Affinage

RNF111

E3 ubiquitin-protein ligase Arkadia · UniProt Q6ZNA4

Length
994 aa
Mass
108.9 kDa
Annotated
2026-06-10
56 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF111/Arkadia is a nuclear RING-H2 E3 ubiquitin ligase that amplifies TGF-β/Nodal/BMP signaling and was first defined genetically as an essential inducer of the embryonic node acting in extraembryonic tissue downstream of Nodal (PMID:11298452, PMID:11298453). Its core function is to drive signal-dependent polyubiquitination and proteasomal degradation of negative regulators of the pathway: the inhibitory Smads (Smad7 in TGF-β/BMP signaling, the BMP-specific Smad6) and the transcriptional repressors SnoN/SKIL and c-SKI, thereby permitting Smad3/Smad4-dependent transcription (PMID:14657019, PMID:17591695, PMID:17510063, PMID:25762727). Substrate engagement frequently occurs in complex with phosphorylated Smad2/3, and RNF111 also ubiquitinates phospho-Smad2/3 itself, coupling transcriptional activation to signal termination (PMID:17591695, PMID:17341133); systematic ubiquitylome profiling confirms SKI and SKIL/SnoN as its principal degradative substrates upon TGF-β stimulation, with SKIL targeted at Lys343 (PMID:34740826). The RING-H2 domain coordinates two Zn(II) ions in a cross-brace ββα fold and engages E2 enzymes via a defined surface, and the identity of the cooperating E2 dictates ubiquitin chain linkage and hence substrate fate—UbcH5B for proteolytic chains, Ubc13–Mms2 for non-proteolytic K63 chains (PMID:22411132, PMID:28647409, PMID:36831384). Beyond TGF-β, RNF111 acts as a SUMO-targeted ubiquitin ligase: three tandem SUMO-interacting motifs recognize poly-SUMO2/3 chains, enabling K63-linked ubiquitylation of SUMOylated substrates including XPC during nucleotide excision repair and degradation of polysumoylated PML (PMID:23751493, PMID:23530056). It additionally functions as a NEDD8 ligase, catalyzing DNA-damage-induced histone H4 polyneddylation that promotes RNF168, 53BP1 and BRCA1 recruitment, and polyneddylating cGAS at Lys231/Lys421 to enhance cGAS dimerization and antiviral cGAS-STING signaling (PMID:23394999, PMID:33720974). RNF111 activity is tuned by scaffold and stabilizing partners—Axin and RB1CC1/FIP200 promote substrate selection, while FHL2 and UBXN7 stabilize RNF111 by limiting its auto-ubiquitination (PMID:16601693, PMID:21795712, PMID:23212909, PMID:37024974). Physiologically these activities control iTreg/Treg differentiation through SKI/SnoN degradation and definitive hematopoiesis via Smad2/3 (PMID:34473197, PMID:40995370, PMID:39363867).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2001 High

    Established Arkadia/RNF111 as a genetically required positive regulator of Nodal/TGF-β signaling in vivo, defining its biological role before any biochemical mechanism was known.

    Evidence Gene-trap mutagenesis and chimeric embryo analysis with Nodal epistasis in mouse, and overexpression/morpholino assays in Xenopus

    PMID:11298452 PMID:11298453

    Open questions at the time
    • Molecular mechanism of signal potentiation not yet defined
    • Did not identify substrates or enzymatic activity
  2. 2003 High

    Defined the molecular mechanism of pathway amplification: Arkadia is a RING E3 ligase that degrades inhibitory Smad7, distinguishing it from receptor-associated Smurf1.

    Evidence Co-IP, ubiquitination assay, and siRNA knockdown with Smad7 accumulation readout

    PMID:14657019

    Open questions at the time
    • E2 partner not identified
    • Chain linkage type not resolved
  3. 2007 High

    Expanded the substrate repertoire to the transcriptional repressors SnoN and c-SKI and to phospho-Smad2/3, showing degradation of repressors activates transcription while phospho-Smad turnover terminates the signal.

    Evidence siRNA screen, Co-IP, ubiquitination assays, reporter assays in cancer cells, and knockout ES cell/chimera analysis

    PMID:17341133 PMID:17510063 PMID:17591695

    Open questions at the time
    • How efficient SnoN degradation requires phospho-Smad complex mechanistically unclear
    • Quantitative substrate hierarchy not established
  4. 2008 High

    Determined the structural basis of catalysis: the RING-H2 domain folds independently and binds the E2 UbcH5b, linking structure to E3 activity.

    Evidence Recombinant expression, NMR spectroscopy, and chemical shift perturbation E2 mapping

    PMID:19032943 PMID:20689703 PMID:22411132

    Open questions at the time
    • Full-length structure with substrate not solved
    • Chain-type determinants not yet mapped
  5. 2012 Medium

    Revealed that Arkadia activity is itself regulated by partners and autoubiquitination, identifying Axin, RB1CC1/FIP200 and FHL2 as substrate-selective or stabilizing cofactors.

    Evidence Co-IP, linkage-specific ubiquitination assays, pulse-chase/cycloheximide, and reporter assays

    PMID:16601693 PMID:21795712 PMID:23212909

    Open questions at the time
    • Single-lab characterization for each cofactor
    • Quantitative contribution to physiological substrate selection unclear
  6. 2013 High

    Reclassified RNF111 as a SUMO-targeted ubiquitin ligase and a NEDD8 ligase, dramatically broadening its function beyond TGF-β to DNA repair, PML turnover, and damage-response neddylation.

    Evidence SIM-deletion mutants, linkage-specific ubiquitination with Ubc13-Mms2, NER recruitment assays, MS identification of H4 neddylation, and damage foci readouts

    PMID:23394999 PMID:23530056 PMID:23751493

    Open questions at the time
    • How RNF111 switches between ubiquitin and NEDD8 ligase modes unclear
    • Full SUMOylated substrate range not defined
  7. 2017 High

    Defined precise RING residues controlling E2 engagement, separating structural integrity from functional signaling output.

    Evidence NMR of W972 mutants, E2 interaction assays, and TGF-β reporter assays

    PMID:28647409

    Open questions at the time
    • Effect of these residues on STUbL/neddylation activities not tested
    • No co-structure with E2 bound
  8. 2021 High

    Pinned down the physiologically relevant degradative substrates (SKI/SKIL) by systematic proteomics and genetic rescue, and demonstrated context-specific roles in iTreg differentiation, antiviral immunity, and hematopoiesis.

    Evidence Quantitative diGly ubiquitylome in CRISPR cells, conditional KO with SKI/SnoN double-KO rescue, cGAS neddylation with KO mice, and zebrafish Rnf111 KO with rescue

    PMID:33720974 PMID:34473197 PMID:34740826 PMID:39363867

    Open questions at the time
    • Tissue-specific substrate selection mechanism not fully resolved
    • Relationship between cGAS neddylation and TGF-β functions unexplored
  9. 2023 Medium

    Established that E2 choice and non-RING elements dictate ubiquitin chain architecture and substrate fate, and identified UBXN7 as a regulator of RNF111 stability.

    Evidence NMR with E2 panel, linkage-specific ubiquitination assays, and Co-IP/binding with UBXN7

    PMID:36142504 PMID:36831384 PMID:37024974

    Open questions at the time
    • In-cell relevance of each chain type to specific substrates not fully mapped
    • Single-lab structural assignments
  10. 2025 High

    Provided structural and mechanistic detail of priming-dependent processive chain assembly across multiple E2s, refining the model of how substrate affinity governs modification extent.

    Evidence Structural analysis of RING-E2 complexes and reconstituted in vitro ubiquitylation assays with an E2 panel

    PMID:40451499

    Open questions at the time
    • In vivo validation of priming requirement lacking
    • How priming integrates with SUMO/NEDD8 targeting unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RNF111 selects among its ubiquitin-, SUMO-, and NEDD8-directed activities in a given cellular context and how partner proteins coordinate this switch.
  • No unified model of modifier-type and substrate selection
  • Schwann cell Merlin-SKOR2 complex and Nrf2 stabilization rest on single low-confidence reports

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 5 GO:0016740 transferase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-73894 DNA Repair 2
Partners
AXIN1FHL2RB1CC1SKISKIL/SNONSMAD6SMAD7UBXN7
Complex memberships
Merlin(NF2)-Arkadia-SKOR2 complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Arkadia (RNF111) is a nuclear RING domain-containing protein essential for node induction in the mammalian embryo; genetic interaction with Nodal revealed by chimera analysis showing Arkadia functions in extraembryonic tissues to induce the node and is required for HNF3beta expression in the anterior primitive streak. Gene-trap mutagenesis, chimeric embryo analysis, genetic epistasis with Nodal Nature High 11298452 11298453
2001 Arkadia specifically potentiates the mesendoderm-inducing activity of a subset of TGF-beta/Nodal family members in Xenopus; it functions as a nuclear protein that enhances Nodal signaling when co-expressed and can act in cells adjacent to those producing the Nodal signal. Xenopus overexpression, morpholino knockdown, genetic interaction with extracellular Nodal blockade Nature High 11298453
2003 Arkadia physically interacts with inhibitory Smad7, induces its poly-ubiquitination and proteasome-dependent degradation via its RING domain, thereby amplifying both TGF-beta and BMP signaling; unlike Smurf1, Arkadia does not associate with TGF-beta receptors. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, Western blot for Smad7 accumulation The EMBO journal High 14657019
2006 Axin acts as a scaffold protein that forms a multimeric complex with Smad7 and Arkadia, facilitating Arkadia-mediated Smad7 ubiquitination and degradation to activate TGF-beta signaling; Axin also induces nuclear export of Smad7. Co-immunoprecipitation, siRNA knockdown, pulse-chase experiment, nuclear export assay The EMBO journal High 16601693
2007 Arkadia is absolutely required for TGF-beta-induced Smad3/Smad4-dependent transcription; it activates this transcription by inducing signal-dependent degradation of transcriptional repressor SnoN. Arkadia interacts with SnoN and ubiquitinates it constitutively, but efficient degradation requires a complex of Arkadia, SnoN, and phosphorylated Smad2 or Smad3. siRNA library screen, dominant-negative mutant overexpression, luciferase reporter assay, Co-IP, ubiquitination assay, rescue experiment in SEG-1 cancer cells Molecular and cellular biology High 17591695
2007 Arkadia induces ubiquitin-dependent degradation of SnoN and c-Ski (in addition to Smad7) via its C-terminal RING domain; Arkadia interacts with SnoN and c-Ski both in their free forms and when bound to Smad proteins. Co-immunoprecipitation, ubiquitination assay, Western blot for protein levels, RING domain mutant analysis The Journal of biological chemistry High 17510063
2007 Arkadia interacts with and ubiquitinates phospho-Smad2/3 (P-Smad2/3), inducing their degradation; this is mediated by the same domains required for enhancing their transcriptional activity. Loss of Arkadia causes nuclear accumulation of hypoactive P-Smad2/3. Arkadia thus couples degradation of P-Smad2/3 with activation of target gene transcription, providing a signaling termination mechanism. Knockout embryonic stem cells, chimeric embryo analysis, Co-IP, ubiquitination assay, gene expression analysis, rescue by reintroduction of Arkadia PLoS biology High 17341133
2008 Arkadia RING-H2 domain was recombinantly expressed and shown by NMR to be a stably folded protein with a RING-H2 type architecture, suitable for structural studies of its E3 ubiquitin ligase activity. Recombinant protein expression, NMR spectroscopy Biochemical and biophysical research communications Medium 19032943
2008 Arkadia regulates myoblast differentiation by inducing degradation of Ski and Ski-bound phospho-Smad2/3 complexes; it binds Smad2/3 via Ski to induce ubiquitination of the Smad2/3 complex, affecting myoblast differentiation through both Smad-dependent and Smad-independent pathways. siRNA knockdown, overexpression, Co-IP, ubiquitination assay, C2C12 differentiation assay Bone Medium 18950738
2010 Arkadia interacts with the mu2 subunit of the clathrin-adaptor AP2 complex through its N-terminal YALL motif binding to the YXXΦ-binding domain of mu2; Arkadia ubiquitylates mu2 at Lys130 and modifies EGFR endocytosis induced by EGF. Arkadia localizes to both nucleus and cytosol. Yeast-two-hybrid screening, Co-IP, ubiquitination assay, endocytosis assay, subcellular fractionation Journal of biochemistry Medium 20965945
2010 The Arkadia RING-H2 domain requires two Zn(II) ions coordinated through a Cys3-His2-Cys3 motif; mutation of Cys955 to Arg (C955R) dramatically reduces zinc-binding affinity and disrupts global structural integrity of the RING domain. Site-directed mutagenesis, recombinant protein expression, atomic absorption spectroscopy, NMR Bioinorganic chemistry and applications Medium 20689703
2012 NMR solution structure of Arkadia's RING-H2 domain revealed a ββbα fold with cross-brace Zn(II) ligation; chemical shift perturbation showed that the RING-H2 domain interacts with the E2 enzyme UbcH5b. NMR spectroscopy, chemical shift perturbation mapping Proteins High 22411132
2012 FHL2 binds Arkadia and increases its half-life by inhibiting K27-linked polyubiquitination of Arkadia, thereby stabilizing Arkadia and enhancing TGF-beta signaling. Arkadia undergoes K63- and K27-linked polyubiquitination, partly via autocatalysis; K27-linked ubiquitination promotes its proteolytic turnover. Co-IP, ubiquitination assay with linkage-specific mutants, cycloheximide chase, siRNA knockdown, luciferase reporter assay The Journal of biological chemistry Medium 23212909
2011 RB1CC1/FIP200 is a substrate-selective cofactor of Arkadia that enhances Arkadia E3 ligase activity specifically toward c-Ski but not SnoN, through direct physical interaction with c-Ski as a scaffold. Co-IP, ubiquitination assay, siRNA knockdown, overexpression, luciferase reporter assay The Journal of biological chemistry Medium 21795712
2013 RNF111/Arkadia is a SUMO-targeted ubiquitin ligase (STUbL) that uses three adjacent SUMO-interacting motifs (SIMs) for specific recognition of poly-SUMO2/3 chains. It uses Ubc13-Mms2 as cognate E2 to promote non-proteolytic K63-linked ubiquitylation of SUMOylated target proteins. RNF111 promotes K63-linked ubiquitylation of SUMOylated XPC and facilitates nucleotide excision repair by regulating XPC recruitment to UV-damaged DNA. SUMO-interaction assay, ubiquitination assay with linkage-specific antibodies, Co-IP, NER recruitment assay, UV damage response, siRNA knockdown The Journal of cell biology High 23751493
2013 Arkadia contains three successive SUMO-interacting motifs (SIMs) that mediate interaction with poly-SUMO2; the third SIM (VVDL) is most relevant. Arkadia functions as a STUbL by ubiquitinating SUMO chains. Arkadia's SIMs are required for its interaction with polysumoylated PML and for arsenic-induced degradation of polysumoylated PML. Arkadia homodimerizes but does not heterodimerize with RNF4. Co-IP, ubiquitination assay, siRNA knockdown, immunofluorescence for PML bodies, dimerization assay Molecular and cellular biology High 23530056
2013 RNF111 promotes DNA damage-induced NEDD8 (neddylation) accumulation at DNA damage sites; this requires the E2 enzyme UBE2M. RNF111 catalyzes polyneddylation of histone H4 at N-terminal lysine residues in response to DNA damage. NEDD8 chains are recognized by the MIU domain of RNF168, and RNF111-dependent neddylation promotes RNF168 foci formation and downstream recruitment of 53BP1 and BRCA1. siRNA/shRNA knockdown, ubiquitin-like modification assay, mass spectrometry, Co-IP, immunofluorescence for damage foci Molecular cell High 23394999
2014 Arkadia/RNF111 colocalizes with CBX4/Pc2 in Polycomb bodies; both the SUMO-interacting motifs (SIMs) and a unique M domain (absent in paralogs ARKL1/ARKL2 and RNF4) redundantly promote this colocalization and activation of a TGF-beta transcriptional reporter. Transcriptome profiling showed Arkadia can both promote and inhibit gene expression depending on epigenetic context. Immunofluorescence colocalization, domain-deletion mutant analysis, TGF-beta reporter assay, RNA-seq transcriptome profiling Molecular and cellular biology Medium 24912682
2015 Arkadia ubiquitylates and induces proteasome-dependent degradation of Smad6 (a BMP-specific inhibitory Smad), as shown by activity of wild-type but not C937A RING-dead mutant Arkadia; elevated Smad6 protein was detected in Arkadia KO MEFs. Arkadia knockdown reduces BMP-induced osteoblast differentiation markers. Ubiquitination assay with RING mutant, Western blot in KO MEFs, siRNA knockdown, BMP differentiation reporter assay Journal of biochemistry Medium 25762727
2015 Arkadia physically interacts with ESRP2 (epithelial splicing regulatory protein 2), induces its polyubiquitination, and modulates its splicing function; Arkadia and ESRP2 cooperate to suppress ccRCC tumor growth. Co-IP, ubiquitination assay, tumor growth assay in vivo, RNA-seq splicing analysis Oncogene Medium 26522722
2017 NMR analysis of Arkadia RING-H2 W972 mutants showed that W972R (but not W972A) disrupts interaction with E2 enzyme UbcH5b, with structural changes in the C-terminal alpha-helix and increased distance between Zn(II) ions; W972R abolishes TGF-beta signaling enhancement while W972A retains full activity. NMR spectroscopy, E2 interaction assay, TGF-beta luciferase reporter assay, site-directed mutagenesis Journal of molecular biology High 28647409
2018 Arkadia/RNF111 ubiquitinates Nrf2 via K48-linked chains, paradoxically stabilizing Nrf2 (rather than degrading it) and promoting Nrf2-dependent gene transcription. This sumoylation-dependent stabilization occurs in PML-nuclear body-enriched fractions. Co-immunoprecipitation, K48-linkage-specific ubiquitin antibody, cycloheximide chase, ARE-luciferase reporter assay Cellular physiology and biochemistry Low 29597191
2021 RNF111 (Rnf111) is the Nedd8 E3 ligase for cGAS; it interacts with and polyneddylates cGAS at Lys231 and Lys421 (identified by mass spectrometry), which promotes cGAS dimerization and enhances its DNA-binding ability, leading to proper cGAS-STING pathway activation and antiviral innate immunity. Co-IP, mass spectrometry identification of neddylation sites, neddylation assay, cGAS dimerization assay, DNA-binding assay, Rnf111 knockout mice susceptibility to HSV-1 PLoS pathogens High 33720974
2021 Arkadia-mediated degradation of SKI and SnoN is required for iTreg (but not Th17) cell differentiation; genetic ablation of SKI and SnoN rescues Arkadia-deficient iTreg differentiation both in vitro and in vivo, establishing SKI/SnoN as the functionally relevant Arkadia substrates in this context. Conditional knockout of Arkadia in CD4+ T cells, double-knockout of SKI and SnoN, in vitro differentiation assay, in vivo intestinal lamina propria analysis The Journal of experimental medicine High 34473197
2021 Quantitative ubiquitylome proteomics in CRISPR-engineered U2OS cells (expressing RING-truncated RNF111) demonstrated that SKI and SKIL/SnoN are the only substrates ubiquitylated and degraded by RNF111 upon TGF-beta signaling; lysine 343 in the SAND domain of SKIL is identified as the RNF111 ubiquitylation target site. CRISPR engineering, label-free quantitative proteomics, diGly immunoprecipitation, ubiquitin pan-nanobody immunoprecipitation, mass spectrometry Molecular & cellular proteomics High 34740826
2022 Non-RING elements of Arkadia (including conserved NRGA and TIER motifs) are required for E2 (UbcH5B) interaction and for efficient auto-ubiquitination; Arkadia isoform-1 does not interact with free ubiquitin, unlike isoform-2 and its homolog Ark2C. NMR interaction studies, UBCH5B C85S oxyester hydrolysis assay, auto-ubiquitination assay, mutant analysis International journal of molecular sciences Medium 36142504
2023 UBXN7 directly interacts with the RING domain of RNF111 through its UAS thioredoxin-like domain, inhibiting RNF111 auto-ubiquitination by preventing E2 conjugating enzyme binding; UBXN7 overexpression stabilizes RNF111, while UBXN7 depletion reduces RNF111 protein levels. This modulates TGF-beta-induced SKIL/SnoN degradation. Co-IP, direct binding assay, ubiquitination assay, siRNA knockdown, overexpression, interactome mass spectrometry BMC biology Medium 37024974
2023 Arkadia RING domain interacts with E2 enzymes UbcH5B, UbcH13, and UbcH7 through a similar interaction surface; cooperation with different E2s results in distinct ubiquitin chain linkages (monoubiquitylation, K63, K48, or K11), determining substrate fate. NMR chemical shift perturbation, ubiquitination assay with linkage-specific E2 enzymes Cancers Medium 36831384
2025 Arkadia and the related E3 Ark2C promote substrate ubiquitylation with multiple E2 enzymes (including Ubc13 and Ube2K) that require a priming ubiquitin before subsequent chain assembly; substrates that bind Arkadia more tightly are more extensively modified, and prior substrate ubiquitylation enhances subsequent ubiquitylation. Crystal/structural analysis of RING-E2 complexes, binding assays, in vitro substrate ubiquitylation assays, activity assays with E2 panel Journal of molecular biology High 40451499
2025 Arkadia interacts with Merlin (NF2) and the SKI family co-repressor SKOR2 in human Schwann cells (validated by Co-IP/MS in hiPSC-derived SCs); this Merlin-Arkadia-SKOR2 complex is required for proper Schwann cell proliferation control. Co-immunoprecipitation followed by mass spectrometry, hiPSC-derived Schwann cell model, NF2 mutant vs wild-type comparison Stem cell research & therapy Low 40188079
2025 Rnf111 deficiency in zebrafish reduces phosphorylation of Smad2/3 in hematopoietic stem and progenitor cells (HSPC), impairing definitive hematopoiesis; restoration of TGF-beta/Smad2 signaling with IDE2 rescues HSPC development. Gcsfr/NO signaling is identified as a downstream target pathway of Smad2/3 in Rnf111-mediated HSPC development. CRISPR/Cas9 Rnf111 knockout zebrafish, phospho-Smad2/3 Western blot, pharmacological rescue with IDE2, genetic epistasis with Gcsfr/NO pathway Haematologica Medium 39363867
2025 Arkadia (E3 ubiquitin ligase for SKI) overexpression reduces SKI protein levels in human Treg cells, enhancing Treg cell stability and immunosuppressive function under TGF-beta inhibition and inflammatory conditions. Lentiviral overexpression of ARKADIA in human Treg subsets, flow cytometry, Western blotting, transcriptomics, co-culture suppression assay Frontiers in immunology Medium 40995370

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7. The EMBO journal 186 14657019
2006 Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. The EMBO journal 151 16601693
2007 Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Molecular and cellular biology 148 17591695
2007 Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signaling. The Journal of biological chemistry 144 17510063
2013 RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response. The Journal of cell biology 133 23751493
2010 Atrial fibrillation induces myocardial fibrosis through angiotensin II type 1 receptor-specific Arkadia-mediated downregulation of Smad7. Circulation research 132 21127293
2013 RNF111-dependent neddylation activates DNA damage-induced ubiquitination. Molecular cell 114 23394999
2007 Arkadia enhances Nodal/TGF-beta signaling by coupling phospho-Smad2/3 activity and turnover. PLoS biology 90 17341133
2001 Induction of the mammalian node requires Arkadia function in the extraembryonic lineages. Nature 89 11298452
2013 Arkadia, a novel SUMO-targeted ubiquitin ligase involved in PML degradation. Molecular and cellular biology 88 23530056
2001 Arkadia enhances nodal-related signalling to induce mesendoderm. Nature 64 11298453
2020 Circ-RNF111 contributes to paclitaxel resistance in breast cancer by elevating E2F3 expression via miR-140-5p. Thoracic cancer 59 32445273
2007 Arkadia regulates TGF-beta signaling during renal tubular epithelial to mesenchymal cell transition. Kidney international 48 18059455
2021 RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response. PLoS pathogens 43 33720974
2010 Trps1 haploinsufficiency promotes renal fibrosis by increasing Arkadia expression. Journal of the American Society of Nephrology : JASN 42 20507941
2007 Arkadia-Smad7-mediated positive regulation of TGF-beta signaling in a rat model of tubulointerstitial fibrosis. American journal of nephrology 42 17347560
2015 The Arkadia-ESRP2 axis suppresses tumor progression: analyses in clear-cell renal cell carcinoma. Oncogene 41 26522722
2009 c-Ski, Smurf2, and Arkadia as regulators of TGF-beta signaling: new targets for managing myofibroblast function and cardiac fibrosis. Canadian journal of physiology and pharmacology 37 19898560
2021 Arkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation. The Journal of experimental medicine 36 34473197
2011 Enhancement of TGF-β signaling responses by the E3 ubiquitin ligase Arkadia provides tumor suppression in colorectal cancer. Cancer research 35 21998011
2013 Arkadia regulates tumor metastasis by modulation of the TGF-β pathway. Cancer research 32 23467611
2009 Context-dependent regulation of the expression of c-Ski protein by Arkadia in human cancer cells. Journal of biochemistry 30 19959502
2012 The four and a half LIM-only protein 2 (FHL2) activates transforming growth factor β (TGF-β) signaling by regulating ubiquitination of the E3 ligase Arkadia. The Journal of biological chemistry 28 23212909
2011 RB1CC1 protein positively regulates transforming growth factor-beta signaling through the modulation of Arkadia E3 ubiquitin ligase activity. The Journal of biological chemistry 28 21795712
2012 NMR-based insights into the conformational and interaction properties of Arkadia RING-H2 E3 Ub ligase. Proteins 25 22411132
2008 High yield expression and NMR characterization of Arkadia E3 ubiquitin ligase RING-H2 finger domain. Biochemical and biophysical research communications 24 19032943
2017 A Residue Specific Insight into the Arkadia E3 Ubiquitin Ligase Activity and Conformational Plasticity. Journal of molecular biology 21 28647409
2018 Arkadia (RING Finger Protein 111) Mediates Sumoylation-Dependent Stabilization of Nrf2 Through K48-Linked Ubiquitination. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 20 29597191
2020 circRNA RNF111 regulates the growth, migration and invasion of gastric cancer cells by binding to miR‑27b‑3p. International journal of molecular medicine 19 33000178
2014 Multiple Arkadia/RNF111 structures coordinate its Polycomb body association and transcriptional control. Molecular and cellular biology 18 24912682
2021 Circ-RNF111 aggravates the malignancy of gastric cancer through miR-876-3p-dependent regulation of KLF12. World journal of surgical oncology 17 34461926
2010 Arkadia--beyond the TGF-β pathway. Journal of biochemistry 16 21109559
2015 Arkadia enhances BMP signalling through ubiquitylation and degradation of Smad6. Journal of biochemistry 15 25762727
2021 Quantitative Ubiquitylome Analysis Reveals the Specificity of RNF111/Arkadia E3 Ubiquitin Ligase for its Degradative Substrates SKI and SKIL/SnoN in TGF-β Signaling Pathway. Molecular & cellular proteomics : MCP 14 34740826
2015 RNF111/Arkadia is regulated by DNA methylation and affects TGF-β/Smad signaling associated invasion in NSCLC cells. Lung cancer (Amsterdam, Netherlands) 13 26238425
2010 Zinc Binding Properties of Engineered RING Finger Domain of Arkadia E3 Ubiquitin Ligase. Bioinorganic chemistry and applications 13 20689703
2010 Arkadia complexes with clathrin adaptor AP2 and regulates EGF signalling. Journal of biochemistry 13 20965945
2008 Arkadia represses the expression of myoblast differentiation markers through degradation of Ski and the Ski-bound Smad complex in C2C12 myoblasts. Bone 12 18950738
2010 Effects of Arkadia on airway remodeling through enhancing TGF-beta signaling in allergic rats. Laboratory investigation; a journal of technical methods and pathology 10 20386537
2007 Opposing effects of Arkadia and Smurf on TGFbeta1-induced IgA isotype expression. Molecules and cells 7 17978583
2024 Deleterious variants in RNF111 impair female fertility and induce premature ovarian insufficiency in humans and mice. Science China. Life sciences 6 38874713
2025 Rnf111 has a pivotal role in regulating development of definitive hematopoietic stem and progenitor cells through the Smad2/3-Gcsfr/NO axis in zebrafish. Haematologica 4 39363867
2023 Induction of perineural invasion in salivary adenoid cystic carcinoma by circular RNA RNF111. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 4 37222950
2023 E2 Partner Tunes the Ubiquitylation Specificity of Arkadia E3 Ubiquitin Ligase. Cancers 3 36831384
2023 The UAS thioredoxin-like domain of UBXN7 regulates E3 ubiquitin ligase activity of RNF111/Arkadia. BMC biology 3 37024974
2022 Unveiling the Essential Role of Arkadia's Non-RING Elements in the Ubiquitination Process. International journal of molecular sciences 3 36142504
2015 Zebrafish Rnf111 is encoded by multiple transcripts and is required for epiboly progression and prechordal plate development. Differentiation; research in biological diversity 3 25619648
2009 Does Arkadia contribute to TGF-β1-induced IgA expression through up-regulation of Smad signaling in IgA nephropathy? International urology and nephrology 3 19941070
2024 Circ-RNF111 Promotes Proliferation of Ovarian Cancer Cell SKOV-3 by Targeting the MiR-556-5p/CCND1 Axis. Biochemical genetics 2 38376577
2022 Impact of a Single Nucleotide Polymorphism on the 3D Protein Structure and Ubiquitination Activity of E3 Ubiquitin Ligase Arkadia. Frontiers in molecular biosciences 2 35281275
2006 The roles of Arkadia in renal tubular epithelial to mesenchymal transition. Medical hypotheses 2 16797872
2025 Arkadia and Ark2C Promote Substrate Ubiquitylation with Multiple E2 Enzymes. Journal of molecular biology 1 40451499
2001 Vertebrate development: Et in Arkadia. Current biology : CB 1 11516970
2025 Interactions among Merlin, Arkadia, and SKOR2 mediate NF2-associated human Schwann cell proliferation. Stem cell research & therapy 0 40188079
2025 Differential regulation of Treg stability in human naïve and effector Treg subsets by TGFβ-signaling via ARKADIA-SKI axis. Frontiers in immunology 0 40995370
2024 Interactions among Merlin, Arkadia, and SKOR2 mediate NF2-associated Schwann cell proliferation in human. bioRxiv : the preprint server for biology 0 39386608

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