Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7PS8O1)

• DOT Name: Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1)
• Synonyms: Cadherin family member 9; Flamingo homolog 2; hFmi2
• Gene Name: CELSR1
• Related Disease:
  Anencephaly
  Cardiac failure
  Hepatocellular carcinoma
  Lymphatic malformation 1
  Lymphatic malformation 9
  Neural tube defect
  Non-insulin dependent diabetes
  Pneumocystis pneumonia
  Prostate cancer
  Chronic obstructive pulmonary disease
  Isolated congenital microcephaly
  Neural tube defects, susceptibility to
  Stroke
  Digestive system neoplasm
  Ductal breast carcinoma in situ
• UniProt ID: CELR1_HUMAN
• PDB ID: 7SZ8; 8D40
• Pfam ID: PF00002 ; PF00028 ; PF00008 ; PF16489 ; PF01825 ; PF02793 ; PF00053 ; PF02210
• Sequence:
  MAPPPPPVLPVLLLLAAAAALPAMGLRAAAWEPRVPGGTRAFALRPGCTYAVGAACTPRA
  PRELLDVGRDGRLAGRRRVSGAGRPLPLQVRLVARSAPTALSRRLRARTHLPGCGARARL
  CGTGARLCGALCFPVPGGCAAAQHSALAAPTTLPACRCPPRPRPRCPGRPICLPPGGSVR
  LRLLCALRRAAGAVRVGLALEAATAGTPSASPSPSPPLPPNLPEARAGPARRARRGTSGR
  GSLKFPMPNYQVALFENEPAGTLILQLHAHYTIEGEEERVSYYMEGLFDERSRGYFRIDS
  ATGAVSTDSVLDRETKETHVLRVKAVDYSTPPRSATTYITVLVKDTNDHSPVFEQSEYRE
  RVRENLEVGYEVLTIRASDRDSPINANLRYRVLGGAWDVFQLNESSGVVSTRAVLDREEA
  AEYQLLVEANDQGRNPGPLSATATVYIEVEDENDNYPQFSEQNYVVQVPEDVGLNTAVLR
  VQATDRDQGQNAAIHYSILSGNVAGQFYLHSLSGILDVINPLDFEDVQKYSLSIKAQDGG
  RPPLINSSGVVSVQVLDVNDNEPIFVSSPFQATVLENVPLGYPVVHIQAVDADSGENARL
  HYRLVDTASTFLGGGSAGPKNPAPTPDFPFQIHNSSGWITVCAELDREEVEHYSFGVEAV
  DHGSPPMSSSTSVSITVLDVNDNDPVFTQPTYELRLNEDAAVGSSVLTLQARDRDANSVI
  TYQLTGGNTRNRFALSSQRGGGLITLALPLDYKQEQQYVLAVTASDGTRSHTAHVLINVT
  DANTHRPVFQSSHYTVSVSEDRPVGTSIATLSANDEDTGENARITYVIQDPVPQFRIDPD
  SGTMYTMMELDYENQVAYTLTIMAQDNGIPQKSDTTTLEILILDANDNAPQFLWDFYQGS
  IFEDAPPSTSILQVSATDRDSGPNGRLLYTFQGGDDGDGDFYIEPTSGVIRTQRRLDREN
  VAVYNLWALAVDRGSPTPLSASVEIQVTILDINDNAPMFEKDELELFVEENNPVGSVVAK
  IRANDPDEGPNAQIMYQIVEGDMRHFFQLDLLNGDLRAMVELDFEVRREYVLVVQATSAP
  LVSRATVHILLVDQNDNPPVLPDFQILFNNYVTNKSNSFPTGVIGCIPAHDPDVSDSLNY
  TFVQGNELRLLLLDPATGELQLSRDLDNNRPLEALMEVSVSDGIHSVTAFCTLRVTIITD
  DMLTNSITVRLENMSQEKFLSPLLALFVEGVAAVLSTTKDDVFVFNVQNDTDVSSNILNV
  TFSALLPGGVRGQFFPSEDLQEQIYLNRTLLTTISTQRVLPFDDNICLREPCENYMKCVS
  VLRFDSSAPFLSSTTVLFRPIHPINGLRCRCPPGFTGDYCETEIDLCYSDPCGANGRCRS
  REGGYTCECFEDFTGEHCEVDARSGRCANGVCKNGGTCVNLLIGGFHCVCPPGEYERPYC
  EVTTRSFPPQSFVTFRGLRQRFHFTISLTFATQERNGLLLYNGRFNEKHDFIALEIVDEQ
  VQLTFSAGETTTTVAPKVPSGVSDGRWHSVQVQYYNKPNIGHLGLPHGPSGEKMAVVTVD
  DCDTTMAVRFGKDIGNYSCAAQGTQTGSKKSLDLTGPLLLGGVPNLPEDFPVHNRQFVGC
  MRNLSVDGKNVDMAGFIANNGTREGCAARRNFCDGRRCQNGGTCVNRWNMYLCECPLRFG
  GKNCEQAMPHPQLFSGESVVSWSDLNIIISVPWYLGLMFRTRKEDSVLMEATSGGPTSFR
  LQILNNYLQFEVSHGPSDVESVMLSGLRVTDGEWHHLLIELKNVKEDSEMKHLVTMTLDY
  GMDQNKADIGGMLPGLTVRSVVVGGASEDKVSVRRGFRGCMQGVRMGGTPTNVATLNMNN
  ALKVRVKDGCDVDDPCTSSPCPPNSRCHDAWEDYSCVCDKGYLGINCVDACHLNPCENMG
  ACVRSPGSPQGYVCECGPSHYGPYCENKLDLPCPRGWWGNPVCGPCHCAVSKGFDPDCNK
  TNGQCQCKENYYKLLAQDTCLPCDCFPHGSHSRTCDMATGQCACKPGVIGRQCNRCDNPF
  AEVTTLGCEVIYNGCPKAFEAGIWWPQTKFGQPAAVPCPKGSVGNAVRHCSGEKGWLPPE
  LFNCTTISFVDLRAMNEKLSRNETQVDGARALQLVRALRSATQHTGTLFGNDVRTAYQLL
  GHVLQHESWQQGFDLAATQDADFHEDVIHSGSALLAPATRAAWEQIQRSEGGTAQLLRRL
  EGYFSNVARNVRRTYLRPFVIVTANMILAVDIFDKFNFTGARVPRFDTIHEEFPRELESS
  VSFPADFFRPPEEKEGPLLRPAGRRTTPQTTRPGPGTEREAPISRRRRHPDDAGQFAVAL
  VIIYRTLGQLLPERYDPDRRSLRLPHRPIINTPMVSTLVYSEGAPLPRPLERPVLVEFAL
  LEVEERTKPVCVFWNHSLAVGGTGGWSARGCELLSRNRTHVACQCSHTASFAVLMDISRR
  ENGEVLPLKIVTYAAVSLSLAALLVAFVLLSLVRMLRSNLHSIHKHLAVALFLSQLVFVI
  GINQTENPFLCTVVAILLHYIYMSTFAWTLVESLHVYRMLTEVRNIDTGPMRFYYVVGWG
  IPAIVTGLAVGLDPQGYGNPDFCWLSLQDTLIWSFAGPIGAVIIINTVTSVLSAKVSCQR
  KHHYYGKKGIVSLLRTAFLLLLLISATWLLGLLAVNRDALSFHYLFAIFSGLQGPFVLLF
  HCVLNQEVRKHLKGVLGGRKLHLEDSATTRATLLTRSLNCNTTFGDGPDMLRTDLGESTA
  SLDSIVRDEGIQKLGVSSGLVRGSHGEPDASLMPRSCKDPPGHDSDSDSELSLDEQSSSY
  ASSHSSDSEDDGVGAEEKWDPARGAVHSTPKGDAVANHVPAGWPDQSLAESDSEDPSGKP
  RLKVETKVSVELHREEQGSHRGEYPPDQESGGAARLASSQPPEQRKGILKNKVTYPPPLT
  LTEQTLKGRLREKLADCEQSPTSSRTSSLGSGGPDCAITVKSPGREPGRDHLNGVAMNVR
  TGSAQADGSDSEKP
• Function: Receptor that may have an important role in cell/cell signaling during nervous system formation.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anencephaly	DISIYW6T	Strong	Genetic Variation	[1]
Cardiac failure	DISDC067	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Lymphatic malformation 1	DIS857QZ	Strong	Biomarker	[4]
Lymphatic malformation 9	DIS0VF8U	Strong	Autosomal dominant	[5]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[7]
Pneumocystis pneumonia	DISFSOM3	Strong	Genetic Variation	[8]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[9]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[10]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[11]
Neural tube defects, susceptibility to	DISHA84K	Moderate	Autosomal dominant	[12]
Stroke	DISX6UHX	moderate	Genetic Variation	[13]
Digestive system neoplasm	DISPOJCT	Limited	Biomarker	[14]
Ductal breast carcinoma in situ	DISLCJY7	Limited	Biomarker	[15]

4 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 1 (CELSR1).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[22]

9 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 Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[26]
Manganese	DMKT129	Investigative	Manganese increases the expression of Cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1).	[27]

References

• [1] Digenic variants of planar cell polarity genes in human neural tube defect patients.Mol Genet Metab. 2018 May;124(1):94-100. doi: 10.1016/j.ymgme.2018.03.005. Epub 2018 Mar 18.
• [2] Genetics of heart rate in heart failure patients (GenHRate).Hum Genomics. 2019 May 21;13(1):22. doi: 10.1186/s40246-019-0206-6.
• [3] Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma.Int J Cancer. 2012 Mar 15;130(6):1319-28. doi: 10.1002/ijc.26136. Epub 2011 Jul 21.
• [4] Increasing evidence of hereditary lymphedema caused by CELSR1 loss-of-function variants.Am J Med Genet A. 2019 Sep;179(9):1718-1724. doi: 10.1002/ajmg.a.61269. Epub 2019 Jun 18.
• [5] A novel mutation in CELSR1 is associated with hereditary lymphedema. Vasc Cell. 2016 Feb 5;8:1. doi: 10.1186/s13221-016-0035-5. eCollection 2016.
• [6] 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.
• [7] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [8] Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice.Sci Rep. 2018 Feb 20;8(1):3325. doi: 10.1038/s41598-018-21718-x.
• [9] A genome-wide association study of prostate cancer in West African men.Hum Genet. 2014 May;133(5):509-21. doi: 10.1007/s00439-013-1387-z. Epub 2013 Nov 2.
• [10] Sex-Based Genetic Association Study Identifies CELSR1 as a Possible Chronic Obstructive Pulmonary Disease Risk Locus among Women.Am J Respir Cell Mol Biol. 2017 Mar;56(3):332-341. doi: 10.1165/rcmb.2016-0172OC.
• [11] Neural progenitor fate decision defects, cortical hypoplasia and behavioral impairment in Celsr1-deficient mice.Mol Psychiatry. 2018 Mar;23(3):723-734. doi: 10.1038/mp.2017.236. Epub 2017 Dec 19.
• [12] Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis. Hum Mutat. 2012 Feb;33(2):440-7. doi: 10.1002/humu.21662. Epub 2011 Dec 20.
• [13] Replication of the CELSR1 association with ischemic stroke in a Portuguese case-control cohort.Atherosclerosis. 2011 Jul;217(1):260-2. doi: 10.1016/j.atherosclerosis.2011.03.022. Epub 2011 Mar 29.
• [14] Comparative integromics on non-canonical WNT or planar cell polarity signaling molecules: transcriptional mechanism of PTK7 in colorectal cancer and that of SEMA6A in undifferentiated ES cells.Int J Mol Med. 2007 Sep;20(3):405-9.
• [15] Validation of an oligo-gene signature for the prognostic stratification of ductal carcinoma in situ (DCIS).Breast Cancer Res Treat. 2016 Jun;157(3):447-59. doi: 10.1007/s10549-016-3838-4. Epub 2016 Jun 1.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [21] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [22] 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.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] 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.
• [25] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [26] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [27] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.