Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM7PSUR)

• DOT Name: Low-density lipoprotein receptor-related protein 6 (LRP6)
• Synonyms: LRP-6
• Gene Name: LRP6
• Related Disease:
  Tooth agenesis
  Tooth agenesis, selective, 7
  Coronary artery disease, autosomal dominant 2
• UniProt ID: LRP6_HUMAN
• PDB ID: 3S2K; 3S8V; 3S8Z; 3S94; 3SOB; 3SOQ; 3SOV; 4A0P; 4DG6; 4NM5; 4NM7; 5AIR; 5FWW; 5GJE; 6H15; 6H16; 6L6R; 7NAM; 8CTG; 8DVL; 8DVM; 8DVN; 8FFE
• Pfam ID: PF14670 ; PF00057 ; PF00058
• Sequence:
  MGAVLRSLLACSFCVLLRAAPLLLYANRRDLRLVDATNGKENATIVVGGLEDAAAVDFVF
  SHGLIYWSDVSEEAIKRTEFNKTESVQNVVVSGLLSPDGLACDWLGEKLYWTDSETNRIE
  VSNLDGSLRKVLFWQELDQPRAIALDPSSGFMYWTDWGEVPKIERAGMDGSSRFIIINSE
  IYWPNGLTLDYEEQKLYWADAKLNFIHKSNLDGTNRQAVVKGSLPHPFALTLFEDILYWT
  DWSTHSILACNKYTGEGLREIHSDIFSPMDIHAFSQQRQPNATNPCGIDNGGCSHLCLMS
  PVKPFYQCACPTGVKLLENGKTCKDGATELLLLARRTDLRRISLDTPDFTDIVLQLEDIR
  HAIAIDYDPVEGYIYWTDDEVRAIRRSFIDGSGSQFVVTAQIAHPDGIAVDWVARNLYWT
  DTGTDRIEVTRLNGTMRKILISEDLEEPRAIVLDPMVGYMYWTDWGEIPKIERAALDGSD
  RVVLVNTSLGWPNGLALDYDEGKIYWGDAKTDKIEVMNTDGTGRRVLVEDKIPHIFGFTL
  LGDYVYWTDWQRRSIERVHKRSAEREVIIDQLPDLMGLKATNVHRVIGSNPCAEENGGCS
  HLCLYRPQGLRCACPIGFELISDMKTCIVPEAFLLFSRRADIRRISLETNNNNVAIPLTG
  VKEASALDFDVTDNRIYWTDISLKTISRAFMNGSALEHVVEFGLDYPEGMAVDWLGKNLY
  WADTGTNRIEVSKLDGQHRQVLVWKDLDSPRALALDPAEGFMYWTEWGGKPKIDRAAMDG
  SERTTLVPNVGRANGLTIDYAKRRLYWTDLDTNLIESSNMLGLNREVIADDLPHPFGLTQ
  YQDYIYWTDWSRRSIERANKTSGQNRTIIQGHLDYVMDILVFHSSRQSGWNECASSNGHC
  SHLCLAVPVGGFVCGCPAHYSLNADNRTCSAPTTFLLFSQKSAINRMVIDEQQSPDIILP
  IHSLRNVRAIDYDPLDKQLYWIDSRQNMIRKAQEDGSQGFTVVVSSVPSQNLEIQPYDLS
  IDIYSRYIYWTCEATNVINVTRLDGRSVGVVLKGEQDRPRAVVVNPEKGYMYFTNLQERS
  PKIERAALDGTEREVLFFSGLSKPIALALDSRLGKLFWADSDLRRIESSDLSGANRIVLE
  DSNILQPVGLTVFENWLYWIDKQQQMIEKIDMTGREGRTKVQARIAQLSDIHAVKELNLQ
  EYRQHPCAQDNGGCSHICLVKGDGTTRCSCPMHLVLLQDELSCGEPPTCSPQQFTCFTGE
  IDCIPVAWRCDGFTECEDHSDELNCPVCSESQFQCASGQCIDGALRCNGDANCQDKSDEK
  NCEVLCLIDQFRCANGQCIGKHKKCDHNVDCSDKSDELDCYPTEEPAPQATNTVGSVIGV
  IVTIFVSGTVYFICQRMLCPRMKGDGETMTNDYVVHGPASVPLGYVPHPSSLSGSLPGMS
  RGKSMISSLSIMGGSSGPPYDRAHVTGASSSSSSSTKGTYFPAILNPPPSPATERSHYTM
  EFGYSSNSPSTHRSYSYRPYSYRHFAPPTTPCSTDVCDSDYAPSRRMTSVATAKGYTSDL
  NYDSEPVPPPPTPRSQYLSAEENYESCPPSPYTERSYSHHLYPPPPSPCTDSS
• Function: Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes. Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in bone formation. The Wnt-induced Fzd/LRP6 coreceptor complex recruits DVL1 polymers to the plasma membrane which, in turn, recruits the AXIN1/GSK3B-complex to the cell surface promoting the formation of signalosomes and inhibiting AXIN1/GSK3-mediated phosphorylation and destruction of beta-catenin. Required for posterior patterning of the epiblast during gastrulation.
• Tissue Specificity: Widely coexpressed with LRP5 during embryogenesis and in adult tissues.
• KEGG Pathway:
  mTOR sig.ling pathway (hsa04150)
  Wnt sig.ling pathway (hsa04310)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Pathways in cancer (hsa05200)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Negative regulation of TCF-dependent signaling by WNT ligand antagonists (R-HSA-3772470)
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  Regulation of FZD by ubiquitination (R-HSA-4641263)
  Signaling by RNF43 mutants (R-HSA-5340588)
  TCF dependent signaling in response to WNT (R-HSA-201681)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tooth agenesis	DIS1PWC7	Definitive	Autosomal dominant	[1]
Tooth agenesis, selective, 7	DISAT156	Strong	Autosomal dominant	[1]
Coronary artery disease, autosomal dominant 2	DISFH29B	Limited	Unknown	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Low-density lipoprotein receptor-related protein 6 (LRP6) decreases the response to substance of Ethanol.	[18]

2 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 Low-density lipoprotein receptor-related protein 6 (LRP6).	[3]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Low-density lipoprotein receptor-related protein 6 (LRP6).	[11]

15 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 Low-density lipoprotein receptor-related protein 6 (LRP6).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[7]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[14]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[15]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[16]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Low-density lipoprotein receptor-related protein 6 (LRP6).	[17]

References

• [1] Loss-of-Function Mutations in the WNT Co-receptor LRP6 Cause Autosomal-Dominant Oligodontia. Am J Hum Genet. 2015 Oct 1;97(4):621-6. doi: 10.1016/j.ajhg.2015.08.014. Epub 2015 Sep 17.
• [2] LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science. 2007 Mar 2;315(5816):1278-82. doi: 10.1126/science.1136370.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [13] Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet. 2012 Sep 15;21(18):4104-14. doi: 10.1093/hmg/dds239. Epub 2012 Jun 20.
• [14] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [15] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [16] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [17] Lithium chloride regulates the proliferation of stem-like cells in retinoblastoma cell lines: a potential role for the canonical Wnt signaling pathway. Mol Vis. 2010 Jan 13;16:36-45.
• [18] The LRP6 functional mutation rs2302685 contributes to individual susceptibility to alcoholic liver injury related to the Wnt/-catenin-TCF1-CYP2E1 signaling pathway. Arch Toxicol. 2019 Jun;93(6):1679-1695. doi: 10.1007/s00204-019-02447-0. Epub 2019 Apr 11.