Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2WUIIP)

• DOT Name: C-type lectin domain family 4 member M (CLEC4M)
• Synonyms: CD209 antigen-like protein 1; DC-SIGN-related protein; DC-SIGNR; Dendritic cell-specific ICAM-3-grabbing non-integrin 2; DC-SIGN2; Liver/lymph node-specific ICAM-3-grabbing non-integrin; L-SIGN; CD antigen CD299
• Gene Name: CLEC4M
• Related Disease:
  Hepatocellular carcinoma
  Latent tuberculosis infection
  Tuberculosis
  Colon cancer
  Colon carcinoma
  Gastric cancer
  Hepatitis C virus infection
  Non-small-cell lung cancer
  Stomach cancer
  Von willebrand disease
  Von Willebrand disease 1
  Von Willebrand disease 2
  HIV infectious disease
  Severe acute respiratory syndrome (SARS)
• UniProt ID: CLC4M_HUMAN
• PDB ID: 1K9J; 1SL6; 1XAR; 1XPH; 3JQH
• Pfam ID: PF00059
• Sequence:
  MSDSKEPRVQQLGLLEEDPTTSGIRLFPRDFQFQQIHGHKSSTGCLGHGALVLQLLSFML
  LAGVLVAILVQVSKVPSSLSQEQSEQDAIYQNLTQLKAAVGELSEKSKLQEIYQELTQLK
  AAVGELPEKSKLQEIYQELTRLKAAVGELPEKSKLQEIYQELTRLKAAVGELPEKSKLQE
  IYQELTRLKAAVGELPEKSKLQEIYQELTELKAAVGELPEKSKLQEIYQELTQLKAAVGE
  LPDQSKQQQIYQELTDLKTAFERLCRHCPKDWTFFQGNCYFMSNSQRNWHDSVTACQEVR
  AQLVVIKTAEEQNFLQLQTSRSNRFSWMGLSDLNQEGTWQWVDGSPLSPSFQRYWNSGEP
  NNSGNEDCAEFSGSGWNDNRCDVDNYWICKKPAACFRDE
• Function: Probable pathogen-recognition receptor involved in peripheral immune surveillance in liver. May mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. Is a receptor for ICAM3, probably by binding to mannose-like carbohydrates; (Microbial infection) Acts as an attachment receptor for Ebolavirus; (Microbial infection) Acts as an attachment receptor for Hepatitis C virus; (Microbial infection) Acts as an attachment receptor for HIV-1; (Microbial infection) Acts as an attachment receptor for Human coronavirus 229E; (Microbial infection) Acts as an attachment receptor for Human cytomegalovirus/HHV-5; (Microbial infection) Acts as an attachment receptor for Influenzavirus; (Microbial infection) Acts as an attachment receptor for SARS-CoV; (Microbial infection) Acts as an attachment receptor for West-nile virus; (Microbial infection) Acts as an attachment receptor for Japanese encephalitis virus; (Microbial infection) Acts as an attachment receptor for Marburg virus glycoprotein; (Microbial infection) Recognition of M.bovis by dendritic cells may occur partially via this molecule.
• Tissue Specificity: Predominantly highly expressed in liver sinusoidal endothelial cells and in lymph node. Found in placental endothelium but not in macrophages. Expressed in type II alveolar cells and lung endothelial cells.
• KEGG Pathway:
  Virion - Human immunodeficiency virus (hsa03260)
  Virion - Flavivirus (hsa03264)
  Phagosome (hsa04145)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Tuberculosis (hsa05152)
  Measles (hsa05162)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Latent tuberculosis infection	DIS6R1EH	Definitive	Genetic Variation	[2]
Tuberculosis	DIS2YIMD	Definitive	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Von willebrand disease	DIS3TZCH	Strong	Altered Expression	[6]
Von Willebrand disease 1	DISUGLZA	Strong	Genetic Variation	[7]
Von Willebrand disease 2	DISEYUBR	Strong	Altered Expression	[6]
HIV infectious disease	DISO97HC	moderate	Biomarker	[8]
Severe acute respiratory syndrome (SARS)	DISYW14W	moderate	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of C-type lectin domain family 4 member M (CLEC4M).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of C-type lectin domain family 4 member M (CLEC4M).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of C-type lectin domain family 4 member M (CLEC4M).	[13]

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 decreases the methylation of C-type lectin domain family 4 member M (CLEC4M).	[12]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] Association of CD209 and CD209L polymorphisms with tuberculosis infection in a Northeastern Brazilian population.Mol Biol Rep. 2014 Aug;41(8):5449-57. doi: 10.1007/s11033-014-3416-y. Epub 2014 May 30.
• [3] DC-SIGN mediates gastric cancer progression by regulating the JAK2/STAT3 signaling pathway and affecting LncRNA RP11-181G12.2 expression.Biomed Pharmacother. 2020 Jan;121:109644. doi: 10.1016/j.biopha.2019.109644. Epub 2019 Nov 19.
• [4] CLEC4M-positive and CD81-negative Huh7 cells are not susceptible to JFH-1 HCVcc infection but mediate transinfection.Arch Virol. 2014 Nov;159(11):2949-55. doi: 10.1007/s00705-014-2150-z. Epub 2014 Jun 26.
• [5] CLEC4M is associated with poor prognosis and promotes cisplatin resistance in NSCLC patients.J Cancer. 2019 Oct 19;10(25):6374-6383. doi: 10.7150/jca.30139. eCollection 2019.
• [6] CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease.J Thromb Haemost. 2015 Jun;13(6):956-66. doi: 10.1111/jth.12927. Epub 2015 May 9.
• [7] Genetic variation in the C-type lectin receptor CLEC4M in type 1 von Willebrand Disease patients.PLoS One. 2018 Feb 1;13(2):e0192024. doi: 10.1371/journal.pone.0192024. eCollection 2018.
• [8] The VNTR polymorphism of the CLEC4M gene and susceptibility to HIV-1 infection in Han Chinese population.Infect Genet Evol. 2013 Jul;17:137-41. doi: 10.1016/j.meegid.2013.04.007. Epub 2013 Apr 17.
• [9] Polymorphisms in the C-type lectin genes cluster in chromosome 19 and predisposition to severe acute respiratory syndrome coronavirus (SARS-CoV) infection.J Med Genet. 2008 Nov;45(11):752-8. doi: 10.1136/jmg.2008.058966. Epub 2008 Aug 12.
• [10] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [11] 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.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.