Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO3QT6Q)

DOT Name E3 ubiquitin-protein ligase Arkadia (RNF111)
Synonyms EC 2.3.2.27; RING finger protein 111; hRNF111; RING-type E3 ubiquitin transferase Arkadia
Gene Name RNF111
Related Disease
Carcinoma of esophagus ( )
Esophageal cancer ( )
Neoplasm of esophagus ( )
Advanced cancer ( )
Asthma ( )
Atopic dermatitis ( )
Cardiac failure ( )
Clear cell renal carcinoma ( )
Congestive heart failure ( )
Lung carcinoma ( )
Lung neoplasm ( )
Metastatic malignant neoplasm ( )
Neoplasm ( )
Non-small-cell lung cancer ( )
Renal fibrosis ( )
Colorectal carcinoma ( )
Colorectal neoplasm ( )
Dilated cardiomyopathy ( )
UniProt ID
RN111_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2KIZ; 5LG0; 5LG7; 7P2K
EC Number
2.3.2.27
Pfam ID
PF15303 ; PF13639
Sequence
MSQWTPEYNELYTLKVDMKSEIPSDAPKTQESLKGILLHPEPIGAAKSFPAGVEMINSKV
GNEFSHLCDDSQKQEKEMNGNQQEQEKSLVVRKKRKSQQAGPSYVQNCVKENQGILGLRQ
HLGTPSDEDNDSSFSDCLSSPSSSLHFGDSDTVTSDEDKEVSVRHSQTILNAKSRSHSAR
SHKWPRTETESVSGLLMKRPCLHGSSLRRLPCRKRFVKNNSSQRTQKQKERILMQRKKRE
VLARRKYALLPSSSSSSENDLSSESSSSSSTEGEEDLFVSASENHQNNPAVPSGSIDEDV
VVIEASSTPQVTANEEINVTSTDSEVEIVTVGESYRSRSTLGHSRSHWSQGSSSHASRPQ
EPRNRSRISTVIQPLRQNAAEVVDLTVDEDEPTVVPTTSARMESQATSASINNSNPSTSE
QASDTASAVTSSQPSTVSETSATLTSNSTTGTSIGDDSRRTTSSAVTETGPPAMPRLPSC
CPQHSPCGGSSQNHHALGHPHTSCFQQHGHHFQHHHHHHHTPHPAVPVSPSFSDPACPVE
RPPQVQAPCGANSSSGTSYHEQQALPVDLSNSGIRSHGSGSFHGASAFDPCCPVSSSRAA
IFGHQAAAAAPSQPLSSIDGYGSSMVAQPQPQPPPQPSLSSCRHYMPPPYASLTRPLHHQ
ASACPHSHGNPPPQTQPPPQVDYVIPHPVHAFHSQISSHATSHPVAPPPPTHLASTAAPI
PQHLPPTHQPISHHIPATAPPAQRLHPHEVMQRMEVQRRRMMQHPTRAHERPPPHPHRMH
PNYGHGHHIHVPQTMSSHPRQAPERSAWELGIEAGVTAATYTPGALHPHLAHYHAPPRLH
HLQLGALPLMVPDMAGYPHIRYISSGLDGTSFRGPFRGNFEELIHLEERLGNVNRGASQG
TIERCTYPHKYKKVTTDWFSQRKLHCKQDGEEGTEEDTEEKCTICLSILEEGEDVRRLPC
MHLFHQVCVDQWLITNKKCPICRVDIEAQLPSES
Function
E3 ubiquitin-protein ligase. Required for mesoderm patterning during embryonic development. Acts as an enhancer of the transcriptional responses of the SMAD2/SMAD3 effectors, which are activated downstream of BMP. Acts by mediating ubiquitination and degradation of SMAD inhibitors such as SMAD7, inducing their proteasomal degradation and thereby enhancing the transcriptional activity of TGF-beta and BMP. In addition to enhance transcription of SMAD2/SMAD3 effectors, also regulates their turnover by mediating their ubiquitination and subsequent degradation, coupling their activation with degradation, thereby ensuring that only effectors 'in use' are degraded. Activates SMAD3/SMAD4-dependent transcription by triggering signal-induced degradation of SNON isoform of SKIL. Associates with UBE2D2 as an E2 enzyme. Specifically binds polysumoylated chains via SUMO interaction motifs (SIMs) and mediates ubiquitination of sumoylated substrates. Catalyzes 'Lys-63'-linked ubiquitination of sumoylated XPC in response to UV irradiation, promoting nucleotide excision repair. Mediates ubiquitination and degradation of sumoylated PML. The regulation of the BMP-SMAD signaling is however independent of sumoylation and is not dependent of SUMO interaction motifs (SIMs).
Tissue Specificity Broadly expressed.
Reactome Pathway
SMAD2/SMAD3 (R-HSA-2173796 )
Formation of Incision Complex in GG-NER (R-HSA-5696395 )
Antigen processing (R-HSA-983168 )
Downregulation of SMAD2/3 (R-HSA-2173795 )

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Carcinoma of esophagus DISS6G4D Definitive Altered Expression [1]
Esophageal cancer DISGB2VN Definitive Altered Expression [1]
Neoplasm of esophagus DISOLKAQ Definitive Altered Expression [1]
Advanced cancer DISAT1Z9 Strong Biomarker [2]
Asthma DISW9QNS Strong Biomarker [3]
Atopic dermatitis DISTCP41 Strong Genetic Variation [4]
Cardiac failure DISDC067 Strong Altered Expression [5]
Clear cell renal carcinoma DISBXRFJ Strong Biomarker [6]
Congestive heart failure DIS32MEA Strong Altered Expression [5]
Lung carcinoma DISTR26C Strong Biomarker [2]
Lung neoplasm DISVARNB Strong Biomarker [7]
Metastatic malignant neoplasm DIS86UK6 Strong Biomarker [2]
Neoplasm DISZKGEW Strong Altered Expression [6]
Non-small-cell lung cancer DIS5Y6R9 Strong Biomarker [7]
Renal fibrosis DISMHI3I Strong Biomarker [8]
Colorectal carcinoma DIS5PYL0 Disputed Biomarker [9]
Colorectal neoplasm DISR1UCN Disputed Genetic Variation [9]
Dilated cardiomyopathy DISX608J Limited Altered Expression [10]
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⏷ Show the Full List of 18 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
4 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the expression of E3 ubiquitin-protein ligase Arkadia (RNF111). [11]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of E3 ubiquitin-protein ligase Arkadia (RNF111). [12]
Selenium DM25CGV Approved Selenium decreases the expression of E3 ubiquitin-protein ligase Arkadia (RNF111). [13]
Tocopherol DMBIJZ6 Phase 2 Tocopherol decreases the expression of E3 ubiquitin-protein ligase Arkadia (RNF111). [13]
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1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of E3 ubiquitin-protein ligase Arkadia (RNF111). [14]
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References

1 Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation.Mol Cell Biol. 2007 Sep;27(17):6068-83. doi: 10.1128/MCB.00664-07. Epub 2007 Jun 25.
2 Arkadia regulates tumor metastasis by modulation of the TGF- pathway.Cancer Res. 2013 Mar 15;73(6):1800-10. doi: 10.1158/0008-5472.CAN-12-1916. Epub 2013 Mar 6.
3 The beta-adrenoceptor. Am J Respir Crit Care Med. 1998 Nov;158(5 Pt 3):S146-53.
4 A genome-wide association study reveals 2 new susceptibility loci for atopic dermatitis.J Allergy Clin Immunol. 2015 Sep;136(3):802-6. doi: 10.1016/j.jaci.2015.01.047. Epub 2015 Apr 10.
5 Expression of beta-arrestins and beta-adrenergic receptor kinases in the failing human heart.Circ Res. 1994 Feb;74(2):206-13. doi: 10.1161/01.res.74.2.206.
6 The Arkadia-ESRP2 axis suppresses tumor progression: analyses in clear-cell renal cell carcinoma.Oncogene. 2016 Jul 7;35(27):3514-23. doi: 10.1038/onc.2015.412. Epub 2015 Nov 2.
7 RNF111/Arkadia is regulated by DNA methylation and affects TGF-/Smad signaling associated invasion in NSCLC cells.Lung Cancer. 2015 Oct;90(1):32-40. doi: 10.1016/j.lungcan.2015.07.010. Epub 2015 Jul 26.
8 SnoN upregulation ameliorates renal fibrosis in diabetic nephropathy.PLoS One. 2017 Mar 28;12(3):e0174471. doi: 10.1371/journal.pone.0174471. eCollection 2017.
9 Enhancement of TGF- signaling responses by the E3 ubiquitin ligase Arkadia provides tumor suppression in colorectal cancer.Cancer Res. 2011 Oct 15;71(20):6438-49. doi: 10.1158/0008-5472.CAN-11-1645.
10 Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart.Circulation. 1993 Feb;87(2):454-63. doi: 10.1161/01.cir.87.2.454.
11 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
12 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.
13 Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
14 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.