GCN2, or General Control Nonderepressible-2, is a kinase belonging to the protein kinase family. It is known for its ability to phosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2α), thereby downregulating protein synthesis under various cellular stress conditions. GCN2 is activated in response to amino acid deprivation and binds to uncharged tRNAs, and it may also be activated under conditions of glucose deprivation and viral infections. Phosphorylated GCN2 (phospho T899) is a key regulatory point for the kinase activity of GCN2. When GCN2 is phosphorylated at the Thr899 site, it can more effectively phosphorylate Ser51 of eIF2α, which in turn inhibits global protein translation rates and reduces the consumption of amino acids within the cell. This mechanism makes GCN2 an important sensor and regulator in the cellular response to amino acid starvation and other stress conditions. In the tumor microenvironment, the activation of GCN2 is associated with the modulation of immune responses. Studies have shown that the activation of GCN2 can lead to T cell anergy and apoptosis, enhance myeloid-derived suppressor cell (MDSC)-dependent immunosuppression, and promote tumor cell survival. Therefore, the inhibition of GCN2 may have direct anti-cancer effects and immune-activating effects, making it a potential therapeutic target for cancer treatment.
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