title: HPV16 E5 protein disrupts the c-Cbl-EGFR interaction and EGFR ubiquitination in human foreskin keratinocytes.
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.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202-5120, USA.
authors.forename: Benyue
authors.initials: B
authors.lastname: Zhang
authors.forename: Anjaiah
authors.initials: A
authors.lastname: Srirangam
authors.forename: David A
authors.initials: DA
authors.lastname: Potter
authors.forename: Ann
authors.initials: A
authors.lastname: Roman
mesh_terms: D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000502:physiology; D008297:Male; D009856:Oncogene Proteins, Viral / Q000494:pharmacology*; D027383:Papillomaviridae; D010413:Penis / Q000166:cytology; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000494:pharmacology*; D015854:Up-Regulation; D000086082:Viroporin Proteins
chemical_list: D066246:ErbB Receptors; D009856:Oncogene Proteins, Viral; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins
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