# Human Cancer Suppressor Functions of Protein Phosphatase 2A

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $1,613,905

## Abstract

Summary
 This Program encompasses three tightly connected themes. The primary theme is centered on protein
phosphatase 2A (PP2A), an established tumor suppressor. Understanding how PP2A serves as a tumor
suppressor has been challenging for several reasons. First, PP2A is a heterotrimeric enzyme composed of A,
B and C subunits, each with several members giving rise to > 80 possible PP2A holoenzymes. Genome
characterization studies show that many of the PP2A subunits are recurrently mutated or deleted in human
cancers in a manner that disrupts PP2A assembly or catalytic activity. Thus, PP2A is a highly complex and
diverse enzyme family, making deconvolution of its tumor suppressing functions problematic. This Program
has developed a global phosphopeptide analysis system that has begun to identify new PP2A substrates and
promises to accelerate progress in deconvoluting the nature of its complex and diverse tumor suppression
roles. The second theme of this Program is the use of DNA tumor virus oncoproteins as smart probes to
understand PP2A tumor suppressor function. All members of this program have shown that PP2A is a critical
player in cell growth regulation and transformation and that viral oncoproteins interact with PP2A in ways that
interfere with PP2A tumor suppressing activity and contribute to transformation. The third theme begins with
the knowledge that ~ 20% of global cancer is caused by infectious agents. Merkel cell polyomavirus (MCPyV)
is the clear cause of most Merkel cell carcinomas (MCC), a highly lethal skin cancer. MCPyV encodes a small
T antigen (ST) that is essential for MCC and can transform human cells on its own. MCPyV ST interacts with
PP2A and this Program will investigate the functional output of Merkel ST - PP2A interactions and search for
novel insights into the mechanisms by which MCPyV contributes to MCC.
 The goals of this Program are: (1) To identify PP2A-driven signaling cascades that contribute to clinically
important examples of tumor suppression; (2) To identify cancer-relevant PP2A substrates. (3) To seek ways
to restore or activate mutant PP2A function. Each of the four Projects and the Functional Proteomics Core will
focus on how specific PP2A perturbation, whether by mutation or association with oncoproteins, targets
pathways that control cancer development. Project 1 will study the affects of MCPyV ST on MTOR signaling
and DNA break repair. Project 2 will assess the effects of murine polyomavirus interactions with PP2A upon
YAP - Hippo signaling. Project 3 will study the tumor suppressor activity of the PP2A-Aβ subunit that influences
AKT and SRC signaling pathways. Project 4 will study the newly detected role of specific perturbations of the
PP2A-STRIPAK complex in the molecular pathogenesis of cancer. The Functional Proteomics Core will
identify the subunit composition of relevant PP2A complexes and their phospho-protein substrates. This
Program will bring important, new insights into the largely uncharact...

## Key facts

- **NIH application ID:** 9981664
- **Project number:** 5P01CA203655-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** James A. DeCaprio
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,613,905
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981664

## Citation

> US National Institutes of Health, RePORTER application 9981664, Human Cancer Suppressor Functions of Protein Phosphatase 2A (5P01CA203655-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9981664. Licensed CC0.

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