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Journal of Virology, March 2007, p. 2231-2239, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.01979-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Degradation of Tyrosine Phosphatase PTPN3 (PTPH1) by Association with Oncogenic Human Papillomavirus E6 Proteins{triangledown}

Ming Jing,1 Joanna Bohl,2 Nicole Brimer,2 Michael Kinter,3 and Scott B. Vande Pol1,2*

Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia,2 Institute of Pathology, Case Western Reserve University,1 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio3

Received 11 September 2006/ Accepted 1 December 2006

Oncoproteins from DNA tumor viruses associate with critical cellular proteins to regulate cell proliferation, survival, and differentiation.Human papillomavirus (HPV) E6 oncoproteins have been previously shown to associate with a cellular HECT domain ubiquitin ligase termed E6AP (UBE3A). Here we show that the E6-E6AP complex associates with and targets the degradation of the protein tyrosine phosphatase PTPN3 (PTPH1) in vitro and in living cells. PTPN3 is a membrane-associated tyrosine phosphatase with FERM, PDZ, and PTP domains previously implicated in regulating tyrosine phosphorylation of growth factor receptors and p97 VCP (valosin-containing protein, termed Cdc48 in Saccharomyces cerevisiae) and is mutated in a subset of colon cancers. Degradation of PTPN3 by E6 requires E6AP, the proteasome, and an interaction between the carboxy terminus of E6 and the PDZ domain of PTPN3. In transduced keratinocytes, E6 confers reduced growth factor requirements, a function that requires the PDZ ligand of E6 and that can in part be replicated by inhibiting the expression of PTPN3. This report demonstrates the potential of E6 to regulate phosphotyrosine metabolism through the targeted degradation of a tyrosine phosphatase.

* Corresponding author. Mailing address: Department of Pathology, University of Virginia, P.O. Box 800904, Charlottesville, VA 22908. Phone: (434) 924-1603. Fax: (434) 924-1545. E-mail: vandepol{at}virginia.edu.

{triangledown} Published ahead of print on 13 December 2006.

Journal of Virology, March 2007, p. 2231-2239, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.01979-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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