Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3AMK0C)

• DOT Name: Ephrin type-A receptor 4 (EPHA4)
• Synonyms: EC 2.7.10.1; EPH-like kinase 8; EK8; hEK8; Tyrosine-protein kinase TYRO1; Tyrosine-protein kinase receptor SEK
• Gene Name: EPHA4
• Related Disease: Complex neurodevelopmental disorder
• UniProt ID: EPHA4_HUMAN
• PDB ID: 2LW8; 2WO1; 2WO2; 2WO3; 3CKH; 3GXU; 4BK4; 4BK5; 4BKA; 4BKF; 4M4P; 4M4R; 4W4Z; 4W50; 5JR2; 7OFV
• EC Number: 2.7.10.1
• Pfam ID: PF14575 ; PF01404 ; PF07699 ; PF00041 ; PF07714 ; PF07647
• Sequence:
  MAGIFYFALFSCLFGICDAVTGSRVYPANEVTLLDSRSVQGELGWIASPLEGGWEEVSIM
  DEKNTPIRTYQVCNVMEPSQNNWLRTDWITREGAQRVYIEIKFTLRDCNSLPGVMGTCKE
  TFNLYYYESDNDKERFIRENQFVKIDTIAADESFTQVDIGDRIMKLNTEIRDVGPLSKKG
  FYLAFQDVGACIALVSVRVFYKKCPLTVRNLAQFPDTITGADTSSLVEVRGSCVNNSEEK
  DVPKMYCGADGEWLVPIGNCLCNAGHEERSGECQACKIGYYKALSTDATCAKCPPHSYSV
  WEGATSCTCDRGFFRADNDAASMPCTRPPSAPLNLISNVNETSVNLEWSSPQNTGGRQDI
  SYNVVCKKCGAGDPSKCRPCGSGVHYTPQQNGLKTTKVSITDLLAHTNYTFEIWAVNGVS
  KYNPNPDQSVSVTVTTNQAAPSSIALVQAKEVTRYSVALAWLEPDRPNGVILEYEVKYYE
  KDQNERSYRIVRTAARNTDIKGLNPLTSYVFHVRARTAAGYGDFSEPLEVTTNTVPSRII
  GDGANSTVLLVSVSGSVVLVVILIAAFVISRRRSKYSKAKQEADEEKHLNQGVRTYVDPF
  TYEDPNQAVREFAKEIDASCIKIEKVIGVGEFGEVCSGRLKVPGKREICVAIKTLKAGYT
  DKQRRDFLSEASIMGQFDHPNIIHLEGVVTKCKPVMIITEYMENGSLDAFLRKNDGRFTV
  IQLVGMLRGIGSGMKYLSDMSYVHRDLAARNILVNSNLVCKVSDFGMSRVLEDDPEAAYT
  TRGGKIPIRWTAPEAIAYRKFTSASDVWSYGIVMWEVMSYGERPYWDMSNQDVIKAIEEG
  YRLPPPMDCPIALHQLMLDCWQKERSDRPKFGQIVNMLDKLIRNPNSLKRTGTESSRPNT
  ALLDPSSPEFSAVVSVGDWLQAIKMDRYKDNFTAAGYTTLEAVVHVNQEDLARIGITAIT
  HQNKILSSVQAMRTQMQQMHGRMVPV
• Function: Receptor tyrosine kinase which binds membrane-bound ephrin 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. Highly promiscuous, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. In addition to its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at 'Tyr-15' which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, also plays a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium. During development of the cochlear organ of Corti, regulates pillar cell separation by forming a ternary complex with ADAM10 and CADH1 which facilitates the cleavage of CADH1 by ADAM10 and disruption of adherens junctions. Phosphorylates CAPRIN1, promoting CAPRIN1-dependent formation of a membraneless compartment.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  EPHA-mediated growth cone collapse (R-HSA-3928663)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Somitogenesis (R-HSA-9824272)
  EPH-Ephrin signaling (R-HSA-2682334)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Disputed	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Brilinta	DMBR01X	Approved	Ephrin type-A receptor 4 (EPHA4) increases the Peripheral sensory neuropathy ADR of Brilinta.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ephrin type-A receptor 4 (EPHA4).	[2]
Epinephrine	DM3KJBC	Approved	Epinephrine increases the phosphorylation of Ephrin type-A receptor 4 (EPHA4).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ephrin type-A receptor 4 (EPHA4).	[16]
adenosine diphosphate	DMFUHKP	Investigative	adenosine diphosphate increases the phosphorylation of Ephrin type-A receptor 4 (EPHA4).	[14]

25 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 Ephrin type-A receptor 4 (EPHA4).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ephrin type-A receptor 4 (EPHA4).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[9]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Ephrin type-A receptor 4 (EPHA4).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Ephrin type-A receptor 4 (EPHA4).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[12]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Ephrin type-A receptor 4 (EPHA4).	[13]
Estrone	DM5T6US	Approved	Estrone decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[12]
Mestranol	DMG3F94	Approved	Mestranol decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Ephrin type-A receptor 4 (EPHA4).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ephrin type-A receptor 4 (EPHA4).	[17]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Ephrin type-A receptor 4 (EPHA4).	[18]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[12]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Ephrin type-A receptor 4 (EPHA4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ephrin type-A receptor 4 (EPHA4).	[21]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Ephrin type-A receptor 4 (EPHA4).	[22]

References

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• [14] The platelet P2Y12 receptor contributes to granule secretion through Ephrin A4 receptor. Platelets. 2012;23(8):617-25. doi: 10.3109/09537104.2011.645924. Epub 2012 Jan 24.
• [15] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [16] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
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• [18] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [19] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [20] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [23] Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy. J Med Genet. 2013 Sep;50(9):599-605. doi: 10.1136/jmedgenet-2012-101466. Epub 2013 Jun 17.