Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOB10MO)

• DOT Name: GATOR1 complex protein NPRL2 (NPRL2)
• Synonyms: Gene 21 protein; G21 protein; Nitrogen permease regulator 2-like protein; NPR2-like protein; Tumor suppressor candidate 4
• Gene Name: NPRL2
• Related Disease:
  Adenocarcinoma
  Breast cancer
  Breast carcinoma
  Focal epilepsy
  Squamous cell carcinoma
  Adenoma
  Benign prostatic hyperplasia
  Bone osteosarcoma
  Castration-resistant prostate carcinoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal adenoma
  Epilepsy
  Epilepsy, familial focal, with variable foci 2
  Glioma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Macular corneal dystrophy
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Advanced cancer
  Familial focal epilepsy with variable foci
  Fleck corneal dystrophy
  Colorectal carcinoma
  Kidney cancer
  Pachyonychia congenita 3
  Renal carcinoma
• UniProt ID: NPRL2_HUMAN
• PDB ID: 6CES; 6CET; 7T3A; 7T3B; 7T3C; 8FW5
• Pfam ID: PF06218
• Sequence:
  MGSGCRIECIFFSEFHPTLGPKITYQVPEDFISRELFDTVQVYIITKPELQNKLITVTAM
  EKKLIGCPVCIEHKKYSRNALLFNLGFVCDAQAKTCALEPIVKKLAGYLTTLELESSFVS
  MEESKQKLVPIMTILLEELNASGRCTLPIDESNTIHLKVIEQRPDPPVAQEYDVPVFTKD
  KEDFFNSQWDLTTQQILPYIDGFRHIQKISAEADVELNLVRIAIQNLLYYGVVTLVSILQ
  YSNVYCPTPKVQDLVDDKSLQEACLSYVTKQGHKRASLRDVFQLYCSLSPGTTVRDLIGR
  HPQQLQHVDERKLIQFGLMKNLIRRLQKYPVRVTREEQSHPARLYTGCHSYDEICCKTGM
  SYHELDERLENDPNIIICWK
• 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. 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. In the presence of abundant amino acids, the GATOR1 complex is ubiquitinated and inhibited by GATOR2. 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 ; 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.
• Tissue Specificity: 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 . Expressed in most lung cancer cell lines tested.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Definitive	Biomarker	[2]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[2]
Focal epilepsy	DIS4LY5L	Definitive	Autosomal dominant	[3]
Squamous cell carcinoma	DISQVIFL	Definitive	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[4]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Altered Expression	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[8]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[9]
Colorectal adenoma	DISTSVHM	Strong	Altered Expression	[4]
Epilepsy	DISBB28L	Strong	Biomarker	[10]
Epilepsy, familial focal, with variable foci 2	DISP4DGS	Strong	Autosomal dominant	[11]
Glioma	DIS5RPEH	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[13]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[14]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[14]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[15]
Macular corneal dystrophy	DISOLD0H	Strong	Genetic Variation	[16]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[17]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Altered Expression	[5]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[5]
Schizophrenia	DISSRV2N	Strong	Biomarker	[18]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[19]
Familial focal epilepsy with variable foci	DIS50BKW	Moderate	Autosomal dominant	[20]
Fleck corneal dystrophy	DISERQJ1	Disputed	Biomarker	[21]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[22]
Kidney cancer	DISBIPKM	Limited	Biomarker	[19]
Pachyonychia congenita 3	DISZLC6C	Limited	Biomarker	[23]
Renal carcinoma	DISER9XT	Limited	Biomarker	[19]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GATOR1 complex protein NPRL2 (NPRL2).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GATOR1 complex protein NPRL2 (NPRL2).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of GATOR1 complex protein NPRL2 (NPRL2).	[26]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of GATOR1 complex protein NPRL2 (NPRL2).	[27]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of GATOR1 complex protein NPRL2 (NPRL2).	[26]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of GATOR1 complex protein NPRL2 (NPRL2).	[26]
Gentamicin	DMKINJO	Approved	Gentamicin decreases the expression of GATOR1 complex protein NPRL2 (NPRL2).	[26]

References

• [1] Quantitative analysis of mRNA expression levels and DNA methylation profiles of three neighboring genes: FUS1, NPRL2/G21 and RASSF1A in non-small cell lung cancer patients.Respir Res. 2015 Jun 26;16(1):76. doi: 10.1186/s12931-015-0230-6.
• [2] TUSC4 functions as a tumor suppressor by regulating BRCA1 stability.Cancer Res. 2015 Jan 15;75(2):378-86. doi: 10.1158/0008-5472.CAN-14-2315. Epub 2014 Dec 5.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Relationship between tumor and peripheral blood NPRL2 mRNA levels in patients with colorectal adenoma and colorectal cancer.Cancer Biol Ther. 2014 May;15(5):489-95. doi: 10.4161/cbt.28016. Epub 2014 Feb 12.
• [5] NPRL2 enhances autophagy and the resistance to Everolimus in castration-resistant prostate cancer.Prostate. 2019 Jan;79(1):44-53. doi: 10.1002/pros.23709. Epub 2018 Sep 3.
• [6] NPRL2 is an independent prognostic factor of osteosarcoma.Cancer Biomark. 2012-2013;12(1):31-6. doi: 10.3233/CBM-120290.
• [7] Decreased expression of NPRL2 in renal cancer cells is associated with unfavourable pathological, proliferation and apoptotic features.Pathol Oncol Res. 2014 Oct;20(4):829-37. doi: 10.1007/s12253-014-9761-2. Epub 2014 May 1.
• [8] Overexpression of Nitrogen Permease Regulator Like-2 (NPRL2) Enhances Sensitivity to Irinotecan (CPT-11) in Colon Cancer Cells by Activating the DNA Damage Checkpoint Pathway.Med Sci Monit. 2018 Mar 9;24:1424-1433. doi: 10.12659/msm.909186.
• [9] NPRL2 gene expression in the progression of colon tumors.Genet Mol Res. 2012 Sep 12;11(4):4810-6. doi: 10.4238/2012.September.12.3.
• [10] mTOR signaling pathway genes in focal epilepsies.Prog Brain Res. 2016;226:61-79. doi: 10.1016/bs.pbr.2016.04.013. Epub 2016 Jun 7.
• [11] Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2. Cell Rep. 2015 Jul 21;12(3):371-9. doi: 10.1016/j.celrep.2015.06.042. Epub 2015 Jul 9.
• [12] Downregulation of nitrogen permease regulator like-2 activates PDK1-AKT1 and contributes to the malignant growth of glioma cells.Mol Carcinog. 2016 Nov;55(11):1613-1626. doi: 10.1002/mc.22413. Epub 2015 Oct 12.
• [13] The tumor suppressor NPRL2 in hepatocellular carcinoma plays an important role in progression and can be served as an independent prognostic factor.J Surg Oncol. 2009 Oct 1;100(5):358-63. doi: 10.1002/jso.21241.
• [14] Simultaneous down-regulation of tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A in primary non-small cell lung cancer.BMC Cancer. 2010 Mar 1;10:75. doi: 10.1186/1471-2407-10-75.
• [15] [Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer].Mol Biol (Mosk). 2008 Nov-Dec;42(6):965-76.
• [16] GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations.Epilepsia. 2019 Nov;60(11):2163-2173. doi: 10.1111/epi.16370. Epub 2019 Oct 17.
• [17] NPRL2 sensitizes human non-small cell lung cancer (NSCLC) cells to cisplatin treatment by regulating key components in the DNA repair pathway.PLoS One. 2010 Aug 5;5(8):e11994. doi: 10.1371/journal.pone.0011994.
• [18] Exome sequencing supports a de novo mutational paradigm for schizophrenia.Nat Genet. 2011 Aug 7;43(9):864-8. doi: 10.1038/ng.902.
• [19] Biological characteristics of renal cancer cells after CTP-mediated cancer suppressor gene NPRL2 protein treatment.Biol Chem. 2016 Nov 1;397(11):1163-1171. doi: 10.1515/hsz-2016-0143.
• [20] Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol. 2016 Jan;79(1):120-31. doi: 10.1002/ana.24547. Epub 2015 Dec 12.
• [21] Functional screening of GATOR1 complex variants reveals a role for mTORC1 deregulation in FCD and focal epilepsy.Neurobiol Dis. 2020 Feb;134:104640. doi: 10.1016/j.nbd.2019.104640. Epub 2019 Oct 19.
• [22] Nitrogen Permease Regulator-Like-2 Exhibited Anti-Tumor Effects And Enhanced The Sensitivity Of Colorectal Cancer Cells To Oxaliplatin And 5-Fluorouracil.Onco Targets Ther. 2019 Oct 18;12:8637-8644. doi: 10.2147/OTT.S219562. eCollection 2019.
• [23] Targeting NPRL2 to enhance the efficacy of Olaparib in castration-resistant prostate cancer.Biochem Biophys Res Commun. 2019 Jan 8;508(2):620-625. doi: 10.1016/j.bbrc.2018.11.062. Epub 2018 Dec 3.
• [24] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2010 Oct 15;401(2):245-50. doi: 10.1016/j.bbrc.2010.09.039. Epub 2010 Sep 16.
• [27] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.