Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTILCB4K)

• DOT Name: Hematopoietic cell signal transducer (HCST)
• Synonyms: DNAX-activation protein 10; Membrane protein DAP10; Transmembrane adapter protein KAP10
• Gene Name: HCST
• Related Disease:
  Abdominal aortic aneurysm
  Acute graft versus host disease
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Adult lymphoma
  Adult respiratory distress syndrome
  Advanced cancer
  Autoimmune disease
  Beta-thalassemia major
  Childhood acute lymphoblastic leukemia
  Hemorrhagic cystitis
  Lymphoma
  Neoplasm
  Pediatric lymphoma
  Tuberculosis
  Gastric cancer
  Pulmonary tuberculosis
  Stomach cancer
• UniProt ID: HCST_HUMAN
• Pfam ID: PF07213
• Sequence:
  MIHLGHILFLLLLPVAAAQTTPGERSSLPAFYPGTSGSCSGCGSLSLPLLAGLVAADAVA
  SLLIVGAVFLCARPRRSPAQEDGKVYINMPGRG
• Function: Transmembrane adapter protein which associates with KLRK1 to form an activation receptor KLRK1-HCST in lymphoid and myeloid cells; this receptor plays a major role in triggering cytotoxicity against target cells expressing cell surface ligands such as MHC class I chain-related MICA and MICB, and UL16-binding proteins (ULBPs); these ligands are up-regulated by stress conditions and pathological state such as viral infection and tumor transformation. Functions as a docking site for PI3-kinase PIK3R1 and GRB2. Interaction of ULBPs with KLRK1-HCST triggers calcium mobilization and activation of the PIK3R1, MAP2K/ERK, and JAK2/STAT5 signaling pathways. Both PIK3R1 and GRB2 are required for full KLRK1-HCST-mediated activation and ultimate killing of target cells. In NK cells, KLRK1-HCST signaling directly induces cytotoxicity and enhances cytokine production initiated via DAP12/TYROBP-associated receptors. In T-cells, it provides primarily costimulation for TCR-induced signals. KLRK1-HCST receptor plays a role in immune surveillance against tumors and is required for cytolysis of tumors cells; indeed, melanoma cells that do not express KLRK1 ligands escape from immune surveillance mediated by NK cells.
• Tissue Specificity: Predominantly expressed in hemopoietic cells such as NK cells, subset of T-cells and monocytes. Detected in leukocytes, spleen, and thymus.
• KEGG Pathway: .tural killer cell mediated cytotoxicity (hsa04650)
• Reactome Pathway: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[1]
Acute graft versus host disease	DIS8KLVM	Strong	Genetic Variation	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[4]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Biomarker	[7]
Beta-thalassemia major	DISW06BV	Strong	Biomarker	[8]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[3]
Hemorrhagic cystitis	DIS3UA8E	Strong	Biomarker	[9]
Lymphoma	DISN6V4S	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[4]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[10]
Gastric cancer	DISXGOUK	moderate	Biomarker	[11]
Pulmonary tuberculosis	DIS6FLUM	Limited	Biomarker	[10]
Stomach cancer	DISKIJSX	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Hematopoietic cell signal transducer (HCST).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hematopoietic cell signal transducer (HCST).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Hematopoietic cell signal transducer (HCST).	[14]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Hematopoietic cell signal transducer (HCST).	[15]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Hematopoietic cell signal transducer (HCST).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Hematopoietic cell signal transducer (HCST).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Hematopoietic cell signal transducer (HCST).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hematopoietic cell signal transducer (HCST).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Hematopoietic cell signal transducer (HCST).	[20]

References

• [1] Immunohistochemical analysis of the natural killer cell cytotoxicity pathway in human abdominal aortic aneurysms.Int J Mol Sci. 2015 May 18;16(5):11196-212. doi: 10.3390/ijms160511196.
• [2] Peripheral Blood CD38 Bright CD8+ Effector Memory T Cells Predict Acute Graft-versus-Host Disease.Biol Blood Marrow Transplant. 2015 Jul;21(7):1215-22. doi: 10.1016/j.bbmt.2015.04.010. Epub 2015 Apr 13.
• [3] Motor skill delays in pre-school children with leukemia one year after treatment: Hematopoietic stem cell transplantation therapy as an important risk factor.PLoS One. 2017 Oct 24;12(10):e0186787. doi: 10.1371/journal.pone.0186787. eCollection 2017.
• [4] Adoptive transfer of murine T cells expressing a chimeric-PD1-Dap10 receptor as an immunotherapy for lymphoma.Immunology. 2017 Nov;152(3):472-483. doi: 10.1111/imm.12784. Epub 2017 Jul 27.
• [5] Whole blood RNA sequencing reveals a unique transcriptomic profile in patients with ARDS following hematopoietic stem cell transplantation.Respir Res. 2019 Jan 21;20(1):15. doi: 10.1186/s12931-019-0981-6.
• [6] Immunobiology of human NKG2D and its ligands.Curr Top Microbiol Immunol. 2006;298:121-38. doi: 10.1007/3-540-27743-9_6.
• [7] A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia.Blood. 2009 Apr 2;113(14):3226-34. doi: 10.1182/blood-2008-07-168245. Epub 2008 Dec 15.
• [8] Haploidentical haematopoietic stem cell transplantation for thalassaemia major based on an FBCA conditioning regimen.Br J Haematol. 2018 Aug;182(4):554-558. doi: 10.1111/bjh.15438. Epub 2018 Jul 1.
• [9] Intravesicular cidofovir for BK hemorrhagic cystitis in pediatric patients after hematopoietic stem cell transplant.Pediatr Transplant. 2018 May;22(3):e13141. doi: 10.1111/petr.13141. Epub 2018 Feb 1.
• [10] DAP10 contributes to CD8(+) T cell-mediated cytotoxic effector mechanisms during Mycobacterium tuberculosis infection.Immunobiology. 2011 May;216(5):639-47. doi: 10.1016/j.imbio.2010.09.010. Epub 2010 Sep 24.
• [11] Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer.J Hematol Oncol. 2019 Feb 18;12(1):18. doi: 10.1186/s13045-019-0704-y.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] 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.
• [14] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [15] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [16] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [17] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [18] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [19] 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.
• [20] 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.