown that EGFR could be regulated by EGFR gene amplification [28] or by HPV oncoproteins, namely the HPV E5 and E6, which are linked with increased EGFR levels, through inhibition of EGFR internalization and degradation [34,35]. "
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