Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT4N86S)

• DOT Name: NKG2-C type II integral membrane protein (KLRC2)
• Synonyms: CD159 antigen-like family member C; NK cell receptor C; NKG2-C-activating NK receptor; CD antigen CD159c
• Gene Name: KLRC2
• Related Disease:
  Multiple sclerosis
  Arthritis
  Chronic fatigue syndrome
  Coeliac disease
  Creutzfeldt Jacob disease
  Eclampsia
  Hepatitis C virus infection
  HIV infectious disease
  Influenza
  Inherited Creutzfeldt-Jakob disease
  Prolymphocytic leukaemia
  Psoriasis
  Rheumatoid arthritis
  Systemic lupus erythematosus
  Tuberculosis
  Advanced cancer
  Colorectal neoplasm
  Graft-versus-host disease
  Atrial septal defect
  Autism spectrum disorder
  Chronic graft versus host disease
  Human papillomavirus infection
  Neoplasm
• UniProt ID: NKG2C_HUMAN
• PDB ID: 2L35
• Pfam ID: PF00059
• Sequence:
  MNKQRGTFSEVSLAQDPKRQQRKPKGNKSSISGTEQEIFQVELNLQNPSLNHQGIDKIYD
  CQGLLPPPEKLTAEVLGIICIVLMATVLKTIVLIPFLEQNNFSPNTRTQKARHCGHCPEE
  WITYSNSCYYIGKERRTWEESLLACTSKNSSLLSIDNEEEMKFLASILPSSWIGVFRNSS
  HHPWVTINGLAFKHKIKDSDNAELNCAVLQVNRLKSAQCGSSMIYHCKHKL
• Function: Immune activating receptor involved in self-nonself discrimination. In complex with KLRD1 on cytotoxic lymphocyte subsets, recognizes non-classical major histocompatibility (MHC) class Ib HLA-E loaded with signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules, likely playing a role in the generation and effector functions of adaptive natural killer (NK) cells and in maternal-fetal tolerance during pregnancy. Regulates the effector functions of terminally differentiated cytotoxic lymphocyte subsets, and in particular may play a role in adaptive NK cell response to viral infection. Upon HLA-E-peptide binding, transmits intracellular signals via the adapter protein TYROBP/DAP12, triggering the phosphorylation of proximal signaling molecules and cell activation.
• Tissue Specificity: Expressed in NK cell subsets, in particular in adaptive CD57-positive NK cells (at protein level) . Expressed in terminally differentiated cytotoxic gamma-delta T cells (at protein level) . Expressed in alpha-beta T cells subsets (at protein level) . KLRD1-KLRC1 and KLRD1-KLRC2 are differentially expressed within NK and T cell populations, with only minor subsets expressing both receptor complexes (at protein level) .
• KEGG Pathway:
  Antigen processing and presentation (hsa04612)
  .tural killer cell mediated cytotoxicity (hsa04650)
• Reactome Pathway:
  DAP12 signaling (R-HSA-2424491)
  DAP12 interactions (R-HSA-2172127)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[1]
Arthritis	DIST1YEL	Strong	Biomarker	[2]
Chronic fatigue syndrome	DIS34WJ5	Strong	Biomarker	[3]
Coeliac disease	DISIY60C	Strong	Altered Expression	[4]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Biomarker	[5]
Eclampsia	DISWPO8U	Strong	Genetic Variation	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[7]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[8]
Influenza	DIS3PNU3	Strong	Genetic Variation	[9]
Inherited Creutzfeldt-Jakob disease	DIS3TXG8	Strong	Biomarker	[5]
Prolymphocytic leukaemia	DISDPPHX	Strong	Biomarker	[10]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[11]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[13]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[14]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[15]
Colorectal neoplasm	DISR1UCN	moderate	Altered Expression	[15]
Graft-versus-host disease	DIS0QADF	moderate	Biomarker	[16]
Atrial septal defect	DISJT76B	Limited	Altered Expression	[17]
Autism spectrum disorder	DISXK8NV	Limited	Altered Expression	[17]
Chronic graft versus host disease	DIS1MM9J	Limited	Biomarker	[18]
Human papillomavirus infection	DISX61LX	Limited	Genetic Variation	[19]
Neoplasm	DISZKGEW	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	NKG2-C type II integral membrane protein (KLRC2) affects the response to substance of Methotrexate.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of NKG2-C type II integral membrane protein (KLRC2).	[21]
Marinol	DM70IK5	Approved	Marinol increases the expression of NKG2-C type II integral membrane protein (KLRC2).	[22]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of NKG2-C type II integral membrane protein (KLRC2).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NKG2-C type II integral membrane protein (KLRC2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of NKG2-C type II integral membrane protein (KLRC2).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NKG2-C type II integral membrane protein (KLRC2).	[25]

References

• [1] Adaptive Features of Natural Killer Cells in Multiple Sclerosis.Front Immunol. 2019 Oct 15;10:2403. doi: 10.3389/fimmu.2019.02403. eCollection 2019.
• [2] Association of CD94/NKG2A, CD94/NKG2C, and its ligand HLA-E polymorphisms with Behcet's disease.Tissue Antigens. 2007 Oct;70(4):307-13. doi: 10.1111/j.1399-0039.2007.00907.x.
• [3] Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).Front Immunol. 2018 May 9;9:1028. doi: 10.3389/fimmu.2018.01028. eCollection 2018.
• [4] NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study.Gut. 2019 Aug;68(8):1396-1405. doi: 10.1136/gutjnl-2018-317371. Epub 2018 Nov 17.
• [5] Snord 3A: a molecular marker and modulator of prion disease progression.PLoS One. 2013;8(1):e54433. doi: 10.1371/journal.pone.0054433. Epub 2013 Jan 21.
• [6] Influence of NKG2C gene deletion and CCR532 in Pre-eclampsia-Approaching the effect of innate immune gene variants in pregnancy.Int J Immunogenet. 2019 Apr;46(2):82-87. doi: 10.1111/iji.12416. Epub 2019 Feb 20.
• [7] The Clinical Features of Patients with Chronic Hepatitis C Virus Infections Are Associated with Killer Cell Immunoglobulin-Like Receptor Genes and Their Expression on the Surface of Natural Killer Cells.Front Immunol. 2018 Jan 5;8:1912. doi: 10.3389/fimmu.2017.01912. eCollection 2017.
• [8] Cytomegalovirus-Driven Adaption of Natural Killer Cells in NKG2C(null) Human Immunodeficiency Virus-Infected Individuals.Viruses. 2019 Mar 9;11(3):239. doi: 10.3390/v11030239.
• [9] NKG2C gene deletion in the Mexican population and lack of association to respiratory viral infections.Int J Immunogenet. 2014 Apr;41(2):126-30. doi: 10.1111/iji.12104. Epub 2013 Dec 5.
• [10] Pretransplant adaptive NKG2C+ NK cells protect against cytomegalovirus infection in kidney transplant recipients.Am J Transplant. 2020 Mar;20(3):663-676. doi: 10.1111/ajt.15658. Epub 2019 Nov 19.
• [11] Deletion of the activating NKG2C receptor and a functional polymorphism in its ligand HLA-E in psoriasis susceptibility.Exp Dermatol. 2013 Oct;22(10):679-81. doi: 10.1111/exd.12233.
• [12] Inhibitory NKG2A and activating NKG2D and NKG2C natural killer cell receptor genes: susceptibility for rheumatoid arthritis.Tissue Antigens. 2008 Oct;72(4):342-6. doi: 10.1111/j.1399-0039.2008.01110.x. Epub 2008 Aug 12.
• [13] Molecular genetic analyses of human NKG2C (KLRC2) gene deletion.Int Immunol. 2004 Jan;16(1):163-8. doi: 10.1093/intimm/dxh013.
• [14] Changes in the NK Cell Repertoire Related to Initiation of TB Treatment and Onset of Immune Reconstitution Inflammatory Syndrome in TB/HIV Co-infected Patients in Rio de Janeiro, Brazil-ANRS 12274.Front Immunol. 2019 Aug 13;10:1800. doi: 10.3389/fimmu.2019.01800. eCollection 2019.
• [15] Expansion of CMV-mediated NKG2C+ NK cells associates with the development of specific de novo malignancies in liver-transplanted patients.J Immunol. 2014 Jan 1;192(1):503-11. doi: 10.4049/jimmunol.1301951. Epub 2013 Dec 4.
• [16] The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease.Int J Mol Sci. 2016 Oct 27;17(11):1797. doi: 10.3390/ijms17111797.
• [17] Persistence of dysfunctional natural killer cells in adults with high-functioning autism spectrum disorders: stigma/consequence of unresolved early infectious events?.Mol Autism. 2019 May 15;10:22. doi: 10.1186/s13229-019-0269-1. eCollection 2019.
• [18] Alterations in NKG2A and NKG2C Subsets of Natural Killer Cells Following Epstein-Barr Virus Reactivation in CTLA4Ig-based Haploidentical Transplantation Is Associated With Increased Chronic Graft-Versus-Host Disease.Transplantation. 2020 Jan;104(1):e23-e30. doi: 10.1097/TP.0000000000002941.
• [19] Evaluation of the association of NKG2C copy number variations with susceptibility to human papillomavirus-induced cervical lesions.Hum Immunol. 2013 Oct;74(10):1352-6. doi: 10.1016/j.humimm.2013.07.006. Epub 2013 Jul 31.
• [20] Adaptive reconfiguration of the human NK-cell compartment in response to cytomegalovirus: a different perspective of the host-pathogen interaction.Eur J Immunol. 2013 May;43(5):1133-41. doi: 10.1002/eji.201243117.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [23] 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.
• [24] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [25] 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.
• [26] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [27] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.