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

Oncogene volume 24, pages 2585–2588 (2005)Cite this article

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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Acknowledgements

The research was supported in part by a grant from the Lilly Center for Women's Health (AR), INGEN (AR), the Thoracic Oncology Program, Indiana University (DP), a Clarian Values Foundation grant (DP) and NIH Grant 1P20-GM66402 (DP). The Indiana Genomics Initiative (INGEN) of Indiana University is supported in part by Lilly Endowment Inc. We thank Mae Lewis and Wei Chen for technical assistance and Denise Galloway for providing the L(16E5)SN packaging cell line.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    Benyue Zhang & Ann Roman

  2. Departments of Medicine and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    Anjaiah Srirangam & David A Potter

  3. The Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Benyue Zhang, Anjaiah Srirangam, David A Potter & Ann Roman

  4. Walther Cancer Institute, Indianapolis, IN, USA

    Benyue Zhang, Anjaiah Srirangam, David A Potter & Ann Roman

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  1. Benyue Zhang
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Correspondence to Ann Roman.

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Zhang, B., Srirangam, A., Potter, D. et al. HPV16 E5 protein disrupts the c-Cbl–EGFR interaction and EGFR ubiquitination in human foreskin keratinocytes. Oncogene 24, 2585–2588 (2005). https://doi.org/10.1038/sj.onc.1208453

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