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HPV18 E7 inhibits LATS1 kinase and activates YAP1 by degrading PTPN14

William J Blakely1, Joshua Hatterschide1,2, Elizabeth A White1

  • 1Department of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Biorxiv : the Preprint Server for Biology
|March 18, 2024
PubMed

Insights

High-risk human papillomavirus (HPV) E7 oncoproteins degrade PTPN14, reducing Hippo pathway activity. This promotes YAP1 activation, inhibiting keratinocyte differentiation and contributing to cancer development.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Virology

Background:

  • High-risk human papillomavirus (HPV) oncoproteins disrupt cellular tumor suppressors, reprogramming host signaling pathways.
  • The Hippo pathway, a critical regulator of epithelial cell stemness, is frequently inactivated in cancers.
  • YAP1, a transcriptional coactivator, drives cell proliferation and is inhibited by the Hippo pathway.

Purpose of the Study:

  • To investigate the impact of high-risk HPV18 E7 oncoprotein on Hippo pathway activity.
  • To elucidate the role of PTPN14 in HPV-mediated inhibition of keratinocyte differentiation.
  • To understand the molecular mechanisms linking HPV infection to altered cell signaling and cancer progression.

Main Methods:

  • Utilized PTPN14 knockout and HPV18 E7 expression in human keratinocytes.
  • Assessed phosphorylation status of LATS1 (at T1079) and YAP1 (at S127) using immunoblotting.
  • Monitored keratinocyte differentiation markers and YAP1 nuclear localization.

Main Results:

  • PTPN14 knockout or HPV18 E7-mediated degradation of PTPN14 decreased LATS1 T1079 and YAP1 S127 phosphorylation.
  • Inhibition of keratinocyte differentiation was observed upon PTPN14 loss or HPV18 E7 expression.
  • PTPN14-dependent keratinocyte differentiation required LATS kinases, but not MST1/2 kinases or a PTPN14 phosphatase active site.

Conclusions:

  • HPV18 E7-induced PTPN14 degradation reduces LATS1 kinase activity.
  • This leads to YAP1 activation, promoting epithelial cell stemness and inhibiting differentiation.
  • These findings highlight a mechanism by which HPV contributes to carcinogenesis by subverting normal cellular signaling pathways.
Keywords:
Biological SciencesHippoHuman papillomavirusMicrobiologyPTPN14YAP1differentiationkeratinocytetumor suppressor

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