# Investigating the mechanism by which PTPN14 degradation by HPV E7 represses epithelial differentiation

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $42,099

## Abstract

PROJECT SUMMARY/ABSTRACT:
Persistent infection with oncogenic genotypes of human papillomavirus (HPV) can cause oropharyngeal and
anogenital cancers. The HPV E7 oncoprotein is both a central driver of HPV-mediated oncogenesis and an
important accessory protein for sustaining HPV infection. This proposal focuses on a highly conserved activity
of HPV E7: degradation of the host protein tyrosine phosphatase, PTPN14. It was recently discovered that
PTPN14 degradation by HPV E7 repress epithelial differentiation. PTPN14 was previously not characterized as
a regulator of differentiation, and repression of differentiation through PTPN14 is significant because HPV+
cancers are often poorly differentiated. In an HPV infected stratified epithelium, HPV establishes the stable
maintenance phase of its life cycle undifferentiated basal keratinocytes, and HPV exits this phase of its life cycle
and commits to productive replication when an infected cell differentiates. Therefore, repression of differentiation
through PTPN14 degradation by HPV E7 is also significant because it could play a role in regulating the transition
between these phases of the HPV life cycle. However, the mechanism by which PTPN14 degradation by HPV
E7 represses differentiation is not defined, and the impact of repressing differentiation on the HPV life cycle has
yet to be identified.
PTPN14 is a tumor suppressor that can inhibit the transcriptional regulators Yes-associated protein (YAP) and
TAZ. PTPN14 can also bind to the scaffolding protein, KIBRA, to inhibit YAP/TAZ. YAP/TAZ are oncogenes that
promote epithelial basal cell identity and repress differentiation. Therefore, PTPN14 degradation by HPV E7 may
repress differentiation by disrupting PTPN14- and KIBRA-containing signaling complexes and activating
YAP/TAZ. Preliminary data gathered for this proposal implicate YAP/TAZ and KIBRA in mechanisms surrounding
PTPN14 in keratinocytes. The objectives of this proposal are to determine the mechanism by which PTPN14
degradation by E7 represses differentiation and to determine how this mechanism impacts the HPV life cycle.
The specific aims of this proposal are 1) to determine if PTPN14 degradation by HPV E7 activates YAP/TAZ
and regulates the HPV life cycle, and 2) to determine if PTPN14 degradation by HPV E7 disrupts KIBRA-
mediated signaling. Aim 1 will test if PTPN14 degradation by HPV E7 activates YAP/TAZ and promotes the
transcription of YAP/TAZ transcriptional targets in oral epithelial keratinocytes. Furthermore, it will test how
constitutively active YAP/TAZ impact the HPV life cycle. Aim 2 will test if PTPN14 requires KIBRA to induce
differentiation in oral keratinocytes, and test whether PTPN14 degradation by HPV E7 disrupts KIBRA-containing
signaling complexes. Defining this mechanism will augment our understanding of the HPV E7 oncoprotein, which
has implications for both its carcinogenic activities and its role in HPV infection. Completing the proposed aims
will provide traini...

## Key facts

- **NIH application ID:** 10326841
- **Project number:** 5F31DE030365-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Joshua Hatterschide
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $42,099
- **Award type:** 5
- **Project period:** 2020-09-01 → 2022-06-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326841

## Citation

> US National Institutes of Health, RePORTER application 10326841, Investigating the mechanism by which PTPN14 degradation by HPV E7 represses epithelial differentiation (5F31DE030365-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10326841. Licensed CC0.

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