The Highly Recurrent PP2A Aα-Subunit Mutation P179R Alters Protein Structure and Impairs PP2A Enzyme Function to Promote Endometrial Tumorigenesis
Abstract
Somatic mutation of the protein phosphatase 2A (PP2A) Aα-subunit gene PPP2R1A is highly prevalent in high-grade endometrial carcinoma. The structural, molecular, and biological basis by which the most recurrent endometrial carcinoma–specific mutation site P179 facilitates features of endometrial carcinoma malignancy has yet to be fully determined. Here, we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function. Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile. A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation. Binding to the PP2A catalytic subunit was significantly impaired, disrupting holoenzyme formation and enzymatic activity. Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wild-type Aα in a patient-derived P179R-mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis in vivo. Furthermore, small molecule–mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity in vivo. These outcomes implicate PP2A functional inactivation as a critical component of high-grade endometrial carcinoma disease pathogenesis. Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R PPP2R1A mutations.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 15, 2019
- Source ID
- 10.1158/0008-5472.can-19-0218
Entities
People
- Amy J Armstrong
- Analisa DiFeo
- Caitlin M O'Connor
- Christa Nagel
- Corinne Lavasseur
- Daniel Leonard
- Goutham Narla
- Guobo Shen
- Haichi Song
- Jaya Sangodkar
- Kimberly Resnick
- Kristine Zanotti
- Mark W. Jackson
- Sarah E. Taylor
- Sareena Singh
- Shozeb Haider
- Stefanie Avril
- Steven Waggoner
- Wenqing Xu
- Zhizhi Wang
Organizations
- Aultman Hospital
- Case Western Reserve University
- MetroHealth
- National Institutes of Health
- UH Cleveland Medical Center
- United States Department of Defense
- University College London
- University of Michigan
- University of Washington