Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTON6JSZ)

• DOT Name: Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2)
• Synonyms: Cadherin family member 10; Epidermal growth factor-like protein 2; EGF-like protein 2; Flamingo homolog 3; Multiple epidermal growth factor-like domains protein 3; Multiple EGF-like domains protein 3
• Gene Name: CELSR2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Pneumocystis pneumonia
  Acute coronary syndrome
  Advanced cancer
  Atrial fibrillation
  Atypical endometrial hyperplasia
  Breast neoplasm
  Cardiac failure
  Cardiovascular disease
  Carotid artery disease
  Coronary atherosclerosis
  Coronary heart disease
  Familial hypercholesterolemia
  Hydrocephalus
  Hypercholesterolemia, familial, 1
  Neoplasm
  Peripheral arterial disease
  Stroke
  Type-1/2 diabetes
  Myocardial infarction
• UniProt ID: CELR2_HUMAN
• Pfam ID: PF00002 ; PF00028 ; PF00008 ; PF16489 ; PF01825 ; PF00053 ; PF02210
• Sequence:
  MRSPATGVPLPTPPPPLLLLLLLLLPPPLLGDQVGPCRSLGSRGRGSSGACAPMGWLCPS
  SASNLWLYTSRCRDAGTELTGHLVPHHDGLRVWCPESEAHIPLPPAPEGCPWSCRLLGIG
  GHLSPQGKLTLPEEHPCLKAPRLRCQSCKLAQAPGLRAGERSPEESLGGRRKRNVNTAPQ
  FQPPSYQATVPENQPAGTPVASLRAIDPDEGEAGRLEYTMDALFDSRSNQFFSLDPVTGA
  VTTAEELDRETKSTHVFRVTAQDHGMPRRSALATLTILVTDTNDHDPVFEQQEYKESLRE
  NLEVGYEVLTVRATDGDAPPNANILYRLLEGSGGSPSEVFEIDPRSGVIRTRGPVDREEV
  ESYQLTVEASDQGRDPGPRSTTAAVFLSVEDDNDNAPQFSEKRYVVQVREDVTPGAPVLR
  VTASDRDKGSNAVVHYSIMSGNARGQFYLDAQTGALDVVSPLDYETTKEYTLRVRAQDGG
  RPPLSNVSGLVTVQVLDINDNAPIFVSTPFQATVLESVPLGYLVLHVQAIDADAGDNARL
  EYRLAGVGHDFPFTINNGTGWISVAAELDREEVDFYSFGVEARDHGTPALTASASVSVTV
  LDVNDNNPTFTQPEYTVRLNEDAAVGTSVVTVSAVDRDAHSVITYQITSGNTRNRFSITS
  QSGGGLVSLALPLDYKLERQYVLAVTASDGTRQDTAQIVVNVTDANTHRPVFQSSHYTVN
  VNEDRPAGTTVVLISATDEDTGENARITYFMEDSIPQFRIDADTGAVTTQAELDYEDQVS
  YTLAITARDNGIPQKSDTTYLEILVNDVNDNAPQFLRDSYQGSVYEDVPPFTSVLQISAT
  DRDSGLNGRVFYTFQGGDDGDGDFIVESTSGIVRTLRRLDRENVAQYVLRAYAVDKGMPP
  ARTPMEVTVTVLDVNDNPPVFEQDEFDVFVEENSPIGLAVARVTATDPDEGTNAQIMYQI
  VEGNIPEVFQLDIFSGELTALVDLDYEDRPEYVLVIQATSAPLVSRATVHVRLLDRNDNP
  PVLGNFEILFNNYVTNRSSSFPGGAIGRVPAHDPDISDSLTYSFERGNELSLVLLNASTG
  ELKLSRALDNNRPLEAIMSVLVSDGVHSVTAQCALRVTIITDEMLTHSITLRLEDMSPER
  FLSPLLGLFIQAVAATLATPPDHVVVFNVQRDTDAPGGHILNVSLSVGQPPGPGGGPPFL
  PSEDLQERLYLNRSLLTAISAQRVLPFDDNICLREPCENYMRCVSVLRFDSSAPFIASSS
  VLFRPIHPVGGLRCRCPPGFTGDYCETEVDLCYSRPCGPHGRCRSREGGYTCLCRDGYTG
  EHCEVSARSGRCTPGVCKNGGTCVNLLVGGFKCDCPSGDFEKPYCQVTTRSFPAHSFITF
  RGLRQRFHFTLALSFATKERDGLLLYNGRFNEKHDFVALEVIQEQVQLTFSAGESTTTVS
  PFVPGGVSDGQWHTVQLKYYNKPLLGQTGLPQGPSEQKVAVVTVDGCDTGVALRFGSVLG
  NYSCAAQGTQGGSKKSLDLTGPLLLGGVPDLPESFPVRMRQFVGCMRNLQVDSRHIDMAD
  FIANNGTVPGCPAKKNVCDSNTCHNGGTCVNQWDAFSCECPLGFGGKSCAQEMANPQHFL
  GSSLVAWHGLSLPISQPWYLSLMFRTRQADGVLLQAITRGRSTITLQLREGHVMLSVEGT
  GLQASSLRLEPGRANDGDWHHAQLALGASGGPGHAILSFDYGQQRAEGNLGPRLHGLHLS
  NITVGGIPGPAGGVARGFRGCLQGVRVSDTPEGVNSLDPSHGESINVEQGCSLPDPCDSN
  PCPANSYCSNDWDSYSCSCDPGYYGDNCTNVCDLNPCEHQSVCTRKPSAPHGYTCECPPN
  YLGPYCETRIDQPCPRGWWGHPTCGPCNCDVSKGFDPDCNKTSGECHCKENHYRPPGSPT
  CLLCDCYPTGSLSRVCDPEDGQCPCKPGVIGRQCDRCDNPFAEVTTNGCEVNYDSCPRAI
  EAGIWWPRTRFGLPAAAPCPKGSFGTAVRHCDEHRGWLPPNLFNCTSITFSELKGFAERL
  QRNESGLDSGRSQQLALLLRNATQHTAGYFGSDVKVAYQLATRLLAHESTQRGFGLSATQ
  DVHFTENLLRVGSALLDTANKRHWELIQQTEGGTAWLLQHYEAYASALAQNMRHTYLSPF
  TIVTPNIVISVVRLDKGNFAGAKLPRYEALRGEQPPDLETTVILPESVFRETPPVVRPAG
  PGEAQEPEELARRQRRHPELSQGEAVASVIIYRTLAGLLPHNYDPDKRSLRVPKRPIINT
  PVVSISVHDDEELLPRALDKPVTVQFRLLETEERTKPICVFWNHSILVSGTGGWSARGCE
  VVFRNESHVSCQCNHMTSFAVLMDVSRRENGEILPLKTLTYVALGVTLAALLLTFFFLTL
  LRILRSNQHGIRRNLTAALGLAQLVFLLGINQADLPFACTVIAILLHFLYLCTFSWALLE
  ALHLYRALTEVRDVNTGPMRFYYMLGWGVPAFITGLAVGLDPEGYGNPDFCWLSIYDTLI
  WSFAGPVAFAVSMSVFLYILAARASCAAQRQGFEKKGPVSGLQPSFAVLLLLSATWLLAL
  LSVNSDTLLFHYLFATCNCIQGPFIFLSYVVLSKEVRKALKLACSRKPSPDPALTTKSTL
  TSSYNCPSPYADGRLYQPYGDSAGSLHSTSRSGKSQPSYIPFLLREESALNPGQGPPGLG
  DPGSLFLEGQDQQHDPDTDSDSDLSLEDDQSGSYASTHSSDSEEEEEEEEEEAAFPGEQG
  WDSLLGPGAERLPLHSTPKDGGPGPGKAPWPGDFGTTAKESSGNGAPEERLRENGDALSR
  EGSLGPLPGSSAQPHKGILKKKCLPTISEKSSLLRLPLEQCTGSSRGSSASEGSRGGPPP
  RPPPRQSLQEQLNGVMPIAMSIKAGTVDEDSSGSEFLFFNFLH
• Function: Receptor that may have an important role in cell/cell signaling during nervous system formation.
• Tissue Specificity: Highest expression in brain and testis.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Pneumocystis pneumonia	DISFSOM3	Definitive	Genetic Variation	[2]
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[4]
Atypical endometrial hyperplasia	DIS2POYG	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Cardiac failure	DISDC067	Strong	Genetic Variation	[4]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Carotid artery disease	DISLRVLT	Strong	Genetic Variation	[7]
Coronary atherosclerosis	DISKNDYU	Strong	Altered Expression	[8]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[9]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[10]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[11]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[12]
Stroke	DISX6UHX	Strong	Genetic Variation	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[4]
Myocardial infarction	DIS655KI	moderate	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2) affects the response to substance of Cisplatin.	[27]

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 Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[24]

10 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 Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2).	[26]

References

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• [2] Genetic analysis of Wnt/PCP genes in neural tube defects.BMC Med Genomics. 2018 Apr 4;11(1):38. doi: 10.1186/s12920-018-0355-9.
• [3] Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib.PLoS One. 2017 Jul 28;12(7):e0182115. doi: 10.1371/journal.pone.0182115. eCollection 2017.
• [4] Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.Front Genet. 2016 Oct 13;7:179. doi: 10.3389/fgene.2016.00179. eCollection 2016.
• [5] Hormonally active doses of isoflavone aglycones promote mammary and endometrial carcinogenesis and alter the molecular tumor environment in Donryu rats.Toxicol Sci. 2012 Mar;126(1):39-51. doi: 10.1093/toxsci/kfs016. Epub 2012 Jan 16.
• [6] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [7] Analysis of recently identified dyslipidemia alleles reveals two loci that contribute to risk for carotid artery disease.Lipids Health Dis. 2009 Dec 1;8:52. doi: 10.1186/1476-511X-8-52.
• [8] CELSR2-PSRC1-SORT1 gene expression and association with coronary artery disease and plasma lipid levels in an Asian Indian cohort.J Cardiol. 2014 Nov;64(5):339-46. doi: 10.1016/j.jjcc.2014.02.012. Epub 2014 Mar 24.
• [9] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [10] Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries.Clin Chem. 2015 Jan;61(1):231-8. doi: 10.1373/clinchem.2014.231365. Epub 2014 Nov 20.
• [11] Congenital hydrocephalus in genetically engineered mice.Vet Pathol. 2012 Jan;49(1):166-81. doi: 10.1177/0300985811415708. Epub 2011 Jul 11.
• [12] Genome-wide association study of peripheral artery disease in the Million Veteran Program.Nat Med. 2019 Aug;25(8):1274-1279. doi: 10.1038/s41591-019-0492-5. Epub 2019 Jul 8.
• [13] A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.Nat Genet. 2015 Oct;47(10):1121-1130. doi: 10.1038/ng.3396. Epub 2015 Sep 7.
• [14] 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.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [16] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [17] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [20] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [21] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [22] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [23] 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.
• [24] 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.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [27] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.