Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSMR85N)

• DOT Name: Natural killer cell receptor 2B4 (CD244)
• Synonyms: NK cell activation-inducing ligand; NAIL; NK cell type I receptor protein 2B4; NKR2B4; h2B4; SLAM family member 4; SLAMF4; Signaling lymphocytic activation molecule 4; CD antigen CD244
• Gene Name: CD244
• Related Disease:
  Leishmaniasis
  X-linked lymphoproliferative syndrome
  Advanced cancer
  Autoimmune disease
  Cytomegalovirus infection
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  HIV infectious disease
  Leukemia
  Liver cirrhosis
  Lupus
  Neoplasm
  Psoriasis
  Systemic lupus erythematosus
  Tuberculosis
  Acute myelogenous leukaemia
  Crohn disease
  leukaemia
  Follicular lymphoma
  Asthma
  Nervous system disease
• UniProt ID: CD244_HUMAN
• Pfam ID: PF11465
• Sequence:
  MLGQVVTLILLLLLKVYQGKGCQGSADHVVSISGVPLQLQPNSIQTKVDSIAWKKLLPSQ
  NGFHHILKWENGSLPSNTSNDRFSFIVKNLSLLIKAAQQQDSGLYCLEVTSISGKVQTAT
  FQVFVFESLLPDKVEKPRLQGQGKILDRGRCQVALSCLVSRDGNVSYAWYRGSKLIQTAG
  NLTYLDEEVDINGTHTYTCNVSNPVSWESHTLNLTQDCQNAHQEFRFWPFLVIIVILSAL
  FLGTLACFCVWRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMI
  QSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSR
  KELENFDVYS
• Function: Heterophilic receptor of the signaling lymphocytic activation molecule (SLAM) family; its ligand is CD48. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. Acts as activating natural killer (NK) cell receptor. Activating function implicates association with SH2D1A and FYN. Downstreaming signaling involves predominantly VAV1, and, to a lesser degree, INPP5D/SHIP1 and CBL. Signal attenuation in the absence of SH2D1A is proposed to be dependent on INPP5D and to a lesser extent PTPN6/SHP-1 and PTPN11/SHP-2. Stimulates NK cell cytotoxicity, production of IFN-gamma and granule exocytosis. Optimal expansion and activation of NK cells seems to be dependent on the engagement of CD244 with CD48 expressed on neighboring NK cells. Acts as costimulator in NK activation by enhancing signals by other NK receptors such as NCR3 and NCR1. At early stages of NK cell differentiation may function as an inhibitory receptor possibly ensuring the self-tolerance of developing NK cells. Involved in the regulation of CD8(+) T-cell proliferation; expression on activated T-cells and binding to CD48 provides costimulatory-like function for neighboring T-cells. Inhibits inflammatory responses in dendritic cells (DCs).
• Tissue Specificity: Expressed in spleen, PBL, followed by lung, liver, testis and small intestine. Expressed in all natural killer (NK) cells, monocytes and basophils, TCR-gamma/delta+ T-cells, monocytes, basophils, and on a subset of CD8(+) T-cells.
• KEGG Pathway: .tural killer cell mediated cytotoxicity (hsa04650)
• Reactome Pathway: Cell surface interactions at the vascular wall (R-HSA-202733)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leishmaniasis	DISABTW7	Definitive	Biomarker	[1]
X-linked lymphoproliferative syndrome	DISA7MJ4	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Cytomegalovirus infection	DISCEMGC	Strong	Altered Expression	[5]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[6]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[8]
Leukemia	DISNAKFL	Strong	Biomarker	[9]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[6]
Lupus	DISOKJWA	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Psoriasis	DIS59VMN	Strong	Biomarker	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[3]
Tuberculosis	DIS2YIMD	Strong	Altered Expression	[13]
Acute myelogenous leukaemia	DISCSPTN	moderate	Altered Expression	[14]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[15]
leukaemia	DISS7D1V	moderate	Biomarker	[9]
Follicular lymphoma	DISVEUR6	Disputed	Altered Expression	[16]
Asthma	DISW9QNS	Limited	Biomarker	[17]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[18]

2 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 Natural killer cell receptor 2B4 (CD244).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Natural killer cell receptor 2B4 (CD244).	[22]

3 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 Natural killer cell receptor 2B4 (CD244).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Natural killer cell receptor 2B4 (CD244).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Natural killer cell receptor 2B4 (CD244).	[23]

References

• [1] Phenotypic and Functional Profiles of Antigen-Specific CD4(+) and CD8(+) T Cells Associated With Infection Control in Patients With Cutaneous Leishmaniasis.Front Cell Infect Microbiol. 2018 Nov 19;8:393. doi: 10.3389/fcimb.2018.00393. eCollection 2018.
• [2] Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease.J Immunol. 2005 Apr 15;174(8):4551-8. doi: 10.4049/jimmunol.174.8.4551.
• [3] 2B4 (CD244, SLAMF4) and CS1 (CD319, SLAMF7) in systemic lupus erythematosus and cancer.Clin Immunol. 2019 Jul;204:50-56. doi: 10.1016/j.clim.2018.10.009. Epub 2018 Oct 19.
• [4] Cutting Edge: 2B4-Mediated Coinhibition of CD4(+) T Cells Underlies Mortality in Experimental Sepsis.J Immunol. 2017 Sep 15;199(6):1961-1966. doi: 10.4049/jimmunol.1700375. Epub 2017 Aug 2.
• [5] Cytomegalovirus-Induced Expression of CD244 after Liver Transplantation Is Associated with CD8+ T Cell Hyporesponsiveness to Alloantigen.J Immunol. 2015 Aug 15;195(4):1838-48. doi: 10.4049/jimmunol.1500440. Epub 2015 Jul 13.
• [6] Association of genetic polymorphisms in CD8+ T cell inhibitory genes and susceptibility to and progression of chronic HBV infection.Infect Genet Evol. 2015 Dec;36:467-474. doi: 10.1016/j.meegid.2015.08.018. Epub 2015 Aug 18.
• [7] Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells.PLoS Pathog. 2011 May;7(5):e1002045. doi: 10.1371/journal.ppat.1002045. Epub 2011 May 19.
• [8] Negative Checkpoint Regulatory Molecule 2B4 (CD244) Upregulation Is Associated with Invariant Natural Killer T Cell Alterations and Human Immunodeficiency Virus Disease Progression.Front Immunol. 2017 Mar 27;8:338. doi: 10.3389/fimmu.2017.00338. eCollection 2017.
• [9] CD244 maintains the proliferation ability of leukemia initiating cells through SHP-2/p27(kip1) signaling.Haematologica. 2017 Apr;102(4):707-718. doi: 10.3324/haematol.2016.151555. Epub 2017 Jan 25.
• [10] Cutting edge: an NK cell-independent role for Slamf4 in controlling humoral autoimmunity.J Immunol. 2011 Jul 1;187(1):21-5. doi: 10.4049/jimmunol.1100510. Epub 2011 May 27.
• [11] The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment.Front Immunol. 2018 Nov 28;9:2809. doi: 10.3389/fimmu.2018.02809. eCollection 2018.
• [12] Comparison of NAPSI and N-NAIL for evaluation of fingernail psoriasis in patients with moderate-to-severe plaque psoriasis treated using ustekinumab.J Dermatolog Treat. 2019 Mar;30(2):123-128. doi: 10.1080/09546634.2018.1476649. Epub 2018 May 25.
• [13] Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection.Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):E3883-92. doi: 10.1073/pnas.1501662112. Epub 2015 Jul 6.
• [14] Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML.Leukemia. 2019 Jan;33(1):64-74. doi: 10.1038/s41375-018-0180-3. Epub 2018 Jun 26.
• [15] Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.Nat Genet. 2010 Dec;42(12):1118-25. doi: 10.1038/ng.717.
• [16] T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling.Clin Cancer Res. 2018 Feb 15;24(4):870-881. doi: 10.1158/1078-0432.CCR-17-2337. Epub 2017 Dec 7.
• [17] CD48 on blood leukocytes and in serum of asthma patients varies with severity.Allergy. 2017 Jun;72(6):888-895. doi: 10.1111/all.13082. Epub 2016 Dec 1.
• [18] High expression of CD244 and SAP regulated CD8 T cell responses of patients with HTLV-I associated neurologic disease.PLoS Pathog. 2009 Dec;5(12):e1000682. doi: 10.1371/journal.ppat.1000682. Epub 2009 Dec 4.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.