Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI6QNX2)

• DOT Name: Ephrin type-A receptor 2 (EPHA2)
• Synonyms: EC 2.7.10.1; Epithelial cell kinase; Tyrosine-protein kinase receptor ECK
• Gene Name: EPHA2
• Related Disease:
  Cataract 6 multiple types
  Early-onset nuclear cataract
  Early-onset posterior polar cataract
  Early-onset posterior subcapsular cataract
  Total early-onset cataract
• UniProt ID: EPHA2_HUMAN
• PDB ID: 1MQB ; 2E8N ; 2K9Y ; 2KSO ; 2X10 ; 2X11 ; 3C8X ; 3CZU ; 3FL7 ; 3HEI ; 3HPN ; 3KKA ; 3MBW ; 3MX0 ; 3SKJ ; 4P2K ; 4PDO ; 4TRL ; 5EK7 ; 5I9U ; 5I9V ; 5I9W ; 5I9X ; 5I9Y ; 5I9Z ; 5IA0 ; 5IA1 ; 5IA2 ; 5IA3 ; 5IA4 ; 5IA5 ; 5NJZ ; 5NK0 ; 5NK1 ; 5NK2 ; 5NK3 ; 5NK4 ; 5NK5 ; 5NK6 ; 5NK7 ; 5NK8 ; 5NK9 ; 5NKA ; 5NKB ; 5NKC ; 5NKD ; 5NKE ; 5NKF ; 5NKG ; 5NKH ; 5NKI ; 5NZ9 ; 6B9L ; 6F7M ; 6F7N ; 6FNF ; 6FNG ; 6FNH ; 6HES ; 6HET ; 6HEU ; 6HEV ; 6HEW ; 6HEX ; 6HEY ; 6NJZ ; 6NK0 ; 6NK1 ; 6NK2 ; 6NKP ; 6Q7B ; 6Q7C ; 6Q7D ; 6Q7E ; 6Q7F ; 6Q7G ; 6RW2 ; 7B7N ; 7CZE ; 7CZF ; 7KJA ; 7KJB ; 7KJC ; 8BIN ; 8BIO ; 8BK0 ; 8BOC ; 8BOD ; 8BOF ; 8BOG ; 8BOH ; 8BOI ; 8BOK ; 8BOM ; 8QQY ; 8TRS ; 8TRT
• EC Number: 2.7.10.1
• Pfam ID: PF14575 ; PF01404 ; PF00041 ; PF07714 ; PF00536
• Sequence:
  MELQAARACFALLWGCALAAAAAAQGKEVVLLDFAAAGGELGWLTHPYGKGWDLMQNIMN
  DMPIYMYSVCNVMSGDQDNWLRTNWVYRGEAERIFIELKFTVRDCNSFPGGASSCKETFN
  LYYAESDLDYGTNFQKRLFTKIDTIAPDEITVSSDFEARHVKLNVEERSVGPLTRKGFYL
  AFQDIGACVALLSVRVYYKKCPELLQGLAHFPETIAGSDAPSLATVAGTCVDHAVVPPGG
  EEPRMHCAVDGEWLVPIGQCLCQAGYEKVEDACQACSPGFFKFEASESPCLECPEHTLPS
  PEGATSCECEEGFFRAPQDPASMPCTRPPSAPHYLTAVGMGAKVELRWTPPQDSGGREDI
  VYSVTCEQCWPESGECGPCEASVRYSEPPHGLTRTSVTVSDLEPHMNYTFTVEARNGVSG
  LVTSRSFRTASVSINQTEPPKVRLEGRSTTSLSVSWSIPPPQQSRVWKYEVTYRKKGDSN
  SYNVRRTEGFSVTLDDLAPDTTYLVQVQALTQEGQGAGSKVHEFQTLSPEGSGNLAVIGG
  VAVGVVLLLVLAGVGFFIHRRRKNQRARQSPEDVYFSKSEQLKPLKTYVDPHTYEDPNQA
  VLKFTTEIHPSCVTRQKVIGAGEFGEVYKGMLKTSSGKKEVPVAIKTLKAGYTEKQRVDF
  LGEAGIMGQFSHHNIIRLEGVISKYKPMMIITEYMENGALDKFLREKDGEFSVLQLVGML
  RGIAAGMKYLANMNYVHRDLAARNILVNSNLVCKVSDFGLSRVLEDDPEATYTTSGGKIP
  IRWTAPEAISYRKFTSASDVWSFGIVMWEVMTYGERPYWELSNHEVMKAINDGFRLPTPM
  DCPSAIYQLMMQCWQQERARRPKFADIVSILDKLIRAPDSLKTLADFDPRVSIRLPSTSG
  SEGVPFRTVSEWLESIKMQQYTEHFMAAGYTAIEKVVQMTNDDIKRIGVRLPGHQKRIAY
  SLLGLKDQVNTVGIPI
• Function: Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis; (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins; Acts as a receptor for human cytomegalovirus (HCMV) to mediate viral entry and fusion in glioblastoma cells.
• Tissue Specificity: Expressed in brain and glioma tissue and glioma cell lines (at protein level). Expressed most highly in tissues that contain a high proportion of epithelial cells, e.g. skin, intestine, lung, and ovary.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  PI3K-Akt sig.ling pathway (hsa04151)
  Axon guidance (hsa04360)
• Reactome Pathway:
  EPHA-mediated growth cone collapse (R-HSA-3928663)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOG GTPase cycle (R-HSA-9013408)
  RHOU GTPase cycle (R-HSA-9013420)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOV GTPase cycle (R-HSA-9013424)
  RND3 GTPase cycle (R-HSA-9696264)
  RND2 GTPase cycle (R-HSA-9696270)
  RND1 GTPase cycle (R-HSA-9696273)
  EPH-Ephrin signaling (R-HSA-2682334)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract 6 multiple types	DISF1WRD	Strong	Autosomal dominant	[1]
Early-onset nuclear cataract	DISGIHUY	Supportive	Autosomal dominant	[2]
Early-onset posterior polar cataract	DISJFK9W	Supportive	Autosomal dominant	[3]
Early-onset posterior subcapsular cataract	DISB7SJS	Supportive	Autosomal dominant	[2]
Total early-onset cataract	DISACMEZ	Supportive	Autosomal dominant	[3]

21 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 Ephrin type-A receptor 2 (EPHA2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ephrin type-A receptor 2 (EPHA2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ephrin type-A receptor 2 (EPHA2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Ephrin type-A receptor 2 (EPHA2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ephrin type-A receptor 2 (EPHA2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ephrin type-A receptor 2 (EPHA2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ephrin type-A receptor 2 (EPHA2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ephrin type-A receptor 2 (EPHA2).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ephrin type-A receptor 2 (EPHA2).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ephrin type-A receptor 2 (EPHA2).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ephrin type-A receptor 2 (EPHA2).	[4]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Ephrin type-A receptor 2 (EPHA2).	[16]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Ephrin type-A receptor 2 (EPHA2).	[17]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of Ephrin type-A receptor 2 (EPHA2).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ephrin type-A receptor 2 (EPHA2).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ephrin type-A receptor 2 (EPHA2).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ephrin type-A receptor 2 (EPHA2).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Ephrin type-A receptor 2 (EPHA2).	[21]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Ephrin type-A receptor 2 (EPHA2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ephrin type-A receptor 2 (EPHA2).	[24]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ephrin type-A receptor 2 (EPHA2).	[25]

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 Ephrin type-A receptor 2 (EPHA2).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Ephrin type-A receptor 2 (EPHA2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ephrin type-A receptor 2 (EPHA2).	[22]

References

• [1] The EPHA2 gene is associated with cataracts linked to chromosome 1p. Mol Vis. 2008;14:2042-55. Epub 2008 Nov 12.
• [2] Mutations in the EPHA2 gene are a major contributor to inherited cataracts in South-Eastern Australia. PLoS One. 2013 Aug 27;8(8):e72518. doi: 10.1371/journal.pone.0072518. eCollection 2013.
• [3] Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract. Hum Mutat. 2009 May;30(5):E603-11. doi: 10.1002/humu.20995.
• [4] 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.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells. Cancer Chemother Pharmacol. 2007 Mar;59(4):515-25. doi: 10.1007/s00280-006-0293-7. Epub 2006 Aug 10.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] 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.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] 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.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry. 2007 Aug 7;46(31):8920-32. doi: 10.1021/bi7000328. Epub 2007 Jul 14.
• [16] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [17] Genomic and proteomic profiling of responses to toxic metals in human lung cells. Environ Health Perspect. 2003 May;111(6):825-35.
• [18] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [19] The MT1G Gene in LUHMES Neurons Is a Sensitive Biomarker of Neurotoxicity. Neurotox Res. 2020 Dec;38(4):967-978. doi: 10.1007/s12640-020-00272-3. Epub 2020 Sep 1.
• [20] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [25] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.