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Journal of Virology, March 2008, p. 2493-2500, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.02188-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth{triangledown}

William C. Spanos,1 Andrew Hoover,1 George F. Harris,1 Shu Wu,1 Guinevere L. Strand,2 Mary E. Anderson,1 Aloysius J. Klingelhutz,3 Wiljan Hendriks,4 Aaron D. Bossler,2 and John H. Lee1*

University of Iowa Department of Otolaryngology—Head and Neck Surgery, Iowa City, Iowa 52242,1 University of Iowa Department of Pathology, Iowa City, Iowa 52242,2 University of Iowa Microbiology Department, Iowa City, Iowa 52242,3 Radboud University Department of Cell Biology, Nijmegen, The Netherlands4

Received 5 October 2007/ Accepted 14 December 2007

The human papillomavirus (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 HPV type 16 (HPV16) E6 interacts with and induces loss of a protein tyrosine phosphatase (PTPN13) in a PDZBM-dependent manner. PTPN13 loss induced either by the presence of E6 or by a short hairpin RNA strategy allows for anchorage-independent growth (AIG) and synergy with a known oncogene, Rasv12, 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 for further evaluation of the mechanisms by which PTPN13 loss/Ras expression leads to invasive growth, the results of which will be important for treatment of HPV-related and non-HPV cancer.

* Corresponding author. Mailing address: 2 PFP, 200 Hawkins Dr., University of Iowa Department of Otolaryngology—Head and Neck Surgery, Iowa City, IA 52242. Phone: (319) 356-2174. Fax: (319) 384-6603. E-mail: john-h-lee{at}uiowa.edu

{triangledown} Published ahead of print on 26 December 2007.

Journal of Virology, March 2008, p. 2493-2500, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.02188-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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