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

A. C. Hoover, G. L. Strand, P. N. Nowicki, M. E. Anderson, P. D. Vermeer, A. J. Klingelhutz, A. D. Bossler, J. V. Pottala, W. J.A.J. Hendriks, J. H. Lee

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3960-3970
Number of pages11
JournalOncogene
Volume28
Issue number45
DOIs
StatePublished - Nov 2009

Keywords

  • ErbB2
  • HPV E6 oncogene
  • Human papilloma virus
  • MAP Kinase
  • PTPN13

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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