Impaired PTPN13 phosphatase activity in spontaneous or HPV-induced squamous cell carcinomas potentiates oncogene signaling through the MAP kinase pathway

Oncogene. 2009 Nov 12;28(45):3960-70. doi: 10.1038/onc.2009.251. Epub 2009 Sep 7.


Human papillomaviruses (HPVs) are a causative factor in over 90% of cervical and 25% of head and neck squamous cell carcinomas (HNSCCs). The C terminus of the high-risk HPV 16 E6 oncoprotein physically associates with and degrades a non-receptor protein tyrosine phosphatase (PTPN13), and PTPN13 loss synergizes with H-Ras(V12) or ErbB2 for invasive growth in vivo. Oral keratinocytes that have lost PTPN13 and express H-Ras(V12) or ErbB2 show enhanced Ras/RAF/MEK/Erk signaling. In co-transfection studies, wild-type PTPN13 inhibited Ras/RAF/MEK/Erk signaling in HEK 293 cells that overexpress ErbB2, EGFR or H-Ras(V12), whereas an enzymatically inactive PTPN13 did not. Twenty percent of HPV-negative HNSCCs had PTPN13 phosphatase mutations that did not inhibit Ras/RAF/MEK/Erk signaling. Inhibition of Ras/RAF/MEK/Erk signaling using MEK inhibitor U0126 blocked anchorage-independent growth in cells lacking PTPN13. These findings show that PTPN13 phosphatase activity has a physiologically significant role in regulating MAP kinase signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Butadienes / pharmacology
  • Carcinoma, Squamous Cell / enzymology*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Human papillomavirus 16
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Inbred C57BL
  • Nitriles / pharmacology
  • Oncogene Proteins, Viral
  • Papillomavirus Infections / enzymology*
  • Papillomavirus Infections / pathology
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism*
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / metabolism
  • Repressor Proteins


  • Butadienes
  • E6 protein, Human papillomavirus type 16
  • Nitriles
  • Oncogene Proteins, Viral
  • Repressor Proteins
  • U 0126
  • Receptor, ErbB-2
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13