TGM2, also known as tissue transglutaminase 2, is a multifunctional enzyme with transglutaminase crosslinking (TGase), G protein signaling and kinase activities. It participates in various biological processes such as cell adhesion, migration, and is involved in multiple pathways. Its abnormal expression is associated with numerous diseases, highlighting its biological importance [5]. Genetic models like knockout (KO) or conditional knockout (CKO) mouse models are valuable for studying its functions.

In glioblastoma, knocking down SDC1 and TGM2 inhibited the fusion of autophagosomes with lysosomes and enhanced radiosensitivity, suggesting TGM2's role in radioresistance [1]. In gastric cancer, TGM2 promoted cell proliferation, migration, and invasion by suppressing STAT1 ubiquitination/degradation [2]. In hepatocellular carcinoma, TGM2-mediated H3Q5ser modifications promoted HCC progression via the MYC pathway, and TGM2 inhibitors suppressed HCC progression [3]. In ductular reaction, deletion of Tgm2 in mice affected the functionality and maturity of proliferative cholangiocytes and suppressed BMP-mediated hepatocyte-to-cholangiocyte metaplasia [4].

In conclusion, TGM2 is involved in a wide range of biological functions including cell-related processes and disease-associated pathways. Studies using KO/CKO mouse models have revealed its significance in diseases such as glioblastoma, gastric cancer, hepatocellular carcinoma, and in the context of ductular reaction, providing insights into potential therapeutic targets for these diseases.

References:

1. Zheng, Wang, Chen, Qianping, Liu, Hongxia, Pan, Yan, Shao, Chunlin. 2022. SDC1-dependent TGM2 determines radiosensitivity in glioblastoma by coordinating EPG5-mediated fusion of autophagosomes with lysosomes. In Autophagy, 19, 839-857. doi:10.1080/15548627.2022.2105562. https://pubmed.ncbi.nlm.nih.gov/35913916/

2. Zhang, Lu, Li, Qingya, Yang, Jing, Xu, Jianghao, Xu, Zekuan. 2022. Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21-mediated ubiquitination/degradation of STAT1 in a GTP binding-dependent modality. In Cancer communications (London, England), 43, 123-149. doi:10.1002/cac2.12386. https://pubmed.ncbi.nlm.nih.gov/36353796/

3. Dong, Renshun, Wang, Tianci, Dong, Wei, Zhang, Bixiang, Zhang, Xuewu. 2025. TGM2-mediated histone serotonylation promotes HCC progression via MYC signalling pathway. In Journal of hepatology, , . doi:10.1016/j.jhep.2024.12.038. https://pubmed.ncbi.nlm.nih.gov/39788430/

4. Chen, Yaqing, Yan, Yi, Li, Yujing, Zhu, Xianmin, Zhang, Lisheng. 2024. Deletion of Tgm2 suppresses BMP-mediated hepatocyte-to-cholangiocyte metaplasia in ductular reaction. In Cell proliferation, 57, e13646. doi:10.1111/cpr.13646. https://pubmed.ncbi.nlm.nih.gov/38623945/

5. Lai, Thung-S, Greenberg, Charles S. 2013. TGM2 and implications for human disease: role of alternative splicing. In Frontiers in bioscience (Landmark edition), 18, 504-19. doi:. https://pubmed.ncbi.nlm.nih.gov/23276939/