Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGJ1997)

• DOT Name: Neogenin (NEO1)
• Synonyms: Immunoglobulin superfamily DCC subclass member 2
• Gene Name: NEO1
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Lung adenocarcinoma
  Ovarian neoplasm
  Autism spectrum disorder
  Colon cancer
  Colon carcinoma
  Dental caries
  Esophageal squamous cell carcinoma
  Glioma
  Glomerulonephritis
  Hydrocephalus
  Neoplasm
  Neuralgia
  Neuroblastoma
  Pancreatic cancer
  Pneumonia
  Pneumonitis
  Polyneuropathy
  Postmenopausal osteoporosis
  Breast cancer
  Breast carcinoma
  Acute myelogenous leukaemia
  Blindness
  Gastric cancer
  Hereditary hemochromatosis
  Melanoma
  Microphthalmia
  Stomach cancer
• UniProt ID: NEO1_HUMAN
• PDB ID: 1X5F; 1X5G; 1X5H; 1X5I; 1X5J; 1X5K; 3P4L
• Pfam ID: PF00041 ; PF07679 ; PF13895 ; PF13927 ; PF06583
• Sequence:
  MAAERGARRLLSTPSFWLYCLLLLGRRAPGAAAARSGSAPQSPGASIRTFTPFYFLVEPV
  DTLSVRGSSVILNCSAYSEPSPKIEWKKDGTFLNLVSDDRRQLLPDGSLFISNVVHSKHN
  KPDEGYYQCVATVESLGTIISRTAKLIVAGLPRFTSQPEPSSVYAGNNAILNCEVNADLV
  PFVRWEQNRQPLLLDDRVIKLPSGMLVISNATEGDGGLYRCVVESGGPPKYSDEVELKVL
  PDPEVISDLVFLKQPSPLVRVIGQDVVLPCVASGLPTPTIKWMKNEEALDTESSERLVLL
  AGGSLEISDVTEDDAGTYFCIADNGNETIEAQAELTVQAQPEFLKQPTNIYAHESMDIVF
  ECEVTGKPTPTVKWVKNGDMVIPSDYFKIVKEHNLQVLGLVKSDEGFYQCIAENDVGNAQ
  AGAQLIILEHAPATTGPLPSAPRDVVASLVSTRFIKLTWRTPASDPHGDNLTYSVFYTKE
  GIARERVENTSHPGEMQVTIQNLMPATVYIFRVMAQNKHGSGESSAPLRVETQPEVQLPG
  PAPNLRAYAASPTSITVTWETPVSGNGEIQNYKLYYMEKGTDKEQDVDVSSHSYTINGLK
  KYTEYSFRVVAYNKHGPGVSTPDVAVRTLSDVPSAAPQNLSLEVRNSKSIMIHWQPPAPA
  TQNGQITGYKIRYRKASRKSDVTETLVSGTQLSQLIEGLDRGTEYNFRVAALTINGTGPA
  TDWLSAETFESDLDETRVPEVPSSLHVRPLVTSIVVSWTPPENQNIVVRGYAIGYGIGSP
  HAQTIKVDYKQRYYTIENLDPSSHYVITLKAFNNVGEGIPLYESAVTRPHTDTSEVDLFV
  INAPYTPVPDPTPMMPPVGVQASILSHDTIRITWADNSLPKHQKITDSRYYTVRWKTNIP
  ANTKYKNANATTLSYLVTGLKPNTLYEFSVMVTKGRRSSTWSMTAHGTTFELVPTSPPKD
  VTVVSKEGKPKTIIVNWQPPSEANGKITGYIIYYSTDVNAEIHDWVIEPVVGNRLTHQIQ
  ELTLDTPYYFKIQARNSKGMGPMSEAVQFRTPKADSSDKMPNDQASGSGGKGSRLPDLGS
  DYKPPMSGSNSPHGSPTSPLDSNMLLVIIVSVGVITIVVVVIIAVFCTRRTTSHQKKKRA
  ACKSVNGSHKYKGNSKDVKPPDLWIHHERLELKPIDKSPDPNPIMTDTPIPRNSQDITPV
  DNSMDSNIHQRRNSYRGHESEDSMSTLAGRRGMRPKMMMPFDSQPPQPVISAHPIHSLDN
  PHHHFHSSSLASPARSHLYHPGSPWPIGTSMSLSDRANSTESVRNTPSTDTMPASSSQTC
  CTDHQDPEGATSSSYLASSQEEDSGQSLPTAHVRPSHPLKSFAVPAIPPPGPPTYDPALP
  STPLLSQQALNHHIHSVKTASIGTLGRSRPPMPVVVPSAPEVQETTRMLEDSESSYEPDE
  LTKEMAHLEGLMKDLNAITTA
• Function: Multi-functional cell surface receptor regulating cell adhesion in many diverse developmental processes, including neural tube and mammary gland formation, myogenesis and angiogenesis. Receptor for members of the BMP, netrin, and repulsive guidance molecule (RGM) families. Netrin-Neogenin interactions result in a chemoattractive axon guidance response and cell-cell adhesion, the interaction between NEO1/Neogenin and RGMa and RGMb induces a chemorepulsive response.
• Tissue Specificity: Widely expressed and also in cancer cell lines.
• KEGG Pathway:
  TGF-beta sig.ling pathway (hsa04350)
  Axon guidance (hsa04360)
  Cell adhesion molecules (hsa04514)
• Reactome Pathway:
  Myogenesis (R-HSA-525793)
  Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[2]
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Dental caries	DISRBCMD	Strong	Genetic Variation	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[7]
Glioma	DIS5RPEH	Strong	Posttranslational Modification	[8]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[9]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Neuralgia	DISWO58J	Strong	Biomarker	[12]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[13]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[14]
Pneumonia	DIS8EF3M	Strong	Biomarker	[15]
Pneumonitis	DIS88E0K	Strong	Biomarker	[15]
Polyneuropathy	DISB9G3W	Strong	Altered Expression	[16]
Postmenopausal osteoporosis	DISS0RQZ	Strong	Biomarker	[17]
Breast cancer	DIS7DPX1	moderate	Biomarker	[18]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[18]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[19]
Blindness	DISTIM10	Limited	Biomarker	[20]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[21]
Hereditary hemochromatosis	DISVG5MT	Limited	Genetic Variation	[22]
Melanoma	DIS1RRCY	Limited	Altered Expression	[23]
Microphthalmia	DISGEBES	Limited	Biomarker	[20]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Neogenin (NEO1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Neogenin (NEO1).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Neogenin (NEO1).	[25]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neogenin (NEO1).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neogenin (NEO1).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neogenin (NEO1).	[28]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Neogenin (NEO1).	[29]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neogenin (NEO1).	[30]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Neogenin (NEO1).	[31]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Neogenin (NEO1).	[31]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Neogenin (NEO1).	[32]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Neogenin (NEO1).	[33]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Neogenin (NEO1).	[34]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Neogenin (NEO1).	[35]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Neogenin (NEO1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Neogenin (NEO1).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Neogenin (NEO1).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Neogenin (NEO1).	[40]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Neogenin (NEO1).	[41]

References

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• [2] Survival trees for analyzing clinical outcome in lung adenocarcinomas based on gene expression profiles: identification of neogenin and diacylglycerol kinase alpha expression as critical factors.J Comput Biol. 2005 Jun;12(5):534-44. doi: 10.1089/cmb.2005.12.534.
• [3] Profiling follicle stimulating hormone-induced gene expression changes in normal and malignant human ovarian surface epithelial cells.Oncogene. 2003 Jul 3;22(27):4243-56. doi: 10.1038/sj.onc.1206437.
• [4] Unmasking a novel disease gene NEO1 associated with autism spectrum disorders by a hemizygous deletion on chromosome 15 and a functional polymorphism.Behav Brain Res. 2016 Mar 1;300:135-42. doi: 10.1016/j.bbr.2015.10.041. Epub 2015 Oct 27.
• [5] Netrin-4 Mediates Corneal Hemangiogenesis but Not Lymphangiogenesis in the Mouse-Model of Suture-Induced Neovascularization.Invest Ophthalmol Vis Sci. 2017 Mar 1;58(3):1387-1396. doi: 10.1167/iovs.16-19249.
• [6] Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.Nat Commun. 2019 Jun 24;10(1):2773. doi: 10.1038/s41467-019-10630-1.
• [7] Identification of differentially expressed genes in esophageal squamous cell carcinoma (ESCC) by cDNA expression array: overexpression of Fra-1, Neogenin, Id-1, and CDC25B genes in ESCC.Clin Cancer Res. 2001 Aug;7(8):2213-21.
• [8] Down-regulation of neogenin accelerated glioma progression through promoter Methylation and its overexpression in SHG-44 Induced Apoptosis.PLoS One. 2012;7(5):e38074. doi: 10.1371/journal.pone.0038074. Epub 2012 May 29.
• [9] Small Red Blood Cell Fraction on the UF-1000i Urine Analyzer as a Screening Tool to Detect Dysmorphic Red Blood Cells for Diagnosing Glomerulonephritis.Ann Lab Med. 2019 May;39(3):271-277. doi: 10.3343/alm.2019.39.3.271.
• [10] Neogenin Recruitment of the WAVE Regulatory Complex to Ependymal and Radial Progenitor Adherens Junctions Prevents Hydrocephalus.Cell Rep. 2017 Jul 11;20(2):370-383. doi: 10.1016/j.celrep.2017.06.051.
• [11] Loss of Neogenin1 in human colorectal carcinoma cells causes a partial EMT and wound-healing response.Sci Rep. 2019 Mar 11;9(1):4110. doi: 10.1038/s41598-019-40886-y.
• [12] RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury.Sci Rep. 2017 Sep 5;7(1):10529. doi: 10.1038/s41598-017-10987-7.
• [13] The Netrin-4/Laminin 1/Neogenin-1 complex mediates migration in SK-N-SH neuroblastoma cells.Cell Adh Migr. 2019 Dec;13(1):33-40. doi: 10.1080/19336918.2018.1506652. Epub 2018 Aug 30.
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• [16] Reduced gene expression of netrin family members in skin and sural nerve specimens of patients with painful peripheral neuropathies.J Neurol. 2019 Nov;266(11):2812-2820. doi: 10.1007/s00415-019-09496-6. Epub 2019 Aug 7.
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• [19] A case of childhood acute myeloid leukemia AML (M5) with a neocentric chromosome neo(1)(qter-->q23 approximately 24::q23 approximately 24-->q43-->neo-->q43-->qter) and tetrasomy of chromosomes 8 and 21.Cancer Genet Cytogenet. 2009 Sep;193(2):123-6. doi: 10.1016/j.cancergencyto.2009.05.001.
• [20] Neogenin-loss in neural crest cells results in persistent hyperplastic primary vitreous formation.J Mol Cell Biol. 2020 Jan 22;12(1):17-31. doi: 10.1093/jmcb/mjz076.
• [21] Netrin-1 promotes cell neural invasion in gastric cancer via its receptor neogenin.J Cancer. 2019 Jun 2;10(14):3197-3207. doi: 10.7150/jca.30230. eCollection 2019.
• [22] Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells.J Biol Chem. 2005 Oct 7;280(40):33885-94. doi: 10.1074/jbc.M506207200. Epub 2005 Aug 15.
• [23] Neogenin, Defined as a GD3-associated Molecule by Enzyme-mediated Activation of Radical Sources, Confers Malignant Properties via Intracytoplasmic Domain in Melanoma Cells.J Biol Chem. 2016 Aug 5;291(32):16630-43. doi: 10.1074/jbc.M115.708834. Epub 2016 Jun 10.
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• [26] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
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• [28] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
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• [30] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [31] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
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• [33] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [34] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [35] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [36] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
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• [39] 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.
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• [41] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.