Details of Drug Off-Target (DOT)

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

• DOT Name: Envoplakin (EVPL)
• Synonyms: 210 kDa cornified envelope precursor protein; 210 kDa paraneoplastic pemphigus antigen; p210
• Gene Name: EVPL
• Related Disease:
  Squamous cell carcinoma
  Abetalipoproteinemia
  Acute leukaemia
  Acute megakaryoblastic leukemia
  Acute monocytic leukemia
  Acute myelomonocytic leukemia M4
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  B-cell acute lymphoblastic leukaemia
  Childhood acute lymphoblastic leukemia
  Childhood acute megakaryoblastic leukemia
  Childhood myelodysplastic syndrome
  Chronic myelogenous leukaemia
  Chronic myelomonocytic leukaemia
  Esophageal cancer
  Leukemia
  Lymphoid leukemia
  Myelodysplastic syndrome
  Myeloid leukaemia
  Neoplasm
  Retinoblastoma
  Systemic lupus erythematosus
  Vibrio cholerae infection
  Acute myelogenous leukaemia
  Essential thrombocythemia
  leukaemia
  Carcinoma of esophagus
  Chromosomal disorder
  Glycogen storage disease VI
  Neoplasm of esophagus
  Thyroid gland follicular carcinoma
  Tourette syndrome
• UniProt ID: EVPL_HUMAN
• PDB ID: 4QMD
• Pfam ID: PF00681 ; PF17902 ; PF21020
• Sequence:
  MFKGLSKGSQGKGSPKGSPAKGSPKGSPSRHSRAATQELALLISRMQANADQVERDILET
  QKRLQQDRLNSEQSQALQHQQETGRSLKEAEVLLKDLFLDVDKARRLKHPQAEEIEKDIK
  QLHERVTQECAEYRALYEKMVLPPDVGPRVDWARVLEQKQKQVCAGQYGPGMAELEQQIA
  EHNILQKEIDAYGQQLRSLVGPDAATIRSQYRDLLKAASWRGQSLGSLYTHLQGCTRQLS
  ALAEQQRRILQQDWSDLMADPAGVRREYEHFKQHELLSQEQSVNQLEDDGERMVELRHPA
  VGPIQAHQEALKMEWQNFLNLCICQETQLQHVEDYRRFQEEADSVSQTLAKLNSNLDAKY
  SPAPGGPPGAPTELLQQLEAEEKRLAVTERATGDLQRRSRDVAPLPQRRNPPQQPLHVDS
  ICDWDSGEVQLLQGERYKLVDNTDPHAWVVQGPGGETKRAPAACFCIPAPDPDAVARASR
  LASELQALKQKLATVQSRLKASAVESLRPSQQAPSGSDLANPQAQKLLTQMTRLDGDLGQ
  IERQVLAWARAPLSRPTPLEDLEGRIHSHEGTAQRLQSLGTEKETAQKECEAFLSTRPVG
  PAALQLPVALNSVKNKFSDVQVLCSLYGEKAKAALDLERQIQDADRVIRGFEATLVQEAP
  IPAEPGALQERVSELQRQRRELLEQQTCVLRLHRALKASEHACAALQNNFQEFCQDLPRQ
  QRQVRALTDRYHAVGDQLDLREKVVQDAALTYQQFKNCKDNLSSWLEHLPRSQVRPSDGP
  SQIAYKLQAQKRLTQEIQSRERDRATASHLSQALQAALQDYELQADTYRCSLEPTLAVSA
  PKRPRVAPLQESIQAQEKNLAKAYTEVAAAQQQLLQQLEFARKMLEKKELSEDIRRTHDA
  KQGSESPAQAGRESEALKAQLEEERKRVARVQHELEAQRSQLLQLRTQRPLERLEEKEVV
  EFYRDPQLEGSLSRVKAQVEEEGKRRAGLQADLEVAAQKVVQLESKRKTMQPHLLTKEVT
  QVERDPGLDSQAAQLRIQIQQLRGEDAVISARLEGLKKELLALEKREVDVKEKVVVKEVV
  KVEKNLEMVKAAQALRLQMEEDAARRKQAEEAVAKLQARIEDLERAISSVEPKVIVKEVK
  KVEQDPGLLQESSRLRSLLEEERTKNATLARELSDLHSKYSVVEKQRPKVQLQERVHEIF
  QVDPETEQEITRLKAKLQEMAGKRSGVEKEVEKLLPDLEVLRAQKPTVEYKEVTQEVVRH
  ERSPEVLREIDRLKAQLNELVNSHGRSQEQLIRLQGERDEWRRERAKVETKTVSKEVVRH
  EKDPVLEKEAERLRQEVREAAQKRRAAEDAVYELQSKRLLLERRKPEEKVVVQEVVVTQK
  DPKLREEHSRLSGSLDEEVGRRRQLELEVQQLRAGVEEQEGLLSFQEDRSKKLAVERELR
  QLTLRIQELEKRPPTVQEKIIMEEVVKLEKDPDLEKSTEALRWDLDQEKTQVTELNRECK
  NLQVQIDVLQKAKSQEKTIYKEVIRVQKDRVLEDERARVWEMLNRERTARQAREEEARRL
  RERIDRAETLGRTWSREESELQRARDQADQECGRLQQELRALERQKQQQTLQLQEESKLL
  SQKTESERQKAAQRGQELSRLEAAILREKDQIYEKERTLRDLHAKVSREELSQETQTRET
  NLSTKISILEPETGKDMSPYEAYKRGIIDRGQYLQLQELECDWEEVTTSGPCGEESVLLD
  RKSGKQYSIEAALRCRRISKEEYHLYKDGHLPISEFALLVAGETKPSSSLSIGSIISKSP
  LASPAPQSTSFFSPSFSLGLGDDSFPIAGIYDTTTDNKCSIKTAVAKNMLDPITGQKLLE
  AQAATGGIVDLLSRERYSVHKAMERGLIENTSTQRLLNAQKAFTGIEDPVTKKRLSVGEA
  VQKGWMPRESVLPHLQVQHLTGGLIDPKRTGRIPIQQALLSGMISEELAQLLQDESSYEK
  DLTDPISKERLSYKEAMGRCRKDPLSGLLLLPAALEGYRCYRSASPTVPRSLR
• Function: Component of the cornified envelope of keratinocytes. May link the cornified envelope to desmosomes and intermediate filaments.
• Tissue Specificity: Exclusively expressed in stratified squamous epithelia.
• Reactome Pathway: Formation of the cornified envelope (R-HSA-6809371)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Squamous cell carcinoma	DISQVIFL	Definitive	Genetic Variation	[1]
Abetalipoproteinemia	DISMSS7T	Strong	Biomarker	[2]
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[3]
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Genetic Variation	[4]
Acute monocytic leukemia	DIS28NEL	Strong	Genetic Variation	[5]
Acute myelomonocytic leukemia M4	DISRRMV2	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[7]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[8]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[8]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Biomarker	[9]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Posttranslational Modification	[10]
Childhood acute megakaryoblastic leukemia	DIS5VZDR	Strong	Genetic Variation	[4]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Biomarker	[11]
Chronic myelogenous leukaemia	DIS0301E	Strong	Genetic Variation	[12]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Altered Expression	[13]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[14]
Lymphoid leukemia	DIS65TYQ	Strong	Posttranslational Modification	[10]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[11]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[17]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[18]
Vibrio cholerae infection	DISW7E3U	Strong	Biomarker	[8]
Acute myelogenous leukaemia	DISCSPTN	moderate	Biomarker	[19]
Essential thrombocythemia	DISWWK11	moderate	Genetic Variation	[20]
leukaemia	DISS7D1V	moderate	Biomarker	[14]
Carcinoma of esophagus	DISS6G4D	Limited	Biomarker	[21]
Chromosomal disorder	DISM5BB5	Limited	Biomarker	[22]
Glycogen storage disease VI	DIS46FMA	Limited	Altered Expression	[23]
Neoplasm of esophagus	DISOLKAQ	Limited	Biomarker	[21]
Thyroid gland follicular carcinoma	DISFK2QT	Limited	Genetic Variation	[24]
Tourette syndrome	DISX9D54	No Known	Unknown	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Envoplakin (EVPL) decreases the response to substance of Arsenic trioxide.	[31]

2 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 Envoplakin (EVPL).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Envoplakin (EVPL).	[29]

2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Envoplakin (EVPL).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Envoplakin (EVPL).	[30]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Envoplakin (EVPL).	[28]

References

• [1] Infrequent mutation of the human envoplakin gene is closely linked to the tylosis oesophageal cancer locus in sporadic oesophageal squamous cell carcinomas.Oncol Rep. 2005 Apr;13(4):703-7.
• [2] p210(Bcr-Abl) desensitizes Cdc42 GTPase signaling for SDF-1alpha-directed migration in chronic myeloid leukemia cells.Oncogene. 2009 Nov 19;28(46):4105-15. doi: 10.1038/onc.2009.260. Epub 2009 Aug 31.
• [3] Acute leukemias expressing p210-and p 190-type bcr/abl mRNAs: report of two cases and review of the literature.Acta Haematol. 1996;96(2):99-104. doi: 10.1159/000203724.
• [4] De novo acute megakaryoblastic leukemia with p210 BCR/ABL and t(1;16) translocation but not t(9;22) Ph chromosome.J Hematol Oncol. 2011 Nov 10;4:45. doi: 10.1186/1756-8722-4-45.
• [5] Establishment of a novel human myeloid leukaemia cell line (HNT-34) with t(3;3)(q21;q26), t(9;22)(q34;q11) and the expression of EVI1 gene, P210 and P190 BCR/ABL chimaeric transcripts from a patient with AML after MDS with 3q21q26 syndrome.Br J Haematol. 1997 Aug;98(2):399-407. doi: 10.1046/j.1365-2141.1997.2143029.x.
• [6] p210 BCR/ABL1 as a secondary change in a patient with acute myelomonocytic leukemia (M4Eo) with inv(16).Int J Hematol. 2012 Dec;96(6):814-7. doi: 10.1007/s12185-012-1190-y. Epub 2012 Oct 11.
• [7] Characterization of the CDR3 structure of the V21 T cell clone in patients with P210(BCR-ABL)-positive chronic myeloid leukemia and B-cell acute lymphoblastic leukemia.Hum Immunol. 2011 Oct;72(10):798-804. doi: 10.1016/j.humimm.2011.06.015. Epub 2011 Jul 20.
• [8] B cells treated with CTB-p210 acquire a regulatory phenotype in vitro and reduce atherosclerosis in apolipoprotein E deficient mice.Vascul Pharmacol. 2018 Dec;111:54-61. doi: 10.1016/j.vph.2018.09.002. Epub 2018 Sep 19.
• [9] Pre-B acute lymphoblastic leukemia with b3a2 (p210) and e1a2 (p190) BCR-ABL fusion transcripts relapsing as chronic myelogenous leukemia with a less differentiated b3a2 (p210) clone.Leukemia. 1999 Dec;13(12):2007-11. doi: 10.1038/sj.leu.2401598.
• [10] Pak1 gene functioned differentially in different BCR-ABL subtypes in leukemiagenesis and treatment response through STAT5 pathway.Leuk Res. 2019 Apr;79:6-16. doi: 10.1016/j.leukres.2019.01.012. Epub 2019 Jan 24.
• [11] Late-appearing Philadelphia chromosome in a patient with acute nonlymphocytic leukaemia derived from myelodysplastic syndrome: detection of P210- and P190-type bcr/abl fusion gene transcripts at the leukaemic stage.Br J Haematol. 1994 May;87(1):51-6. doi: 10.1111/j.1365-2141.1994.tb04869.x.
• [12] Effective Concentration of a Multikinase Inhibitor within Bone Marrow Correlates with In Vitro Cell Killing in Therapy-Resistant Chronic Myeloid Leukemia.Mol Cancer Ther. 2016 May;15(5):899-910. doi: 10.1158/1535-7163.MCT-15-0577-T. Epub 2016 Feb 4.
• [13] Childhood chronic myeloid leukemia with monocytosis.Indian J Pediatr. 2010 Oct;77(10):1143-5. doi: 10.1007/s12098-010-0200-4. Epub 2010 Sep 30.
• [14] Disparate effects of Shb gene deficiency on disease characteristics in murine models of myeloid, B-cell, and T-cell leukemia.Tumour Biol. 2018 Apr;40(4):1010428318771472. doi: 10.1177/1010428318771472.
• [15] Leukemia patient-derived lymphoblastoid cell lines exhibit increased induction of leukemia-associated transcripts following high-dose irradiation.Exp Hematol. 1999 Sep;27(9):1397-401. doi: 10.1016/s0301-472x(99)00082-x.
• [16] Droplet digital PCR for BCR/ABL(P210) detection of chronic myeloid leukemia: A high sensitive method of the minimal residual disease and disease progression.Eur J Haematol. 2018 Sep;101(3):291-296. doi: 10.1111/ejh.13084. Epub 2018 Jul 12.
• [17] The presence of the Rb c-box peptide in the cytoplasm inhibits p210bcr-abl transforming function.Oncogene. 1999 Feb 25;18(8):1589-95. doi: 10.1038/sj.onc.1202479.
• [18] RETRACTED: Bach2 regulates aberrant activation of B cell in systemic lupus erythematosus and can be negatively regulated by BCR-ABL/PI3K.Exp Cell Res. 2018 Apr 1;365(1):138-144. doi: 10.1016/j.yexcr.2018.02.034. Epub 2018 Mar 6.
• [19] Coexistence of p210(BCR-ABL) and CBF-MYH11 fusion genes in myeloid leukemia: A report of 4 cases.Oncol Lett. 2017 Nov;14(5):5171-5178. doi: 10.3892/ol.2017.6812. Epub 2017 Aug 24.
• [20] Concomitant presence of JAK2V617F mutation and BCRABL translocation in two patients: A new entity or a variant of myeloproliferative neoplasms (Case report).Mol Med Rep. 2018 Jul;18(1):1001-1006. doi: 10.3892/mmr.2018.9032. Epub 2018 May 17.
• [21] Envoplakin, a possible candidate gene for focal NEPPK/esophageal cancer (TOC): the integration of genetic and physical maps of the TOC region on 17q25.Genomics. 1999 Jul 15;59(2):234-42. doi: 10.1006/geno.1999.5857.
• [22] Acquired loss of p53 induces blastic transformation in p210(bcr/abl)-expressing hematopoietic cells: a transgenic study for blast crisis of human CML.Blood. 2000 Feb 15;95(4):1144-50.
• [23] A Philadelphia chromosome positive acute lymphoblastic leukemia of donor origin after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase.Bone Marrow Transplant. 2000 Jun;25(11):1209-11. doi: 10.1038/sj.bmt.1702418.
• [24] Selected single-nucleotide polymorphisms in FOXE1, SERPINA5, FTO, EVPL, TICAM1 and SCARB1 are associated with papillary and follicular thyroid cancer risk: replication study in a German population.Carcinogenesis. 2016 Jul;37(7):677-684. doi: 10.1093/carcin/bgw047. Epub 2016 Apr 28.
• [25] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [26] 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.
• [27] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [28] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [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] Unique bisphenol A transcriptome in prostate cancer: novel effects on ERbeta expression that correspond to androgen receptor mutation status. Environ Health Perspect. 2007 Nov;115(11):1646-53. doi: 10.1289/ehp.10283.
• [31] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.