Abstract
ABSTRACTThe 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.
Highlights
The major transformation activity of the high-risk human papillomaviruses (HPV) is associated with the E7 oncoprotein
Independent immunoprecipitation-tandem mass spectrometry (IP-MS/MS) experiments determined that the murine papillomavirus MmuPV1 E7 and the genus gamma HPV197 E7 bind to PTPN14 (Miranda Grace and Karl Münger, unpublished results)
Lysates from N/Tert-1 cell lines expressing HPV E7 proteins tagged at the C terminus with a dual Flag and hemagglutinin (HA) epitope tag or control vector-transduced N/Tert cell lines were analyzed by Western blotting for steady-state PTPN14 levels (Fig. 1A, top panels)
Summary
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; this interaction does not fully account for the high-risk E7-specific cellular immortalization and transformation activities. 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. The high-risk HPV oncoproteins are important for their role in the development of HPV-associated cancers and because they represent simple and tractable research tools that can be used to study tumor suppressor pathways in human cells. Dysregulated expression of E6 and E7 promotes genomic instability leading to transformation and cancer [16]
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