Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTII30MY)

• DOT Name: NT-3 growth factor receptor (NTRK3)
• Synonyms: EC 2.7.10.1; GP145-TrkC; Trk-C; Neurotrophic tyrosine kinase receptor type 3; TrkC tyrosine kinase
• Gene Name: NTRK3
• Related Disease: Congenital heart disease
• UniProt ID: NTRK3_HUMAN
• PDB ID: 1WWC; 3V5Q; 4YMJ; 6KZC; 6KZD
• EC Number: 2.7.10.1
• Pfam ID: PF07679 ; PF00047 ; PF13855 ; PF16920 ; PF01462 ; PF07714
• Sequence:
  MDVSLCPAKCSFWRIFLLGSVWLDYVGSVLACPANCVCSKTEINCRRPDDGNLFPLLEGQ
  DSGNSNGNASINITDISRNITSIHIENWRSLHTLNAVDMELYTGLQKLTIKNSGLRSIQP
  RAFAKNPHLRYINLSSNRLTTLSWQLFQTLSLRELQLEQNFFNCSCDIRWMQLWQEQGEA
  KLNSQNLYCINADGSQLPLFRMNISQCDLPEISVSHVNLTVREGDNAVITCNGSGSPLPD
  VDWIVTGLQSINTHQTNLNWTNVHAINLTLVNVTSEDNGFTLTCIAENVVGMSNASVALT
  VYYPPRVVSLEEPELRLEHCIEFVVRGNPPPTLHWLHNGQPLRESKIIHVEYYQEGEISE
  GCLLFNKPTHYNNGNYTLIAKNPLGTANQTINGHFLKEPFPESTDNFILFDEVSPTPPIT
  VTHKPEEDTFGVSIAVGLAAFACVLLVVLFVMINKYGRRSKFGMKGPVAVISGEEDSASP
  LHHINHGITTPSSLDAGPDTVVIGMTRIPVIENPQYFRQGHNCHKPDTYVQHIKRRDIVL
  KRELGEGAFGKVFLAECYNLSPTKDKMLVAVKALKDPTLAARKDFQREAELLTNLQHEHI
  VKFYGVCGDGDPLIMVFEYMKHGDLNKFLRAHGPDAMILVDGQPRQAKGELGLSQMLHIA
  SQIASGMVYLASQHFVHRDLATRNCLVGANLLVKIGDFGMSRDVYSTDYYRLFNPSGNDF
  CIWCEVGGHTMLPIRWMPPESIMYRKFTTESDVWSFGVILWEIFTYGKQPWFQLSNTEVI
  ECITQGRVLERPRVCPKEVYDVMLGCWQREPQQRLNIKEIYKILHALGKATPIYLDILG
• Function: Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation.
• Tissue Specificity: Widely expressed but mainly in nervous tissue. Isoform 2 is expressed at higher levels in adult brain than in fetal brain.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neurotrophin sig.ling pathway (hsa04722)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  NTF3 activates NTRK3 signaling (R-HSA-9034013)
  Signaling by NTRK3 (TRKC) (R-HSA-9034015)
  Activated NTRK3 signals through PLCG1 (R-HSA-9034793)
  Activated NTRK3 signals through RAS (R-HSA-9034864)
  Activated NTRK3 signals through PI3K (R-HSA-9603381)
  NTRK3 as a dependence receptor (R-HSA-9603505)
  Receptor-type tyrosine-protein phosphatases (R-HSA-388844)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital heart disease	DISQBA23	Disputed	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of NT-3 growth factor receptor (NTRK3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NT-3 growth factor receptor (NTRK3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NT-3 growth factor receptor (NTRK3).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NT-3 growth factor receptor (NTRK3).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of NT-3 growth factor receptor (NTRK3).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of NT-3 growth factor receptor (NTRK3).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of NT-3 growth factor receptor (NTRK3).	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of NT-3 growth factor receptor (NTRK3).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of NT-3 growth factor receptor (NTRK3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NT-3 growth factor receptor (NTRK3).	[14]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of NT-3 growth factor receptor (NTRK3).	[15]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of NT-3 growth factor receptor (NTRK3).	[16]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NT-3 growth factor receptor (NTRK3).	[5]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of NT-3 growth factor receptor (NTRK3).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NT-3 growth factor receptor (NTRK3).	[13]

References

• [1] 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.
• [2] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Arsenic trioxide induces cell cycle arrest and affects Trk receptor expression in human neuroblastoma SK-N-SH cells. Biol Res. 2018 Jun 13;51(1):18. doi: 10.1186/s40659-018-0167-6.
• [7] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [10] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [11] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016 Feb 18;35(7):833-45.
• [15] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [16] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.