Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2R9YDP)

• DOT Name: E3 ubiquitin-protein ligase RNF43 (RNF43)
• Synonyms: EC 2.3.2.27; RING finger protein 43; RING-type E3 ubiquitin transferase RNF43
• Gene Name: RNF43
• Related Disease:
  Sessile serrated polyposis cancer syndrome
  Hyperplastic polyposis syndrome
• UniProt ID: RNF43_HUMAN
• PDB ID: 4KNG
• EC Number: 2.3.2.27
• Pfam ID: PF13639 ; PF18212
• Sequence:
  MSGGHQLQLAALWPWLLMATLQAGFGRTGLVLAAAVESERSAEQKAIIRVIPLKMDPTGK
  LNLTLEGVFAGVAEITPAEGKLMQSHPLYLCNASDDDNLEPGFISIVKLESPRRAPRPCL
  SLASKARMAGERGASAVLFDITEDRAAAEQLQQPLGLTWPVVLIWGNDAEKLMEFVYKNQ
  KAHVRIELKEPPAWPDYDVWILMTVVGTIFVIILASVLRIRCRPRHSRPDPLQQRTAWAI
  SQLATRRYQASCRQARGEWPDSGSSCSSAPVCAICLEEFSEGQELRVISCLHEFHRNCVD
  PWLHQHRTCPLCMFNITEGDSFSQSLGPSRSYQEPGRRLHLIRQHPGHAHYHLPAAYLLG
  PSRSAVARPPRPGPFLPSQEPGMGPRHHRFPRAAHPRAPGEQQRLAGAQHPYAQGWGLSH
  LQSTSQHPAACPVPLRRARPPDSSGSGESYCTERSGYLADGPASDSSSGPCHGSSSDSVV
  NCTDISLQGVHGSSSTFCSSLSSDFDPLVYCSPKGDPQRVDMQPSVTSRPRSLDSVVPTG
  ETQVSSHVHYHRHRHHHYKKRFQWHGRKPGPETGVPQSRPPIPRTQPQPEPPSPDQQVTR
  SNSAAPSGRLSNPQCPRALPEPAPGPVDASSICPSTSSLFNLQKSSLSARHPQRKRRGGP
  SEPTPGSRPQDATVHPACQIFPHYTPSVAYPWSPEAHPLICGPPGLDKRLLPETPGPCYS
  NSQPVWLCLTPRQPLEPHPPGEGPSEWSSDTAEGRPCPYPHCQVLSAQPGSEEELEELCE
  QAV
• Function: E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination, endocytosis and subsequent degradation of Wnt receptor complex components Frizzled. Acts on both canonical and non-canonical Wnt signaling pathway. Along with RSPO2 and ZNRF3, constitutes a master switch that governs limb specification.
• Tissue Specificity: Expressed in fetal kidney, fetal lung, in colon cancer tissues, hepatocellular carcinomas and lung adenocarcinomas. Overexpressed in colorectal cancer cell lines.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway:
  Signaling by RNF43 mutants (R-HSA-5340588)
  Regulation of FZD by ubiquitination (R-HSA-4641263)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sessile serrated polyposis cancer syndrome	DIS84VIN	Definitive	Autosomal dominant	[1]
Hyperplastic polyposis syndrome	DISVLOYP	Supportive	Autosomal dominant	[2]

16 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 E3 ubiquitin-protein ligase RNF43 (RNF43).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase RNF43 (RNF43).	[18]

2 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 RNF43 (RNF43).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase RNF43 (RNF43).	[16]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred. Hum Genome Var. 2015 Apr 16;2:15013. doi: 10.1038/hgv.2015.13. eCollection 2015.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] 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.
• [17] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.