Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT19WV30)

• DOT Name: C-type lectin domain family 5 member A (CLEC5A)
• Synonyms: C-type lectin superfamily member 5; Myeloid DAP12-associating lectin 1; MDL-1
• Gene Name: CLEC5A
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
  Adenovirus infection
  Adult glioblastoma
  Arteriosclerosis
  Atherosclerosis
  Glioblastoma multiforme
  Glioblastoma of brain
  Glioma
  Influenza
  Listeriosis
  Myelodysplastic syndrome
  Osteoarthritis
  Rheumatoid arthritis
  Dengue
  Mycoplasma pneumoniae pneumonia
  Arthritis
• UniProt ID: CLC5A_HUMAN
• PDB ID: 2YHF
• Pfam ID: PF00059
• Sequence:
  MNWHMIISGLIVVVLKVVGMTLFLLYFPQIFNKSNDGFTTTRSYGTVSQIFGSSSPSPNG
  FITTRSYGTVCPKDWEFYQARCFFLSTSESSWNESRDFCKGKGSTLAIVNTPEKLKFLQD
  ITDAEKYFIGLIYHREEKRWRWINNSVFNGNVTNQNQNFNCATIGLTKTFDAASCDISYR
  RICEKNAK
• Function: Functions as a positive regulator of osteoclastogenesis. Cell surface receptor that signals via TYROBP. Regulates inflammatory responses; (Microbial infection) Critical macrophage receptor for dengue virus serotypes 1-4. The binding of dengue virus to CLEC5A triggers signaling through the phosphorylation of TYROBP. This interaction does not result in viral entry, but stimulates pro-inflammatory cytokine release.
• Tissue Specificity: Highly expressed in bone marrow with lower levels in synovium, lung and bronchus . Expressed in peripheral blood monocytes and in the monocyte/macrophage cell lines U-937 and Mono-Mac-6, but not in cell lines of other origins . Expression is down-regulated when monocytes differentiate into dendritic cells .
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  DAP12 interactions (R-HSA-2172127)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[1]
Adenovirus infection	DISUYSBZ	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[2]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[2]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Glioblastoma of brain	DISESTHB	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Influenza	DIS3PNU3	Strong	Biomarker	[5]
Listeriosis	DISKMQBM	Strong	Biomarker	[6]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[7]
Osteoarthritis	DIS05URM	Strong	Biomarker	[8]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[8]
Dengue	DISKH221	moderate	Genetic Variation	[9]
Mycoplasma pneumoniae pneumonia	DIS1AW2Z	moderate	Biomarker	[10]
Arthritis	DIST1YEL	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of C-type lectin domain family 5 member A (CLEC5A).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of C-type lectin domain family 5 member A (CLEC5A).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of C-type lectin domain family 5 member A (CLEC5A).	[14]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of C-type lectin domain family 5 member A (CLEC5A).	[15]
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the expression of C-type lectin domain family 5 member A (CLEC5A).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of C-type lectin domain family 5 member A (CLEC5A).	[18]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of C-type lectin domain family 5 member A (CLEC5A).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of C-type lectin domain family 5 member A (CLEC5A).	[17]

References

• [1] Transcription factor CEBPB inhibits the proliferation of osteosarcoma by regulating downstream target gene CLEC5A.J Clin Lab Anal. 2019 Nov;33(9):e22985. doi: 10.1002/jcla.22985. Epub 2019 Jul 31.
• [2] The macrophage C-type lectin receptor CLEC5A (MDL-1) expression is associated with early plaque progression and promotes macrophage survival.J Transl Med. 2017 Nov 10;15(1):234. doi: 10.1186/s12967-017-1336-z.
• [3] C-type lectin domain family 5, member A (CLEC5A, MDL-1) promotes brain glioblastoma tumorigenesis by regulating PI3K/Akt signalling.Cell Prolif. 2019 May;52(3):e12584. doi: 10.1111/cpr.12584. Epub 2019 Mar 4.
• [4] CLEC5A expressed on myeloid cells as a M2 biomarker relates to immunosuppression and decreased survival in patients with glioma.Cancer Gene Ther. 2020 Sep;27(9):669-679. doi: 10.1038/s41417-019-0140-8. Epub 2019 Oct 8.
• [5] CLEC5A-Mediated Enhancement of the Inflammatory Response in Myeloid Cells Contributes to Influenza Virus Pathogenicity In Vivo.J Virol. 2016 Dec 16;91(1):e01813-16. doi: 10.1128/JVI.01813-16. Print 2017 Jan 1.
• [6] CLEC5A is a critical receptor in innate immunity against Listeria infection.Nat Commun. 2017 Aug 21;8(1):299. doi: 10.1038/s41467-017-00356-3.
• [7] Myelodysplastic syndromes are induced by histone methylationaltering ASXL1 mutations.J Clin Invest. 2013 Nov;123(11):4627-40. doi: 10.1172/JCI70739.
• [8] A potential role of myeloid DAP12-associating lectin (MDL)-1 in the regulation of inflammation in rheumatoid arthritis patients.PLoS One. 2014 Jan 21;9(1):e86105. doi: 10.1371/journal.pone.0086105. eCollection 2014.
• [9] Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects.Hum Immunol. 2017 Oct;78(10):649-656. doi: 10.1016/j.humimm.2017.07.013. Epub 2017 Jul 29.
• [10] Transcriptome analysis of bronchoalveolar lavage fluid from children with severe Mycoplasma pneumoniae pneumonia reveals novel gene expression and immunodeficiency.Hum Genomics. 2017 Mar 16;11(1):4. doi: 10.1186/s40246-017-0101-y.
• [11] Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis.J Exp Med. 2010 Mar 15;207(3):579-89. doi: 10.1084/jem.20090516. Epub 2010 Mar 8.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] Preliminary discovery of novel markers for human cell line activation test (h-CLAT). Toxicol In Vitro. 2021 Aug;74:105154. doi: 10.1016/j.tiv.2021.105154. Epub 2021 Mar 25.
• [16] Human Mincle Binds to Cholesterol Crystals and Triggers Innate Immune Responses. J Biol Chem. 2015 Oct 16;290(42):25322-32. doi: 10.1074/jbc.M115.645234. Epub 2015 Aug 20.
• [17] 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.
• [18] 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.