{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNPRL2 is a critical component of the GATOR1 complex that negatively regulates mTOR complex 1 (mTORC1) signaling. Functional studies have shown that mutations and dysregulation in NPRL2, along with its GATOR1 partners, contribute to aberrant mTOR activity and have been implicated in familial focal epilepsies. These studies suggest that NPRL2’s activity underlies important neuronal processes by modulating cell growth and synaptic function via mTOR inhibition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n \nIn addition to its role in epilepsy pathogenesis, NPRL2 functions as a multifaceted tumor suppressor in various human cancers. Decreased expression or inactivating mutations of NPRL2 have been observed in lung, colorectal, glioma, renal, prostate, and hepatocellular carcinomas. Mechanistic studies indicate that loss of NPRL2 disrupts DNA mismatch repair, cell cycle checkpoints, and apoptotic signaling, as well as deregulating PI3K/AKT/mTOR and related oncogenic pathways. Its interaction with key regulators such as PDK1 and components of ubiquitin and neddylation systems further underpins its role in controlling cell proliferation, migration, and survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "23"}]}, {"type": "t", "text": "\n \nMoreover, dysregulation of NPRL2 has been linked to altered responses to anticancer therapies. Overexpression or restoration of NPRL2 enhances chemosensitivity by promoting apoptosis, enforcing cell cycle arrest, and modulating autophagy. This improved drug response has been observed with agents including cisplatin, docetaxel, oxaliplatin, and PARP inhibitors, and NPRL2 expression levels correlate with clinical outcomes in refractory cancers such as castration-resistant prostate cancer and clear cell renal carcinoma. These findings underscore its promise as both a prognostic biomarker and a potential therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael G Ricos, Bree L Hodgson, Tommaso Pippucci, et al. 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