Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ6W681)

• DOT Name: Low-density lipoprotein receptor-related protein 2 (LRP2)
• Synonyms: LRP-2; Glycoprotein 330; gp330; Megalin
• Gene Name: LRP2
• Related Disease:
  Donnai-Barrow syndrome
  Stickler syndrome
  Intellectual disability, autosomal dominant 40
• UniProt ID: LRP2_HUMAN
• PDB ID: 2M0P
• Pfam ID: PF12662 ; PF07645 ; PF14670 ; PF00057 ; PF00058
• Sequence:
  MDRGPAAVACTLLLALVACLAPASGQECDSAHFRCGSGHCIPADWRCDGTKDCSDDADEI
  GCAVVTCQQGYFKCQSEGQCIPNSWVCDQDQDCDDGSDERQDCSQSTCSSHQITCSNGQC
  IPSEYRCDHVRDCPDGADENDCQYPTCEQLTCDNGACYNTSQKCDWKVDCRDSSDEINCT
  EICLHNEFSCGNGECIPRAYVCDHDNDCQDGSDEHACNYPTCGGYQFTCPSGRCIYQNWV
  CDGEDDCKDNGDEDGCESGPHDVHKCSPREWSCPESGRCISIYKVCDGILDCPGREDENN
  TSTGKYCSMTLCSALNCQYQCHETPYGGACFCPPGYIINHNDSRTCVEFDDCQIWGICDQ
  KCESRPGRHLCHCEEGYILERGQYCKANDSFGEASIIFSNGRDLLIGDIHGRSFRILVES
  QNRGVAVGVAFHYHLQRVFWTDTVQNKVFSVDINGLNIQEVLNVSVETPENLAVDWVNNK
  IYLVETKVNRIDMVNLDGSYRVTLITENLGHPRGIAVDPTVGYLFFSDWESLSGEPKLER
  AFMDGSNRKDLVKTKLGWPAGVTLDMISKRVYWVDSRFDYIETVTYDGIQRKTVVHGGSL
  IPHPFGVSLFEGQVFFTDWTKMAVLKANKFTETNPQVYYQASLRPYGVTVYHSLRQPYAT
  NPCKDNNGGCEQVCVLSHRTDNDGLGFRCKCTFGFQLDTDERHCIAVQNFLIFSSQVAIR
  GIPFTLSTQEDVMVPVSGNPSFFVGIDFDAQDSTIFFSDMSKHMIFKQKIDGTGREILAA
  NRVENVESLAFDWISKNLYWTDSHYKSISVMRLADKTRRTVVQYLNNPRSVVVHPFAGYL
  FFTDWFRPAKIMRAWSDGSHLLPVINTTLGWPNGLAIDWAASRLYWVDAYFDKIEHSTFD
  GLDRRRLGHIEQMTHPFGLAIFGEHLFFTDWRLGAIIRVRKADGGEMTVIRSGIAYILHL
  KSYDVNIQTGSNACNQPTHPNGDCSHFCFPVPNFQRVCGCPYGMRLASNHLTCEGDPTNE
  PPTEQCGLFSFPCKNGRCVPNYYLCDGVDDCHDNSDEQLCGTLNNTCSSSAFTCGHGECI
  PAHWRCDKRNDCVDGSDEHNCPTHAPASCLDTQYTCDNHQCISKNWVCDTDNDCGDGSDE
  KNCNSTETCQPSQFNCPNHRCIDLSFVCDGDKDCVDGSDEVGCVLNCTASQFKCASGDKC
  IGVTNRCDGVFDCSDNSDEAGCPTRPPGMCHSDEFQCQEDGICIPNFWECDGHPDCLYGS
  DEHNACVPKTCPSSYFHCDNGNCIHRAWLCDRDNDCGDMSDEKDCPTQPFRCPSWQWQCL
  GHNICVNLSVVCDGIFDCPNGTDESPLCNGNSCSDFNGGCTHECVQEPFGAKCLCPLGFL
  LANDSKTCEDIDECDILGSCSQHCYNMRGSFRCSCDTGYMLESDGRTCKVTASESLLLLV
  ASQNKIIADSVTSQVHNIYSLVENGSYIVAVDFDSISGRIFWSDATQGKTWSAFQNGTDR
  RVVFDSSIILTETIAIDWVGRNLYWTDYALETIEVSKIDGSHRTVLISKNLTNPRGLALD
  PRMNEHLLFWSDWGHHPRIERASMDGSMRTVIVQDKIFWPCGLTIDYPNRLLYFMDSYLD
  YMDFCDYNGHHRRQVIASDLIIRHPYALTLFEDSVYWTDRATRRVMRANKWHGGNQSVVM
  YNIQWPLGIVAVHPSKQPNSVNPCAFSRCSHLCLLSSQGPHFYSCVCPSGWSLSPDLLNC
  LRDDQPFLITVRQHIIFGISLNPEVKSNDAMVPIAGIQNGLDVEFDDAEQYIYWVENPGE
  IHRVKTDGTNRTVFASISMVGPSMNLALDWISRNLYSTNPRTQSIEVLTLHGDIRYRKTL
  IANDGTALGVGFPIGITVDPARGKLYWSDQGTDSGVPAKIASANMDGTSVKTLFTGNLEH
  LECVTLDIEEQKLYWAVTGRGVIERGNVDGTDRMILVHQLSHPWGIAVHDSFLYYTDEQY
  EVIERVDKATGANKIVLRDNVPNLRGLQVYHRRNAAESSNGCSNNMNACQQICLPVPGGL
  FSCACATGFKLNPDNRSCSPYNSFIVVSMLSAIRGFSLELSDHSETMVPVAGQGRNALHV
  DVDVSSGFIYWCDFSSSVASDNAIRRIKPDGSSLMNIVTHGIGENGVRGIAVDWVAGNLY
  FTNAFVSETLIEVLRINTTYRRVLLKVTVDMPRHIVVDPKNRYLFWADYGQRPKIERSFL
  DCTNRTVLVSEGIVTPRGLAVDRSDGYVYWVDDSLDIIARIRINGENSEVIRYGSRYPTP
  YGITVFENSIIWVDRNLKKIFQASKEPENTEPPTVIRDNINWLRDVTIFDKQVQPRSPAE
  VNNNPCLENNGGCSHLCFALPGLHTPKCDCAFGTLQSDGKNCAISTENFLIFALSNSLRS
  LHLDPENHSPPFQTINVERTVMSLDYDSVSDRIYFTQNLASGVGQISYATLSSGIHTPTV
  IASGIGTADGIAFDWITRRIYYSDYLNQMINSMAEDGSNRTVIARVPKPRAIVLDPCQGY
  LYWADWDTHAKIERATLGGNFRVPIVNSSLVMPSGLTLDYEEDLLYWVDASLQRIERSTL
  TGVDREVIVNAAVHAFGLTLYGQYIYWTDLYTQRIYRANKYDGSGQIAMTTNLLSQPRGI
  NTVVKNQKQQCNNPCEQFNGGCSHICAPGPNGAECQCPHEGNWYLANNRKHCIVDNGERC
  GASSFTCSNGRCISEEWKCDNDNDCGDGSDEMESVCALHTCSPTAFTCANGRCVQYSYRC
  DYYNDCGDGSDEAGCLFRDCNATTEFMCNNRRCIPREFICNGVDNCHDNNTSDEKNCPDR
  TCQSGYTKCHNSNICIPRVYLCDGDNDCGDNSDENPTYCTTHTCSSSEFQCASGRCIPQH
  WYCDQETDCFDASDEPASCGHSERTCLADEFKCDGGRCIPSEWICDGDNDCGDMSDEDKR
  HQCQNQNCSDSEFLCVNDRPPDRRCIPQSWVCDGDVDCTDGYDENQNCTRRTCSENEFTC
  GYGLCIPKIFRCDRHNDCGDYSDERGCLYQTCQQNQFTCQNGRCISKTFVCDEDNDCGDG
  SDELMHLCHTPEPTCPPHEFKCDNGRCIEMMKLCNHLDDCLDNSDEKGCGINECHDPSIS
  GCDHNCTDTLTSFYCSCRPGYKLMSDKRTCVDIDECTEMPFVCSQKCENVIGSYICKCAP
  GYLREPDGKTCRQNSNIEPYLIFSNRYYLRNLTIDGYFYSLILEGLDNVVALDFDRVEKR
  LYWIDTQRQVIERMFLNKTNKETIINHRLPAAESLAVDWVSRKLYWLDARLDGLFVSDLN
  GGHRRMLAQHCVDANNTFCFDNPRGLALHPQYGYLYWADWGHRAYIGRVGMDGTNKSVII
  STKLEWPNGITIDYTNDLLYWADAHLGYIEYSDLEGHHRHTVYDGALPHPFAITIFEDTI
  YWTDWNTRTVEKGNKYDGSNRQTLVNTTHRPFDIHVYHPYRQPIVSNPCGTNNGGCSHLC
  LIKPGGKGFTCECPDDFRTLQLSGSTYCMPMCSSTQFLCANNEKCIPIWWKCDGQKDCSD
  GSDELALCPQRFCRLGQFQCSDGNCTSPQTLCNAHQNCPDGSDEDRLLCENHHCDSNEWQ
  CANKRCIPESWQCDTFNDCEDNSDEDSSHCASRTCRPGQFRCANGRCIPQAWKCDVDNDC
  GDHSDEPIEECMSSAHLCDNFTEFSCKTNYRCIPKWAVCNGVDDCRDNSDEQGCEERTCH
  PVGDFRCKNHHCIPLRWQCDGQNDCGDNSDEENCAPRECTESEFRCVNQQCIPSRWICDH
  YNDCGDNSDERDCEMRTCHPEYFQCTSGHCVHSELKCDGSADCLDASDEADCPTRFPDGA
  YCQATMFECKNHVCIPPYWKCDGDDDCGDGSDEELHLCLDVPCNSPNRFRCDNNRCIYSH
  EVCNGVDDCGDGTDETEEHCRKPTPKPCTEYEYKCGNGHCIPHDNVCDDADDCGDWSDEL
  GCNKGKERTCAENICEQNCTQLNEGGFICSCTAGFETNVFDRTSCLDINECEQFGTCPQH
  CRNTKGSYECVCADGFTSMSDRPGKRCAAEGSSPLLLLPDNVRIRKYNLSSERFSEYLQD
  EEYIQAVDYDWDPKDIGLSVVYYTVRGEGSRFGAIKRAYIPNFESGRNNLVQEVDLKLKY
  VMQPDGIAVDWVGRHIYWSDVKNKRIEVAKLDGRYRKWLISTDLDQPAAIAVNPKLGLMF
  WTDWGKEPKIESAWMNGEDRNILVFEDLGWPTGLSIDYLNNDRIYWSDFKEDVIETIKYD
  GTDRRVIAKEAMNPYSLDIFEDQLYWISKEKGEVWKQNKFGQGKKEKTLVVNPWLTQVRI
  FHQLRYNKSVPNLCKQICSHLCLLRPGGYSCACPQGSSFIEGSTTECDAAIELPINLPPP
  CRCMHGGNCYFDETDLPKCKCPSGYTGKYCEMAFSKGISPGTTAVAVLLTILLIVVIGAL
  AIAGFFHYRRTGSLLPALPKLPSLSSLVKPSENGNGVTFRSGADLNMDIGVSGFGPETAI
  DRSMAMSEDFVMEMGKQPIIFENPMYSARDSAVKVVQPIQVTVSENVDNKNYGSPINPSE
  IVPETNPTSPAADGTQVTKWNLFKRKSKQTTNFENPIYAQMENEQKESVAATPPPSPSLP
  AKPKPPSRRDPTPTYSATEDTFKDTANLVKEDSEV
• Function: Multiligand endocytic receptor. Acts together with CUBN to mediate endocytosis of high-density lipoproteins. Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B. In the kidney, mediates the tubular uptake and clearance of leptin. Also mediates transport of leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium. Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight. Mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells. Mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP. Mediates renal uptake of metallothionein-bound heavy metals. Together with CUBN, mediates renal reabsorption of myoglobin. Mediates renal uptake and subsequent lysosomal degradation of APOM. Plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1. Mediates renal uptake of the antiapoptotic protein BIRC5/survivin which may be important for functional integrity of the kidney. Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1. Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH. Also mediates ShhN transcytosis. In the embryonic neuroepithelium, mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube and plays a role in patterning of the ventral telencephalon. Required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH. During neurulation, required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1 which is necessary for neural tube closure. In the adult brain, negatively regulates BMP signaling in the subependymal zone which enables neurogenesis to proceed. In astrocytes, mediates endocytosis of ALB which is required for the synthesis of the neurotrophic factor oleic acid. Involved in neurite branching. During optic nerve development, required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells. Mediates endocytic uptake and clearance of SHH in the retinal margin which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent. Plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG. Mediates endocytosis of angiotensin-2. Also mediates endocytosis of angiotensis 1-7. Binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation. Required for embryonic heart development. Required for normal hearing, possibly through interaction with estrogen in the inner ear.
• Tissue Specificity: Expressed in first and third trimester cytotrophoblasts in the placenta (at protein level) . Absorptive epithelia, including renal proximal tubules.
• KEGG Pathway:
  Hedgehog sig.ling pathway (hsa04340)
  Thyroid hormone synthesis (hsa04918)
  Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Retinoid metabolism and transport (R-HSA-975634)
  Transport of RCbl within the body (R-HSA-9758890)
  Vitamin D (calciferol) metabolism (R-HSA-196791)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Donnai-Barrow syndrome	DISG7BES	Definitive	Autosomal recessive	[1]
Stickler syndrome	DISQWFHN	Moderate	Autosomal dominant	[2]
Intellectual disability, autosomal dominant 40	DISAI0IH	Limited	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Low-density lipoprotein receptor-related protein 2 (LRP2) increases the Ototoxicity ADR of Cisplatin.	[17]

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 2 (LRP2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Low-density lipoprotein receptor-related protein 2 (LRP2).	[14]

14 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 2 (LRP2).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[7]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[11]
Methimazole	DM25FL8	Approved	Methimazole increases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[12]
Propylthiouracil	DM6D7N8	Approved	Propylthiouracil decreases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Low-density lipoprotein receptor-related protein 2 (LRP2).	[16]

References

• [1] A 56-year-old female patient with facio-oculo-acoustico-renal syndrome (FOAR) syndrome. Report on the natural history and of a novel mutation. Eur J Med Genet. 2009 Sep-Oct;52(5):341-3. doi: 10.1016/j.ejmg.2009.06.005. Epub 2009 Jul 3.
• [2] Broadening the phenotype of LRP2 mutations: a new mutation in LRP2 causes a predominantly ocular phenotype suggestive of Stickler syndrome. Clin Genet. 2014 Sep;86(3):282-6. doi: 10.1111/cge.12265. Epub 2013 Sep 23.
• [3] Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Nov 15;367(20):1921-9. doi: 10.1056/NEJMoa1206524. Epub 2012 Oct 3.
• [4] 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.
• [5] 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.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [12] Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways. Toxicol Appl Pharmacol. 2012 Apr 1;260(1):81-8. doi: 10.1016/j.taap.2012.01.029. Epub 2012 Feb 8.
• [13] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [14] 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.
• [15] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [17] Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin. Pharmacogenomics J. 2008 Feb;8(1):23-8. doi: 10.1038/sj.tpj.6500455. Epub 2007 Apr 24.