ITFG2 is a core component of the KICSTOR complex, a lysosomal-anchored protein assembly that negatively regulates mTORC1 signaling in response to nutrient availability 1. As part of KICSTOR alongside KPTN, C12orf66, and SZT2, ITFG2 recruits and positions the GATOR1 GTPase-activating protein on lysosomal membranes, enabling GATOR1 to interact with RAG GTPases and suppress mTORC1 activation during amino acid and glucose deprivation 12. Structural studies reveal ITFG2 forms a heterodimer with KPTN that binds the SZT2 scaffold, facilitating the assembly of the GATOR1-KICSTOR supercomplex required for nutrient-dependent mTORC1 inhibition 2. Loss of KICSTOR function results in constitutive mTORC1 activation, mimicking GATOR1 inactivation 2. Beyond nutrient sensing, ITFG2 functions as a NEDD4-2 inhibitor in cardiac tissue, stabilizing SERCA2a and maintaining calcium homeostasis during ischemic stress 3. Mutations in ITFG2 and other KICSTOR components are associated with severe neurodevelopmental disorders and epilepsy 14, while ITFG2 loss confers resistance to PI3K inhibitors in breast cancer by sustaining mTOR signaling 5. Additionally, circular RNA ITFG2 acts as a tumor suppressor in lung cancer by regulating autophagy and immune responses 6.