Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUIOEU3)

• DOT Name: Erythropoietin receptor (EPOR)
• Synonyms: EPO-R
• Gene Name: EPOR
• Related Disease: Primary familial polycythemia due to EPO receptor mutation
• UniProt ID: EPOR_HUMAN
• PDB ID: 1CN4; 1EBA; 1EBP; 1EER; 1ERN; 2JIX; 2MV6; 4Y5V; 4Y5X; 4Y5Y; 6E2Q; 6MOE; 6MOF; 6MOH; 6MOI; 6MOJ; 6MOK; 6MOL
• Pfam ID: PF09067 ; PF00041
• Sequence:
  MDHLGASLWPQVGSLCLLLAGAAWAPPPNLPDPKFESKAALLAARGPEELLCFTERLEDL
  VCFWEEAASAGVGPGNYSFSYQLEDEPWKLCRLHQAPTARGAVRFWCSLPTADTSSFVPL
  ELRVTAASGAPRYHRVIHINEVVLLDAPVGLVARLADESGHVVLRWLPPPETPMTSHIRY
  EVDVSAGNGAGSVQRVEILEGRTECVLSNLRGRTRYTFAVRARMAEPSFGGFWSAWSEPV
  SLLTPSDLDPLILTLSLILVVILVLLTVLALLSHRRALKQKIWPGIPSPESEFEGLFTTH
  KGNFQLWLYQNDGCLWWSPCTPFTEDPPASLEVLSERCWGTMQAVEPGTDDEGPLLEPVG
  SEHAQDTYLVLDKWLLPRNPPSEDLPGPGGSVDIVAMDEGSEASSCSSALASKPSPEGAS
  AASFEYTILDPSSQLLRPWTLCPELPPTPPHLKYLYLVVSDSGISTDYSSGDSQGAQGGL
  SDGPYSNPYENSLIPAAEPLPPSYVACS
• Function: Receptor for erythropoietin. Mediates erythropoietin-induced erythroblast proliferation and differentiation. Upon EPO stimulation, EPOR dimerizes triggering the JAK2/STAT5 signaling cascade. In some cell types, can also activate STAT1 and STAT3. May also activate the LYN tyrosine kinase.; Isoform EPOR-T acts as a dominant-negative receptor of EPOR-mediated signaling.
• Tissue Specificity: Erythroid cells and erythroid progenitor cells. Isoform EPOR-F is the most abundant form in EPO-dependent erythroleukemia cells and in late-stage erythroid progenitors. Isoform EPOR-S and isoform EPOR-T are the predominant forms in bone marrow. Isoform EPOR-T is the most abundant from in early-stage erythroid progenitor cells.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Efferocytosis (hsa04148)
  PI3K-Akt sig.ling pathway (hsa04151)
  JAK-STAT sig.ling pathway (hsa04630)
  Hematopoietic cell lineage (hsa04640)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Erythropoietin activates Phosphoinositide-3-kinase (PI3K) (R-HSA-9027276)
  Erythropoietin activates Phospholipase C gamma (PLCG) (R-HSA-9027277)
  Erythropoietin activates STAT5 (R-HSA-9027283)
  Erythropoietin activates RAS (R-HSA-9027284)
  Signaling by Erythropoietin (R-HSA-9006335)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary familial polycythemia due to EPO receptor mutation	DISFVI97	Strong	Autosomal dominant	[1]

15 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 Erythropoietin receptor (EPOR).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Erythropoietin receptor (EPOR).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Erythropoietin receptor (EPOR).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Erythropoietin receptor (EPOR).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Erythropoietin receptor (EPOR).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Erythropoietin receptor (EPOR).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Erythropoietin receptor (EPOR).	[8]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Erythropoietin receptor (EPOR).	[9]
Gefitinib	DM15F0X	Approved	Gefitinib increases the expression of Erythropoietin receptor (EPOR).	[10]
Aluminium	DM6ECN9	Approved	Aluminium affects the expression of Erythropoietin receptor (EPOR).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Erythropoietin receptor (EPOR).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Erythropoietin receptor (EPOR).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Erythropoietin receptor (EPOR).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Erythropoietin receptor (EPOR).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride affects the expression of Erythropoietin receptor (EPOR).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Erythropoietin receptor (EPOR).	[14]

References

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• [2] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] In vitro dual effect of arsenic trioxide on hemopoiesis: inhibition of erythropoiesis and stimulation of megakaryocytic maturation. Blood Cells Mol Dis. 2006 Jan-Feb;36(1):59-76. doi: 10.1016/j.bcmd.2005.10.005. Epub 2005 Dec 15.
• [8] 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.
• [9] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [10] Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer. Oncol Rep. 2006 Jun;15(6):1453-60.
• [11] The distinct erythropoietin functions that promote cell survival and proliferation are affected by aluminum exposure through mechanisms involving erythropoietin receptor. Biochim Biophys Acta. 2005 Mar 22;1743(1-2):29-36. doi: 10.1016/j.bbamcr.2004.08.004.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [14] 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.
• [15] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [16] 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.
• [17] Toxicity of nickel ions and comprehensive analysis of nickel ion-associated gene expression profiles in THP-1 cells. Mol Med Rep. 2015 Sep;12(3):3273-3278. doi: 10.3892/mmr.2015.3878. Epub 2015 Jun 3.