Details of Drug Off-Target (DOT)

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

• DOT Name: Cation-independent mannose-6-phosphate receptor (IGF2R)
• Synonyms: CI Man-6-P receptor; CI-MPR; M6PR; 300 kDa mannose 6-phosphate receptor; MPR 300; Insulin-like growth factor 2 receptor; Insulin-like growth factor II receptor; IGF-II receptor; M6P/IGF2 receptor; M6P/IGF2R; CD antigen CD222
• Gene Name: IGF2R
• UniProt ID: MPRI_HUMAN
• PDB ID: 1E6F; 1GP0; 1GP3; 1GQB; 1JPL; 1JWG; 1LF8; 2CNJ; 2L29; 2L2A; 2M68; 2M6T; 2V5N; 2V5O; 2V5P; 5IEI; 6N5X; 6N5Y; 6P8I; 6V02; 6Z30; 6Z31; 6Z32; 8AFZ
• Pfam ID: PF00878 ; PF00040
• Sequence:
  MGAAAGRSPHLGPAPARRPQRSLLLLQLLLLVAAPGSTQAQAAPFPELCSYTWEAVDTKN
  NVLYKINICGSVDIVQCGPSSAVCMHDLKTRTYHSVGDSVLRSATRSLLEFNTTVSCDQQ
  GTNHRVQSSIAFLCGKTLGTPEFVTATECVHYFEWRTTAACKKDIFKANKEVPCYVFDEE
  LRKHDLNPLIKLSGAYLVDDSDPDTSLFINVCRDIDTLRDPGSQLRACPPGTAACLVRGH
  QAFDVGQPRDGLKLVRKDRLVLSYVREEAGKLDFCDGHSPAVTITFVCPSERREGTIPKL
  TAKSNCRYEIEWITEYACHRDYLESKTCSLSGEQQDVSIDLTPLAQSGGSSYISDGKEYL
  FYLNVCGETEIQFCNKKQAAVCQVKKSDTSQVKAAGRYHNQTLRYSDGDLTLIYFGGDEC
  SSGFQRMSVINFECNKTAGNDGKGTPVFTGEVDCTYFFTWDTEYACVKEKEDLLCGATDG
  KKRYDLSALVRHAEPEQNWEAVDGSQTETEKKHFFINICHRVLQEGKARGCPEDAAVCAV
  DKNGSKNLGKFISSPMKEKGNIQLSYSDGDDCGHGKKIKTNITLVCKPGDLESAPVLRTS
  GEGGCFYEFEWHTAAACVLSKTEGENCTVFDSQAGFSFDLSPLTKKNGAYKVETKKYDFY
  INVCGPVSVSPCQPDSGACQVAKSDEKTWNLGLSNAKLSYYDGMIQLNYRGGTPYNNERH
  TPRATLITFLCDRDAGVGFPEYQEEDNSTYNFRWYTSYACPEEPLECVVTDPSTLEQYDL
  SSLAKSEGGLGGNWYAMDNSGEHVTWRKYYINVCRPLNPVPGCNRYASACQMKYEKDQGS
  FTEVVSISNLGMAKTGPVVEDSGSLLLEYVNGSACTTSDGRQTTYTTRIHLVCSRGRLNS
  HPIFSLNWECVVSFLWNTEAACPIQTTTDTDQACSIRDPNSGFVFNLNPLNSSQGYNVSG
  IGKIFMFNVCGTMPVCGTILGKPASGCEAETQTEELKNWKPARPVGIEKSLQLSTEGFIT
  LTYKGPLSAKGTADAFIVRFVCNDDVYSGPLKFLHQDIDSGQGIRNTYFEFETALACVPS
  PVDCQVTDLAGNEYDLTGLSTVRKPWTAVDTSVDGRKRTFYLSVCNPLPYIPGCQGSAVG
  SCLVSEGNSWNLGVVQMSPQAAANGSLSIMYVNGDKCGNQRFSTRITFECAQISGSPAFQ
  LQDGCEYVFIWRTVEACPVVRVEGDNCEVKDPRHGNLYDLKPLGLNDTIVSAGEYTYYFR
  VCGKLSSDVCPTSDKSKVVSSCQEKREPQGFHKVAGLLTQKLTYENGLLKMNFTGGDTCH
  KVYQRSTAIFFYCDRGTQRPVFLKETSDCSYLFEWRTQYACPPFDLTECSFKDGAGNSFD
  LSSLSRYSDNWEAITGTGDPEHYLINVCKSLAPQAGTEPCPPEAAACLLGGSKPVNLGRV
  RDGPQWRDGIIVLKYVDGDLCPDGIRKKSTTIRFTCSESQVNSRPMFISAVEDCEYTFAW
  PTATACPMKSNEHDDCQVTNPSTGHLFDLSSLSGRAGFTAAYSEKGLVYMSICGENENCP
  PGVGACFGQTRISVGKANKRLRYVDQVLQLVYKDGSPCPSKSGLSYKSVISFVCRPEARP
  TNRPMLISLDKQTCTLFFSWHTPLACEQATECSVRNGSSIVDLSPLIHRTGGYEAYDESE
  DDASDTNPDFYINICQPLNPMHGVPCPAGAAVCKVPIDGPPIDIGRVAGPPILNPIANEI
  YLNFESSTPCLADKHFNYTSLIAFHCKRGVSMGTPKLLRTSECDFVFEWETPVVCPDEVR
  MDGCTLTDEQLLYSFNLSSLSTSTFKVTRDSRTYSVGVCTFAVGPEQGGCKDGGVCLLSG
  TKGASFGRLQSMKLDYRHQDEAVVLSYVNGDRCPPETDDGVPCVFPFIFNGKSYEECIIE
  SRAKLWCSTTADYDRDHEWGFCRHSNSYRTSSIIFKCDEDEDIGRPQVFSEVRGCDVTFE
  WKTKVVCPPKKLECKFVQKHKTYDLRLLSSLTGSWSLVHNGVSYYINLCQKIYKGPLGCS
  ERASICRRTTTGDVQVLGLVHTQKLGVIGDKVVVTYSKGYPCGGNKTASSVIELTCTKTV
  GRPAFKRFDIDSCTYYFSWDSRAACAVKPQEVQMVNGTITNPINGKSFSLGDIYFKLFRA
  SGDMRTNGDNYLYEIQLSSITSSRNPACSGANICQVKPNDQHFSRKVGTSDKTKYYLQDG
  DLDVVFASSSKCGKDKTKSVSSTIFFHCDPLVEDGIPEFSHETADCQYLFSWYTSAVCPL
  GVGFDSENPGDDGQMHKGLSERSQAVGAVLSLLLVALTCCLLALLLYKKERRETVISKLT
  TCCRRSSNVSYKYSKVNKEEETDENETEWLMEEIQLPPPRQGKEGQENGHITTKSVKALS
  SLHGDDQDSEDEVLTIPEVKVHSGRGAGAESSHPVRNAQSNALQEREDDRVGLVRGEKAR
  KGKSSSAQQKTVSSTKLVSFHDDSDEDLLHI
• Function: Mediates the transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelysosomal compartment where the low pH mediates the dissociation of the complex. The receptor is then recycled back to the Golgi for another round of trafficking through its binding to the retromer. This receptor also binds IGF2. Acts as a positive regulator of T-cell coactivation by binding DPP4.
• KEGG Pathway:
  Virion - Herpesvirus (hsa03266)
  Lysosome (hsa04142)
  Endocytosis (hsa04144)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Retrograde transport at the Trans-Golgi-Network (R-HSA-6811440)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Cation-independent mannose-6-phosphate receptor (IGF2R) increases the response to substance of Arsenic.	[27]

26 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[12]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[13]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[14]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[15]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[16]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[17]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Cation-independent mannose-6-phosphate receptor (IGF2R).	[26]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Cation-independent mannose-6-phosphate receptor (IGF2R).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cation-independent mannose-6-phosphate receptor (IGF2R).	[24]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] 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.
• [9] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [10] 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.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] 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.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [15] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [16] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [17] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [20] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [21] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [22] 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.
• [23] 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.
• [24] Effect of prenatal bisphenol A exposure on early childhood body mass index through epigenetic influence on the insulin-like growth factor 2 receptor (IGF2R) gene. Environ Int. 2020 Oct;143:105929. doi: 10.1016/j.envint.2020.105929. Epub 2020 Jul 6.
• [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] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [27] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.