Details of Drug Off-Target (DOT)

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

• DOT Name: Interferon alpha/beta receptor 2 (IFNAR2)
• Synonyms: IFN-R-2; IFN-alpha binding protein; IFN-alpha/beta receptor 2; Interferon alpha binding protein; Type I interferon receptor 2
• Gene Name: IFNAR2
• Related Disease: Immunodeficiency 45
• UniProt ID: INAR2_HUMAN
• PDB ID: 1N6U; 1N6V; 2HYM; 2KZ1; 2LAG; 3S8W; 3S9D; 3SE3; 3SE4
• Pfam ID: PF09294 ; PF01108
• Sequence:
  MLLSQNAFIFRSLNLVLMVYISLVFGISYDSPDYTDESCTFKISLRNFRSILSWELKNHS
  IVPTHYTLLYTIMSKPEDLKVVKNCANTTRSFCDLTDEWRSTHEAYVTVLEGFSGNTTLF
  SCSHNFWLAIDMSFEPPEFEIVGFTNHINVMVKFPSIVEEELQFDLSLVIEEQSEGIVKK
  HKPEIKGNMSGNFTYIIDKLIPNTNYCVSVYLEHSDEQAVIKSPLKCTLLPPGQESESAE
  SAKIGGIITVFLIALVLTSTIVTLKWIGYICLRNSLPKVLNFHNFLAWPFPNLPPLEAMD
  MVEVIYINRKKKVWDYNYDDESDSDTEAAPRTSGGGYTMHGLTVRPLGQASATSTESQLI
  DPESEEEPDLPEVDVELPTMPKDSPQQLELLSGPCERRKSPLQDPFPEEDYSSTEGSGGR
  ITFNVDLNSVFLRVLDDEDSDDLEAPLMLSSHLEEMVDPEDPDNVQSNHLLASGEGTQPT
  FPSPSSEGLWSEDAPSDQSDTSESDVDLGDGYIMR
• Function: Together with IFNAR1, forms the heterodimeric receptor for type I interferons (including interferons alpha, beta, epsilon, omega and kappa). Type I interferon binding activates the JAK-STAT signaling cascade, resulting in transcriptional activation or repression of interferon-regulated genes that encode the effectors of the interferon response. Mechanistically, type I interferon-binding brings the IFNAR1 and IFNAR2 subunits into close proximity with one another, driving their associated Janus kinases (JAKs) (TYK2 bound to IFNAR1 and JAK1 bound to IFNAR2) to cross-phosphorylate one another. The activated kinases phosphorylate specific tyrosine residues on the intracellular domains of IFNAR1 and IFNAR2, forming docking sites for the STAT transcription factors (STAT1, STAT2 and STAT). STAT proteins are then phosphorylated by the JAKs, promoting their translocation into the nucleus to regulate expression of interferon-regulated genes ; [Isoform 3]: Potent inhibitor of type I IFN receptor activity.
• Tissue Specificity: Isoform 3 is detected in the urine (at protein level) . Expressed in blood cells. Expressed in lymphoblastoid and fibrosarcoma cell lines.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  PI3K-Akt sig.ling pathway (hsa04151)
  Necroptosis (hsa04217)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  JAK-STAT sig.ling pathway (hsa04630)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Hepatitis C (hsa05160)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 45	DISUPB0X	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Interferon alpha/beta receptor 2 (IFNAR2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Interferon alpha/beta receptor 2 (IFNAR2).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interferon alpha/beta receptor 2 (IFNAR2).	[5]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Interferon alpha/beta receptor 2 (IFNAR2).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Interferon alpha/beta receptor 2 (IFNAR2).	[7]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Interferon alpha/beta receptor 2 (IFNAR2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Interferon alpha/beta receptor 2 (IFNAR2).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interferon alpha/beta receptor 2 (IFNAR2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Interferon alpha/beta receptor 2 (IFNAR2).	[11]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Interferon alpha/beta receptor 2 (IFNAR2).	[13]

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 Interferon alpha/beta receptor 2 (IFNAR2).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Interferon alpha/beta receptor 2 (IFNAR2).	[12]

References

• [1] Human IFNAR2 deficiency: Lessons for antiviral immunity. Sci Transl Med. 2015 Sep 30;7(307):307ra154. doi: 10.1126/scitranslmed.aac4227.
• [2] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [3] 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.
• [4] 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.
• [5] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [6] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [7] 5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells. Anticancer Res. 2005 Sep-Oct;25(5):3271-8.
• [8] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [9] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [10] 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.
• [11] 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.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.