Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLWQAX1)

• DOT Name: C-type mannose receptor 2 (MRC2)
• Synonyms: C-type lectin domain family 13 member E; Endocytic receptor 180; Macrophage mannose receptor 2; Urokinase-type plasminogen activator receptor-associated protein; UPAR-associated protein; Urokinase receptor-associated protein; CD antigen CD280
• Gene Name: MRC2
• UniProt ID: MRC2_HUMAN
• PDB ID: 5AO5; 5AO6; 5E4K; 5E4L; 5EW6
• Pfam ID: PF00040 ; PF00059
• Sequence:
  MGPGRPAPAPWPRHLLRCVLLLGCLHLGRPGAPGDAALPEPNVFLIFSHGLQGCLEAQGG
  QVRVTPACNTSLPAQRWKWVSRNRLFNLGTMQCLGTGWPGTNTTASLGMYECDREALNLR
  WHCRTLGDQLSLLLGARTSNISKPGTLERGDQTRSGQWRIYGSEEDLCALPYHEVYTIQG
  NSHGKPCTIPFKYDNQWFHGCTSTGREDGHLWCATTQDYGKDERWGFCPIKSNDCETFWD
  KDQLTDSCYQFNFQSTLSWREAWASCEQQGADLLSITEIHEQTYINGLLTGYSSTLWIGL
  NDLDTSGGWQWSDNSPLKYLNWESDQPDNPSEENCGVIRTESSGGWQNRDCSIALPYVCK
  KKPNATAEPTPPDRWANVKVECEPSWQPFQGHCYRLQAEKRSWQESKKACLRGGGDLVSI
  HSMAELEFITKQIKQEVEELWIGLNDLKLQMNFEWSDGSLVSFTHWHPFEPNNFRDSLED
  CVTIWGPEGRWNDSPCNQSLPSICKKAGQLSQGAAEEDHGCRKGWTWHSPSCYWLGEDQV
  TYSEARRLCTDHGSQLVTITNRFEQAFVSSLIYNWEGEYFWTALQDLNSTGSFFWLSGDE
  VMYTHWNRDQPGYSRGGCVALATGSAMGLWEVKNCTSFRARYICRQSLGTPVTPELPGPD
  PTPSLTGSCPQGWASDTKLRYCYKVFSSERLQDKKSWVQAQGACQELGAQLLSLASYEEE
  HFVANMLNKIFGESEPEIHEQHWFWIGLNRRDPRGGQSWRWSDGVGFSYHNFDRSRHDDD
  DIRGCAVLDLASLQWVAMQCDTQLDWICKIPRGTDVREPDDSPQGRREWLRFQEAEYKFF
  EHHSTWAQAQRICTWFQAELTSVHSQAELDFLSHNLQKFSRAQEQHWWIGLHTSESDGRF
  RWTDGSIINFISWAPGKPRPVGKDKKCVYMTASREDWGDQRCLTALPYICKRSNVTKETQ
  PPDLPTTALGGCPSDWIQFLNKCFQVQGQEPQSRVKWSEAQFSCEQQEAQLVTITNPLEQ
  AFITASLPNVTFDLWIGLHASQRDFQWVEQEPLMYANWAPGEPSGPSPAPSGNKPTSCAV
  VLHSPSAHFTGRWDDRSCTEETHGFICQKGTDPSLSPSPAALPPAPGTELSYLNGTFRLL
  QKPLRWHDALLLCESRNASLAYVPDPYTQAFLTQAARGLRTPLWIGLAGEEGSRRYSWVS
  EEPLNYVGWQDGEPQQPGGCTYVDVDGAWRTTSCDTKLQGAVCGVSSGPPPPRRISYHGS
  CPQGLADSAWIPFREHCYSFHMELLLGHKEARQRCQRAGGAVLSILDEMENVFVWEHLQS
  YEGQSRGAWLGMNFNPKGGTLVWQDNTAVNYSNWGPPGLGPSMLSHNSCYWIQSNSGLWR
  PGACTNITMGVVCKLPRAEQSSFSPSALPENPAALVVVLMAVLLLLALLTAALILYRRRQ
  SIERGAFEGARYSRSSSSPTEATEKNILVSDMEMNEQQE
• Function: May play a role as endocytotic lectin receptor displaying calcium-dependent lectin activity. Internalizes glycosylated ligands from the extracellular space for release in an endosomal compartment via clathrin-mediated endocytosis. May be involved in plasminogen activation system controlling the extracellular level of PLAUR/PLAU, and thus may regulate protease activity at the cell surface. May contribute to cellular uptake, remodeling and degradation of extracellular collagen matrices. May play a role during cancer progression as well as in other chronic tissue destructive diseases acting on collagen turnover. May participate in remodeling of extracellular matrix cooperating with the matrix metalloproteinases (MMPs).
• Tissue Specificity: Ubiquitous with low expression in brain, placenta, lung, kidney, pancreas, spleen, thymus and colon. Expressed in endothelial cells, fibroblasts and macrophages. Highly expressed in fetal lung and kidney.
• KEGG Pathway:
  Phagosome (hsa04145)
  Tuberculosis (hsa05152)
• Reactome Pathway: Cross-presentation of soluble exogenous antigens (endosomes) (R-HSA-1236978)

Molecular Interaction Atlas (MIA) of This DOT

5 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 C-type mannose receptor 2 (MRC2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of C-type mannose receptor 2 (MRC2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of C-type mannose receptor 2 (MRC2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of C-type mannose receptor 2 (MRC2).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of C-type mannose receptor 2 (MRC2).	[15]

11 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 C-type mannose receptor 2 (MRC2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of C-type mannose receptor 2 (MRC2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of C-type mannose receptor 2 (MRC2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of C-type mannose receptor 2 (MRC2).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of C-type mannose receptor 2 (MRC2).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of C-type mannose receptor 2 (MRC2).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of C-type mannose receptor 2 (MRC2).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of C-type mannose receptor 2 (MRC2).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of C-type mannose receptor 2 (MRC2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of C-type mannose receptor 2 (MRC2).	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of C-type mannose receptor 2 (MRC2).	[16]

References

• [1] 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.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.