Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCC4JPH)

• DOT Name: Low-density lipoprotein receptor-related protein 5 (LRP5)
• Synonyms: LRP-5; Low-density lipoprotein receptor-related protein 7; LRP-7
• Gene Name: LRP5
• Related Disease:
  Autosomal dominant osteopetrosis 1
  Autosomal dominant osteosclerosis, Worth type
  Exudative vitreoretinopathy 4
  Inherited retinal dystrophy
  Obsolete bone mineral density quantitative trait locus 1
  Osteoporosis-pseudoglioma syndrome
  Polycystic liver disease 4 with or without kidney cysts
  Exudative vitreoretinopathy
  Hyperostosis corticalis generalisata
  Osteosclerosis-developmental delay-craniosynostosis syndrome
  Polycystic liver disease 1
• UniProt ID: LRP5_HUMAN
• Pfam ID: PF14670 ; PF00057 ; PF00058
• Sequence:
  MEAAPPGPPWPLLLLLLLLLALCGCPAPAAASPLLLFANRRDVRLVDAGGVKLESTIVVS
  GLEDAAAVDFQFSKGAVYWTDVSEEAIKQTYLNQTGAAVQNVVISGLVSPDGLACDWVGK
  KLYWTDSETNRIEVANLNGTSRKVLFWQDLDQPRAIALDPAHGYMYWTDWGETPRIERAG
  MDGSTRKIIVDSDIYWPNGLTIDLEEQKLYWADAKLSFIHRANLDGSFRQKVVEGSLTHP
  FALTLSGDTLYWTDWQTRSIHACNKRTGGKRKEILSALYSPMDIQVLSQERQPFFHTRCE
  EDNGGCSHLCLLSPSEPFYTCACPTGVQLQDNGRTCKAGAEEVLLLARRTDLRRISLDTP
  DFTDIVLQVDDIRHAIAIDYDPLEGYVYWTDDEVRAIRRAYLDGSGAQTLVNTEINDPDG
  IAVDWVARNLYWTDTGTDRIEVTRLNGTSRKILVSEDLDEPRAIALHPVMGLMYWTDWGE
  NPKIECANLDGQERRVLVNASLGWPNGLALDLQEGKLYWGDAKTDKIEVINVDGTKRRTL
  LEDKLPHIFGFTLLGDFIYWTDWQRRSIERVHKVKASRDVIIDQLPDLMGLKAVNVAKVV
  GTNPCADRNGGCSHLCFFTPHATRCGCPIGLELLSDMKTCIVPEAFLVFTSRAAIHRISL
  ETNNNDVAIPLTGVKEASALDFDVSNNHIYWTDVSLKTISRAFMNGSSVEHVVEFGLDYP
  EGMAVDWMGKNLYWADTGTNRIEVARLDGQFRQVLVWRDLDNPRSLALDPTKGYIYWTEW
  GGKPRIVRAFMDGTNCMTLVDKVGRANDLTIDYADQRLYWTDLDTNMIESSNMLGQERVV
  IADDLPHPFGLTQYSDYIYWTDWNLHSIERADKTSGRNRTLIQGHLDFVMDILVFHSSRQ
  DGLNDCMHNNGQCGQLCLAIPGGHRCGCASHYTLDPSSRNCSPPTTFLLFSQKSAISRMI
  PDDQHSPDLILPLHGLRNVKAIDYDPLDKFIYWVDGRQNIKRAKDDGTQPFVLTSLSQGQ
  NPDRQPHDLSIDIYSRTLFWTCEATNTINVHRLSGEAMGVVLRGDRDKPRAIVVNAERGY
  LYFTNMQDRAAKIERAALDGTEREVLFTTGLIRPVALVVDNTLGKLFWVDADLKRIESCD
  LSGANRLTLEDANIVQPLGLTILGKHLYWIDRQQQMIERVEKTTGDKRTRIQGRVAHLTG
  IHAVEEVSLEEFSAHPCARDNGGCSHICIAKGDGTPRCSCPVHLVLLQNLLTCGEPPTCS
  PDQFACATGEIDCIPGAWRCDGFPECDDQSDEEGCPVCSAAQFPCARGQCVDLRLRCDGE
  ADCQDRSDEADCDAICLPNQFRCASGQCVLIKQQCDSFPDCIDGSDELMCEITKPPSDDS
  PAHSSAIGPVIGIILSLFVMGGVYFVCQRVVCQRYAGANGPFPHEYVSGTPHVPLNFIAP
  GGSQHGPFTGIACGKSMMSSVSLMGGRGGVPLYDRNHVTGASSSSSSSTKATLYPPILNP
  PPSPATDPSLYNMDMFYSSNIPATARPYRPYIIRGMAPPTTPCSTDVCDSDYSASRWKAS
  KYYLDLNSDSDPYPPPPTPHSQYLSAEDSCPPSPATERSYFHLFPPPPSPCTDSS
• Function: Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins. Activates the canonical Wnt signaling pathway that controls cell fate determination and self-renewal during embryonic development and adult tissue regeneration. In particular, may play an important role in the development of the posterior patterning of the epiblast during gastrulation. During bone development, regulates osteoblast proliferation and differentiation thus determining bone mass. Mechanistically, the formation of the signaling complex between Wnt ligand, frizzled receptor and LRP5 coreceptor promotes the recruitment of AXIN1 to LRP5, stabilizing beta-catenin/CTNNB1 and activating TCF/LEF-mediated transcriptional programs. Acts as a coreceptor for non-Wnt proteins, such as norrin/NDP. Binding of norrin/NDP to frizzled 4/FZD4-LRP5 receptor complex triggers beta-catenin/CTNNB1-dependent signaling known to be required for retinal vascular development. Plays a role in controlling postnatal vascular regression in retina via macrophage-induced endothelial cell apoptosis.
• Tissue Specificity: Widely expressed, with the highest level of expression in the liver and in aorta.
• 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 LRP5 mutants (R-HSA-5339717)
  Signaling by RNF43 mutants (R-HSA-5340588)
  TCF dependent signaling in response to WNT (R-HSA-201681)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant osteopetrosis 1	DISH0G7D	Definitive	Autosomal dominant	[1]
Autosomal dominant osteosclerosis, Worth type	DIS81RQ9	Definitive	Autosomal dominant	[1]
Exudative vitreoretinopathy 4	DISHQ6Q1	Definitive	Semidominant	[2]
Inherited retinal dystrophy	DISGGL77	Definitive	Autosomal recessive	[3]
Obsolete bone mineral density quantitative trait locus 1	DISFMF3D	Definitive	Autosomal dominant	[4]
Osteoporosis-pseudoglioma syndrome	DISIXWT1	Definitive	Autosomal recessive	[5]
Polycystic liver disease 4 with or without kidney cysts	DISROVPU	Strong	Autosomal dominant	[6]
Exudative vitreoretinopathy	DISWN0TG	Supportive	Autosomal dominant	[7]
Hyperostosis corticalis generalisata	DISR4BHB	Supportive	Autosomal dominant	[1]
Osteosclerosis-developmental delay-craniosynostosis syndrome	DISCI6JU	Supportive	Autosomal dominant	[8]
Polycystic liver disease 1	DIS52T2A	Supportive	Autosomal dominant	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Formaldehyde	DM7Q6M0	Investigative	Low-density lipoprotein receptor-related protein 5 (LRP5) affects the response to substance of Formaldehyde.	[23]

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 Low-density lipoprotein receptor-related protein 5 (LRP5).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Low-density lipoprotein receptor-related protein 5 (LRP5).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Low-density lipoprotein receptor-related protein 5 (LRP5).	[22]

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 Low-density lipoprotein receptor-related protein 5 (LRP5).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Low-density lipoprotein receptor-related protein 5 (LRP5).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Low-density lipoprotein receptor-related protein 5 (LRP5).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Low-density lipoprotein receptor-related protein 5 (LRP5).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Low-density lipoprotein receptor-related protein 5 (LRP5).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Low-density lipoprotein receptor-related protein 5 (LRP5).	[17]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Low-density lipoprotein receptor-related protein 5 (LRP5).	[18]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Low-density lipoprotein receptor-related protein 5 (LRP5).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Low-density lipoprotein receptor-related protein 5 (LRP5).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Low-density lipoprotein receptor-related protein 5 (LRP5).	[21]

References

• [1] Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003 Mar;72(3):763-71. doi: 10.1086/368277. Epub 2003 Feb 10.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density. J Hum Genet. 2004;49(2):80-86. doi: 10.1007/s10038-003-0111-6. Epub 2004 Jan 15.
• [5] LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001 Nov 16;107(4):513-23. doi: 10.1016/s0092-8674(01)00571-2.
• [6] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [7] Familial Exudative Vitreoretinopathy, Autosomal Dominant C RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2005 Mar 21 [updated 2011 Sep 22]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [8] An autosomal dominant high bone mass phenotype in association with craniosynostosis in an extended family is caused by an LRP5 missense mutation. J Bone Miner Res. 2005 Jul;20(7):1254-60. doi: 10.1359/JBMR.050303. Epub 2005 Mar 7.
• [9] Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis. Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5343-8. doi: 10.1073/pnas.1309438111. Epub 2014 Mar 24.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] 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.
• [18] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [19] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [20] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [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] Identification of Genes That Modulate Susceptibility to Formaldehyde and Imatinib by Functional Genomic Screening in Human Haploid KBM7 Cells. Toxicol Sci. 2016 May;151(1):10-22. doi: 10.1093/toxsci/kfw032. Epub 2016 Mar 22.