Castor1-KO Mouse

Castor1, also known as cytosolic arginine sensor for mTORC1 subunit 1, is a key regulator in the mTORC1 pathway. It functions as an arginine sensor, with arginine binding to Castor1 disrupting its complex with GATOR2 to activate mTORC1 [2]. The mTORC1 pathway is central to cell growth, metabolism, and proliferation, making Castor1's role crucial in various biological processes [2,3,4,6,7,8]. Genetic models, such as KO/CKO mouse models, can be valuable in further exploring its function.

In microglia, Castor1 overexpression inhibits M1 polarization by reducing M1-related markers and promotes M2-related gene expression, likely through inhibiting the mTOR signaling pathway. This suggests it could be a target for central nervous system-related diseases [1]. In breast cancer, RNF167-mediated Castor1 degradation activates mTORC1 and promotes cancer progression [3]. In lung adenocarcinoma, Castor1 expression is reduced, and its phosphorylation predicts poor survival in male patients with KRAS mutations [5,7]. Downregulating Castor1 in mammary epithelial cells inhibits heat-stress-induced apoptosis and promotes milk component synthesis [6].

In summary, Castor1 is an important regulator in the mTORC1 pathway. Through model-based research, it has been shown to play roles in processes like microglial polarization, apoptosis, and cell proliferation, with implications in diseases such as central nervous system-related disorders, breast cancer, and lung adenocarcinoma. These findings enhance our understanding of biological processes and disease mechanisms, potentially guiding new therapeutic strategies.

References:

1. Hu, Huiling, Lu, Xiaoxia, Huang, Lisi, Wang, Ying, Duan, Chaohui. 2022. Castor1 overexpression regulates microglia M1/M2 polarization via inhibiting mTOR pathway. In Metabolic brain disease, 38, 699-708. doi:10.1007/s11011-022-01135-w. https://pubmed.ncbi.nlm.nih.gov/36454504/

2. Chantranupong, Lynne, Scaria, Sonia M, Saxton, Robert A, Gygi, Steven P, Sabatini, David M. 2016. The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. In Cell, 165, 153-164. doi:10.1016/j.cell.2016.02.035. https://pubmed.ncbi.nlm.nih.gov/26972053/

3. Li, Tingting, Wang, Xian, Ju, Enguo, Wei, Shan, Gao, Shou-Jiang. 2021. RNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation. In Nature communications, 12, 1055. doi:10.1038/s41467-021-21206-3. https://pubmed.ncbi.nlm.nih.gov/33594058/

4. Valenstein, Max L, Rogala, Kacper B, Lalgudi, Pranav V, Quast, Jan-Philipp, Sabatini, David M. 2022. Structure of the nutrient-sensing hub GATOR2. In Nature, 607, 610-616. doi:10.1038/s41586-022-04939-z. https://pubmed.ncbi.nlm.nih.gov/35831510/

5. Loo, Suet Kee, Sica, Gabriel, Wang, Xian, Stabile, Laura P, Gao, Shou-Jiang. 2024. CASTOR1 phosphorylation predicts poor survival in male patients with KRAS-mutated lung adenocarcinoma. In Cell & bioscience, 14, 127. doi:10.1186/s13578-024-01307-4. https://pubmed.ncbi.nlm.nih.gov/39385301/

6. Gai, Zhongchao, Wang, Yujiao, Wang, Jie, Zhao, Jieqiong, Gong, Guoli. 2022. Downregulation of CASTOR1 Inhibits Heat-Stress-Induced Apoptosis and Promotes Casein and Lipid Synthesis in Mammary Epithelial Cells. In Journal of agricultural and food chemistry, 70, 5386-5395. doi:10.1021/acs.jafc.2c00877. https://pubmed.ncbi.nlm.nih.gov/35442666/

7. Zhou, Xuefeng, Cheng, Zhenshun, Chen, Hao, Orang, Matthew, Zhao, Jinping. 2018. CASTOR1 suppresses the progression of lung adenocarcinoma and predicts poor prognosis. In Journal of cellular biochemistry, 119, 10186-10194. doi:10.1002/jcb.27360. https://pubmed.ncbi.nlm.nih.gov/30132978/

8. Long, Lingyun, Wei, Jun, Lim, Seon Ah, Peng, Junmin, Chi, Hongbo. 2021. CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity. In Nature, 600, 308-313. doi:10.1038/s41586-021-04109-7. https://pubmed.ncbi.nlm.nih.gov/34795452/