The PTPN14 Tumor Suppressor Is a Degradation Target of Human Papillomavirus E7

Autor: Paola Massimi, Lawrence Banks, Anita Szalmás, Suruchi Mittal, József Kónya, Om Basukala, Vjekoslav Tomaić
Rok vydání: 2017
Předmět:
0301 basic medicine
Proteasome Endopeptidase Complex
Papillomavirus E7 Proteins
Ubiquitin-Protein Ligases
Immunology
Uterine Cervical Neoplasms
Protein tyrosine phosphatase
Microbiology
Transformation and Oncogenesis
03 medical and health sciences
Virology
Protein Interaction Mapping
Humans
human papillomavirus
E7
PTPN14
transformation
tyrosine phosphatases
Human papillomavirus 16
biology
Ubiquitination
Retinoblastoma protein
Wnt signaling pathway
Basic Medical Sciences
Orvostudományok
Protein Tyrosine Phosphatases
Non-Receptor
Ubiquitin ligase
Cell biology
Cytoskeletal Proteins
Cell Transformation
Neoplastic
030104 developmental biology
BIOMEDICINE AND HEALTHCARE
Insect Science
Host-Pathogen Interactions
Proteolysis
biology.protein
Calmodulin-Binding Proteins
Female
Egészségtudományok
Signal transduction
PTPN14
Tyrosine kinase
HeLa Cells
Protein Binding
Zdroj: Journal of Virology
ISSN: 1098-5514
0022-538X
DOI: 10.1128/jvi.00057-17
Popis: 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. IMPORTANCE This 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.
Databáze: OpenAIRE
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