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

Oncogene volume 28, pages 3960–3970 (2009)Cite this article

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-RasV12 or ErbB2 for invasive growth in vivo. Oral keratinocytes that have lost PTPN13 and express H-RasV12 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-RasV12, 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.

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Acknowledgements

JHL was supported by an NIDCR 1R01DE018386-01A1 and ACH was supported by an HHMI medical student fellowship. We acknowledge Jan Schepens’ technical expertise for completing the phosphatase assays and Catherine Christopherson for manuscript preparation.

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Authors and Affiliations

  1. Department of Otolaryngology—Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    A C Hoover & M E Anderson

  2. Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    G L Strand & A D Bossler

  3. Gynecologic Oncology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    P N Nowicki

  4. Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD, USA

    P D Vermeer, J V Pottala & J H Lee

  5. Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    A J Klingelhutz

  6. Department of Cell Biology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    WJAJ Hendriks

  7. Sanford ENT-Head and Neck Surgery, Sanford Health, Sioux Falls, SD, USA

    J H Lee

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  1. A C Hoover
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  4. M E Anderson
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Correspondence to J H Lee.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Hoover, A., Strand, G., Nowicki, P. et al. Impaired PTPN13 phosphatase activity in spontaneous or HPV-induced squamous cell carcinomas potentiates oncogene signaling through the MAP kinase pathway. Oncogene 28, 3960–3970 (2009). https://doi.org/10.1038/onc.2009.251

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