Zhang B, Srirangam A, Potter DA, Roman A.. HPV16 E5 protein disrupts the c-Cbl-EGFR interaction and EGFR ubiquitination in human foreskin keratinocytes. Oncogene 24: 2585-2588

Department of Biochemistry and Molecular Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States
Oncogene (Impact Factor: 8.46). 05/2005; 24(15):2585-8. DOI: 10.1038/sj.onc.1208453
Source: PubMed


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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Available from: Benyue Zhang, Oct 15, 2015
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    • "r trafficking in a pH - independent manner , by affecting reorganization of the actin cytoskeleton , or by inhibiting vesicle fusion ( Suprynowicz et al . , 2010 ; Thomsen et al . , 2000 ) . Alternatively , 16E5 may inhibit ubiquitination and subsequent proteasomal degradation of the EGFR by disrupting the binding of Cbl , an E3 ubiquitin ligase ( Zhang et al . , 2005 ) . Finally , 16E5 may modify the lipid composition and dynamics of cell membranes ( Bravo et al . , 2005 ) . This is consistent with the observation that 16E5 increases the plasma membrane expression of caveolin - 1 and the ganglioside GM1 , both components of lipid rafts ( Suprynowicz et al . , 2008 ) . These changes in membrane chemi"
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    ABSTRACT: The E5 proteins are short transmembrane proteins encoded by many animal and human papillomaviruses. These proteins display transforming activity in cultured cells and animals, and they presumably also play a role in the productive virus life cycle. The E5 proteins are thought to act by modulating the activity of cellular proteins. Here, we describe the biological activities of the best-studied E5 proteins and discuss the evidence implicating specific protein targets and pathways in mediating these activities. The primary target of the 44-amino acid BPV1 E5 protein is the PDGF β receptor, whereas the EGF receptor appears to be an important target of the 83-amino acid HPV16 E5 protein. Both E5 proteins also bind to the vacuolar ATPase and affect MHC class I expression and cell-cell communication. Continued studies of the E5 proteins will elucidate important aspects of transmembrane protein-protein interactions, cellular signal transduction, cell biology, virus replication, and tumorigenesis.
    Full-text · Article · May 2013 · Virology
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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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    ABSTRACT: The oncogenic potential of papillomaviruses (PVs) has been appreciated since the 1930s yet the mechanisms of virally-mediated cellular transformation are still being revealed. Reasons for this include: a) the oncoproteins are multifunctional, b) there is an ever-growing list of cellular interacting proteins, c) more than one cellular protein may bind to a given region of the oncoprotein, and d) there is only limited information on the proteins encoded by the corresponding non-oncogenic PVs. The perspective of this review will be to contrast the activities of the viral E6 and E7 proteins encoded by the oncogenic human PVs (termed high-risk HPVs) to those encoded by their non-oncogenic counterparts (termed low-risk HPVs) in an attempt to sort out viral life cycle-related functions from oncogenic functions. The review will emphasize lessons learned from the cell culture studies of the HPVs causing mucosal/genital tract cancers.
    Full-text · Article · Mar 2012 · Virology
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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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    ABSTRACT: Anogenital cancers and head and neck cancers are causally associated with infection by high-risk human papillomavirus (HPV). The mechanism by which high-risk HPVs contribute to oncogenesis is poorly understood. HPV16 encodes three genes (HPV16 E5, E6, and E7) that can transform cells when expressed independently. HPV16 E6 and E7 have well-described roles causing genomic instability and unregulated cell cycle progression. The role of HPV16 E5 in cell transformation remains to be elucidated. Expression of HPV16 E5 results in enlarged, polyploid nuclei that are dependent on the level and duration of HPV16 E5 expression. Live cell imaging data indicate that these changes do not arise from cell-cell fusion or failed cytokinesis. The increase in nuclear size is a continual process that requires DNA synthesis. We conclude that HPV16 E5 produces polyploid cells by endoreplication. These findings provide insight into how HPV16 E5 can contribute to cell transformation.
    Full-text · Article · Sep 2010 · Virology
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