NPRL2
entrez
10641
canonical
uniprot
Q8WTW4
canonical
ensembl
ENSG00000114388
resolver
ensp
ENSP00000232501
resolver
ensp
ENSP00000704123
resolver
genesymbol
NPRL2
resolver
genesymbol_syn
TUSC4
resolver
hgnc
HGNC:24969
resolver
uniprot
A8K831
resolver
uniprot
Q6FGS2
resolver
uniprot
Q9Y249
resolver
uniprot
Q9Y497
resolver
uniprot_entry
NPRL2_HUMAN
resolver
uniprot_sec
A8K831
resolver
uniprot_sec
Q6FGS2
resolver
uniprot_sec
Q9Y249
resolver
uniprot_sec
Q9Y497
resolver
amino_acid_sequence
MGSGCRIECIFFSEFHPTLGPKITYQVPEDFISRELFDTVQVYIITKPELQNKLITVTAMEKKLIGCPVCIEHKKYSRNALLFNLGFVCDAQAKTCALEPIVKKLAGYLTTLELESSFVSMEESKQKLVPIMTILLEELNASGRCTLPIDESNTIHLKVIEQRPDPPVAQEYDVPVFTKDKEDFFNSQWDLTTQQILPYIDGFRHIQKISAEADVELNLVRIAIQNLLYYGVVTLVSILQYSNVYCPTPKVQDLVDDKSLQEACLSYVTKQGHKRASLRDVFQLYCSLSPGTTVRDLIGRHPQQLQHVDERKLIQFGLMKNLIRRLQKYPVRVTREEQSHPARLYTGCHSYDEICCKTGMSYHELDERLENDPNIIICWK
uniprot
proteins
disease_involvement
DISEASE: Note=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). {ECO:0000269|PubMed:23723238}.; DISEASE: Epilepsy, familial focal, with variable foci 2 (FFEVF2) [MIM:617116]: 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. Penetrance of the disorder is incomplete. {ECO:0000269|PubMed:26505888, ECO:0000269|PubMed:27173016}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
function
FUNCTION: 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). {ECO:0000269|PubMed:23723238, ECO:0000269|PubMed:27173016, ECO:0000269|PubMed:29590090, ECO:0000269|PubMed:30651352, ECO:0000269|PubMed:35338845, ECO:0000269|PubMed:36528027, ECO:0000269|PubMed:38006878}.; FUNCTION: 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). {ECO:0000269|PubMed:18616680}.
uniprot
proteins
mass_dalton
43658
uniprot
proteins
mutagenesis
MUTAGEN 17..21; /note="PTLGP->GSGSG: In RL1 mutant; abolished ability of the GATOR1 complex to inhibit mTORC1 signaling."; /evidence="ECO:0000269|PubMed:30651352"; MUTAGEN 20; /note="G->S: Abolished GTPase activating protein activity toward RagA/RRAGA."; /evidence="ECO:0000269|PubMed:30651352"; MUTAGEN 78; /note="R->A: Abolished GTPase activating protein activity toward RagA/RRAGA."; /evidence="ECO:0000269|PubMed:30651352, ECO:0000269|PubMed:35338845"; MUTAGEN 117..121; /note="SFVSM->GSGSG: In RL2 mutant; does not affect ability of the GATOR1 complex to inhibit mTORC1 signaling."; /evidence="ECO:0000269|PubMed:30651352"; MUTAGEN 158; /note="K->R: Decreased ubiquitination by the GATOR2 complex."; /evidence="ECO:0000269|PubMed:36528027"; MUTAGEN 279; /note="R->A: Does not affect the GTPase activating protein activity of the GATOR1 complex."; /evidence="ECO:0000269|PubMed:30651352"; MUTAGEN 295; /note="R->A: Does not affect the GTPase activating protein activity of the GATOR1 complex."; /evidence="ECO:0000269|PubMed:30651352"; MUTAGEN 300; /note="R->A: Does not affect the GTPase activating protein activity of the GATOR1 complex."; /evidence="ECO:0000269|PubMed:30651352"; MUTAGEN 311; /note="R->A: Does not affect the GTPase activating protein activity of the GATOR1 complex."; /evidence="ECO:0000269|PubMed:30651352"; MUTAGEN 324; /note="R->A: Does not affect the GTPase activating protein activity of the GATOR1 complex."; /evidence="ECO:0000269|PubMed:30651352"; MUTAGEN 328; /note="K->R: Does not affect ubiquitination by the GATOR2 complex."; /evidence="ECO:0000269|PubMed:36528027"; MUTAGEN 343; /note="R->A: Does not affect the GTPase activating protein activity of the GATOR1 complex."; /evidence="ECO:0000269|PubMed:30651352"; MUTAGEN 357; /note="K->R: Decreased ubiquitination by the GATOR2 complex."; /evidence="ECO:0000269|PubMed:36528027"; MUTAGEN 368; /note="R->A: Does not affect the GTPase activating protein activity of the GATOR1 complex."; /evidence="ECO:0000269|PubMed:30651352
uniprot
proteins
post_translational_modification
PTM: 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. {ECO:0000269|PubMed:36528027}.; PTM: 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. {ECO:0000269|PubMed:38006878}.
uniprot
proteins
protein_family
NPR2 family
uniprot
proteins
pubmed
11085536
uniprot
proteins
pubmed
11980673
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16641997
uniprot
proteins
pubmed
18616680
uniprot
proteins
pubmed
19521502
uniprot
proteins
pubmed
23723238
uniprot
proteins
pubmed
26505888
uniprot
proteins
pubmed
27173016
uniprot
proteins
pubmed
28199306
uniprot
proteins
pubmed
29590090
uniprot
proteins
pubmed
30651352
uniprot
proteins
pubmed
35338845
uniprot
proteins
pubmed
36007018
uniprot
proteins
pubmed
36528027
uniprot
proteins
pubmed
38006878
uniprot
proteins
sequence_length
380
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:28199306}. Note=Localization to lysosomes is mediated by the KICSTOR complex and is amino acid-independent. {ECO:0000269|PubMed:28199306}.
uniprot
proteins