Acvr2a, or activin receptor type 2A, is a key component in multiple signaling pathways, particularly those involving bone morphogenetic proteins (BMPs) and activin A. It plays a crucial role in embryo implantation by promoting endometrial receptivity through an ACVR2A-SMAD1/SMAD5 axis [1]. It is also involved in pathways related to cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition, which are important in normal development and disease processes [3].

In disease-related research, Acvr2a shows various associations. In non-alcoholic steatohepatitis-related hepatocellular carcinoma (NASH-HCC), it has a higher mutation rate compared to other HCC aetiologies, and its silencing promotes cell proliferation [2]. In colon cancer, the activin A/ACVR2A axis inhibits cell migration, invasion, and epithelial-to-mesenchymal transition by activating SMAD2, and its downregulation may be associated with metastasis [3]. In gastric cancer, microsatellite instability-related Acvr2a mutations are associated with decreased lymph node metastasis, and wild-type Acvr2a promotes cell migration via the Snail/Slug-EMT pathway [5]. In hepatocellular carcinoma, ACVR2A attenuation leads to hyperglycolysis, lactate production, regulatory T cell accumulation, and resistance to immune checkpoint inhibitors [4].

In conclusion, Acvr2a is essential for embryo implantation and plays significant roles in multiple cancer types, including NASH-HCC, colon cancer, and gastric cancer. Mouse models with conditional deletion of Acvr2a, like in the study of endometrial receptivity [1], have been crucial in understanding its function in biological processes and disease conditions, providing insights into potential therapeutic targets for related diseases.

References:

1. Monsivais, Diana, Nagashima, Takashi, Prunskaite-Hyyryläinen, Renata, Lee, Se-Jin, Matzuk, Martin M. 2021. Endometrial receptivity and implantation require uterine BMP signaling through an ACVR2A-SMAD1/SMAD5 axis. In Nature communications, 12, 3386. doi:10.1038/s41467-021-23571-5. https://pubmed.ncbi.nlm.nih.gov/34099644/

2. Pinyol, Roser, Torrecilla, Sara, Wang, Huan, Sia, Daniela, Llovet, Josep M. 2021. Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. In Journal of hepatology, 75, 865-878. doi:10.1016/j.jhep.2021.04.049. https://pubmed.ncbi.nlm.nih.gov/33992698/

3. Zhang, Hui, Ruan, Qiang, Chen, Changjiang, Lin, Ruirong, Zhuo, Changhua. 2023. Activin A/ACVR2A axis inhibits epithelial-to-mesenchymal transition in colon cancer by activating SMAD2. In Molecular carcinogenesis, 62, 1585-1598. doi:10.1002/mc.23601. https://pubmed.ncbi.nlm.nih.gov/37378449/

4. Yasukawa, Koya, Shimada, Shu, Akiyama, Yoshimitsu, Tanabe, Minoru, Tanaka, Shinji. 2025. ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma. In Cell reports. Medicine, 6, 102038. doi:10.1016/j.xcrm.2025.102038. https://pubmed.ncbi.nlm.nih.gov/40139191/

5. Zhao, Liqin, Zhang, Jieyun, Qu, Xiaofei, Wu, Zhenhua, Guo, Weijian. 2020. Microsatellite Instability-Related ACVR2A Mutations Partially Account for Decreased Lymph Node Metastasis in MSI-H Gastric Cancers. In OncoTargets and therapy, 13, 3809-3821. doi:10.2147/OTT.S247757. https://pubmed.ncbi.nlm.nih.gov/32440149/