Details of Drug Off-Target (DOT)

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

• DOT Name: Interleukin-22 receptor subunit alpha-1 (IL22RA1)
• Synonyms: IL-22 receptor subunit alpha-1; IL-22R-alpha-1; IL-22RA1; Cytokine receptor class-II member 9; Cytokine receptor family 2 member 9; CRF2-9; ZcytoR11
• Gene Name: IL22RA1
• Related Disease:
  Adult glioblastoma
  Colitis
  Colon cancer
  Colon carcinoma
  Glioblastoma multiforme
  IgA nephropathy
  Nasal polyp
  Neoplasm
  Psoriasis
  Rheumatoid arthritis
  Influenza
  Pancreatic cancer
  Advanced cancer
  Glaucoma/ocular hypertension
  Pneumococcal infection
  Primary cutaneous T-cell lymphoma
  Thyroid gland papillary carcinoma
• UniProt ID: I22R1_HUMAN
• PDB ID: 3DGC; 3DLQ; 6DF3
• Pfam ID: PF01108
• Sequence:
  MRTLLTILTVGSLAAHAPEDPSDLLQHVKFQSSNFENILTWDSGPEGTPDTVYSIEYKTY
  GERDWVAKKGCQRITRKSCNLTVETGNLTELYYARVTAVSAGGRSATKMTDRFSSLQHTT
  LKPPDVTCISKVRSIQMIVHPTPTPIRAGDGHRLTLEDIFHDLFYHLELQVNRTYQMHLG
  GKQREYEFFGLTPDTEFLGTIMICVPTWAKESAPYMCRVKTLPDRTWTYSFSGAFLFSMG
  FLVAVLCYLSYRYVTKPPAPPNSLNVQRVLTFQPLRFIQEHVLIPVFDLSGPSSLAQPVQ
  YSQIRVSGPREPAGAPQRHSLSEITYLGQPDISILQPSNVPPPQILSPLSYAPNAAPEVG
  PPSYAPQVTPEAQFPFYAPQAISKVQPSSYAPQATPDSWPPSYGVCMEGSGKDSPTGTLS
  SPKHLRPKGQLQKEPPAGSCMLGGLSLQEVTSLAMEESQEAKSLHQPLGICTDRTSDPNV
  LHSGEEGTPQYLKGQLPLLSSVQIEGHPMSLPLQPPSRPCSPSDQGPSPWGLLESLVCPK
  DEAKSPAPETSDLEQPTELDSLFRGLALTVQWES
• Function: Component of the receptor for IL20, IL22 and IL24. Component of IL22 receptor formed by IL22RA1 and IL10RB enabling IL22 signaling via JAK/STAT pathways. IL22 also induces activation of MAPK1/MAPK3 and Akt kinases pathways. Component of one of the receptor for IL20 and IL24 formed by IL22RA1 and IL20RB also signaling through STATs activation. Mediates IL24 antiangiogenic activity as well as IL24 inhibitory effect on endothelial cell tube formation and differentiation.
• Tissue Specificity: Expressed in colon, liver, lung, pancreas and kidney. No expression in immune cells such as monocytes, T-cells, and NK-cells. Expressed in keratinocytes of normal skin as well as in psoriatic skin lesion. Detected in normal blood brain barrier endothelial cells as well as in multiple sclerosis lesions; Strongly expressed on central nervous system vessels within infiltrated multiple sclerosis lesions. Overexpressed in synovial fluid cells from rheumatoid arthritis and spondyloarthropathy patients.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  JAK-STAT sig.ling pathway (hsa04630)
• Reactome Pathway: Interleukin-20 family signaling (R-HSA-8854691)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Colitis	DISAF7DD	Strong	Altered Expression	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
IgA nephropathy	DISZ8MTK	Strong	Altered Expression	[4]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Psoriasis	DIS59VMN	Strong	Altered Expression	[6]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[7]
Influenza	DIS3PNU3	moderate	Biomarker	[8]
Pancreatic cancer	DISJC981	moderate	Biomarker	[9]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[1]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[10]
Pneumococcal infection	DIS6SXQD	Limited	Biomarker	[11]
Primary cutaneous T-cell lymphoma	DIS35WVW	Limited	Biomarker	[12]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[20]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[25]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Interleukin-22 receptor subunit alpha-1 (IL22RA1).	[26]

References

• [1] IL22 furthers malignant transformation of rat mesenchymal stem cells, possibly in association with IL22RA1/STAT3 signaling.Oncol Rep. 2019 Apr;41(4):2148-2158. doi: 10.3892/or.2019.7007. Epub 2019 Feb 11.
• [2] IL10R2 Overexpression Promotes IL22/STAT3 Signaling in Colorectal Carcinogenesis.Cancer Immunol Res. 2015 Nov;3(11):1227-35. doi: 10.1158/2326-6066.CIR-15-0031. Epub 2015 Jun 30.
• [3] Screening of Differentiation-Specific Molecular Biomarkers for Colon Cancer.Cell Physiol Biochem. 2018;46(6):2543-2550. doi: 10.1159/000489660. Epub 2018 May 5.
• [4] A polymorphism of interleukin-22 receptor alpha-1 is associated with the development of childhood IgA nephropathy.J Interferon Cytokine Res. 2013 Oct;33(10):571-7. doi: 10.1089/jir.2012.0097. Epub 2013 May 9.
• [5] Polymorphisms in the interleukin-22 receptor alpha-1 gene are associated with severe chronic rhinosinusitis.Otolaryngol Head Neck Surg. 2009 May;140(5):741-7. doi: 10.1016/j.otohns.2008.12.058. Epub 2009 Feb 28.
• [6] Ultrasound targeting of Q-starch/miR-197 complexes for topical treatment of psoriasis.J Control Release. 2018 Aug 28;284:103-111. doi: 10.1016/j.jconrel.2018.05.040. Epub 2018 Jun 2.
• [7] The IL-20 Cytokine Family in Rheumatoid Arthritis and Spondyloarthritis.Front Immunol. 2018 Sep 25;9:2226. doi: 10.3389/fimmu.2018.02226. eCollection 2018.
• [8] IL-22Ra1 is induced during influenza infection by direct and indirect TLR3 induction of STAT1.Respir Res. 2019 Aug 15;20(1):184. doi: 10.1186/s12931-019-1153-4.
• [9] IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer.Cancer Res. 2018 Jun 15;78(12):3293-3305. doi: 10.1158/0008-5472.CAN-17-3131. Epub 2018 Mar 23.
• [10] LncRNA NR_003923 promotes cell proliferation, migration, fibrosis, and autophagy via the miR-760/miR-215-3p/IL22RA1 axis in human Tenon's capsule fibroblasts.Cell Death Dis. 2019 Aug 7;10(8):594. doi: 10.1038/s41419-019-1829-1.
• [11] Interleukin-22 (IL-22) Binding Protein Constrains IL-22 Activity, Host Defense, and Oxidative Phosphorylation Genes during Pneumococcal Pneumonia.Infect Immun. 2019 Oct 18;87(11):e00550-19. doi: 10.1128/IAI.00550-19. Print 2019 Nov.
• [12] MicroRNA-150 inhibits tumor invasion and metastasis by targeting the chemokine receptor CCR6, in advanced cutaneous T-cell lymphoma.Blood. 2014 Mar 6;123(10):1499-511. doi: 10.1182/blood-2013-09-527739. Epub 2014 Jan 2.
• [13] Interleukin 22 polymorphisms and papillary thyroid cancer.J Endocrinol Invest. 2013 Sep;36(8):584-7. doi: 10.3275/8879. Epub 2013 Feb 27.
• [14] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [15] 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.
• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [20] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [21] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [22] 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.
• [23] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [24] 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.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.