Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXP1QC5)

• DOT Name: Interleukin-15 receptor subunit alpha (IL15RA)
• Synonyms: IL-15 receptor subunit alpha; IL-15R-alpha; IL-15RA; CD antigen CD215
• Gene Name: IL15RA
• UniProt ID: I15RA_HUMAN
• PDB ID: 2ERS; 2Z3Q; 2Z3R; 4GS7
• Sequence:
  MAPRRARGCRTLGLPALLLLLLLRPPATRGITCPPPMSVEHADIWVKSYSLYSRERYICN
  SGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTTAGVTPQPE
  SLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSHGTPSQTTA
  KNWELTASASHQPPGVYPQGHSDTTVAISTSTVLLCGLSAVSLLACYLKSRQTPPLASVE
  MEAMEALPVTWGTSSRDEDLENCSHHL
• Function: High-affinity receptor for interleukin-15. Can signal both in cis and trans where IL15R from one subset of cells presents IL15 to neighboring IL2RG-expressing cells. In neutrophils, binds and activates kinase SYK in response to IL15 stimulation. In neutrophils, required for IL15-induced phagocytosis in a SYK-dependent manner. Expression of different isoforms may alter or interfere with signal transduction ; [Isoform 5]: Does not bind IL15; [Isoform 6]: Does not bind IL15; [Isoform 7]: Does not bind IL15; [Isoform 8]: Does not bind IL15.
• Tissue Specificity: Expressed in neutrophils (at protein level) . Expressed in fetal brain with higher expression in the hippocampus and cerebellum than in cortex and thalamus . Higher levels of soluble sIL-15RA form in comparison with membrane-bound forms is present in all brain structures . Isoforms 1, 3, 4, 5, 6, 7, 8 and 9: Widely expressed .
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  JAK-STAT sig.ling pathway (hsa04630)
  Intesti.l immune network for IgA production (hsa04672)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Pathways in cancer (hsa05200)
• Reactome Pathway: Interleukin-15 signaling (R-HSA-8983432)

Molecular Interaction Atlas (MIA) of This DOT

6 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 Interleukin-15 receptor subunit alpha (IL15RA).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interleukin-15 receptor subunit alpha (IL15RA).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-15 receptor subunit alpha (IL15RA).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interleukin-15 receptor subunit alpha (IL15RA).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interleukin-15 receptor subunit alpha (IL15RA).	[6]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Interleukin-15 receptor subunit alpha (IL15RA).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Interleukin-15 receptor subunit alpha (IL15RA).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Interleukin-15 receptor subunit alpha (IL15RA).	[8]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [7] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [8] 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.