Abstract
The high-risk human papillomavirus (HPV) E6 proteins are consistently expressed in HPV-associated lesions and cancers. HPV16 E6 sustains the activity of the mTORC1 and mTORC2 signaling cascades under conditions of growth factor deprivation. Here we report that HPV16 E6 activated mTORC1 by enhanced signaling through receptor protein tyrosine kinases, including epidermal growth factor receptor and insulin receptor and insulin-like growth factor receptors. This is evidenced by sustained signaling through these receptors for several hours after growth factor withdrawal. HPV16 E6 increased the internalization of activated receptor species, and the signaling adaptor protein GRB2 was shown to be critical for HPV16 E6 mediated enhanced EGFR internalization and mTORC1 activation. As a consequence of receptor protein kinase mediated mTORC1 activation, HPV16 E6 expression increased cellular migration of primary human epithelial cells. This study identifies a previously unappreciated mechanism by which HPV E6 proteins perturb host-signaling pathways presumably to sustain protein synthesis during the viral life cycle that may also contribute to cellular transforming activities of high-risk HPV E6 proteins.
Highlights
Human papillomaviruses (HPVs) are small viruses with double stranded DNA genomes that infect squamous epithelial tissue
We show that HPV16 E6 activates the mTORC1 and MAP kinase signaling pathways through activating receptor protein tyrosine kinases (RPTKs) and increases EGFR internalization, even after growth factor withdrawal
We previously reported that HPV16 E6 activates S6 kinase (S6K) and 4EBP1 through mTORC1 and that persistent AKT phosphorylation under conditions of nutrient deprivation resulted from PDK1 and mTORC2 activation [16]
Summary
Human papillomaviruses (HPVs) are small viruses with double stranded DNA genomes that infect squamous epithelial tissue. A frequent hallmark of HPV-associated carcinogenesis is the integration of the HPV genome into a host chromosome. This results in the dysregulated expression of the viral E6 and HPV E7 proteins. These two proteins together are sufficient to cause cervical carcinoma in a transgenic mouse model and are necessary for the maintenance of the transformed state of cervical cancer cell lines (reviewed in reference [1]). High-risk HPV E6 proteins contribute to the immortalization of the host cell through transcriptional activation of hTERT, the catalytic component of the human telomerase enzyme [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
