title: The PTPN14 Tumor Suppressor Is a Degradation Target of Human Papillomavirus E7.
abstract: Activation of signaling pathways ensuring cell growth is essential for the proliferative competence of human papillomavirus (HPV)-infected cells. Tyrosine kinases and phosphatases are key regulators of cellular growth control pathways. A recently identified potential cellular target of HPV E7 is the cytoplasmic protein tyrosine phosphatase PTPN14, which is a potential tumor suppressor and is linked to the control of the Hippo and Wnt/beta-catenin signaling pathways. In this study, we show that the E7 proteins of both high-risk and low-risk mucosal HPV types can interact with PTPN14. This interaction is independent of retinoblastoma protein (pRb) and involves residues in the carboxy-terminal region of E7. We also show that high-risk E7 induces proteasome-mediated degradation of PTPN14 in cells derived from cervical tumors. This degradation appears to be independent of cullin-1 or cullin-2 but most likely involves the UBR4/p600 ubiquitin ligase. The degree to which E7 downregulates PTPN14 would suggest that this interaction is important for the viral life cycle and potentially also for the development of malignancy. In support of this we find that overexpression of PTPN14 decreases the ability of HPV-16 E7 to cooperate with activated EJ-ras in primary cell transformation assays.IMPORTANCEThis study links HPV E7 to the deregulation of protein tyrosine phosphatase signaling pathways. PTPN14 is classified as a potential tumor suppressor protein, and here we show that it is very susceptible to HPV E7-induced proteasome-mediated degradation. Intriguingly, this appears to use a mechanism that is different from that employed by E7 to target pRb. Therefore, this study has important implications for our understanding of the molecular basis for E7 function and also sheds important light on the potential role of PTPN14 as a tumor suppressor.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy aszalmas@med.unideb.hu.|Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Anita
authors.initials: A
authors.lastname: Szalmás
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.|Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Vjekoslav
authors.initials: V
authors.lastname: Tomaić
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Om
authors.initials: O
authors.lastname: Basukala
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Massimi
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Suruchi
authors.initials: S
authors.lastname: Mittal
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Kónya
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Banks
mesh_terms: D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D050725:Papillomavirus E7 Proteins / Q000737:chemistry / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000737:chemistry / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*
chemical_list: D002148:Calmodulin-Binding Proteins; D003598:Cytoskeletal Proteins; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C505833:UBR4 protein, human; D044767:Ubiquitin-Protein Ligases; C093261:PTPN14 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D046988:Proteasome Endopeptidase Complex
keywords: E7; PTPN14; human papillomavirus; transformation; tyrosine phosphatases