# Defining the role of endometrial cancer PP2A A-alpha mutations in tumorigenesis

> **NIH NIH F30** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $47,425

## Abstract

Project Summary/Abstract
Protein Phosphatase 2A (PP2A) is a ubiquitously expressed serine-threonine phosphatase. It has a direct role
in multiple areas of cellular function by counter-balancing kinase-mediated phosphorylation. PP2A is a hetero-
trimeric enzyme composed of a scaffolding A-subunit, a catalytic C-subunit, and one of several identified
regulatory B-subunits. Study of PP2A inactivation in cancer has described its role as a tumor suppressor. One
major mechanism through which PP2A is altered is somatic mutation to the gene encoding the Aα scaffolding
subunit isoform. Notably, Aα mutations include several hotspot sites that were recurrently mutated across
multiple independent patient tumors. These sites clustered to a specific structural region of the protein, where
the A-subunit makes contact with regulatory B-subunits. Moreover, two mutation sites, residues P179 and
S256, were highly mutated but almost exclusively in endometrial carcinomas (EMCA). 27.3% of serous-type
endometrial carcinomas and 26.8% of endometrial carcinosarcomas harbored Aα mutations, and represented
the cancers with the highest Aα mutation rate overall by more than three-fold. Preliminary characterization of
mutant proteins revealed shifts in Aα conformational dynamics and altered binding with PP2A B- and C-
subunits. Mutant proteins are presumed to have altered regulatory activity against PP2A substrates due to their
impairment of canonical holoenzyme assembly. However, their impact on PP2A-regulated signaling pathways
has not been broadly characterized. Likewise, a role for PP2A-Aα mutations as drivers of disease has not been
directly assessed.
A lack of well-established disease drivers for EMCA has greatly limited the pursuit of effective targeted
therapeutic strategies. And while cancer-related deaths have been declining in the US, mortality rates for
uterine cancers, of which EMCA accounts for the vast majority, have steadily increased. We therefore aim to
better characterize hotspot P179 and S256 Aα mutations that re-occur in EMCA, in order to enhance
understanding of the pathologic mechanisms that facilitate this disease. The first aim of this project will directly
interrogate cancer cell dependence on Aα mutation as a pathogenic driver mutation, and determine its
association with metastatic and invasive phenotypes. The second aim will consider deregulation of GSK3β-
Axin signaling downstream of mutant PP2A-Aα. Highlighting specific pathways with signaling perturbation can
inform the rational design of new, targeted therapy.

## Key facts

- **NIH application ID:** 9965889
- **Project number:** 5F30CA224979-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Sarah Elizabeth Taylor
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,425
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-05-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965889

## Citation

> US National Institutes of Health, RePORTER application 9965889, Defining the role of endometrial cancer PP2A A-alpha mutations in tumorigenesis (5F30CA224979-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9965889. Licensed CC0.

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