{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q8WTW4","secondaryAccessions":["A8K831","Q6FGS2","Q9Y249","Q9Y497"],"uniProtkbId":"NPRL2_HUMAN","entryAudit":{"firstPublicDate":"2004-05-10","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2004-05-10","entryVersion":172,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"GATOR1 complex protein NPRL2"}},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"Reference","id":"Ref.1"}],"value":"Gene 21 protein"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"Reference","id":"Ref.1"}],"value":"G21 protein"}]},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"11085536"}],"value":"Nitrogen permease regulator 2-like protein"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"11085536"}],"value":"NPR2-like protein"}]},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"18616680"}],"value":"Tumor suppressor candidate 4"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"18616680"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:24969"}],"value":"NPRL2"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"18616680"}],"value":"TUSC4"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23723238"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27173016"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29590090"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30651352"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35338845"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36528027"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38006878"}],"value":"Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway (PubMed:23723238, PubMed:29590090, PubMed:35338845, PubMed:38006878). In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling (PubMed:23723238, PubMed:29590090, PubMed:35338845). In the presence of abundant amino acids, the GATOR1 complex is ubiquitinated and inhibited by GATOR2 (PubMed:23723238, PubMed:36528027). Within the GATOR1 complex, NPRL2 constitutes the catalytic subunit that mediates the GTPase activator activity and under methionine-sufficient conditions, the GTPase activator activity is inhibited by PRMT1 through methylation and consequently inducing timely mTORC1 activation (PubMed:27173016, PubMed:30651352, PubMed:35338845)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18616680"}],"value":"Suppresses Src-dependent tyrosine phosphorylation and activation of PDPK1 and its downstream signaling (PubMed:18616680). Down-regulates PDPK1 kinase activity by interfering with tyrosine phosphorylation at 'Tyr-9', 'Tyr-373' and 'Tyr-376' residues (PubMed:18616680). May act as a tumor suppressor (PubMed:18616680). Suppresses cell growth and enhances sensitivity to various anticancer drugs (PubMed:18616680)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18616680"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19521502"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23723238"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29590090"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35338845"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36007018"}],"value":"Within the GATOR complex, component of the GATOR1 subcomplex, made of DEPDC5, NPRL2 and NPRL3 (PubMed:19521502, PubMed:23723238, PubMed:29590090, PubMed:35338845). GATOR1 mediates the strong interaction of the GATOR complex with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD) heterodimers (PubMed:23723238, PubMed:29590090). GATOR1 interacts with GPR155/LYCHOS; interaction takes place in presence of cholesterol and prevents interaction between GATOR1 and KICSTOR (PubMed:36007018). Interacts with PDPK1 (PubMed:18616680)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q8WTW4","intActId":"EBI-1043552"},"interactantTwo":{"uniProtKBAccession":"Q12980","geneName":"NPRL3","intActId":"EBI-2650314"},"numberOfExperiments":10,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28199306"}],"value":"Localization to lysosomes is mediated by the KICSTOR complex and is amino acid-independent"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28199306"}],"value":"Lysosome membrane","id":"SL-0157"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["Q8WTW4-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["Q8WTW4-2"],"sequenceIds":["VSP_010329","VSP_010330","VSP_010331"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26505888"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27173016"}],"value":"Most abundant in skeletal muscle, followed by brain, liver and pancreas, with lower amounts in lung, kidney, placenta and heart. Expressed in the frontal lobe cortex as well as in the temporal, parietal, and occipital lobes (PubMed:26505888, PubMed:27173016). Expressed in most lung cancer cell lines tested"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30651352"}],"value":"The arginine finger is critical for the GTPase-activating mechanism"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36528027"}],"value":"In the presence of abundant amino acids, ubiquitinated at Lys-158 and Lys-357 via 'Lys-6'-linked ubiquitination by the WDR24 component of the GATOR2 complex, thereby inhibiting the GATOR1 complex and promoting mTORC1 activation"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38006878"}],"value":"Asymmetric dimethylation at Arg-78 by PRMT1 inhibits the GTPase activator activity of the GATOR1 complex and consequently inducing timely mTORC1 activation under methionine-sufficient conditions"}],"commentType":"PTM"},{"commentType":"DISEASE","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23723238"}],"value":"Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins, including NPRL2, are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal (PubMed:23723238)"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Epilepsy, familial focal, with variable foci 2","diseaseAccession":"DI-04832","acronym":"FFEVF2","description":"An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. Seizure types commonly include temporal lobe epilepsy, frontal lobe epilepsy, and nocturnal frontal lobe epilepsy. Some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. A subset of patients have structural brain abnormalities. 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