Nitrogen permease regulator-like 2 (NPRL2)

Nitrogen permease regulator-like 2 (NPRL2) is a critical protein subunit of the GATOR1 complex, which serves as a negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway (MedlinePlus Genetics, 2025). By acting as a GTPase-activating protein (GAP) for Rag GTPases, NPRL2 helps suppress mTORC1 activity in response to amino acid deprivation, thereby controlling cell growth, protein synthesis, and autophagy (UniProt, 2026). In oncology, NPRL2 is primarily recognized as a tumor suppressor; its downregulation or loss is associated with various malignancies, including lung, renal, and colorectal cancers, where it often modulates sensitivity to chemotherapeutic agents like cisplatin and oxaliplatin (NIH, 2015; Dovepress, 2019). Conversely, in neurology, loss-of-function mutations in NPRL2 are a significant cause of GATORopathies, a group of disorders characterized by focal epilepsy, cortical malformations, and neurodevelopmental delays (ResearchGate, 2026). While no direct NPRL2-targeting drugs are currently in clinical use, the pathway is therapeutically addressed using mTOR inhibitors like rapamycin to counteract the hyperactivation resulting from NPRL2 deficiency (eNeuro, 2022). Additionally, NPRL2 has been shown to regulate the expression of voltage-gated sodium channels, such as Scn1A, providing a link between metabolic sensing and neuronal excitability (NIH, 2022).

Other names

NPR2-like proteinGATOR1 complex protein NPRL2G21 proteinTumor suppressor candidate 4TUSC4Nitrogen permease regulator 2-like protein

NPRL2 functions as a negative regulator of the mTORC1 pathway by acting as a GTPase-activating protein (GAP) for Rag GTPases within the GATOR1 complex. Drugs like rapamycin and everolimus are used to inhibit the hyperactivated mTORC1 signaling resulting from NPRL2 loss, while NPRL2 itself modulates the cellular response to various chemotherapeutic agents by regulating apoptosis and autophagy pathways.