The PDZ binding motif of HPV 16 E6 induces PTPN13 loss which allows anchorage independent growth and synergizes with Ras for invasive growth

University of Iowa Department of Otolaryngology-Head and Neck Surgery, Iowa City, IA 52242, USA; University of Iowa Department of Pathology, Iowa City, IA 52242, USA; University of Iowa Microbiology Department, Iowa City, IA 52242, USA; Radboud University Department of Cell Biology, Nijmegen, The Netherlands

^* To whom correspondence should be addressed. Email: john-h-lee{at}uiowa.edu.

	Abstract

The HPV oncogene E6 has been shown to perform multiple functions (p53 degradation, telomerase activation etc.) that play a role in oncogenic transformation. Beyond known E6 functions, an undefined mechanism that allows cellular invasion requires the E6 PDZ binding motif (PDZBM). Here, we show that HPV16 E6 interacts with and induces loss of a protein tyrosine phosphatase (PTPN13) in a PDZBM dependent manner. PTPN13 loss either by E6 or an shRNA strategy, allows for anchorage independent growth (AIG) and synergizes with a known oncogene, Ras^v12, resulting in invasive growth in vivo. Restoring PTPN13 expression reverses AIG in cells lacking PTPN13. A genomic analysis of colorectal carcinoma has identified an association between PTPN13 loss of function mutations and aberrant Ras signaling. Our findings support this correlation and provide methods to further evaluate mechanisms of how PTPN13 loss/Ras expression results in invasive growth, which will be important for HPV related and non-HPV cancer.