Human papillomaviruses and the specificity of PDZ domain targeting

The human papillomavirus (HPV) E6 oncoprotein is fundamental to the ability of these viruses to induce human malignancy. A defining characteristic of the HPV E6 oncoproteins found in cancer-causing HPV types is the presence of a PDZ binding motif at their extreme C-terminus. Through this motif, E6 is able to interact with a large number of cellular proteins that contain PDZ domains. Many of these cellular proteins are involved in regulation of processes associated with the control of cell attachment, cell proliferation, cell polarity and cell signaling. How E6 targets multiple proteins containing the same recognition domain is still an open question. In this review, we highlight aspects of E6 function and biology that help to answer this question, and thereby provide insight into the role of these substrates during development of HPV-induced malignancy. This review highlights those interactions of the high-risk human papillomavirus E6 oncoproteins with cellular PDZ domain-containing proteins that are involved in the regulation of processes associated with the control of cell attachment, cell proliferation, cell polarity and cell signaling. Through these interactions, the E6 oncoproteins modulate cellular substrate function, helping to bring about and maintain HPV-induced malignancy.