Slc7a3, also known as CAT3 (cationic amino acid transporter 3), is a member of the solute carrier family 7. It functions as a major L-arginine transporter [2,4,5,6]. Arginine is a semi-essential amino acid involved in multiple biological processes such as the production of urea, nitric oxide, and polyamines. Thus, Slc7a3 is crucial for maintaining cellular arginine levels, which impacts various metabolic pathways and cellular functions [5,6].

In mouse models, knockout of Slc7a3 surprisingly does not affect normal hematopoietic stem cells (HSCs) in steady-state or under stress, nor does it impact T-cell development, activation, or proliferation, or leukemia development driven by Pten loss or the oncogenic Ptpn11E76K mutation. Arginine uptake assays also revealed that L-arginine uptake is not disrupted in Slc7a3 knockout cells, suggesting that although extracellular arginine is important for HSCs, CAT3 is dispensable for normal hematopoiesis and leukemogenesis [2].

In conclusion, Slc7a3 is an important arginine transporter, but its role can be dispensable in certain biological processes like normal hematopoiesis and leukemogenesis as shown by gene knockout mouse models. In addition, it has been implicated in diseases such as osteosarcoma metastasis, where its upregulation via the SIRPA-SP1 axis promotes metastasis, and in breast cancer, where high expression inhibits tumor cell proliferation and predicts a favorable prognosis [1,3].

References:

1. Wang, Peng, Song, Yihui, Li, Hongyu, Ma, Mengjun, Shen, Huiyong. 2023. SIRPA enhances osteosarcoma metastasis by stabilizing SP1 and promoting SLC7A3-mediated arginine uptake. In Cancer letters, 576, 216412. doi:10.1016/j.canlet.2023.216412. https://pubmed.ncbi.nlm.nih.gov/37769797/

2. Yan, Yuhan, Chen, Chao, Li, Zhiguo, Park, Narin, Qu, Cheng-Kui. 2022. Extracellular arginine is required but the arginine transporter CAT3 (Slc7a3) is dispensable for mouse normal and malignant hematopoiesis. In Scientific reports, 12, 21832. doi:10.1038/s41598-022-24554-2. https://pubmed.ncbi.nlm.nih.gov/36528691/

3. He, Lifang, Xu, Yue, Lin, Jiediao, Lin, Stanley Li, Cui, Yukun. . Increased SLC7A3 Expression Inhibits Tumor Cell Proliferation and Predicts a Favorable Prognosis in Breast Cancer. In Recent patents on anti-cancer drug discovery, 20, 55-70. doi:10.2174/0115748928279007231130070056. https://pubmed.ncbi.nlm.nih.gov/38204267/

4. Lowman, Xazmin H, Hanse, Eric A, Yang, Ying, Li, Haiqing, Kong, Mei. . p53 Promotes Cancer Cell Adaptation to Glutamine Deprivation by Upregulating Slc7a3 to Increase Arginine Uptake. In Cell reports, 26, 3051-3060.e4. doi:10.1016/j.celrep.2019.02.037. https://pubmed.ncbi.nlm.nih.gov/30865893/

5. Vanoaica, Liviu, Behera, Alok, Camargo, Simone M R, Forster, Ian C, Verrey, François. 2015. Real-time functional characterization of cationic amino acid transporters using a new FRET sensor. In Pflugers Archiv : European journal of physiology, 468, 563-72. doi:10.1007/s00424-015-1754-9. https://pubmed.ncbi.nlm.nih.gov/26555760/

6. Closs, E I, Boissel, J-P, Habermeier, A, Rotmann, A. 2007. Structure and function of cationic amino acid transporters (CATs). In The Journal of membrane biology, 213, 67-77. doi:. https://pubmed.ncbi.nlm.nih.gov/17417706/