Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC8BWQS)

• DOT Name: Interleukin-31 receptor subunit alpha (IL31RA)
• Synonyms: IL-31 receptor subunit alpha; IL-31R subunit alpha; IL-31R-alpha; IL-31RA; Cytokine receptor-like 3; GLM-R; hGLM-R; Gp130-like monocyte receptor; Gp130-like receptor; ZcytoR17
• Gene Name: IL31RA
• Related Disease:
  Familial primary localized cutaneous amyloidosis
  Amyloidosis, primary localized cutaneous, 2
• UniProt ID: IL31R_HUMAN
• Pfam ID: PF00041 ; PF09240
• Sequence:
  MMWTWALWMLPSLCKFSLAALPAKPENISCVYYYRKNLTCTWSPGKETSYTQYTVKRTYA
  FGEKHDNCTTNSSTSENRASCSFFLPRITIPDNYTIEVEAENGDGVIKSHMTYWRLENIA
  KTEPPKIFRVKPVLGIKRMIQIEWIKPELAPVSSDLKYTLRFRTVNSTSWMEVNFAKNRK
  DKNQTYNLTGLQPFTEYVIALRCAVKESKFWSDWSQEKMGMTEEEAPCGLELWRVLKPAE
  ADGRRPVRLLWKKARGAPVLEKTLGYNIWYYPESNTNLTETMNTTNQQLELHLGGESFWV
  SMISYNSLGKSPVATLRIPAIQEKSFQCIEVMQACVAEDQLVVKWQSSALDVNTWMIEWF
  PDVDSEPTTLSWESVSQATNWTIQQDKLKPFWCYNISVYPMLHDKVGEPYSIQAYAKEGV
  PSEGPETKVENIGVKTVTITWKEIPKSERKGIICNYTIFYQAEGGKGFSKTVNSSILQYG
  LESLKRKTSYIVQVMASTSAGGTNGTSINFKTLSFSVFEIILITSLIGGGLLILIILTVA
  YGLKKPNKLTHLCWPTVPNPAESSIATWHGDDFKDKLNLKESDDSVNTEDRILKPCSTPS
  DKLVIDKLVVNFGNVLQEIFTDEARTGQENNLGGEKNGYVTCPFRPDCPLGKSFEELPVS
  PEIPPRKSQYLRSRMPEGTRPEAKEQLLFSGQSLVPDHLCEEGAPNPYLKNSVTAREFLV
  SEKLPEHTKGEV
• Function: Associates with OSMR to form the interleukin-31 receptor which activates STAT3 and to a lower extent STAT1 and STAT5. May function in skin immunity. Mediates IL31-induced itch, probably in a manner dependent on cation channels TRPA1 and TRPV1. Positively regulates numbers and cycling status of immature subsets of myeloid progenitor cells in bone marrow in vivo and enhances myeloid progenitor cell survival in vitro.
• Tissue Specificity: Expressed in CD14- and CD56-positive blood cells . Expressed in macrophages . Expressed in keratinocytes . Expressed in a subset of dorsal root ganglia neurons (at protein level) . Expressed at low levels in testis, ovary, brain, prostate, placenta, thymus, bone marrow, trachea and skin . Expressed in bronchial and alveolar epithelial cells and pulmonary fibroblasts . Detected in all of the myelomonocytic lineage . Isoform 6: Expressed at higher levels in lesional skin compared to healthy skin of atopic dermatitis patients .
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  JAK-STAT sig.ling pathway (hsa04630)
• Reactome Pathway: IL-6-type cytokine receptor ligand interactions (R-HSA-6788467)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial primary localized cutaneous amyloidosis	DISDIR8A	Supportive	Autosomal dominant	[1]
Amyloidosis, primary localized cutaneous, 2	DISJ2M3P	Limited	Autosomal dominant	[2]

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-31 receptor subunit alpha (IL31RA).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Interleukin-31 receptor subunit alpha (IL31RA).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Interleukin-31 receptor subunit alpha (IL31RA).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Interleukin-31 receptor subunit alpha (IL31RA).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-31 receptor subunit alpha (IL31RA).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Interleukin-31 receptor subunit alpha (IL31RA).	[8]

References

• [1] Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis. Eur J Hum Genet. 2010 Jan;18(1):26-32. doi: 10.1038/ejhg.2009.135.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [7] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [8] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.