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Identification
HMDB Protein ID HMDBP14477
Secondary Accession Numbers None
Name E3 ubiquitin-protein ligase Arkadia
Synonyms
  1. RING finger protein 111
  2. RING-type E3 ubiquitin transferase Arkadia
  3. hRNF111
Gene Name RNF111
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function E3 ubiquitin-protein ligase (PubMed:26656854). Required for mesoderm patterning during embryonic development (By similarity). Acts as an enhancer of the transcriptional responses of the SMAD2/SMAD3 effectors, which are activated downstream of BMP (PubMed:14657019, PubMed:16601693). 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 (PubMed:14657019, PubMed:16601693). 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 (By similarity). Activates SMAD3/SMAD4-dependent transcription by triggering signal-induced degradation of SNON isoform of SKIL (PubMed:17591695). Associates with UBE2D2 as an E2 enzyme (PubMed:22411132). Specifically binds polysumoylated chains via SUMO interaction motifs (SIMs) and mediates ubiquitination of sumoylated substrates (PubMed:23751493). Catalyzes 'Lys-63'-linked ubiquitination of sumoylated XPC in response to UV irradiation, promoting nucleotide excision repair (PubMed:23751493). Mediates ubiquitination and degradation of sumoylated PML (By similarity). The regulation of the BMP-SMAD signaling is however independent of sumoylation and is not dependent of SUMO interaction motifs (SIMs) (By similarity).
Pathways
  • protein ubiquitination
Reactions Not Available
GO Classification
Biological Process
protein polyubiquitination
ubiquitin-dependent SMAD protein catabolic process
pattern specification process
positive regulation of protein ubiquitination
global genome nucleotide-excision repair
ubiquitin-dependent protein catabolic process
positive regulation of transcription, DNA-dependent
positive regulation of transcription from RNA polymerase II promoter
positive regulation of transforming growth factor beta receptor signaling pathway
protein ubiquitination
Cellular Component
cytosol
protein-containing complex
cytoplasm
nucleus
nucleoplasm
PML body
Molecular Function
SUMO polymer binding
metal ion binding
ubiquitin protein ligase activity
SMAD binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 995
Molecular Weight 108860.765
Theoretical pI 7.224
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q6ZNA4
UniProtKB/Swiss-Prot Entry Name RN111_HUMAN
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
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  3. Bechtel S, Rosenfelder H, Duda A, Schmidt CP, Ernst U, Wellenreuther R, Mehrle A, Schuster C, Bahr A, Blocker H, Heubner D, Hoerlein A, Michel G, Wedler H, Kohrer K, Ottenwalder B, Poustka A, Wiemann S, Schupp I: The full-ORF clone resource of the German cDNA Consortium. BMC Genomics. 2007 Oct 31;8:399. [PubMed:17974005 ]
  4. Zody MC, Garber M, Sharpe T, Young SK, Rowen L, O'Neill K, Whittaker CA, Kamal M, Chang JL, Cuomo CA, Dewar K, FitzGerald MG, Kodira CD, Madan A, Qin S, Yang X, Abbasi N, Abouelleil A, Arachchi HM, Baradarani L, Birditt B, Bloom S, Bloom T, Borowsky ML, Burke J, Butler J, Cook A, DeArellano K, DeCaprio D, Dorris L 3rd, Dors M, Eichler EE, Engels R, Fahey J, Fleetwood P, Friedman C, Gearin G, Hall JL, Hensley G, Johnson E, Jones C, Kamat A, Kaur A, Locke DP, Madan A, Munson G, Jaffe DB, Lui A, Macdonald P, Mauceli E, Naylor JW, Nesbitt R, Nicol R, O'Leary SB, Ratcliffe A, Rounsley S, She X, Sneddon KM, Stewart S, Sougnez C, Stone SM, Topham K, Vincent D, Wang S, Zimmer AR, Birren BW, Hood L, Lander ES, Nusbaum C: Analysis of the DNA sequence and duplication history of human chromosome 15. Nature. 2006 Mar 30;440(7084):671-5. [PubMed:16572171 ]
  5. Koinuma D, Shinozaki M, Komuro A, Goto K, Saitoh M, Hanyu A, Ebina M, Nukiwa T, Miyazawa K, Imamura T, Miyazono K: Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7. EMBO J. 2003 Dec 15;22(24):6458-70. [PubMed:14657019 ]
  6. Liu W, Rui H, Wang J, Lin S, He Y, Chen M, Li Q, Ye Z, Zhang S, Chan SC, Chen YG, Han J, Lin SC: Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. EMBO J. 2006 Apr 19;25(8):1646-58. Epub 2006 Apr 6. [PubMed:16601693 ]
  7. Hendriks IA, Lyon D, Young C, Jensen LJ, Vertegaal AC, Nielsen ML: Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat Struct Mol Biol. 2017 Mar;24(3):325-336. doi: 10.1038/nsmb.3366. Epub 2017 Jan 23. [PubMed:28112733 ]
  8. Xiao Z, Chang JG, Hendriks IA, Sigurethsson JO, Olsen JV, Vertegaal AC: System-wide Analysis of SUMOylation Dynamics in Response to Replication Stress Reveals Novel Small Ubiquitin-like Modified Target Proteins and Acceptor Lysines Relevant for Genome Stability. Mol Cell Proteomics. 2015 May;14(5):1419-34. doi: 10.1074/mcp.O114.044792. Epub 2015 Mar 9. [PubMed:25755297 ]
  9. Poulsen SL, Hansen RK, Wagner SA, van Cuijk L, van Belle GJ, Streicher W, Wikstrom M, Choudhary C, Houtsmuller AB, Marteijn JA, Bekker-Jensen S, Mailand N: RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response. J Cell Biol. 2013 Jun 10;201(6):797-807. doi: 10.1083/jcb.201212075. [PubMed:23751493 ]
  10. Levy L, Howell M, Das D, Harkin S, Episkopou V, Hill CS: 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. [PubMed:17591695 ]
  11. Sun H, Hunter T: Poly-small ubiquitin-like modifier (PolySUMO)-binding proteins identified through a string search. J Biol Chem. 2012 Dec 7;287(50):42071-83. doi: 10.1074/jbc.M112.410985. Epub 2012 Oct 18. [PubMed:23086935 ]
  12. Wright JD, Mace PD, Day CL: Secondary ubiquitin-RING docking enhances Arkadia and Ark2C E3 ligase activity. Nat Struct Mol Biol. 2016 Jan;23(1):45-52. doi: 10.1038/nsmb.3142. Epub 2015 Dec 14. [PubMed:26656854 ]