title: High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation.
abstract: The major transformation activity of the high-risk human papillomaviruses (HPV) is associated with the E7 oncoprotein. The interaction of HPV E7 with retinoblastoma family proteins is important for several E7 activities; however, this interaction does not fully account for the high-risk E7-specific cellular immortalization and transformation activities. We have determined that the cellular non-receptor protein tyrosine phosphatase PTPN14 interacts with HPV E7 from many genus alpha and beta HPV types. We find that high-risk genus alpha HPV E7, but not low-risk genus alpha or beta HPV E7, is necessary and sufficient to reduce the steady-state level of PTPN14 in cells. High-risk E7 proteins target PTPN14 for proteasome-mediated degradation, which requires the ubiquitin ligase UBR4, and PTPN14 is degraded by the proteasome in HPV-positive cervical cancer cell lines. Residues in the C terminus of E7 interact with the C-terminal phosphatase domain of PTPN14, and interference with the E7-PTPN14 interaction restores PTPN14 levels in cells. Finally, PTPN14 degradation correlates with the retinoblastoma-independent transforming activity of high-risk HPV E7.
  
  
  
  High-risk human papillomaviruses (HPV) are the cause of cervical cancer, some other anogenital cancers, and a growing fraction of oropharyngeal carcinomas. The high-risk HPV E6 and E7 oncoproteins enable these viruses to cause cancer, and the mechanistic basis of their carcinogenic activity has been the subject of intense study. The high-risk E7 oncoprotein is especially important in the immortalization and transformation of human cells, which makes it a central component of HPV-associated cancer development. E7 oncoproteins interact with retinoblastoma family proteins, but for several decades, it has been recognized that high-risk HPV E7 oncoproteins have additional cancer-associated activities. We have determined that high-risk E7 proteins target the proteolysis of the cellular protein tyrosine phosphatase PTPN14 and find that this activity is correlated with the retinoblastoma-independent transforming activity of E7.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA elizabeth_white@hms.harvard.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: White
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Münger
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Howley
mesh_terms: D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D052162:Human papillomavirus 16 / Q000737:chemistry / Q000472:pathogenicity*; D006801:Humans; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism*; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases; D002583:Uterine Cervical Neoplasms / Q000821:virology
chemical_list: D002148:Calmodulin-Binding Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D050725:Papillomavirus E7 Proteins; C505833:UBR4 protein, human; D044767:Ubiquitin-Protein Ligases; C093261:PTPN14 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D046988:Proteasome Endopeptidase Complex