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.

  • Source
    [Show abstract] [Hide abstract]
    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.
    Virology 03/2012; 424(2):77-98. DOI:10.1016/j.virol.2011.12.018 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Virology 09/2010; 405(2):342-51. DOI:10.1016/j.virol.2010.06.025 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The proto-oncogenic protein c-Cbl was discovered as the cellular form of v-Cbl, a retroviral transforming protein. This was followed over the years by important discoveries, which identified c-Cbl and other Cbl-family proteins as key players in several signaling pathways. c-Cbl has donned the role of a multivalent adaptor protein, capable of interacting with a plethora of proteins, and has been shown to positively influence certain biological processes. The identity of c-Cbl as an E3 ubiquitin ligase unveiled the existence of an important negative regulatory pathway involved in maintaining homeostasis in protein tyrosine kinase (PTK) signaling. Recent years have also seen the emergence of novel regulators of Cbl, which have provided further insights into the complexity of Cbl-influenced pathways. This review will endeavor to provide a summary of current studies focused on the effects of Cbl proteins on various biological processes and the mechanism of these effects. The major sections of the review are as follows: Structure and genomic organization of Cbl proteins; Phosphorylation of Cbl; Interactions of Cbl; Localization of Cbl; Mechanism of effects of Cbl: (a) Ubiquitylation-dependent events: This section elucidates the mechanism of Cbl-mediated downregulation of EGFR and details the PTK and non-PTKs targeted by Cbl. In addition, it addresses the functional requirements for E3 Ubiquitin ligase activity of Cbl and negative regulation of Cbl-mediated downregulation of PTKs, (b) Adaptor functions: This section discusses the mechanisms of adaptor functions of Cbl in mitogen-activated protein kinase (MAPK) activation, insulin signaling, regulation of Ras-related protein 1 (Rap1), PI-3' kinase signaling, and regulation of Rho-family GTPases and cytoskeleton; Biological functions: This section gives an account of the diverse biological functions of Cbl and includes the role of Cbl in transformation, T-cell signaling and thymus development, B-cell signaling, mast-cell degranulation, macrophage functions, bone development, neurite growth, platelet activation, muscle degeneration, and bacterial invasion; Conclusions and perspectives.
    Journal of Cellular Physiology 10/2006; 209(1):21-43. DOI:10.1002/jcp.20694 · 3.87 Impact Factor


1 Download
Available from