TOB1, also known as Transducer of ERBB2.1, is a tumor-suppressor protein that negatively regulates the receptor tyrosine-kinase ERBB2. It is involved in multiple cellular processes such as cell proliferation, apoptosis, and autophagy, and plays a role in various signaling pathways including the AKT/mTOR pathway [7]. Its functions are crucial in maintaining normal cellular homeostasis and are significant in understanding disease mechanisms, with genetic models like gene knockout being valuable for studying its functions.

In gastric cancer, TOB1 modulates neutrophil phenotypes. High levels of cTOB1/nTOB1 + CD66b + neutrophils are linked to a better prognosis. Tumor tissue culture supernatant reduces TOB1 protein and mRNA levels in neutrophils, increasing apoptosis. Neutrophils with attenuated TOB1 gene expression enhance the malignant phenotype of gastric cancer cells. Also, high TOB1 combined with neutrophils shows a better immunotherapy response [1]. In pancreatic cancer, TOB1 is downregulated, and its overexpression reduces the proliferation of K-Ras wild-type pancreatic cancer cells by regulating calcium pathway genes [3]. In muscle, loss of Tob1 in mice promotes muscle regeneration through muscle stem cell expansion, suggesting a potential therapeutic target for muscular diseases [4]. In FMDV infection, TOB1-knockout significantly inhibits FMDV infection in pigs, as it positively regulates the expression of RIG-I and MDA5, and inhibits FMDV adsorption and internalization mediated by the EGFR/ERBB2 pathway [2]. In IBD, TOB1 expression is decreased in IBD patients. Overexpression of TOB1 restrains intestinal mucosal inflammation by suppressing Th1/Th17 cell-mediated immune responses via the Smad4/5-ID2 pathway [5]. In antiviral response, TOB1 attenuates IRF3-directed IFN-β expression by recruiting HDAC8 to the Ifnb1 promoter region, and Tob1 deficiency enhances the antiviral response in vivo [6].

In conclusion, TOB1 is a multifunctional protein involved in tumor suppression, immune regulation, muscle regeneration, and viral infection. Gene knockout mouse models have been instrumental in revealing its role in diseases such as cancer, IBD, and FMDV infection, providing insights into potential therapeutic targets for these conditions.

References:

1. Zhang, Jinfeng, Li, Yunlong, Chen, Jing, Fu, Songbin, Yu, Jingcui. 2024. TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy. In Frontiers in immunology, 15, 1369087. doi:10.3389/fimmu.2024.1369087. https://pubmed.ncbi.nlm.nih.gov/38617839/

2. Peng, Gaochuang, Liu, Tianran, Qi, Xiaolan, Li, Dan, Zheng, Haixue. 2024. A genome-wide CRISPR screening uncovers that TOB1 acts as a key host factor for FMDV infection via both IFN and EGFR mediated pathways. In PLoS pathogens, 20, e1012104. doi:10.1371/journal.ppat.1012104. https://pubmed.ncbi.nlm.nih.gov/38512977/

3. Bai, Yuru, Qiao, Lu, Xie, Ning, Wang, Jinhai, Liu, Na. 2019. TOB1 suppresses proliferation in K-Ras wild-type pancreatic cancer. In Cancer medicine, 9, 1503-1514. doi:10.1002/cam4.2756. https://pubmed.ncbi.nlm.nih.gov/31891232/

4. Kitajima, Yasuo, Yoshioka, Kiyoshi, Mikumo, Yoko, Ohkawa, Yasuyuki, Ono, Yusuke. 2024. Loss of Tob1 promotes muscle regeneration through muscle stem cell expansion. In Journal of cell science, 137, . doi:10.1242/jcs.261886. https://pubmed.ncbi.nlm.nih.gov/39037211/

5. Lin, Ritian, Ma, Caiyun, Fang, Leilei, Cong, Yingzi, Liu, Zhanju. 2021. TOB1 Blocks Intestinal Mucosal Inflammation Through Inducing ID2-Mediated Suppression of Th1/Th17 Cell Immune Responses in IBD. In Cellular and molecular gastroenterology and hepatology, 13, 1201-1221. doi:10.1016/j.jcmgh.2021.12.007. https://pubmed.ncbi.nlm.nih.gov/34920145/

6. Yu, Zhongxia, Wang, Lijuan, Zhao, Jing, Zhao, Wei, Jia, Mutian. 2022. TOB1 attenuates IRF3-directed antiviral responses by recruiting HDAC8 to specifically suppress IFN-β expression. In Communications biology, 5, 943. doi:10.1038/s42003-022-03911-x. https://pubmed.ncbi.nlm.nih.gov/36085336/

7. Lee, Hun Seok, Kundu, Juthika, Kim, Ryong Nam, Shin, Young Kee. 2015. Transducer of ERBB2.1 (TOB1) as a Tumor Suppressor: A Mechanistic Perspective. In International journal of molecular sciences, 16, 29815-28. doi:10.3390/ijms161226203. https://pubmed.ncbi.nlm.nih.gov/26694352/