Affinage

RNF111

E3 ubiquitin-protein ligase Arkadia · UniProt Q6ZNA4

Length
994 aa
Mass
108.9 kDa
Annotated
2026-04-28
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF111 (Arkadia) is a nuclear RING-H2 E3 ubiquitin ligase that serves as a central amplifier of TGF-β/Nodal signaling and additionally functions as a SUMO-targeted ubiquitin ligase (STUbL) and NEDD8 E3 ligase in DNA damage repair and innate immunity. In TGF-β signaling, RNF111 ubiquitinates and degrades the inhibitory Smads (Smad6, Smad7) and the transcriptional corepressors c-Ski and SnoN/SKIL—with SKI and SKIL identified as its principal TGF-β-dependent substrates by unbiased ubiquitylome proteomics—thereby derepressing Smad3/Smad4-dependent transcription required for mesendoderm induction, iTreg differentiation, and tumor suppression in colorectal cancer (PMID:14657019, PMID:17591695, PMID:34740826, PMID:34473197, PMID:21998011). Its RING-H2 domain adopts a ββα fold that engages E2 enzymes such as UbcH5b through a conserved tryptophan residue (W972), and three clustered SUMO-interacting motifs enable recognition of poly-SUMO2/3 chains to drive K63-linked ubiquitylation of SUMOylated substrates including XPC for nucleotide excision repair and polysumoylated PML for arsenic-induced degradation (PMID:22411132, PMID:28647409, PMID:23751493, PMID:23530056). RNF111 also functions as a NEDD8 E3 ligase, catalyzing histone H4 polyneddylation at DNA damage sites to recruit RNF168/53BP1/BRCA1 and neddylating cGAS to promote its dimerization and cGAS-STING antiviral signaling (PMID:23394999, PMID:33720974).

Mechanistic history

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

    The fundamental question of RNF111's biological role was answered when gene-trap mutagenesis in mice and overexpression in Xenopus demonstrated that Arkadia is essential for Nodal signaling, mammalian node induction, and mesendoderm specification.

    Evidence Gene-trap null mice lacking Arkadia fail to form the node; Xenopus injection shows potentiation of Nodal-related factor activity

    PMID:11298452 PMID:11298453

    Open questions at the time
    • Biochemical mechanism of signal amplification unknown
    • Direct substrates not yet identified
    • Whether Arkadia acts directly on Smad pathway components unresolved
  2. 2003 High

    The mechanism by which Arkadia amplifies TGF-β signaling was established: Arkadia directly ubiquitinates inhibitory Smad7 for proteasomal degradation, removing a key negative feedback component.

    Evidence Co-immunoprecipitation, ubiquitination assay, and siRNA knockdown with reporter assays in mammalian cells

    PMID:14657019

    Open questions at the time
    • Whether other inhibitory Smads (Smad6) are substrates unknown
    • E2 enzyme identity not determined
    • Role of scaffolding partners unexplored
  3. 2006 High

    The question of how substrate recognition is facilitated was partially answered by the discovery that Axin scaffolds a ternary complex with Smad7 and Arkadia, accelerating Smad7 degradation.

    Evidence Co-immunoprecipitation, pulse-chase half-life measurement, and luciferase reporter assays

    PMID:16601693

    Open questions at the time
    • Whether Axin scaffolding is required in all cell contexts unclear
    • How Axin also promotes Smad7 nuclear export relates to degradation not resolved
  4. 2007 High

    The substrate repertoire was expanded and prioritized: Arkadia ubiquitinates the transcriptional corepressors SnoN and c-Ski in a phospho-Smad2/3-dependent manner and also targets activated phospho-Smad2/3 themselves, coupling signal amplification with signal termination.

    Evidence siRNA screen, ubiquitination assays, rescue in Arkadia-null cells, chimera analysis in Arkadia−/− ES cells

    PMID:17341133 PMID:17510063 PMID:17591695

    Open questions at the time
    • Relative contributions of SnoN/Ski vs Smad7 degradation to overall signaling output unresolved
    • Structural basis for substrate discrimination unknown
  5. 2011 High

    Two modulatory mechanisms were revealed: RB1CC1/FIP200 acts as a substrate-selective cofactor enhancing Arkadia activity toward c-Ski but not SnoN, and Arkadia was shown to function as a tumor suppressor in colorectal cancer through SnoN/Ski degradation.

    Evidence Co-IP and ubiquitination assays for FIP200; Arkadia heterozygous mice with carcinogen-induced CRC model and human tumor mutation analysis

    PMID:21795712 PMID:21998011

    Open questions at the time
    • Mechanism of FIP200 substrate selectivity unknown
    • Whether Arkadia loss-of-function mutations are drivers versus passengers in human CRC not definitively shown
  6. 2012 High

    The structural basis for Arkadia's E3 ligase function was defined: NMR revealed a ββα RING-H2 fold that directly contacts E2 enzyme UbcH5b, and FHL2 was found to stabilize Arkadia by blocking autocatalytic K27-linked polyubiquitination.

    Evidence NMR solution structure and chemical shift perturbation mapping; Co-IP, chain-linkage analysis, cycloheximide chase

    PMID:22411132 PMID:23212909

    Open questions at the time
    • Full-length Arkadia structure unavailable
    • How K27-linked chains are recognized for degradation unknown
  7. 2013 High

    A major conceptual expansion occurred: Arkadia was identified as a SUMO-targeted ubiquitin ligase (STUbL) using three clustered SIMs to recognize poly-SUMO2/3 chains and promote K63-linked ubiquitylation of SUMOylated XPC (for NER) and polysumoylated PML, while also serving as a NEDD8 E3 ligase for histone H4 polyneddylation at DNA damage sites.

    Evidence SIM mutagenesis, K63-chain linkage analysis with Ubc13-Mms2, NER functional assay, UV-damage recruitment imaging; in vitro neddylation reconstitution, H4 lysine mutagenesis, RNF168 MIU binding assay

    PMID:23394999 PMID:23530056 PMID:23751493

    Open questions at the time
    • Full scope of STUbL substrates unknown
    • How Arkadia and RNF4 STUbL activities are coordinated on shared substrates (e.g. PML) not resolved
    • Whether NEDD8 ligase and ubiquitin ligase activities are mutually exclusive or context-dependent unknown
  8. 2015 High

    Arkadia's substrate range was extended to inhibitory Smad6 for BMP signaling and to ESRP2 for splicing regulation, broadening its functional scope beyond TGF-β/Nodal.

    Evidence Ubiquitination assays with E3-dead C937A mutant in KO MEFs for Smad6; Co-IP and splicing reporter for ESRP2

    PMID:25762727 PMID:26522722

    Open questions at the time
    • Whether ESRP2 ubiquitination is degradative or regulatory not fully resolved
    • Physiological significance of Smad6 degradation in BMP-dependent developmental contexts untested in vivo
  9. 2017 High

    A critical structural determinant was pinpointed: tryptophan 972 in the RING-H2 C-terminal α-helix is essential for E2 UbcH5b interaction and E3 activity, with the W972R mutation disrupting helix structure while W972A retains function.

    Evidence NMR structural analysis of RING mutants combined with TGF-β luciferase reporter assay

    PMID:28647409

    Open questions at the time
    • Whether W972 is also required for E2s used in STUbL or NEDD8 ligase modes unknown
    • No crystal structure of Arkadia RING–E2 complex available
  10. 2021 High

    Three studies converged to refine the substrate landscape and expand functional roles: unbiased ubiquitylome proteomics confirmed SKI and SKIL as the sole TGF-β-dependent substrates; genetic epistasis in conditional KO mice established Arkadia-SKI/SnoN axis as essential for iTreg differentiation; and RNF111 was identified as the NEDD8 E3 ligase for cGAS, promoting antiviral innate immunity.

    Evidence Quantitative diGly proteomics with CRISPR RNF111 RING-truncation; conditional T-cell Arkadia KO with SKI/SnoN genetic rescue in vivo; mass spectrometry of cGAS neddylation sites with Rnf111 KO mouse HSV-1 infection model

    PMID:33720974 PMID:34473197 PMID:34740826

    Open questions at the time
    • How RNF111 switches between ubiquitin and NEDD8 ligase activities mechanistically unresolved
    • Full-length structural model remains unavailable
    • Whether Arkadia's cGAS neddylation role extends beyond HSV-1 to other viral infections not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for Arkadia's multi-modal catalytic activities (ubiquitin, SUMO-targeted ubiquitin, and NEDD8 E3 ligase), how substrate and E2 selectivity is switched between these modes, and the full physiological scope of its STUbL activity beyond XPC and PML.
  • No full-length structure or cryo-EM model exists
  • Regulatory post-translational modifications beyond autocatalytic ubiquitination incompletely mapped
  • In vivo significance of AP2/EGFR endocytosis regulation and Nrf2 stabilization not independently confirmed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 11 GO:0016874 ligase activity 5
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-392499 Metabolism of proteins 6 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-73894 DNA Repair 2
Partners
AXIN1CGASSKISKILSMAD2SMAD3SMAD7UBE2D2

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Arkadia/RNF111 physically interacts with inhibitory Smad7 and induces its poly-ubiquitination and proteasome-dependent degradation, thereby amplifying TGF-β and BMP signaling. Unlike Smurf1, Arkadia does not associate with TGF-β receptor complexes. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown with reporter assay, Western blot for Smad7 protein levels The EMBO journal High 14657019
2006 Axin forms a multimeric scaffold complex with Smad7 and Arkadia/RNF111, facilitating Arkadia-dependent ubiquitination and degradation of Smad7 and promoting TGF-β signaling; Axin also induces nuclear export of Smad7. Co-immunoprecipitation, siRNA knockdown, pulse-chase experiment measuring Smad7 half-life, luciferase reporter assay The EMBO journal High 16601693
2007 Arkadia/RNF111 is absolutely required for TGF-β-induced Smad3/Smad4-dependent transcription by mediating signal-induced degradation of the transcriptional repressor SnoN. Arkadia interacts with SnoN and ubiquitinates it, but efficient degradation requires formation of a complex with phosphorylated Smad2 or Smad3. siRNA library screen, luciferase reporter assay, Co-immunoprecipitation, ubiquitination assay, dominant-negative mutant overexpression, rescue experiment in Arkadia-null cancer cell line Molecular and cellular biology High 17591695
2007 Arkadia/RNF111 induces ubiquitin-dependent degradation of both SnoN and c-Ski (in addition to Smad7) through its C-terminal RING domain, interacting with these repressors in both free and Smad-bound forms. Co-immunoprecipitation, ubiquitination assay, Western blot for protein levels after Arkadia overexpression The Journal of biological chemistry High 17510063
2007 Arkadia/RNF111 interacts with and ubiquitinates phospho-Smad2/3 (P-Smad2/3), causing their degradation; this dual function couples activation of P-Smad2/3 target gene transcription with termination of signaling. Loss of Arkadia in embryonic cells leads to nuclear accumulation of hypoactive P-Smad2/3. Molecular interaction studies, ubiquitination assay, Arkadia-/- embryonic stem cells, chimera analysis, gene expression analysis PLoS biology High 17341133
2013 RNF111/Arkadia is a SUMO-targeted ubiquitin ligase (STUbL) that uses three adjacent SUMO-interacting motifs (SIMs) to recognize poly-SUMO2/3 chains, and uses Ubc13-Mms2 as cognate E2 to promote non-proteolytic K63-linked ubiquitylation of SUMOylated target proteins, including XPC, thereby facilitating nucleotide excision repair (NER) and recruitment of XPC to UV-damaged DNA. Co-immunoprecipitation, ubiquitination assay with chain-linkage analysis (K63), SIM mutagenesis, NER functional assay, UV-damage recruitment imaging The Journal of cell biology High 23751493
2013 RNF111/Arkadia E3 ubiquitin ligase activity (via UBE2M as E2) mediates DNA damage-induced accumulation of NEDD8 at DNA damage sites and polyneddylation of histone H4 at N-terminal lysine residues; this polyneddylation is recognized by the MIU domain of RNF168 and is required for foci formation of RNF168, 53BP1, and BRCA1. NEDD8 accumulation assay at DNA damage sites, in vitro neddylation assay, mutational analysis of H4 lysines, domain binding assay (MIU of RNF168), functional foci assay by immunofluorescence Molecular cell High 23394999
2013 Arkadia/RNF111 contains three successive SUMO-interacting motifs (SIMs) mediating noncovalent interaction with poly-SUMO2, can ubiquitinate SUMO chains, and is required for arsenic-induced degradation of polysumoylated PML by accumulating in PML nuclear bodies. Arkadia homodimerizes but does not heterodimerize with RNF4. SIM mutagenesis, Co-immunoprecipitation, ubiquitination assay, Arkadia depletion with Western blot for polysumoylated PML, co-localization imaging Molecular and cellular biology High 23530056
2001 Arkadia/RNF111 is essential for induction of the mammalian node and HNF3β expression in the anterior primitive streak; it functions within extraembryonic tissues and genetically interacts with Nodal signaling. Gene-trap mutagenesis generating arkadia null mice, chimera analysis showing extraembryonic requirement, genetic interaction with Nodal Nature High 11298452
2001 Arkadia/RNF111 specifically potentiates the mesendoderm-inducing activity of Xenopus Nodal-related factors (a subset of TGF-β family members), acting as a nuclear modulator of the Nodal signaling cascade. Xenopus embryo injection assay, epistasis with Nodal signaling inhibition, gene expression analysis Nature High 11298453
2012 The NMR solution structure of Arkadia's RING-H2 domain reveals a βββα fold with cross-brace Zn(II)-ligation; chemical shift perturbation analysis demonstrates that this domain directly interacts with E2 ubiquitin-conjugating enzyme UbcH5b. NMR structure determination, chemical shift perturbation mapping of E2 interaction Proteins High 22411132
2017 A conserved tryptophan (W972) in the C-terminal α-helix of Arkadia's RING-H2 domain is critical for interaction with E2 enzyme UbcH5b and E3 ligase activity; W972R mutation causes structural changes in the C-terminal α-helix and loss of E2 interaction, while W972A retains activity. NMR structural analysis of RING mutants, E2 binding assay by NMR, TGF-β-responsive luciferase reporter assay in vivo Journal of molecular biology High 28647409
2021 RNF111/Arkadia functions as the NEDD8 E3 ligase for cGAS, polyneddylating cGAS at Lys231 and Lys421, which promotes cGAS dimerization and DNA-binding ability, thereby activating the cGAS-STING innate immune signaling pathway; Rnf111-deficient mice show impaired antiviral responses and increased susceptibility to HSV-1. Mass spectrometry identification of neddylation sites, Co-immunoprecipitation, cGAS dimerization assay, DNA-binding assay, Rnf111 knockout mouse infection model, siRNA knockdown with interferon induction assay PLoS pathogens High 33720974
2011 RB1CC1/FIP200 is a novel positive regulator of TGF-β signaling that acts as a substrate-selective cofactor of Arkadia/RNF111, enhancing Arkadia E3 ligase activity specifically toward c-Ski (but not SnoN) through physical interaction with the substrate. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, TGF-β target gene expression analysis The Journal of biological chemistry High 21795712
2012 FHL2 (four-and-a-half LIM-only protein 2) binds Arkadia/RNF111 and stabilizes it by inhibiting K27-linked polyubiquitination, thereby prolonging Arkadia half-life and enhancing TGF-β signaling. Arkadia undergoes autocatalytic K63- and K27-linked polyubiquitination, with K27-linked chains promoting proteolysis. Co-immunoprecipitation, ubiquitination chain-linkage analysis, cycloheximide chase, RING domain mutant analysis, luciferase reporter assay The Journal of biological chemistry High 23212909
2015 Arkadia/RNF111 physically interacts with ESRP2 (epithelial splicing regulatory protein 2), induces its polyubiquitination, and modulates its splicing function; Arkadia and ESRP2 suppress clear-cell renal cell carcinoma tumor growth in a coordinated manner. Co-immunoprecipitation, ubiquitination assay, splicing reporter assay, tumor growth assay Oncogene Medium 26522722
2010 Arkadia/RNF111 interacts with the µ2 subunit of the clathrin-adaptor AP2 complex through an N-terminal YALL motif binding the YXXΦ-binding domain of µ2, ubiquitylates µ2 at Lys130, and modifies EGF-induced endocytosis of EGFR, thereby regulating EGF signaling. Yeast two-hybrid screening, Co-immunoprecipitation, ubiquitination assay, endocytosis assay Journal of biochemistry Medium 20965945
2015 Arkadia/RNF111 induces ubiquitylation and proteasome-dependent degradation of Smad6 (a BMP-specific inhibitory Smad), demonstrated with wild-type but not E3-dead (C937A) mutant Arkadia, thereby positively regulating BMP signaling and osteoblast differentiation. Ubiquitination assay, proteasome inhibitor rescue, Arkadia KO MEFs, transcriptional reporter assay, osteoblast differentiation markers Journal of biochemistry High 25762727
2014 Arkadia/RNF111 contains a SUMO-binding domain (SBD) comprising clustered SIMs that are redundant with an M domain unique to Arkadia; together these promote colocalization with CBX4/Pc2 in Polycomb bodies and activation of TGF-β pathway transcription. Transcriptome profiling shows Arkadia can both promote and inhibit gene expression depending on Polycomb/DNA methylation epigenetic context. Analytical molecular biology, subcellular colocalization imaging, RNA sequencing transcriptome profiling, luciferase reporter assay, SIM/M-domain mutagenesis Molecular and cellular biology Medium 24912682
2018 Arkadia/RNF111 ubiquitinates Nrf2 via K48-linked ubiquitin chains, resulting in stabilization (not degradation) of Nrf2 in PML-NB-enriched fractions, promoting Nrf2-dependent antioxidant gene transcription. Co-immunoprecipitation with anti-Nrf2 and anti-K48 ubiquitin antibodies, cycloheximide chase, ARE-luciferase reporter assay Cellular physiology and biochemistry Medium 29597191
2008 Arkadia/RNF111 represses myoblast differentiation markers through degradation of Ski and Ski-bound Smad complexes; it binds Smad2/3 via Ski and induces ubiquitination of Ski-bound phospho-Smad2/3, acting through both Smad-dependent and Smad-independent pathways in C2C12 myoblasts. siRNA knockdown, overexpression, Co-immunoprecipitation, ubiquitination assay, myoblast differentiation markers Bone Medium 18950738
2021 Arkadia/RNF111 mediates degradation of transcriptional corepressors SKI and SnoN downstream of TGF-β/Smad3 signaling to enable iTreg cell differentiation; genetic ablation of SKI and SnoN rescues Arkadia-deficient iTreg differentiation in vitro and in vivo, placing Arkadia upstream of SKI/SnoN in the iTreg differentiation program. Conditional T cell-specific Arkadia knockout mice, in vitro Treg differentiation assay, genetic rescue by SKI/SnoN ablation, intestinal lamina propria cell analysis The Journal of experimental medicine High 34473197
2021 Quantitative ubiquitylome proteomics identified SKI and SKIL/SnoN as the only targets ubiquitylated and degraded by RNF111 E3 ligase in the presence of TGF-β signaling; lysine 343 in the SAND domain of SKIL is the primary ubiquitylation site targeted by RNF111. Label-free quantitative ubiquitylome proteomics (diGly remnant immunoprecipitation and ubiquitin pan nanobody immunoprecipitation with mass spectrometry), CRISPR-engineered RNF111 RING-truncation clones Molecular & cellular proteomics High 34740826
2011 Arkadia/RNF111 functions as a tumor suppressor in colorectal cancer by degrading SnoN/Ski corepressors to derepress TGF-β signaling; Arkadia heterozygous mice show reduced TGF-β target gene expression and four-fold increased susceptibility to carcinogen-induced colorectal cancer. Arkadia heterozygous mouse model, carcinogen-induced CRC model, TGF-β target gene expression analysis, tumor pathology, identification of loss-of-function mutations in human CRC tumors Cancer research High 21998011
2013 Loss of Arkadia/RNF111 function substantially inhibits lung colonization (metastasis) by TGF-β-driven cancer cells in tail vein injection mouse models, demonstrating a tumor-promoting role for Arkadia through Smad3-dependent TGF-β signaling at metastatic sites. Dominant-negative Arkadia overexpression, siRNA knockdown, tail vein injection mouse metastasis model, soft agar growth assay Cancer research Medium 23467611

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science (New York, N.Y.) 624 7761854
2003 Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7. The EMBO journal 186 14657019
1995 The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding. Molecular and cellular biology 170 7823930
2018 A Micro-Ark for Cells: Highly Open Porous Polyhydroxyalkanoate Microspheres as Injectable Scaffolds for Tissue Regeneration. Advanced materials (Deerfield Beach, Fla.) 161 29920804
2006 Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. The EMBO journal 150 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
2002 The role of ARK in stress-induced apoptosis in Drosophila cells. The Journal of cell biology 140 11901172
2013 RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response. The Journal of cell biology 133 23751493
2019 Biological control agent Rhizobium (=Agrobacterium) vitis strain ARK-1 suppresses expression of the essential and non-essential vir genes of tumorigenic R. vitis. BMC research notes 132 30602384
2010 Atrial fibrillation induces myocardial fibrosis through angiotensin II type 1 receptor-specific Arkadia-mediated downregulation of Smad7. Circulation research 131 21127293
1997 Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation. Oncogene 124 9395235
1999 Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt. Molecular endocrinology (Baltimore, Md.) 115 9973250
2013 RNF111-dependent neddylation activates DNA damage-induced ubiquitination. Molecular cell 114 23394999
2009 Activity of antioxidant enzymes and physiological responses in ark shell, Scapharca broughtonii, exposed to thermal and osmotic stress: effects on hemolymph and biochemical parameters. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 113 19788926
2002 Novel mechanism for gonadotropin-releasing hormone neuronal migration involving Gas6/Ark signaling to p38 mitogen-activated protein kinase. Molecular and cellular biology 111 11756555
1994 Chronic morphine administration increases beta-adrenergic receptor kinase (beta ARK) levels in the rat locus coeruleus. Journal of neurochemistry 91 7931357
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
2000 ARK-1 inhibits EGFR signaling in C. elegans. Molecular cell 88 10949028
2008 Specificity of the chromodomain Y chromosome family of chromodomains for lysine-methylated ARK(S/T) motifs. The Journal of biological chemistry 86 18450745
1998 cDNA cloning, expression, subcellular localization, and chromosomal assignment of mammalian aurora homologues, aurora-related kinase (ARK) 1 and 2. Biochemical and biophysical research communications 74 9514916
2006 The Drosophila melanogaster Apaf-1 homologue ARK is required for most, but not all, programmed cell death. The Journal of cell biology 64 16533943
2001 Arkadia enhances nodal-related signalling to induce mesendoderm. Nature 64 11298453
2011 Defining the core apoptosis pathway in the mosquito disease vector Aedes aegypti: the roles of iap1, ark, dronc, and effector caspases. Apoptosis : an international journal on programmed cell death 62 21107703
2020 Circ-RNF111 contributes to paclitaxel resistance in breast cancer by elevating E2F3 expression via miR-140-5p. Thoracic cancer 59 32445273
2006 ARK, the Apaf-1 related killer in Drosophila, requires diverse domains for its apoptotic activity. Cell death and differentiation 55 16645639
2007 Arkadia regulates TGF-beta signaling during renal tubular epithelial to mesenchymal cell transition. Kidney international 47 18059455
1996 Cleavage and release of a soluble form of the receptor tyrosine kinase ARK in vitro and in vivo. Journal of cellular physiology 44 8816929
2021 RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response. PLoS pathogens 42 33720974
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
2010 Trps1 haploinsufficiency promotes renal fibrosis by increasing Arkadia expression. Journal of the American Society of Nephrology : JASN 41 20507941
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
2012 Complete mitochondrial DNA sequence of the ark shell Scapharca broughtonii: an ultra-large metazoan mitochondrial genome. Comparative biochemistry and physiology. Part D, Genomics & proteomics 34 23291309
2013 Arkadia regulates tumor metastasis by modulation of the TGF-β pathway. Cancer research 32 23467611
2008 Complete genomic sequence analysis of infectious bronchitis virus Ark DPI strain and its evolution by recombination. Virology journal 31 19102764
2009 Context-dependent regulation of the expression of c-Ski protein by Arkadia in human cancer cells. Journal of biochemistry 30 19959502
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 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 27 23212909
2020 The ARK Assay Is a Sensitive and Versatile Method for the Global Detection of DNA-Protein Crosslinks. Cell reports 26 31995761
2012 NMR-based insights into the conformational and interaction properties of Arkadia RING-H2 E3 Ub ligase. Proteins 25 22411132
2012 Blastopirellula cremea sp. nov., isolated from a dead ark clam. International journal of systematic and evolutionary microbiology 24 23159757
2008 High yield expression and NMR characterization of Arkadia E3 ubiquitin ligase RING-H2 finger domain. Biochemical and biophysical research communications 24 19032943
2000 Regional pre- and postsynaptic sympathetic system in the failing human heart--regulation of beta ARK-1. European journal of heart failure 23 10742700
2013 Identification and expression analysis on bactericidal permeability-increasing protein (BPI)/lipopolysaccharide-binding protein (LBP) of ark shell, Scapharca broughtonii. Fish & shellfish immunology 22 23742867
2017 A Residue Specific Insight into the Arkadia E3 Ubiquitin Ligase Activity and Conformational Plasticity. Journal of molecular biology 21 28647409
2015 Ferritin has an important immune function in the ark shell Scapharca broughtonii. Developmental and comparative immunology 21 26724973
1998 Role of beta ARK in long-term agonist-promoted desensitisation of the beta 2-adrenergic receptor. Cellular signalling 21 9607143
2021 Activation of SnRK2 by Raf-like kinase ARK represents a primary mechanism of ABA and abiotic stress responses. Plant physiology 20 33655297
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
2015 A manganese superoxide dismutase (MnSOD) from ark shell, Scapharca broughtonii: Molecular characterization, expression and immune activity analysis. Fish & shellfish immunology 20 25980798
2012 Ruegeria conchae sp. nov., isolated from the ark clam Scapharca broughtonii. International journal of systematic and evolutionary microbiology 20 22228657
2022 Extracellular matrix-mimicking nanofibrous chitosan microspheres as cell micro-ark for tissue engineering. Carbohydrate polymers 19 35725181
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
2006 Endocytic Ark/Prk kinases play a critical role in adriamycin resistance in both yeast and mammalian cells. Cancer research 19 17178891
2000 The animal research kit (ARK) can be used in a multistep double staining method for human tissue specimens. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 19 10990496
2014 Multiple Arkadia/RNF111 structures coordinate its Polycomb body association and transcriptional control. Molecular and cellular biology 18 24912682
2013 Biological control of crown gall on grapevine and root colonization by nonpathogenic Rhizobium vitis strain ARK-1. Microbes and environments 18 23708779
2012 Molecular characterization and expression of a novel big defensin (Sb-BDef1) from ark shell, Scapharca broughtonii. Fish & shellfish immunology 18 23000749
2021 Circ-RNF111 aggravates the malignancy of gastric cancer through miR-876-3p-dependent regulation of KLF12. World journal of surgical oncology 17 34461926
2012 Kistimonas scapharcae sp. nov., isolated from a dead ark clam (Scapharca broughtonii), and emended description of the genus Kistimonas. International journal of systematic and evolutionary microbiology 17 22247211
2002 Cataract- and lens-specific upregulation of ARK receptor tyrosine kinase in Emory mouse cataract. Investigative ophthalmology & visual science 17 12036992
2014 Methylation of CpG island of p14(ARK), p15(INK4b) and p16(INK4a) genes in coke oven workers. Human & experimental toxicology 16 24837742
2013 Rhodopirellula rosea sp. nov., a novel bacterium isolated from an ark clam Scapharca broughtonii. Journal of microbiology (Seoul, Korea) 16 23812809
2010 Arkadia--beyond the TGF-β pathway. Journal of biochemistry 16 21109559
2019 Two novel peptides from ark shell protein stimulate osteoblast differentiation and rescue ovariectomy-induced bone loss. Toxicology and applied pharmacology 15 31697996
2015 Arkadia enhances BMP signalling through ubiquitylation and degradation of Smad6. Journal of biochemistry 15 25762727
2011 Ornithinibacillus scapharcae sp. nov., isolated from a dead ark clam. Antonie van Leeuwenhoek 15 21952732
2007 Population genetic structure of the ark shell Scapharca broughtonii Schrenck from Korea, China, and Russia based on COI gene sequences. Marine biotechnology (New York, N.Y.) 15 17294315
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
2020 Ark shell protein-derived bioactive peptides promote osteoblastic differentiation through upregulation of the canonical Wnt/β-catenin signaling in human bone marrow-derived mesenchymal stem cells. Journal of food biochemistry 13 32808363
2019 The transcriptomic responses of the ark shell, Anadara broughtonii, to sulfide and hypoxia exposure. Molecular biology reports 13 31111368
2017 Biological control for grapevine crown gall using nonpathogenic Rhizobium vitis strain ARK-1. Proceedings of the Japan Academy. Series B, Physical and biological sciences 13 29021507
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
2011 Neptunomonas concharum sp. nov., isolated from a dead ark clam, and emended description of the genus Neptunomonas. International journal of systematic and evolutionary microbiology 13 22199221
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
2014 Dimorphic ovary differentiation in honeybee (Apis mellifera) larvae involves caste-specific expression of homologs of ark and buffy cell death genes. PloS one 12 24844304
2011 Moa's Ark or volant ghosts of Gondwana? Insights from nineteen years of ancient DNA research on the extinct moa (Aves: Dinornithiformes) of New Zealand. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft 12 21596537
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
2015 Roseovarius scapharcae sp. nov., isolated from ark shell Scapharca broughtonii. International journal of systematic and evolutionary microbiology 11 26410220
2015 Evaluation of the Nonpathogenic Agrobacterium vitis Strain ARK-1 for Crown Gall Control in Diverse Plant Species. Plant disease 11 30699696
2007 Daxx-like protein of Drosophila interacts with Dmp53 and affects longevity and Ark mRNA level. The Journal of biological chemistry 11 17933869
2018 Molecular cloning, expression and biochemical characterization of hemoglobin gene from ark shell Scapharca broughtonii. Fish & shellfish immunology 10 29649584
2018 Validation of housekeeping genes for quantitative mRNA expression analysis in OsHV-1 infected ark clam, Scapharca broughtonii. Journal of invertebrate pathology 10 29723493
2017 Infectious Bronchitis Virus S2 of 4/91 Expressed from Recombinant Virus Does Not Protect Against Ark-Type Challenge. Avian diseases 10 28957002
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
2000 Cell death: drosophila Apaf-1 - no longer in the (d)Ark. Current biology : CB 10 10704400
2022 Anti-inflammatory action of ark shell (Scapharca subcrenata) protein hydrolysate in LPS-stimulated RAW264.7 murine macrophages. Journal of food biochemistry 9 36309949
2021 Transcriptomic analyses provide insights into the adaptive responses to heat stress in the ark shells, Scapharca subcrenata. Comparative biochemistry and physiology. Part D, Genomics & proteomics 9 33611220
2021 Chromosome-level genome assembly of Scapharca kagoshimensis reveals the expanded molecular basis of heme biosynthesis in ark shells. Molecular ecology resources 9 34214251
2021 Comparison of ultra-performance liquid chromatography and ARK immunoassay for therapeutic drug monitoring of voriconazole. Annals of clinical biochemistry 9 34482744
2016 Changes in hemolymph characteristics of ark shell Scapharaca broughtonii dealt with Vibrio anguillarum challenge in vivo and various of anticoagulants in vitro. Fish & shellfish immunology 8 27845210
2014 Complete mitochondrial genome of Ark shell Scapharca subcrenata. Mitochondrial DNA. Part A, DNA mapping, sequencing, and analysis 8 25050874
2014 Reduction in pathogen populations at grapevine wound sites is associated with the mechanism underlying the biological control of crown gall by rhizobium vitis strain ARK-1. Microbes and environments 8 25077443
2007 Opposing effects of Arkadia and Smurf on TGFbeta1-induced IgA isotype expression. Molecules and cells 7 17978583