Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMDE844)

• DOT Name: Pro-neuregulin-2, membrane-bound isoform (NRG2)
• Synonyms: Pro-NRG2
• Gene Name: NRG2
• Related Disease:
  Breast cancer
  Breast neoplasm
  Charcot marie tooth disease
  Schizophrenia
  Gastric cancer
  Glaucoma/ocular hypertension
  Lung neoplasm
  Mental disorder
  Open-angle glaucoma
  Stomach cancer
• UniProt ID: NRG2_HUMAN
• Pfam ID: PF07679 ; PF02158
• Sequence:
  MRQVCCSALPPPPLEKGRCSSYSDSSSSSSERSSSSSSSSSESGSSSRSSSNNSSISRPA
  APPEPRPQQQPQPRSPAARRAAARSRAAAAGGMRRDPAPGFSMLLFGVSLACYSPSLKSV
  QDQAYKAPVVVEGKVQGLVPAGGSSSNSTREPPASGRVALVKVLDKWPLRSGGLQREQVI
  SVGSCVPLERNQRYIFFLEPTEQPLVFKTAFAPLDTNGKNLKKEVGKILCTDCATRPKLK
  KMKSQTGQVGEKQSLKCEAAAGNPQPSYRWFKDGKELNRSRDIRIKYGNGRKNSRLQFNK
  VKVEDAGEYVCEAENILGKDTVRGRLYVNSVSTTLSSWSGHARKCNETAKSYCVNGGVCY
  YIEGINQLSCKCPNGFFGQRCLEKLPLRLYMPDPKQKAEELYQKRVLTITGICVALLVVG
  IVCVVAYCKTKKQRKQMHNHLRQNMCPAHQNRSLANGPSHPRLDPEEIQMADYISKNVPA
  TDHVIRRETETTFSGSHSCSPSHHCSTATPTSSHRHESHTWSLERSESLTSDSQSGIMLS
  SVGTSKCNSPACVEARARRAAAYNLEERRRATAPPYHDSVDSLRDSPHSERYVSALTTPA
  RLSPVDFHYSLATQVPTFEITSPNSAHAVSLPPAAPISYRLAEQQPLLRHPAPPGPGPGP
  GPGPGPGADMQRSYDSYYYPAAGPGPRRGTCALGGSLGSLPASPFRIPEDDEYETTQECA
  PPPPPRPRARGASRRTSAGPRRWRRSRLNGLAAQRARAARDSLSLSSGSGGGSASASDDD
  ADDADGALAAESTPFLGLRGAHDALRSDSPPLCPAADSRTYYSLDSHSTRASSRHSRGPP
  PRAKQDSAPL
• Function: Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. May also promote the heterodimerization with the EGF receptor.
• Tissue Specificity: Restricted to the cerebellum in the adult.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  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)
  GRB7 events in ERBB2 signaling (R-HSA-1306955)
  Downregulation of ERBB2 (R-HSA-1358803)
  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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[3]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[4]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[5]
Lung neoplasm	DISVARNB	Limited	Biomarker	[6]
Mental disorder	DIS3J5R8	Limited	Biomarker	[7]
Open-angle glaucoma	DISSZEE8	Limited	Biomarker	[5]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[14]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[16]
Manganese	DMKT129	Investigative	Manganese increases the expression of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[18]

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-2, membrane-bound isoform (NRG2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Pro-neuregulin-2, membrane-bound isoform (NRG2).	[15]

References

• [1] 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.
• [2] The human neuregulin-2 (NRG2) gene: cloning, mapping and evaluation as a candidate for the autosomal recessive form of Charcot-Marie-Tooth disease linked to 5q.Hum Genet. 1999 Apr;104(4):326-32. doi: 10.1007/s004390050961.
• [3] Neuregulin-2 ablation results in dopamine dysregulation and severe behavioral phenotypes relevant to psychiatric disorders.Mol Psychiatry. 2018 May;23(5):1233-1243. doi: 10.1038/mp.2017.22. Epub 2017 Mar 21.
• [4] Cross-Database Analysis Reveals Sensitive Biomarkers for Combined Therapy for ERBB2+ Gastric Cancer.Front Pharmacol. 2018 Aug 3;9:861. doi: 10.3389/fphar.2018.00861. eCollection 2018.
• [5] Fine mapping of new glaucoma locus GLC1M and exclusion of neuregulin 2 as the causative gene.Mol Vis. 2007 May 23;13:779-84.
• [6] Asbestos-associated genome-wide DNA methylation changes in lung cancer.Int J Cancer. 2017 Nov 15;141(10):2014-2029. doi: 10.1002/ijc.30897. Epub 2017 Aug 2.
• [7] Proteolytic Processing of Neuregulin 2.Mol Neurobiol. 2020 Apr;57(4):1799-1813. doi: 10.1007/s12035-019-01846-9. Epub 2019 Dec 14.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [12] 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.
• [13] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] 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.
• [16] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [17] 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.
• [18] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.