Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOL603T)

• DOT Name: Hepatitis A virus cellular receptor 2 (HAVCR2)
• Synonyms: HAVcr-2; T-cell immunoglobulin and mucin domain-containing protein 3; TIMD-3; T-cell immunoglobulin mucin receptor 3; TIM-3; T-cell membrane protein 3; CD antigen CD366
• Gene Name: HAVCR2
• Related Disease:
  Hepatitis B virus infection
  Melanoma
  Arteriosclerosis
  Asthma
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Clear cell renal carcinoma
  Colon cancer
  Colorectal carcinoma
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Glioma
  Head and neck cancer
  Head and neck carcinoma
  Head-neck squamous cell carcinoma
  Hemophagocytic syndrome
  Hepatitis A virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Hereditary hemophagocytic lymphohistiocytosis
  HIV infectious disease
  Immunodeficiency
  Leukemia
  Metastatic malignant neoplasm
  Myelodysplastic syndrome
  Nervous system inflammation
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Systemic lupus erythematosus
  T-cell lymphoma
  Bone osteosarcoma
  Colon carcinoma
  Liver cirrhosis
  Osteosarcoma
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Chronic hepatitis B virus infection
  Lung adenocarcinoma
  Pancreatic cancer
• UniProt ID: HAVR2_HUMAN
• PDB ID: 5DZL; 5F71; 6DHB; 6TXZ; 7KQL; 7M3Y; 7M3Z; 7M41; 8HGJ
• Pfam ID: PF07686
• Sequence:
  MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPV
  FECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMND
  EKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLA
  NELRDSRLANDLRDSGATIRIGIYIGAGICAGLALALIFGALIFKWYSHSKEKIQNLSLI
  SLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPNEYYCYVSSRQQPSQPLGCRFAM
  P
• Function: Cell surface receptor implicated in modulating innate and adaptive immune responses. Generally accepted to have an inhibiting function. Reports on stimulating functions suggest that the activity may be influenced by the cellular context and/or the respective ligand. Regulates macrophage activation. Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance. In CD8+ cells attenuates TCR-induced signaling, specifically by blocking NF-kappaB and NFAT promoter activities resulting in the loss of IL-2 secretion. The function may implicate its association with LCK proposed to impair phosphorylation of TCR subunits, and/or LGALS9-dependent recruitment of PTPRC to the immunological synapse. In contrast, shown to activate TCR-induced signaling in T-cells probably implicating ZAP70, LCP2, LCK and FYN. Expressed on Treg cells can inhibit Th17 cell responses. Receptor for LGALS9. Binding to LGALS9 is believed to result in suppression of T-cell responses; the resulting apoptosis of antigen-specific cells may implicate HAVCR2 phosphorylation and disruption of its association with BAG6. Binding to LGALS9 is proposed to be involved in innate immune response to intracellular pathogens. Expressed on Th1 cells interacts with LGALS9 expressed on Mycobacterium tuberculosis-infected macrophages to stimulate antibactericidal activity including IL-1 beta secretion and to restrict intracellular bacterial growth. However, the function as receptor for LGALS9 has been challenged. Also reported to enhance CD8+ T-cell responses to an acute infection such as by Listeria monocytogenes. Receptor for phosphatidylserine (PtSer); PtSer-binding is calcium-dependent. May recognize PtSer on apoptotic cells leading to their phagocytosis. Mediates the engulfment of apoptotic cells by dendritic cells. Expressed on T-cells, promotes conjugation but not engulfment of apoptotic cells. Expressed on dendritic cells (DCs) positively regulates innate immune response and in synergy with Toll-like receptors promotes secretion of TNF-alpha. In tumor-imfiltrating DCs suppresses nucleic acid-mediated innate immune repsonse by interaction with HMGB1 and interfering with nucleic acid-sensing and trafficking of nucleid acids to endosomes. Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9. In contrast, shown to suppress NK cell-mediated cytotoxicity. Negatively regulates NK cell function in LPS-induced endotoxic shock.
• Tissue Specificity: Expressed in T-helper type 1 (Th1) lymphocytes. Expressed on regulatory T (Treg) cells after TCR stimulation. Expressed in dendritic cells and natural killer (NK) cells. Expressed in epithelial tissues. Expression is increased on CD4+ and CD8+ T-cells in chronic hepatitis C virus (HCV) infection. In progressive HIV-1 infection, expression is up-regulated on HIV-1-specific CD8 T-cells.
• KEGG Pathway: Efferocytosis (hsa04148)
• Reactome Pathway: Interleukin-2 family signaling (R-HSA-451927)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis B virus infection	DISLQ2XY	Definitive	Genetic Variation	[1]
Melanoma	DIS1RRCY	Definitive	Altered Expression	[2]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[3]
Asthma	DISW9QNS	Strong	Altered Expression	[4]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[11]
Glioma	DIS5RPEH	Strong	Altered Expression	[12]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[13]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[13]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[2]
Hemophagocytic syndrome	DIS3TMN4	Strong	Biomarker	[14]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[15]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[17]
Hereditary hemophagocytic lymphohistiocytosis	DISQP21Z	Strong	Biomarker	[14]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[18]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[19]
Leukemia	DISNAKFL	Strong	Altered Expression	[20]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[21]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[22]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[23]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[13]
Prostate cancer	DISF190Y	Strong	Altered Expression	[24]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[24]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[7]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[25]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[26]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[13]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[8]
Liver cirrhosis	DIS4G1GX	moderate	Altered Expression	[27]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[13]
Acute monocytic leukemia	DIS28NEL	Limited	Altered Expression	[28]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[29]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Biomarker	[30]
Lung adenocarcinoma	DISD51WR	Limited	Biomarker	[31]
Pancreatic cancer	DISJC981	Limited	Biomarker	[32]

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 Hepatitis A virus cellular receptor 2 (HAVCR2).	[33]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Hepatitis A virus cellular receptor 2 (HAVCR2).	[34]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Hepatitis A virus cellular receptor 2 (HAVCR2).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Hepatitis A virus cellular receptor 2 (HAVCR2).	[36]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Hepatitis A virus cellular receptor 2 (HAVCR2).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Hepatitis A virus cellular receptor 2 (HAVCR2).	[38]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Hepatitis A virus cellular receptor 2 (HAVCR2).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the methylation of Hepatitis A virus cellular receptor 2 (HAVCR2).	[39]

References

• [1] Genetic association and interaction of PD1 and TIM3 polymorphisms in susceptibility of chronic hepatitis B virus infection and hepatocarcinogenesis.Discov Med. 2019 Feb;27(147):79-92.
• [2] Immune-Checkpoint Blockade Opposes CD8(+) T-cell Suppression in Human and Murine Cancer.Cancer Immunol Res. 2019 Mar;7(3):510-525. doi: 10.1158/2326-6066.CIR-18-0054. Epub 2019 Feb 6.
• [3] Statins reduce the expressions of Tim-3 on NK cells and NKT cells in atherosclerosis.Eur J Pharmacol. 2018 Feb 15;821:49-56. doi: 10.1016/j.ejphar.2017.12.050. Epub 2017 Dec 27.
• [4] Elevated Expression of Tim-3 and PD-1 Immune Checkpoint Receptors on T-CD4+ Lymphocytes of Patients with Asthma.Iran J Allergy Asthma Immunol. 2018 Dec 2;17(6):517-525.
• [5] Interaction of Breast Cancer and Insulin Resistance on PD1 and TIM3 Expression in Peripheral Blood CD8 T Cells.Pathol Oncol Res. 2019 Jul;25(3):1233-1243. doi: 10.1007/s12253-019-00610-7. Epub 2019 Feb 13.
• [6] Regulation of TIM-3 expression in a human T cell line by tumor-conditioned media and cyclic AMP-dependent signaling.Mol Immunol. 2019 Jan;105:224-232. doi: 10.1016/j.molimm.2018.12.006. Epub 2018 Dec 13.
• [7] Differential expression of TIM-3 between primary and metastatic sites in renal cell carcinoma.BMC Cancer. 2019 Jan 10;19(1):49. doi: 10.1186/s12885-019-5273-5.
• [8] Tim-3 suppresses the killing effect of V9V2T cells on colon cancer cells by reducing perforin and granzyme B expression.Exp Cell Res. 2020 Jan 1;386(1):111719. doi: 10.1016/j.yexcr.2019.111719. Epub 2019 Nov 11.
• [9] Down-regulated expression of Tim-3 promotes invasion and metastasis of colorectal cancer cells.Neoplasma. 2017;64(1):101-107. doi: 10.4149/neo_2017_112.
• [10] Expression of multiple immune checkpoint molecules on T cells in malignant ascites from epithelial ovarian carcinoma.Oncol Lett. 2018 May;15(5):6457-6468. doi: 10.3892/ol.2018.8101. Epub 2018 Feb 21.
• [11] RARRES1 is a novel immune-related biomarker in GBM.Am J Transl Res. 2019 Sep 15;11(9):5655-5663. eCollection 2019.
• [12] Tim-3 expression in glioma cells is associated with drug resistance.J Cancer Res Ther. 2019;15(4):882-888. doi: 10.4103/jcrt.JCRT_630_18.
• [13] TIM-3 expression and its association with overall survival in primary osteosarcoma.Oncol Lett. 2019 Nov;18(5):5294-5300. doi: 10.3892/ol.2019.10855. Epub 2019 Sep 12.
• [14] Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome.Nat Genet. 2018 Dec;50(12):1650-1657. doi: 10.1038/s41588-018-0251-4. Epub 2018 Oct 29.
• [15] Identification, characterization, expression profiles of OlHavcr2 in medaka (Oryzias latipes).Gen Comp Endocrinol. 2019 Jun 1;277:30-37. doi: 10.1016/j.ygcen.2018.10.023. Epub 2018 Nov 3.
• [16] Expression of programmed cell death protein 1 and T-cell immunoglobulin- and mucin-domain-containing molecule-3 on peripheral blood CD4+CD8+ double positive T cells in patients with chronic hepatitis C virus infection and in subjects who spontaneously cleared the virus.J Viral Hepat. 2019 Aug;26(8):942-950. doi: 10.1111/jvh.13108. Epub 2019 Apr 29.
• [17] Tim-3 Hampers Tumor Surveillance of Liver-Resident and Conventional NK Cells by Disrupting PI3K Signaling.Cancer Res. 2020 Mar 1;80(5):1130-1142. doi: 10.1158/0008-5472.CAN-19-2332. Epub 2019 Dec 17.
• [18] Expression of PD-1 and Tim-3 markers of T-cell exhaustion is associated with CD4 dynamics during the course of untreated and treated HIV infection.PLoS One. 2018 Mar 8;13(3):e0193829. doi: 10.1371/journal.pone.0193829. eCollection 2018.
• [19] Levels of Human Immunodeficiency Virus DNA Are Determined Before ART Initiation and Linked to CD8 T-Cell Activation and Memory Expansion.J Infect Dis. 2020 Mar 16;221(7):1135-1145. doi: 10.1093/infdis/jiz563.
• [20] Murine pre-B-cell ALL induces T-cell dysfunction not fully reversed by introduction of a chimeric antigen receptor.Blood. 2018 Nov 1;132(18):1899-1910. doi: 10.1182/blood-2017-12-815548. Epub 2018 Sep 12.
• [21] Altered frequency and function of spleen CTLA-4+Tim-3+ T cells are associated with miscarriage?"Wang S. Sun F
• [22] CD8(+) T cells exhaustion induced by myeloid-derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal-9 pathway.J Cell Mol Med. 2020 Jan;24(1):1046-1058. doi: 10.1111/jcmm.14825. Epub 2019 Nov 22.
• [23] The TIM-3 pathway ameliorates Theiler's murine encephalomyelitis virus-induced demyelinating disease.Int Immunol. 2014 Jul;26(7):369-81. doi: 10.1093/intimm/dxt056. Epub 2014 Jan 31.
• [24] Significance of the detection of TIM-3 and FOXJ1 in prostate cancer.J BUON. 2017 Jul-Aug;22(4):1017-1021.
• [25] Frontline Science: Tim-3-mediated dysfunctional engulfment of apoptotic cells in SLE.J Leukoc Biol. 2017 Dec;102(6):1313-1322. doi: 10.1189/jlb.3HI0117-005RR. Epub 2017 Jul 28.
• [26] Expression of the checkpoint receptors LAG-3, TIM-3 and VISTA in peripheral T cell lymphomas.J Clin Pathol. 2020 Apr;73(4):197-203. doi: 10.1136/jclinpath-2019-206117. Epub 2019 Oct 31.
• [27] Dysregulation of FTX/miR-545 signaling pathway downregulates Tim-3 and is responsible for the abnormal activation of macrophage in cirrhosis.J Cell Biochem. 2019 Feb;120(2):2336-2346. doi: 10.1002/jcb.27562. Epub 2018 Oct 10.
• [28] Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy.J Immunother Cancer. 2019 Jul 10;7(1):175. doi: 10.1186/s40425-019-0611-3.
• [29] IL-21-mediated expansion of V9V2 T cells is limited by the Tim-3 pathway.Int Immunopharmacol. 2019 Apr;69:136-142. doi: 10.1016/j.intimp.2019.01.027. Epub 2019 Jan 29.
• [30] Tim-3 regulates inflammatory cytokine expression and Th17 cell response induced by monocytes from patients with chronic hepatitis B.Scand J Immunol. 2019 May;89(5):e12755. doi: 10.1111/sji.12755. Epub 2019 Mar 18.
• [31] TOX3 is a favorable prognostic indicator and potential immunomodulatory factor in lung adenocarcinoma.Oncol Lett. 2019 Oct;18(4):4144-4152. doi: 10.3892/ol.2019.10748. Epub 2019 Aug 16.
• [32] Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer.J Exp Clin Cancer Res. 2017 Feb 28;36(1):36. doi: 10.1186/s13046-017-0509-1.
• [33] 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.
• [34] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [35] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [36] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [37] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [38] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [39] Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women. Environ Health Perspect. 2022 Apr;130(4):47001. doi: 10.1289/EHP10174. Epub 2022 Apr 4.
• [40] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.