Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIFZ5CT)

• DOT Name: Pro-neuregulin-3, membrane-bound isoform (NRG3)
• Synonyms: Pro-NRG3
• Gene Name: NRG3
• Related Disease:
  Hirschsprung disease
  Tuberculosis
  Alzheimer disease
  Attention deficit hyperactivity disorder
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Epithelial ovarian cancer
  Epstein barr virus infection
  Major depressive disorder
  Mood disorder
  Myocardial infarction
  Nervous system disease
  Neurodevelopmental disorder
  Nicotine dependence
  Plasma cell myeloma
  Acute myelogenous leukaemia
  Anxiety
  Anxiety disorder
  Cognitive impairment
• UniProt ID: NRG3_HUMAN
• Sequence:
  MSEGAAAASPPGAASAAAASAEEGTAAAAAAAAAGGGPDGGGEGAAEPPRELRCSDCIVW
  NRQQTWLCVVPLFIGFIGLGLSLMLLKWIVVGSVKEYVPTDLVDSKGMGQDPFFLSKPSS
  FPKAMETTTTTTSTTSPATPSAGGAASSRTPNRISTRLTTITRAPTRFPGHRVPIRASPR
  STTARNTAAPATVPSTTAPFFSSSTLGSRPPVPGTPSTQAMPSWPTAAYATSSYLHDSTP
  SWTLSPFQDAASSSSSSSSSATTTTPETSTSPKFHTTTYSTERSEHFKPCRDKDLAYCLN
  DGECFVIETLTGSHKHCRCKEGYQGVRCDQFLPKTDSILSDPTDHLGIEFMESEEVYQRQ
  VLSISCIIFGIVIVGMFCAAFYFKSKKQAKQIQEQLKVPQNGKSYSLKASSTMAKSENLV
  KSHVQLQNYSKVERHPVTALEKMMESSFVGPQSFPEVPSPDRGSQSVKHHRSLSSCCSPG
  QRSGMLHRNAFRRTPPSPRSRLGGIVGPAYQQLEESRIPDQDTIPCQGIEVRKTISHLPI
  QLWCVERPLDLKYSSSGLKTQRNTSINMQLPSRETNPYFNSLEQKDLVGYSSTRASSVPI
  IPSVGLEETCLQMPGISEVKSIKWCKNSYSADVVNVSIPVSDCLIAEQQEVKILLETVQE
  QIRILTDARRSEDYELASVETEDSASENTAFLPLSPTAKSEREAQFVLRNEIQRDSALTK
• Function: Direct ligand for the ERBB4 tyrosine kinase receptor. Binding results in ligand-stimulated tyrosine phosphorylation and activation of the receptor. Does not bind to the EGF receptor, ERBB2 or ERBB3 receptors. May be a survival factor for oligodendrocytes.
• Tissue Specificity: Highly expressed in most regions of the brain with the exception of corpus callosum. Expressed at lower level in testis. Not detected in heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, ovary, small intestine, colon and peripheral blood leukocytes.
• KEGG Pathway:
  ErbB sig.ling pathway (hsa04012)
  Amyotrophic lateral sclerosis (hsa05014)
• Reactome Pathway:
  Signaling by ERBB4 (R-HSA-1236394)
  SHC1 events in ERBB2 signaling (R-HSA-1250196)
  PI3K events in ERBB4 signaling (R-HSA-1250342)
  SHC1 events in ERBB4 signaling (R-HSA-1250347)
  Nuclear signaling by ERBB4 (R-HSA-1251985)
  PIP3 activates AKT signaling (R-HSA-1257604)
  GRB2 events in ERBB2 signaling (R-HSA-1963640)
  PI3K events in ERBB2 signaling (R-HSA-1963642)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  RAF/MAP kinase cascade (R-HSA-5673001)
  ERBB2 Regulates Cell Motility (R-HSA-6785631)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  ERBB2 Activates PTK6 Signaling (R-HSA-8847993)
  Downregulation of ERBB2 signaling (R-HSA-8863795)
  Signaling by ERBB2 KD Mutants (R-HSA-9664565)
  Signaling by ERBB2 TMD/JMD mutants (R-HSA-9665686)
  Signaling by ERBB2 (R-HSA-1227986)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hirschsprung disease	DISUUSM1	Definitive	Genetic Variation	[1]
Tuberculosis	DIS2YIMD	Definitive	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[7]
Epstein barr virus infection	DISOO0WT	Strong	Genetic Variation	[8]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[9]
Mood disorder	DISLVMWO	Strong	Biomarker	[9]
Myocardial infarction	DIS655KI	Strong	Biomarker	[10]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[9]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[11]
Nicotine dependence	DISZD9W7	Strong	Genetic Variation	[12]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[13]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[14]
Anxiety	DISIJDBA	Limited	Altered Expression	[15]
Anxiety disorder	DISBI2BT	Limited	Altered Expression	[15]
Cognitive impairment	DISH2ERD	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Pro-neuregulin-3, membrane-bound isoform (NRG3).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Pro-neuregulin-3, membrane-bound isoform (NRG3).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Pro-neuregulin-3, membrane-bound isoform (NRG3).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Pro-neuregulin-3, membrane-bound isoform (NRG3).	[20]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Pro-neuregulin-3, membrane-bound isoform (NRG3).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Pro-neuregulin-3, membrane-bound isoform (NRG3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Pro-neuregulin-3, membrane-bound isoform (NRG3).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pro-neuregulin-3, membrane-bound isoform (NRG3).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Pro-neuregulin-3, membrane-bound isoform (NRG3).	[25]

References

• [1] Effects of RET, NRG1 and NRG3 Polymorphisms in a Chinese Population with Hirschsprung Disease.Sci Rep. 2017 Mar 3;7:43222. doi: 10.1038/srep43222.
• [2] Investigating the Role of Gene-Gene Interactions in TB Susceptibility.PLoS One. 2015 Apr 28;10(4):e0123970. doi: 10.1371/journal.pone.0123970. eCollection 2014.
• [3] NRG3 gene is associated with the risk and age at onset of Alzheimer disease.J Neural Transm (Vienna). 2014 Feb;121(2):183-92. doi: 10.1007/s00702-013-1091-0. Epub 2013 Sep 24.
• [4] Neuregulin 3 is associated with attention deficits in schizophrenia and bipolar disorder.Int J Neuropsychopharmacol. 2013 Apr;16(3):549-56. doi: 10.1017/S1461145712000697. Epub 2012 Jul 25.
• [5] The role of NRG3 in mammary development.J Mammary Gland Biol Neoplasia. 2008 Jun;13(2):195-203. doi: 10.1007/s10911-008-9082-8. Epub 2008 Apr 17.
• [6] ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis.Ann Oncol. 2008 Jan;19(1):73-80. doi: 10.1093/annonc/mdm431. Epub 2007 Oct 24.
• [7] Pharmacogenomics in epithelial ovarian cancer first-line treatment outcome: validation of GWAS-associated NRG3 rs1649942 and BRE rs7572644 variants in an independent cohort.Pharmacogenomics J. 2019 Feb;19(1):25-32. doi: 10.1038/s41397-018-0056-y. Epub 2018 Oct 5.
• [8] Genetic factors affecting EBV copy number in lymphoblastoid cell lines derived from the 1000 Genome Project samples.PLoS One. 2017 Jun 27;12(6):e0179446. doi: 10.1371/journal.pone.0179446. eCollection 2017.
• [9] Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders.Am J Psychiatry. 2017 Mar 1;174(3):256-265. doi: 10.1176/appi.ajp.2016.16060721. Epub 2016 Oct 24.
• [10] Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia.Mol Psychiatry. 2009 Nov;14(11):1024-31. doi: 10.1038/mp.2008.52. Epub 2008 Jun 3.
• [11] Thyroid hormone influences brain gene expression programs and behaviors in later generations by altering germ line epigenetic information.Mol Psychiatry. 2020 May;25(5):939-950. doi: 10.1038/s41380-018-0281-4. Epub 2018 Oct 24.
• [12] Neuregulin 3 Signaling Mediates Nicotine-Dependent Synaptic Plasticity in the Orbitofrontal Cortex and Cognition.Neuropsychopharmacology. 2018 May;43(6):1343-1354. doi: 10.1038/npp.2017.278. Epub 2017 Nov 7.
• [13] Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease.Oncotarget. 2014 Sep 30;5(18):8284-305. doi: 10.18632/oncotarget.2058.
• [14] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [15] Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence.Mol Psychiatry. 2014 Jul;19(7):801-10. doi: 10.1038/mp.2013.104. Epub 2013 Sep 3.
• [16] NRG3 contributes to cognitive deficits in chronic patients with schizophrenia.Schizophr Res. 2020 Jan;215:134-139. doi: 10.1016/j.schres.2019.10.060. Epub 2019 Nov 18.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [19] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [20] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] 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.
• [23] 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.
• [24] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [25] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.