Details of Drug Off-Target (DOT)

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

• DOT Name: Ephrin-A3 (EFNA3)
• Synonyms: EFL-2; EHK1 ligand; EHK1-L; EPH-related receptor tyrosine kinase ligand 3; LERK-3
• Gene Name: EFNA3
• Related Disease:
  Angiosarcoma
  Breast cancer
  Breast carcinoma
  Lung cancer
  Lung carcinoma
  Malignant peripheral nerve sheath tumor
  Medulloblastoma
  Myocardial infarction
  Neurofibroma
  Hepatocellular carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Spinocerebellar ataxia type 3
• UniProt ID: EFNA3_HUMAN
• Pfam ID: PF00812
• Sequence:
  MAAAPLLLLLLLVPVPLLPLLAQGPGGALGNRHAVYWNSSNQHLRREGYTVQVNVNDYLD
  IYCPHYNSSGVGPGAGPGPGGGAEQYVLYMVSRNGYRTCNASQGFKRWECNRPHAPHSPI
  KFSEKFQRYSAFSLGYEFHAGHEYYYISTPTHNLHWKCLRMKVFVCCASTSHSGEKPVPT
  LPQFTMGPNVKINVLEDFEGENPQVPKLEKSISGTSPKREHLPLAVGIAFFLMTFLAS
• Function: Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors 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.
• Tissue Specificity: Expressed in brain, skeletal muscle, spleen, thymus, prostate, testis, ovary, small intestine, and peripheral blood leukocytes.
• 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)
  MicroR.s in cancer (hsa05206)
• Reactome Pathway:
  EPHA-mediated growth cone collapse (R-HSA-3928663)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  EPH-Ephrin signaling (R-HSA-2682334)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Angiosarcoma	DISIYS9W	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[3]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[3]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Biomarker	[4]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[5]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[6]
Neurofibroma	DISIJJMH	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[8]
Neoplasm	DISZKGEW	moderate	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[9]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Altered Expression	[10]

9 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 Ephrin-A3 (EFNA3).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ephrin-A3 (EFNA3).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Ephrin-A3 (EFNA3).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Ephrin-A3 (EFNA3).	[15]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Ephrin-A3 (EFNA3).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Ephrin-A3 (EFNA3).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ephrin-A3 (EFNA3).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Ephrin-A3 (EFNA3).	[20]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Ephrin-A3 (EFNA3).	[21]

2 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-A3 (EFNA3).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ephrin-A3 (EFNA3).	[17]

References

• [1] The role of miR-210, E2F3 and ephrin A3 in angiosarcoma cell proliferation.Eur J Dermatol. 2017 Oct 1;27(5):464-471. doi: 10.1684/ejd.2017.3084.
• [2] EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination.Oncogene. 2015 May 14;34(20):2609-20. doi: 10.1038/onc.2014.200. Epub 2014 Jul 14.
• [3] Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers.Clin Chem. 2004 Mar;50(3):490-9. doi: 10.1373/clinchem.2003.026849. Epub 2004 Jan 15.
• [4] Dissecting the roles of Ephrin-A3 in malignant peripheral nerve sheath tumor by TALENs.Oncol Rep. 2015 Jul;34(1):391-8. doi: 10.3892/or.2015.3966. Epub 2015 May 8.
• [5] EphrinB1 expression is dysregulated and promotes oncogenic signaling in medulloblastoma.J Neurooncol. 2015 Jan;121(1):109-18. doi: 10.1007/s11060-014-1618-8. Epub 2014 Sep 26.
• [6] Mesenchymal stem cells-derived extracellular vesicles, via miR-210, improve infarcted cardiac function by promotion of angiogenesis.Biochim Biophys Acta Mol Basis Dis. 2017 Aug;1863(8):2085-2092. doi: 10.1016/j.bbadis.2017.02.023. Epub 2017 Feb 27.
• [7] MicroRNA-210 promotes proliferation and invasion of peripheral nerve sheath tumor cells targeting EFNA3.Oncol Res. 2013;21(3):145-54. doi: 10.3727/096504013X13841340689573.
• [8] Euphorbia factor L2 inhibits TGF--induced cell growth and migration of hepatocellular carcinoma through AKT/STAT3.Phytomedicine. 2019 Sep;62:152931. doi: 10.1016/j.phymed.2019.152931. Epub 2019 Apr 17.
• [9] Expression analysis of angiogenesis-related genes in Bulgarian patients with early-stage non-small cell lung cancer.Tumori. 2011 Jan-Feb;97(1):86-94. doi: 10.1177/030089161109700116.
• [10] Loss of the Spinocerebellar Ataxia type 3 disease protein ATXN3 alters transcription of multiple signal transduction pathways.PLoS One. 2018 Sep 19;13(9):e0204438. doi: 10.1371/journal.pone.0204438. eCollection 2018.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [16] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [21] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.