Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7JJW8P)

DOT Name	Ephrin-B1 (EFNB1)
Synonyms	EFL-3; ELK ligand; ELK-L; EPH-related receptor tyrosine kinase ligand 2; LERK-2
Gene Name	EFNB1
Related Disease	Astrocytoma ( ) Craniofrontonasal syndrome ( ) Glioblastoma multiforme ( ) Acute lymphocytic leukaemia ( ) Adenocarcinoma ( ) Arteriosclerosis ( ) Atherosclerosis ( ) Childhood acute lymphoblastic leukemia ( ) Craniosynostosis 4 ( ) Frontonasal dysplasia ( ) Gastric cancer ( ) Gastric neoplasm ( ) Hepatocellular carcinoma ( ) High blood pressure ( ) Hypogonadism ( ) leukaemia ( ) Leukemia ( ) Medulloblastoma ( ) Neoplasm ( ) Nephropathy ( ) Obesity ( ) Osteosarcoma ( ) Prostate cancer ( ) Prostate carcinoma ( ) Saethre-Chotzen syndrome ( ) Stomach cancer ( ) Synostosis ( ) Trigonocephaly ( ) TWIST1-related craniosynostosis ( ) Amyotrophic lateral sclerosis ( ) Atrial septal defect ( ) Colorectal carcinoma ( ) Craniosynostosis ( ) Rheumatoid arthritis ( )
UniProt ID	EFNB1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	6THG
Pfam ID	PF00812
Sequence	MARPGQRWLGKWLVAMVVWALCRLATPLAKNLEPVSWSSLNPKFLSGKGLVIYPKIGDKL DIICPRAEAGRPYEYYKLYLVRPEQAAACSTVLDPNVLVTCNRPEQEIRFTIKFQEFSPN YMGLEFKKHHDYYITSTSNGSLEGLENREGGVCRTRTMKIIMKVGQDPNAVTPEQLTTSR PSKEADNTVKMATQAPGSRGSLGDSDGKHETVNQEEKSGPGASGGSSGDPDGFFNSKVAL FAAVGAGCVIFLLIIIFLTVLLLKLRKRHRKHTQQRAAALSLSTLASPKGGSGTAGTEPS DIIIPLRTTENNYCPHYEKVSGDYGHPVYIVQEMPPQSPANIYYKV
Function	Cell surface transmembrane ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binding to Eph receptors residing on adjacent cells leads to contact-dependent bidirectional signaling into neighboring cells. Shows high affinity for the receptor tyrosine kinase EPHB1/ELK. Can also bind EPHB2 and EPHB3. Binds to, and induces collapse of, commissural axons/growth cones in vitro. May play a role in constraining the orientation of longitudinally projecting axons.
Tissue Specificity	Widely expressed . Detected in both neuronal and non-neuronal tissues . Seems to have particularly strong expression in retina, sciatic nerve, heart and spinal cord .
KEGG Pathway	Axon guidance (hsa04360 )
Reactome Pathway	EPHB-mediated forward signaling (R-HSA-3928662 ) Ephrin signaling (R-HSA-3928664 ) EPH-ephrin mediated repulsion of cells (R-HSA-3928665 ) EPH-Ephrin signaling (R-HSA-2682334 )

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Astrocytoma	DISL3V18	Definitive	Altered Expression	[1]
Craniofrontonasal syndrome	DISSO9WK	Definitive	X-linked	[2]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[4]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[5]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[3]
Craniosynostosis 4	DISZX1GK	Strong	Biomarker	[6]
Frontonasal dysplasia	DISXV4YX	Strong	Genetic Variation	[7]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[4]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
High blood pressure	DISY2OHH	Strong	Biomarker	[9]
Hypogonadism	DISICMNI	Strong	Genetic Variation	[9]
leukaemia	DISS7D1V	Strong	Biomarker	[3]
Leukemia	DISNAKFL	Strong	Biomarker	[3]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Nephropathy	DISXWP4P	Strong	Biomarker	[12]
Obesity	DIS47Y1K	Strong	Biomarker	[13]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[14]
Prostate cancer	DISF190Y	Strong	Biomarker	[15]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[15]
Saethre-Chotzen syndrome	DIS3A437	Strong	Genetic Variation	[16]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[4]
Synostosis	DISXGMZW	Strong	Genetic Variation	[17]
Trigonocephaly	DISHV6BA	Strong	Biomarker	[6]
TWIST1-related craniosynostosis	DISGRP2G	Strong	Biomarker	[6]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[18]
Atrial septal defect	DISJT76B	Limited	Genetic Variation	[19]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[20]
Craniosynostosis	DIS6J405	Limited	Genetic Variation	[21]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[22]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

3 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 Ephrin-B1 (EFNB1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ephrin-B1 (EFNB1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ephrin-B1 (EFNB1).	[32]
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7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ephrin-B1 (EFNB1).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Ephrin-B1 (EFNB1).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ephrin-B1 (EFNB1).	[26]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ephrin-B1 (EFNB1).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ephrin-B1 (EFNB1).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Ephrin-B1 (EFNB1).	[30]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Ephrin-B1 (EFNB1).	[31]
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⏷ Show the Full List of 7 Drug(s)

References

1	The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion.Int J Cancer. 2010 Mar 1;126(5):1155-65. doi: 10.1002/ijc.24849.
2	Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
3	Aberrant DNA methylation and epigenetic inactivation of Eph receptor tyrosine kinases and ephrin ligands in acute lymphoblastic leukemia.Blood. 2010 Mar 25;115(12):2412-9. doi: 10.1182/blood-2009-05-222208. Epub 2010 Jan 8.
4	Expression profile of EFNB1, EFNB2, two ligands of EPHB2 in human gastric cancer.J Cancer Res Clin Oncol. 2002 Jul;128(7):343-8. doi: 10.1007/s00432-002-0355-0. Epub 2002 Jun 26.
5	Expression and function of ephrin-B1 and its cognate receptor EphB2 in human atherosclerosis: from an aspect of chemotaxis.Clin Sci (Lond). 2008 May;114(10):643-50. doi: 10.1042/CS20070339.
6	Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8652-7. doi: 10.1073/pnas.0402819101. Epub 2004 May 27.
7	Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes.Hum Mol Genet. 2013 Apr 15;22(8):1654-62. doi: 10.1093/hmg/ddt015. Epub 2013 Jan 17.
8	Expression of ephrin-B1 in hepatocellular carcinoma: possible involvement in neovascularization.J Hepatol. 2003 Dec;39(6):991-6. doi: 10.1016/s0168-8278(03)00498-7.
9	Analysis of the association of EPHB6, EFNB1 and EFNB3 variants with hypertension risks in males with hypogonadism.Sci Rep. 2018 Sep 27;8(1):14497. doi: 10.1038/s41598-018-32836-x.
10	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.
11	UTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma.Nat Commun. 2018 Jul 13;9(1):2720. doi: 10.1038/s41467-018-05084-w.
12	Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway.J Am Soc Nephrol. 2018 May;29(5):1462-1474. doi: 10.1681/ASN.2017090993. Epub 2018 Mar 30.
13	A novel role for adipose ephrin-B1 in inflammatory response.PLoS One. 2013 Oct 1;8(10):e76199. doi: 10.1371/journal.pone.0076199. eCollection 2013.
14	Human osteosarcoma expresses specific ephrin profiles: implications for tumorigenicity and prognosis.Cancer. 2002 Aug 15;95(4):862-9. doi: 10.1002/cncr.10749.
15	Chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating expression of ephrin-B1.Cancer Sci. 2018 Oct;109(10):3159-3170. doi: 10.1111/cas.13754. Epub 2018 Aug 29.
16	Nonsyndromic craniosynostosis: novel coding variants.Pediatr Res. 2019 Mar;85(4):463-468. doi: 10.1038/s41390-019-0274-2. Epub 2019 Jan 14.
17	Syndromic craniosynostosis: from history to hydrogen bonds.Orthod Craniofac Res. 2007 May;10(2):67-81. doi: 10.1111/j.1601-6343.2007.00389.x.
18	A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models.Nat Commun. 2017 Oct 27;8(1):1164. doi: 10.1038/s41467-017-01283-z.
19	Craniofrontonasal Syndrome: Atrial Septal Defect With a Novel EFNB1 Gene Mutation.Cleft Palate Craniofac J. 2015 Mar;52(2):234-6. doi: 10.1597/13-354. Epub 2014 Jun 11.
20	Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB.Cell. 2002 Oct 18;111(2):251-63. doi: 10.1016/s0092-8674(02)01015-2.
21	Genetic Analysis of Syndromic and Nonsyndromic Patients With Craniosynostosis Identifies Novel Mutations in the TWIST1 and EFNB1 Genes.Cleft Palate Craniofac J. 2018 Sep;55(8):1092-1102. doi: 10.1177/1055665618760412. Epub 2018 Mar 21.
22	Role of EFNB1 and EFNB2 in Mouse Collagen-Induced Arthritis and Human Rheumatoid Arthritis.Arthritis Rheumatol. 2015 Jul;67(7):1778-88. doi: 10.1002/art.39116.
23	Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
24	Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
25	Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
26	Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
27	Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
28	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
29	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.
30	Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
31	Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
32	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.