Ppp2r3a, also known as protein phosphatase 2 regulatory subunit B''alpha, is involved in multiple biological processes. It is associated with pathways related to cell growth, division, and signaling. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In various disease-related studies, PPP2R3A has been implicated in several conditions. In pulmonary fibrosis, its expression in inflammatory-proliferative fibroblasts, along with GREM1, initiates early pathological changes by enhancing cell viability, proliferation, and migration [1]. In myocardial cells, silencing PPP2R3A inhibits cell proliferation, arrests the cell cycle in the S phase, and promotes apoptosis, and 19 potential interacting proteins like COL1A2 were identified [2]. In colon cancer, its expression is downregulated due to hypermethylation, suggesting a suppressor role [3]. In hepatic fibrosis, BMSC-derived exosomal miR-192-5p targets PPP2R3A and inhibits hepatic stellate cell activation [4]. In liver cancer, PPP2R3A knockdown inhibits tumor cell proliferation, migration, and invasion, while overexpression promotes these processes, and it may regulate tumor growth via the p53 pathway [5]. Pathogenic mutations in PPP2R3A were found in a Zhuang family with coronary artery disease, indicating its potential role in CAD [6]. It was also identified as a shared risk gene between kidney diseases and sepsis [7]. In hepatocellular carcinoma, PPP2R3A promotes glycolysis by regulating hexokinase 1 [8], and high PPP2R3A expression predicts poor outcome in HCC patients after liver transplantation [9]. In celiac disease, PPP2R3A expression is downregulated, and this alteration is not fully reversible even after a gluten-free diet, suggesting a genetic implication [10].

In conclusion, PPP2R3A plays crucial roles in multiple biological processes and is involved in various diseases, including pulmonary fibrosis, heart-related diseases, cancer, and celiac disease. The use of gene knockout or conditional knockout mouse models has provided valuable insights into its functions in these disease conditions, helping to understand the underlying molecular mechanisms and potentially identify new therapeutic targets.

References:

1. Shi, Xiaoni, Wang, Jing, Zhang, Xinxin, Cheng, Yusi, Chao, Jie. 2022. GREM1/PPP2R3A expression in heterogeneous fibroblasts initiates pulmonary fibrosis. In Cell & bioscience, 12, 123. doi:10.1186/s13578-022-00860-0. https://pubmed.ncbi.nlm.nih.gov/35933397/

2. Wu, C-Y, Liang, Y, Li, X-F, Song, G-B. . The potential mechanism of PPP2R3A in myocardial cells and its interacting proteins. In European review for medical and pharmacological sciences, 25, 7913-7925. doi:10.26355/eurrev_202112_27641. https://pubmed.ncbi.nlm.nih.gov/34982454/

3. Dmitriev, A A, Beniaminov, A D, Melnikova, N V, Kudryavtseva, A V, Kashuba, V I. . [Functional Hypermethylation of ALDH1L1, PLCL2, and PPP2R3A in Colon Cancer]. In Molekuliarnaia biologiia, 54, 204-211. doi:10.1134/S002689842001005X. https://pubmed.ncbi.nlm.nih.gov/32392189/

4. Tan, Jie, Chen, Mingtao, Liu, Meng, Tian, Xia, Chen, Wei. 2023. Exosomal miR-192-5p secreted by bone marrow mesenchymal stem cells inhibits hepatic stellate cell activation and targets PPP2R3A. In Journal of histotechnology, 46, 158-169. doi:10.1080/01478885.2023.2215151. https://pubmed.ncbi.nlm.nih.gov/37226801/

5. Chen, Huijuan, Xu, Jing, Wang, Peixiao, Chen, Xinguo, Zhang, Qing. 2019. Protein phosphatase 2 regulatory subunit B''Alpha silencing inhibits tumor cell proliferation in liver cancer. In Cancer medicine, 8, 7741-7753. doi:10.1002/cam4.2620. https://pubmed.ncbi.nlm.nih.gov/31647192/

6. Li, Mei, Wen, Yun, Wen, Hong, Huang, Feng, Zeng, Zhiyu. 2018. Discovery of PPP2R3A and TMX3 pathogenic variants in a Zhuang family with coronary artery disease using whole-exome sequencing. In International journal of clinical and experimental pathology, 11, 3678-3684. doi:. https://pubmed.ncbi.nlm.nih.gov/31949749/

7. Zhang, Tianlong, Cui, Ying, Jiang, Siyi, Yao, Jiali, Li, Min. 2024. Shared genetic correlations between kidney diseases and sepsis. In Frontiers in endocrinology, 15, 1396041. doi:10.3389/fendo.2024.1396041. https://pubmed.ncbi.nlm.nih.gov/39086896/

8. Jiao, Ning, Ji, Wan Sheng, Zhang, Biao, Yue, Wen, Zhang, Qing. . Overexpression of Protein Phosphatase 2 Regulatory Subunit B"Alpha Promotes Glycolysis by Regulating Hexokinase 1 in Hepatocellular Carcinoma. In Biomedical and environmental sciences : BES, 35, 622-632. doi:10.3967/bes2022.082. https://pubmed.ncbi.nlm.nih.gov/35945177/

9. He, Jia-Jia, Shang, Lei, Yu, Qun-Wei, Tian, Yun-Er, Zhang, Qing. . High expression of protein phosphatase 2 regulatory subunit B'' alpha predicts poor outcome in hepatocellular carcinoma patients after liver transplantation. In World journal of gastrointestinal oncology, 13, 716-731. doi:10.4251/wjgo.v13.i7.716. https://pubmed.ncbi.nlm.nih.gov/34322200/

10. Jauregi-Miguel, Amaia, Fernandez-Jimenez, Nora, Irastorza, Iñaki, Vitoria, Juan Carlos, Bilbao, Jose Ramon. . Alteration of tight junction gene expression in celiac disease. In Journal of pediatric gastroenterology and nutrition, 58, 762-7. doi:10.1097/MPG.0000000000000338. https://pubmed.ncbi.nlm.nih.gov/24552675/