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Protein

Nitrogen permease regulator 2-like protein

Gene

NPRL2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Suppresses Src-dependent tyrosine phosphorylation and activation of PDPK1 and its downstream signaling. Down-regulates PDPK1 kinase activity by interfering with tyrosine phosphorylation at 'Tyr-9', 'Tyr-373' and 'Tyr-376' residues. May act as a tumor suppressor. Suppresses cell growth and enhances sensitivity to various anticancer drugs. As a component of the GATOR1 complex, inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling.2 Publications

GO - Molecular functioni

  • GTPase activator activity Source: UniProtKB-KW
  • protein kinase activity Source: UniProtKB

GO - Biological processi

  • cellular response to amino acid starvation Source: UniProtKB
  • negative regulation of kinase activity Source: UniProtKB
  • negative regulation of TOR signaling Source: SGD
  • positive regulation of GTPase activity Source: GOC
  • protein phosphorylation Source: GOC
Complete GO annotation...

Keywords - Molecular functioni

GTPase activation

Names & Taxonomyi

Protein namesi
Recommended name:
Nitrogen permease regulator 2-like protein
Short name:
NPR2-like protein
Alternative name(s):
Gene 21 protein
Short name:
G21 protein
Tumor suppressor candidate 4
Gene namesi
Name:NPRL2
Synonyms:TUSC4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:24969. NPRL2.

Subcellular locationi

GO - Cellular componenti

  • Iml1 complex Source: SGD
Complete GO annotation...

Pathology & Biotechi

Involvement in diseasei

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).

Keywords - Diseasei

Tumor suppressor

Organism-specific databases

PharmGKBiPA165697981.

Polymorphism and mutation databases

BioMutaiNPRL2.
DMDMi47117604.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 380380Nitrogen permease regulator 2-like proteinPRO_0000213319Add
BLAST

Proteomic databases

EPDiQ8WTW4.
MaxQBiQ8WTW4.
PaxDbiQ8WTW4.
PRIDEiQ8WTW4.

PTM databases

iPTMnetiQ8WTW4.
PhosphoSiteiQ8WTW4.

Expressioni

Tissue specificityi

Most abundant in skeletal muscle, followed by brain, liver and pancreas, with lower amounts in lung, kidney, placenta and heart. Expressed in most lung cancer cell lines tested.

Gene expression databases

BgeeiQ8WTW4.
CleanExiHS_TUSC4.
ExpressionAtlasiQ8WTW4. baseline and differential.
GenevisibleiQ8WTW4. HS.

Organism-specific databases

HPAiHPA038196.
HPA038197.

Interactioni

Subunit structurei

Forms a heterodimer with NPRL3. Interacts with PDPK1. Within the GATOR complex, component of the GATOR1 subcomplex, made of DEPDC5, NPRL2 and NPRL3. GATOR1 mediates the strong interaction of the GATOR complex with RRAGA/RRAGC and RRAGB/RRAGC heterodimers.3 Publications

Protein-protein interaction databases

BioGridi115885. 18 interactions.
IntActiQ8WTW4. 3 interactions.
MINTiMINT-3046340.
STRINGi9606.ENSP00000232501.

Structurei

3D structure databases

ProteinModelPortaliQ8WTW4.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 133133Interaction with PDPK1Add
BLAST

Sequence similaritiesi

Belongs to the NPR2 family.Curated

Phylogenomic databases

eggNOGiKOG3789. Eukaryota.
ENOG410XP7B. LUCA.
GeneTreeiENSGT00390000001414.
HOGENOMiHOG000007022.
HOVERGENiHBG055255.
InParanoidiQ8WTW4.
OMAiQKYPVKV.
OrthoDBiEOG7N63MM.
PhylomeDBiQ8WTW4.
TreeFamiTF106159.

Family and domain databases

InterProiIPR009348. NPR2.
[Graphical view]
PANTHERiPTHR12991. PTHR12991. 1 hit.
PfamiPF06218. NPR2. 2 hits.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8WTW4-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MGSGCRIECI FFSEFHPTLG PKITYQVPED FISRELFDTV QVYIITKPEL
60 70 80 90 100
QNKLITVTAM EKKLIGCPVC IEHKKYSRNA LLFNLGFVCD AQAKTCALEP
110 120 130 140 150
IVKKLAGYLT TLELESSFVS MEESKQKLVP IMTILLEELN ASGRCTLPID
160 170 180 190 200
ESNTIHLKVI EQRPDPPVAQ EYDVPVFTKD KEDFFNSQWD LTTQQILPYI
210 220 230 240 250
DGFRHIQKIS AEADVELNLV RIAIQNLLYY GVVTLVSILQ YSNVYCPTPK
260 270 280 290 300
VQDLVDDKSL QEACLSYVTK QGHKRASLRD VFQLYCSLSP GTTVRDLIGR
310 320 330 340 350
HPQQLQHVDE RKLIQFGLMK NLIRRLQKYP VRVTREEQSH PARLYTGCHS
360 370 380
YDEICCKTGM SYHELDERLE NDPNIIICWK
Length:380
Mass (Da):43,658
Last modified:May 10, 2004 - v2
Checksum:i5ECA201CE073F964
GO
Isoform 2 (identifier: Q8WTW4-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-120: Missing.
     312-323: KLIQFGLMKNLI → SEENLLGHLGVT
     324-380: Missing.

Note: No experimental confirmation available.
Show »
Length:203
Mass (Da):23,150
Checksum:i221068DD133A9BA1
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti17 – 171P → L in AAH21984 (PubMed:15489334).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 120120Missing in isoform 2. 2 PublicationsVSP_010329Add
BLAST
Alternative sequencei312 – 32312KLIQF…MKNLI → SEENLLGHLGVT in isoform 2. 2 PublicationsVSP_010330Add
BLAST
Alternative sequencei324 – 38057Missing in isoform 2. 2 PublicationsVSP_010331Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF040707 mRNA. Translation: AAC62535.1.
AF040708 mRNA. Translation: AAC62536.1.
AK292196 mRNA. Translation: BAF84885.1.
CR542035 mRNA. Translation: CAG46832.1.
AC002481 Genomic DNA. Translation: AAB67310.1.
CH471055 Genomic DNA. Translation: EAW65106.1.
CH471055 Genomic DNA. Translation: EAW65107.1.
BC021984 mRNA. Translation: AAH21984.1.
BC056861 mRNA. Translation: AAH56861.1.
CCDSiCCDS2826.1. [Q8WTW4-1]
RefSeqiNP_006536.3. NM_006545.4. [Q8WTW4-1]
UniGeneiHs.437083.

Genome annotation databases

EnsembliENST00000232501; ENSP00000232501; ENSG00000114388. [Q8WTW4-1]
GeneIDi10641.
KEGGihsa:10641.
UCSCiuc003daj.2. human. [Q8WTW4-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF040707 mRNA. Translation: AAC62535.1.
AF040708 mRNA. Translation: AAC62536.1.
AK292196 mRNA. Translation: BAF84885.1.
CR542035 mRNA. Translation: CAG46832.1.
AC002481 Genomic DNA. Translation: AAB67310.1.
CH471055 Genomic DNA. Translation: EAW65106.1.
CH471055 Genomic DNA. Translation: EAW65107.1.
BC021984 mRNA. Translation: AAH21984.1.
BC056861 mRNA. Translation: AAH56861.1.
CCDSiCCDS2826.1. [Q8WTW4-1]
RefSeqiNP_006536.3. NM_006545.4. [Q8WTW4-1]
UniGeneiHs.437083.

3D structure databases

ProteinModelPortaliQ8WTW4.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi115885. 18 interactions.
IntActiQ8WTW4. 3 interactions.
MINTiMINT-3046340.
STRINGi9606.ENSP00000232501.

PTM databases

iPTMnetiQ8WTW4.
PhosphoSiteiQ8WTW4.

Polymorphism and mutation databases

BioMutaiNPRL2.
DMDMi47117604.

Proteomic databases

EPDiQ8WTW4.
MaxQBiQ8WTW4.
PaxDbiQ8WTW4.
PRIDEiQ8WTW4.

Protocols and materials databases

DNASUi10641.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000232501; ENSP00000232501; ENSG00000114388. [Q8WTW4-1]
GeneIDi10641.
KEGGihsa:10641.
UCSCiuc003daj.2. human. [Q8WTW4-1]

Organism-specific databases

CTDi10641.
GeneCardsiNPRL2.
HGNCiHGNC:24969. NPRL2.
HPAiHPA038196.
HPA038197.
MIMi607072. gene.
neXtProtiNX_Q8WTW4.
PharmGKBiPA165697981.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3789. Eukaryota.
ENOG410XP7B. LUCA.
GeneTreeiENSGT00390000001414.
HOGENOMiHOG000007022.
HOVERGENiHBG055255.
InParanoidiQ8WTW4.
OMAiQKYPVKV.
OrthoDBiEOG7N63MM.
PhylomeDBiQ8WTW4.
TreeFamiTF106159.

Miscellaneous databases

ChiTaRSiNPRL2. human.
GeneWikiiTUSC4.
GenomeRNAii10641.
PROiQ8WTW4.
SOURCEiSearch...

Gene expression databases

BgeeiQ8WTW4.
CleanExiHS_TUSC4.
ExpressionAtlasiQ8WTW4. baseline and differential.
GenevisibleiQ8WTW4. HS.

Family and domain databases

InterProiIPR009348. NPR2.
[Graphical view]
PANTHERiPTHR12991. PTHR12991. 1 hit.
PfamiPF06218. NPR2. 2 hits.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Gene 21, a new candidate human tumor suppressor gene located in the 3p21.3 small cell lung cancer homozygous deletion region homologous to the yeast nitrogen permease regulator NPR2."
    Kondo M., Sekido Y., Latif F., Cundiff S., Duh F.-M., Wei M.-H., Lerman M.I., Minna J.D.
    Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
  2. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
    Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
    , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
    Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Colon.
  3. "Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)."
    Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.
    Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
  4. "The DNA sequence, annotation and analysis of human chromosome 3."
    Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J.
    , Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.
    Nature 440:1194-1198(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Kidney and Skin.
  7. "The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes."
    The international lung cancer chromosome 3p21.3 tumor suppressor gene consortium
    Lerman M.I., Minna J.D.
    Cancer Res. 60:6116-6133(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISCUSSION OF SEQUENCE.
  8. "Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo."
    Ji L., Nishizaki M., Gao B., Burbee D., Kondo M., Kamibayashi C., Xu K., Yen N., Atkinson E.N., Fang B., Lerman M.I., Roth J.A., Minna J.D.
    Cancer Res. 62:2715-2720(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISCUSSION OF SEQUENCE.
  9. "TUSC4/NPRL2, a novel PDK1-interacting protein, inhibits PDK1 tyrosine phosphorylation and its downstream signaling."
    Kurata A., Katayama R., Watanabe T., Tsuruo T., Fujita N.
    Cancer Sci. 99:1827-1834(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH PDPK1.
  10. "A genome-wide screen for regulators of TORC1 in response to amino acid starvation reveals a conserved Npr2/3 complex."
    Neklesa T.K., Davis R.W.
    PLoS Genet. 5:E1000515-E1000515(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NPRL3.
  11. "A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1."
    Bar-Peled L., Chantranupong L., Cherniack A.D., Chen W.W., Ottina K.A., Grabiner B.C., Spear E.D., Carter S.L., Meyerson M., Sabatini D.M.
    Science 340:1100-1106(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, IDENTIFICATION IN GATOR COMPLEX, INTERACTION WITH RRAG PROTEINS.

Entry informationi

Entry nameiNPRL2_HUMAN
AccessioniPrimary (citable) accession number: Q8WTW4
Secondary accession number(s): A8K831
, Q6FGS2, Q9Y249, Q9Y497
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 10, 2004
Last sequence update: May 10, 2004
Last modified: June 8, 2016
This is version 111 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.