Details of Drug Off-Target (DOT)

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

• DOT Name: C-type lectin domain family 2 member D (CLEC2D)
• Synonyms: Lectin-like NK cell receptor; Lectin-like transcript 1; LLT-1; Osteoclast inhibitory lectin
• Gene Name: CLEC2D
• Related Disease:
  Crohn disease
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  B-cell neoplasm
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Triple negative breast cancer
  Type-1 diabetes
  Cutaneous squamous cell carcinoma
• UniProt ID: CLC2D_HUMAN
• PDB ID: 4QKG; 4QKH; 4QKI; 4QKJ; 4WCO; 5MGT
• Pfam ID: PF00059
• Sequence:
  MHDSNNVEKDITPSELPANPGCLHSKEHSIKATLIWRLFFLIMFLTIIVCGMVAALSAIR
  ANCHQEPSVCLQAACPESWIGFQRKCFYFSDDTKNWTSSQRFCDSQDADLAQVESFQELN
  FLLRYKGPSDHWIGLSREQGQPWKWINGTEWTRQFPILGAGECAYLNDKGASSARHYTER
  KWICSKSDIHV
• Function: Receptor for KLRB1 that protects target cells against natural killer cell-mediated lysis. Inhibits osteoclast formation. Inhibits bone resorption. Modulates the release of interferon-gamma. Binds high molecular weight sulfated glycosaminoglycans.
• Tissue Specificity: Detected in peripheral blood leukocytes, osteoblasts, lymph node, thymus and spleen. Isoform 1, isoform 2 and isoform 4 are expressed in T- and B-lymphocytes, and at lower levels in NK cells. They are also expressed in B-cell lines and LPS-matured monocyte-derived dendritic cells.
• Reactome Pathway: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Definitive	Genetic Variation	[1]
Prostate cancer	DISF190Y	Definitive	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[4]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[7]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[8]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Altered Expression	[9]

10 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 lectin domain family 2 member D (CLEC2D).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of C-type lectin domain family 2 member D (CLEC2D).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of C-type lectin domain family 2 member D (CLEC2D).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of C-type lectin domain family 2 member D (CLEC2D).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of C-type lectin domain family 2 member D (CLEC2D).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of C-type lectin domain family 2 member D (CLEC2D).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of C-type lectin domain family 2 member D (CLEC2D).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of C-type lectin domain family 2 member D (CLEC2D).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of C-type lectin domain family 2 member D (CLEC2D).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of C-type lectin domain family 2 member D (CLEC2D).	[16]

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 2 member D (CLEC2D).	[18]

References

• [1] Single nucleotide polymorphisms in C-type lectin genes, clustered in the IBD2 and IBD6 susceptibility loci, may play a role in the pathogenesis of inflammatory bowel diseases.Eur J Gastroenterol Hepatol. 2012 Aug;24(8):965-70. doi: 10.1097/MEG.0b013e328354f3d5.
• [2] Overexpression of LLT1 (OCIL, CLEC2D) on prostate cancer cells inhibits NK cell-mediated killing through LLT1-NKRP1A (CD161) interaction.Oncotarget. 2016 Oct 18;7(42):68650-68661. doi: 10.18632/oncotarget.11896.
• [3] Biological and Clinical Significance of Human NKRP1A/LLT1 Receptor/Ligand Interactions.Crit Rev Immunol. 2018;38(6):479-489. doi: 10.1615/CritRevImmunol.2019029559.
• [4] Vaccinia virus Western Reserve induces rapid surface expression of a host molecule detected by the antibody 4C7 that is distinct from CLEC2D.Microbiol Immunol. 2016 Nov;60(11):754-769. doi: 10.1111/1348-0421.12451.
• [5] Association of ZAP70 and PTPN6, but Not BANK1 or CLEC2D, with inflammatory bowel disease in the Tunisian population.Genet Test Mol Biomarkers. 2013 Apr;17(4):321-6. doi: 10.1089/gtmb.2012.0372. Epub 2013 Feb 13.
• [6] Expression of LLT1 and its receptor CD161 in lung cancer is associated with better clinical outcome.Oncoimmunology. 2018 Jan 29;7(5):e1423184. doi: 10.1080/2162402X.2017.1423184. eCollection 2018.
• [7] Blocking LLT1 (CLEC2D, OCIL)-NKRP1A (CD161) interaction enhances natural killer cell-mediated lysis of triple-negative breast cancer cells.Am J Cancer Res. 2018 Jun 1;8(6):1050-1063. eCollection 2018.
• [8] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature. 2007 Jun 7;447(7145):661-78. doi: 10.1038/nature05911.
• [9] Lectin-like transcript 1 (LLT1) expression is associated with nodal metastasis in patients with head and neck cutaneous squamous cell carcinoma.Arch Dermatol Res. 2019 Jul;311(5):369-376. doi: 10.1007/s00403-019-01916-x. Epub 2019 Apr 6.
• [10] 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.
• [11] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [15] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [18] 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.
• [19] 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.