# PROJECT 3: Pathways Controlled by PP2A A-Beta in Normal, Transformed and Tumor Cells

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $354,245

## Abstract

Responsible for up to 50% of cellular phosphoserine/threonine phosphatase activity, protein phosphatase 2A
(PP2A) regulates almost all cell signaling pathways. PP2A comes as > 80 kinds of heterotrimers, consisting
of a catalytic C subunit and one of many regulatory B subunits bound to an Aα (90% abundant) or (10%
abundant) Aβ subunit scaffold. Our premise is that protein phosphatase 2A (PP2A) using the Aβ scaffold is
fundamentally important for controlling phenotypes of both normal and cancer cells. Moreover, study of
polyomaviruses, which have repeatedly given novel insights into growth control, will be invaluable to
understand Aβ function. Our studies of murine polyomavirus (MuPyV) ST/MT already demonstrate the
importance of Aβ to survival, differentiation and transformation. Our sh/siRNA Aβ knockdowns of confirm its
importance, even in the absence of virus, to pathways important in cancer. Both Akt and c-Src signaling are
regulated by Aβ. In addition, human lung, breast and colon cancers show alterations in Aβ, suggesting that
Aβ-PP2A-mediated signaling is relevant to cancer. Very little work has been done on Aβ, so there is a
pressing need to study its function. In Aim 1 we will use broad-based technologies in a survey of functions
and integrate these approaches to identify pathways altered by Aβ in normal and transformed cells.
Expression analysis by RNA-seq, phosphoproteomic analysis, and NMR metabolomics will identify pathways
specifically targeted by PP2A Aβ. Comparisons of controls with cells expressing MuPyV MT or ST will inform
us whether the oncoproteins are inhibiting Aβ activity and/or redirecting it to new targets. Aim 2, focusing on
Aβ, will determine the Aβ/ST structure. PP2A B subunits and other targets that bind Aβ will be determined.
Genetic analysis of Aβ will uncover sequences responsible for its unique phenotype(s). In Aim 3 Aβ
regulation of tyrosine kinase signaling will be examined to learn the mechanism of c-Src control and to
determine how Aβ broadly controls tyrosine phosphorylation, perhaps via tyrosine phosphatases. ST
mutants defective for Aβ binding will be identified to test the role of Aβ in controlling cell phenotype. Finally,
we will confirm the role of Aβ in Her2/neu and MT tumorigenesis using conditional knockout technology.
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## Key facts

- **NIH application ID:** 9981672
- **Project number:** 5P01CA203655-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** BRIAN S SCHAFFHAUSEN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,245
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981672

## Citation

> US National Institutes of Health, RePORTER application 9981672, PROJECT 3: Pathways Controlled by PP2A A-Beta in Normal, Transformed and Tumor Cells (5P01CA203655-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9981672. Licensed CC0.

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