# PPP2R2A

## Overview
PPP2R2A is a gene that encodes the protein phosphatase 2 regulatory subunit Balpha (PP2A-B55α), a critical component of the protein phosphatase 2 (PP2A) complex. This serine/threonine phosphatase is involved in multiple cellular processes including cell growth, division, DNA replication, and apoptosis. The protein encoded by PPP2R2A plays a pivotal role in the regulation of the DNA damage response, cell cycle checkpoints, and tumor suppression. Its function is essential for maintaining cellular homeostasis and genomic stability, thereby preventing disease progression, particularly in the context of cancer. The protein interacts with various other proteins to influence cellular signaling pathways, highlighting its importance in both normal cellular functions and pathological conditions (Kalev2012Loss; Cheng2011Evaluation).

## Function
PPP2R2A encodes the α isoform of the regulatory B55 subfamily of protein phosphatase 2 (PP2A), a critical serine/threonine phosphatase involved in various cellular processes. This protein plays a pivotal role in the negative regulation of cell growth and division, impacting signal transduction, DNA replication, apoptosis, and cell cycle progression. Specifically, PPP2R2A is integral to the regulation of the DNA damage response, particularly in the homologous recombination repair pathway, by influencing the efficiency of Rad51 foci formation and the expression of BRCA1 and RAD51 post-irradiation (Kalev2012Loss).

PPP2R2A also affects cell cycle checkpoints, notably the G1-S transition, by altering the expression of cell-cycle-promoting phosphatase CDC25A and activating CHK2 kinase. This modulation is crucial for maintaining genomic stability and preventing uncontrolled cell proliferation, which is essential in tumor suppression (Kalev2012Loss; Cheng2011Evaluation). Additionally, PPP2R2A regulates the phosphorylation state of ATM kinase, a key player in the DNA damage response, thereby controlling ATM's retention at DNA double-strand break sites and influencing downstream effector kinase CHK2 (Kalev2012Loss).

In summary, PPP2R2A's function in DNA repair, cell cycle regulation, and checkpoint activation underscores its vital role in maintaining cellular homeostasis and preventing disease progression, particularly in the context of cancer.

## Clinical Significance
PPP2R2A, encoding the B55α regulatory subunit of Protein Phosphatase 2 (PP2A), is implicated in various cancers due to its tumor suppressor functions. In breast carcinoma, deletions in PPP2R2A are associated with a specific subgroup of luminal breast cancer characterized by poor survival outcomes, higher tumor grades, and a higher prevalence of Her-2 overexpression. This subgroup also exhibits significantly shorter disease-free survival (DFS) and overall survival (OS) rates, particularly when combined with high Cyclin D1 expression (Beca2015Altered). 

In prostate cancer, PPP2R2A deletions are frequent, although no direct correlation with clinical features such as prostate cancer-specific death or tumor stage has been established. However, the gene's deletion suggests a potential role in prostate cancer susceptibility (Cheng2011Evaluation). 

PPP2R2A is also linked to lung adenocarcinomas, where its reduced expression correlates with poor outcomes. The gene plays a crucial role in the DNA damage response, particularly in response to replication stress induced by oncogenes like c-Myc, making cells more reliant on the ATR/CHK1 axis for survival (Qiu2020A). 

Furthermore, PPP2R2A deficiency in colorectal cancer leads to increased cell proliferation and colony formation, mediated by miR-892a targeting the 3' untranslated region of PPP2R2A, suppressing its expression and facilitating cancer progression (Liang2015miR-892a). This highlights PPP2R2A's broad impact on cancer development and progression across different cancer types.

## Interactions
PPP2R2A, a regulatory subunit of protein phosphatase 2A (PP2A), engages in several critical protein-protein interactions that influence cellular processes and disease mechanisms. Notably, PPP2R2A interacts with the PP2A catalytic C subunit (PPP2CA) and the scaffolding A subunit (PPP2R1A), forming part of the PP2A holoenzyme complex that is pivotal in dephosphorylation processes essential for cell cycle regulation and apoptosis (Cui2021AMOTL2). Additionally, PPP2R2A has been identified to interact with AMOTL2, a member of the AMOT family proteins. This interaction inhibits the dephosphorylation of the proto-oncogene JUN at threonine 239, a modification crucial for JUN's role in tumorigenesis and cell proliferation in non-small cell lung cancer (NSCLC) cells (Cui2021AMOTL2).

In the context of developmental biology, PPP2R2A, also known as PP2A-B55α, has been shown to interact with transcription factors like cJun, influencing phosphorylation states and transcriptional activity, which are critical in epidermal and neural tissue development (Panicker2020Ppp2r2a). These interactions underscore the multifaceted role of PPP2R2A in regulating various signaling pathways and maintaining cellular homeostasis across different tissues and conditions.


## References


[1. (Beca2015Altered) Francisco Beca, Miguel Pereira, Jorge F Cameselle-Teijeiro, Diana Martins, and Fernando Schmitt. Altered ppp2r2a and cyclin d1 expression defines a subgroup of aggressive luminal-like breast cancer. BMC Cancer, April 2015. URL: http://dx.doi.org/10.1186/s12885-015-1266-1, doi:10.1186/s12885-015-1266-1. (37 citations) 10.1186/s12885-015-1266-1](https://doi.org/10.1186/s12885-015-1266-1)

[2. (Kalev2012Loss) Peter Kalev, Michal Simicek, Iria Vazquez, Sebastian Munck, Liping Chen, Thomas Soin, Natasha Danda, Wen Chen, and Anna Sablina. Loss of ppp2r2a inhibits homologous recombination dna repair and predicts tumor sensitivity to parp inhibition. Cancer Research, 72(24):6414–6424, December 2012. URL: http://dx.doi.org/10.1158/0008-5472.can-12-1667, doi:10.1158/0008-5472.can-12-1667. (138 citations) 10.1158/0008-5472.can-12-1667](https://doi.org/10.1158/0008-5472.can-12-1667)

[3. (Cheng2011Evaluation) Yu Cheng, Wennuan Liu, Seong-Tae Kim, Jishan Sun, Lingyi Lu, Jielin Sun, Siqun Lilly Zheng, William B. Isaacs, and Jianfeng Xu. Evaluation of ppp2r2a as a prostate cancer susceptibility gene: a comprehensive germline and somatic study. Cancer Genetics, 204(7):375–381, July 2011. URL: http://dx.doi.org/10.1016/j.cancergen.2011.05.002, doi:10.1016/j.cancergen.2011.05.002. (103 citations) 10.1016/j.cancergen.2011.05.002](https://doi.org/10.1016/j.cancergen.2011.05.002)

[4. (Qiu2020A) Zhaojun Qiu, Pengyan Fa, Tao Liu, Chandra B. Prasad, Shanhuai Ma, Zhipeng Hong, Ernest R. Chan, Hongbing Wang, Zaibo Li, Kai He, Qi-En Wang, Terence M. Williams, Chunhong Yan, Steven T. Sizemore, Goutham Narla, and Junran Zhang. A genome-wide pooled shrna screen identifies ppp2r2a as a predictive biomarker for the response to atr and chk1 inhibitors. Cancer Research, 80(16):3305–3318, August 2020. URL: http://dx.doi.org/10.1158/0008-5472.can-20-0057, doi:10.1158/0008-5472.can-20-0057. (31 citations) 10.1158/0008-5472.can-20-0057](https://doi.org/10.1158/0008-5472.can-20-0057)

[5. (Cui2021AMOTL2) Renjie Cui, Nan Jiang, Meiqin Zhang, Sichen Du, Huayuan Ou, Runsheng Ge, Duan Ma, and Jin Zhang. Amotl2 inhibits jun thr239 dephosphorylation by binding ppp2r2a to suppress the proliferation in non-small cell lung cancer cells. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1868(1):118858, January 2021. URL: http://dx.doi.org/10.1016/j.bbamcr.2020.118858, doi:10.1016/j.bbamcr.2020.118858. (15 citations) 10.1016/j.bbamcr.2020.118858](https://doi.org/10.1016/j.bbamcr.2020.118858)

[6. (Panicker2020Ppp2r2a) Nikita Panicker, Melody Coutman, Charley Lawlor-O’Neill, Richard G. S. Kahl, Séverine Roselli, and Nicole M. Verrills. Ppp2r2a knockout mice reveal that protein phosphatase 2a regulatory subunit, pp2a-b55α, is an essential regulator of neuronal and epidermal embryonic development. Frontiers in Cell and Developmental Biology, June 2020. URL: http://dx.doi.org/10.3389/fcell.2020.00358, doi:10.3389/fcell.2020.00358. (16 citations) 10.3389/fcell.2020.00358](https://doi.org/10.3389/fcell.2020.00358)

[7. (Liang2015miR-892a) Wen-long Liang, Jie Cao, Bo Xu, Ping Yang, Fei Shen, Zheng Sun, Wang-lin Li, Qiang Wang, and Feng Liu. Mir-892a regulated ppp2r2a expression and promoted cell proliferation of human colorectal cancer cells. Biomedicine & Pharmacotherapy, 72:119–124, May 2015. URL: http://dx.doi.org/10.1016/j.biopha.2015.04.015, doi:10.1016/j.biopha.2015.04.015. (31 citations) 10.1016/j.biopha.2015.04.015](https://doi.org/10.1016/j.biopha.2015.04.015)