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.
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, 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 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.
Spanos
William C
WC
University of Iowa Department of Otolaryngology-Head and Neck Surgery, Iowa City, IA 52242, USA.
Hoover
Andrew
A
Harris
George F
GF
Wu
Shu
S
Strand
Guinevere L
GL
Anderson
Mary E
ME
Klingelhutz
Aloysius J
AJ
Hendriks
Wiljan
W
Bossler
Aaron D
AD
Lee
John H
JH
D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion; D002455:Cell Division; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics*; D027383:Papillomaviridae / Q000378:metabolism*; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*
C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; C516743:Ptpn13 protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)