RNF111

Summary

RNF111 (ring finger protein 111, HGNC:17384) is a protein-coding gene on chromosome 15q22.1-q22.2, encoding E3 ubiquitin-protein ligase Arkadia (Q6ZNA4). E3 ubiquitin-protein ligase.

The protein encoded by this gene is a nuclear RING-domain containing E3 ubiquitin ligase. This protein interacts with the transforming growth factor (TGF) -beta/NODAL signaling pathway by promoting the ubiquitination and proteosomal degradation of negative regulators, like SMAD proteins, and thereby enhances TGF-beta target-gene transcription. As a modulator of the nodal signaling cascade, this gene plays a critical role in the induction of mesoderm during embryonic development. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 54778 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 151 total
• MANE Select transcript: NM_017610

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17384
Approved symbol	RNF111
Name	ring finger protein 111
Location	15q22.1-q22.2
Locus type	gene with protein product
Status	Approved
Aliases	ARK, Arkadia, FLJ38008, DKFZP761D081
Ensembl gene	ENSG00000157450
Ensembl biotype	protein_coding
OMIM	605840
Entrez	54778

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 25 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000348370, ENST00000557998, ENST00000558977, ENST00000559077, ENST00000559160, ENST00000559209, ENST00000559592, ENST00000559757, ENST00000560080, ENST00000560216, ENST00000560952, ENST00000561186, ENST00000895777, ENST00000895778, ENST00000895779, ENST00000895780, ENST00000895781, ENST00000895782, ENST00000895783, ENST00000895784, ENST00000895785, ENST00000895786, ENST00000895787, ENST00000895788, ENST00000895789, ENST00000921246, ENST00000921247, ENST00000921248, ENST00000921249, ENST00000965610

RefSeq mRNA: 5 — MANE Select: NM_017610 NM_001270528, NM_001270529, NM_001270530, NM_001330331, NM_017610

CCDS: CCDS10169, CCDS58365, CCDS58366, CCDS81888

Canonical transcript exons

ENST00000348370 — 14 exons

Exon	Start	End
ENSE00001032681	59080936	59081284
ENSE00001032687	59084129	59084254
ENSE00001125595	59075954	59076215
ENSE00001283576	59066764	59067083
ENSE00001336185	59058356	59058550
ENSE00001336186	59055682	59055845
ENSE00001336187	59052305	59052431
ENSE00001336191	59030804	59031702
ENSE00001904506	59094783	59097419
ENSE00002542304	58987663	58988068
ENSE00003505613	59092537	59092640
ENSE00003512360	59091059	59091154
ENSE00003528633	59085659	59085785
ENSE00003686618	59089667	59089759

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.1404 / max 132.9588, expressed in 1792 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146957	8.6970	1765
146956	4.4435	1646

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.75	gold quality
oocyte	CL:0000023	98.21	gold quality
endothelial cell	CL:0000115	94.68	gold quality
cortical plate	UBERON:0005343	92.75	gold quality
monocyte	CL:0000576	91.83	gold quality
mononuclear cell	CL:0000842	91.75	gold quality
leukocyte	CL:0000738	91.63	gold quality
ganglionic eminence	UBERON:0004023	91.61	gold quality
choroid plexus epithelium	UBERON:0003911	91.37	gold quality
ventricular zone	UBERON:0003053	90.87	gold quality
colonic epithelium	UBERON:0000397	90.17	gold quality
stromal cell of endometrium	CL:0002255	90.00	gold quality
tonsil	UBERON:0002372	89.77	gold quality
sural nerve	UBERON:0015488	89.72	gold quality
calcaneal tendon	UBERON:0003701	89.56	gold quality
blood	UBERON:0000178	89.36	gold quality
corpus epididymis	UBERON:0004359	89.22	gold quality
palpebral conjunctiva	UBERON:0001812	89.13	gold quality
upper leg skin	UBERON:0004262	89.11	gold quality
tibia	UBERON:0000979	89.09	gold quality
embryo	UBERON:0000922	88.83	gold quality
skin of leg	UBERON:0001511	88.78	gold quality
adrenal tissue	UBERON:0018303	88.65	gold quality
caput epididymis	UBERON:0004358	88.55	gold quality
lower esophagus mucosa	UBERON:0035834	88.37	gold quality
bone marrow cell	CL:0002092	88.36	gold quality
prefrontal cortex	UBERON:0000451	88.32	gold quality
vagina	UBERON:0000996	88.32	gold quality
ectocervix	UBERON:0012249	88.32	gold quality
corpus callosum	UBERON:0002336	88.25	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TGFB1, XPC

miRNA regulators (miRDB)

217 targeting RNF111, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-144-3P	99.94	73.98	2698

Literature-anchored findings (GeneRIF, showing 29)

• Functional analysis of the mouse counterpart (PMID:11298452)
• Functional analysis of the mouse counterpart (PMID:11298453)
• Silencing of the Arkadia gene resulted in repression of transcriptional activities induced by TGF-beta and BMP, and accumulation of the Smad7 protein. (PMID:14657019)
• Arkadia induces degradation of SnoN and c-Ski in addition to Smad7. (PMID:17510063)
• Results show that Arkadia specifically activates transcription via Smad3/Smad4 binding sites by inducing degradation of the transcriptional repressor SnoN. (PMID:17591695)
• Arkadia stimulates renal tubular epithelial to mesenchymal cell transition through degradation of Smad7. (PMID:18059455)
• Arkadia protein intensifies TGF-beta-induced effects by marking c-Ski and inhibitory Smad7 for destruction–REVIEW (PMID:19898560)
• findings show that Arkadia regulates the levels of expression of c-Ski protein in cell-type-dependent fashion, and exhibits a tumour suppressor function by inhibiting tumour cell growth (PMID:19959502)
• Arkadia complexes with clathrin adaptor AP2 and regulates EGF signalling. (PMID:20965945)
• RB1CC1 thus appears to play a unique role as a modulator of TGF-beta signaling by restricting substrate specificity of Arkadia. (PMID:21795712)
• Arkadia enhances transforming growth factor-beta signaling responses and supports its tumor-suppressing properties in colorectal cancer. (PMID:21998011)
• Determined the nuclear magnetic resonance solution structure of Arkadia’s RING-H2 domain and revealed a (beta)betabetaalpha fold, fully consistent with the expected “cross-brace” mode of Zn(II)-ligation. (PMID:22411132)
• FHL2 increases the stability of the TGF-beta pathway positive regulator Arkadia by inhibiting its ubiquitination and cooperates with Arkadia to activate TGF-beta signaling. (PMID:23212909)
• We established that ARX polyA alterations damage the regulation of KDM5C expression. (PMID:23246292)
• RNF111-dependent neddylation activates DNA damage-induced ubiquitination (PMID:23394999)
• findings indicate that Arkadia is not critical for regulating tumor growth per se, but is required for the early stages of cancer cell colonization at the sites of metastasis (PMID:23467611)
• Arkadia is involved in arsenic-induced degradation of polysumoylated PML protein. (PMID:23530056)
• Our findings establish RNF111 as a new STUbL that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response. (PMID:23751493)
• Arkadia can both promote and inhibit gene expression, indicating that Arkadia’s activity in transcriptional control may depend on the epigenetic context, defined by Polycomb repressive complexes and DNA methylation. (PMID:24912682)
• These data suggest that RNF111, together with the CRL4(DDB2) ubiquitin ligase complex, is responsible for sequential XPC ubiquitylation, which regulates the recruitment and release of XPC and is crucial for efficient progression of the NER reaction. (PMID:26151477)
• Results suggest that -459CpG methylation in Sp1-binding site of RNF111 promoter transcriptionally decreases RNF111 expression, which inhibits TGF-beta/Smad signaling associated invasion in NSCLC cells. (PMID:26238425)
• Results indicate a tumor-suppressive role of the ring finger protein 111 (Arkadia)-epithelial splicing regulatory protein 2 (ESRP2) axis in clear-cell renal cell carcinoma (ccRCC). (PMID:26522722)
• Study reports that the monomeric RING domains from the human E3 ligases Arkadia and Ark2C bind directly to free ubiquitin with an affinity comparable to that of other dedicated ubiquitin-binding domains. (PMID:26656854)
• These data show that the position occupied by W972 within wild-type Arkadia is critical for the function of its RING domain and that it depends on the nature of the residue at this position. (PMID:28647409)
• rkadia may regulate the pathogenesis and progression of hepatic fibrosis. (PMID:29286088)
• Arkadia/RNF111 is able to lys-48 ubiquitination of Nrf2 protects Nrf2 from degradation thereby allowing Nrf2-dependent gene transcription. (PMID:29597191)
• Arkadia specifically selects substrates carrying SUMO1-capped SUMO2/3 hybrid conjugates and targets them for proteasomal degradation. (PMID:31417085)
• Quantitative Ubiquitylome Analysis Reveals the Specificity of RNF111/Arkadia E3 Ubiquitin Ligase for its Degradative Substrates SKI and SKIL/SnoN in TGF-beta Signaling Pathway. (PMID:34740826)
• Deleterious variants in RNF111 impair female fertility and induce premature ovarian insufficiency in humans and mice. (PMID:38874713)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf111	ENSDARG00000078802
mus_musculus	Rnf111	ENSMUSG00000032217
rattus_norvegicus	Rnf111	ENSRNOG00000060750
drosophila_melanogaster	CG6923	FBGN0037944
caenorhabditis_elegans	toe-4	WBGENE00012194

Paralogs (2): ARK2C (ENSG00000141622), ARK2N (ENSG00000152242)

Protein

Protein identifiers

E3 ubiquitin-protein ligase Arkadia — Q6ZNA4 (reviewed: Q6ZNA4)

Alternative names: RING finger protein 111, RING-type E3 ubiquitin transferase Arkadia

All UniProt accessions (4): Q6ZNA4, H0YKK5, H0YKS2, H0YLK9

UniProt curated annotations — full annotation on UniProt →

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).

Subunit / interactions. Monomer. Interacts with SMAD6, SMAD7, AXIN1, AXIN2 and SKIL isoform SNON. Interacts with (phosphorylated) SMAD2 and SMAD3. Part of a complex containing RNF111, AXIN1 and SMAD7. Interacts (via SIM domains) with SUMO1 and SUMO2.

Subcellular location. Nucleus. Cytoplasm. PML body.

Tissue specificity. Broadly expressed.

Activity regulation. Binds free ubiquitin non-covalently via its RING-type zinc finger. Ubiquitin-binding leads to enhance the E3 ubiquitin-protein ligase activity by stabilizing the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the ‘closed’ conformation and activating ubiquitin transfer.

Domain organisation. The SUMO interaction motifs (SIMs) mediates the binding to polysumoylated substrate. The RING-type zinc finger mediates the E3 ubiquitin-protein ligase activity and binds directly to free ubiquitin. Non-covalent ubiquitin-binding stabilizes the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the ‘closed’ conformation and stimulates ubiquitin transfer.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the Arkadia family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q6ZNA4-1	1	yes
Q6ZNA4-2	2
Q6ZNA4-3	3
Q6ZNA4-4	4

RefSeq proteins (5): NP_001257457, NP_001257458, NP_001257459, NP_001317260, NP_060080* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR029306	RNF111_N	Domain
IPR051073	ZNRF3_Arkadia_E3_ligases	Family

Pfam: PF13639, PF15303

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (82 total): mutagenesis site 16, cross-link 14, region of interest 11, compositionally biased region 10, sequence conflict 9, strand 5, binding site 4, short sequence motif 3, turn 3, splice variant 2, sequence variant 2, chain 1, zinc finger region 1, helix 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2KIZ	SOLUTION NMR
5LG0	SOLUTION NMR
5LG7	SOLUTION NMR
7P2K	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZNA4-F1	46.97	0.08

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 942; 945; 965; 968

Post-translational modifications (14): 19, 28, 34, 47, 59, 73, 87, 96, 110, 173, 198, 218, 923, 927

Mutagenesis-validated functional residues (16):

Position	Phenotype
300–303	abolishes binding to sumoylated proteins and ubiquitination and degradation of xpc; when associated with 326-a–a-329 an
326–329	abolishes binding to sumoylated proteins and ubiquitination and degradation of xpc; when associated with 300-a–a-303 an
382–385	abolishes binding to sumoylated proteins and ubiquitination and degradation of xpc; when associated with 300-a–a-303 an
382	abolishes sumo binding.
382	loss of affinity to sumo1 and sumo2.
382	no loss of affinity toward sumo1 and sumo2.
383	abolishes sumo binding.
383	no loss of affinity toward sumo1 and sumo2.
384	abolishes sumo binding.
384	loss of affinity to sumo1 and sumo2.
385	abolishes sumo binding.
385	loss of affinity to sumo1 and sumo2.
386	abolishes sumo binding.
386	loss of affinity to sumo1 and sumo2.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-5696395	Formation of Incision Complex in GG-NER
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-168256	Immune System
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-212436	Generic Transcription Pathway
R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
R-HSA-5696398	Nucleotide Excision Repair
R-HSA-5696399	Global Genome Nucleotide Excision Repair (GG-NER)
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-73894	DNA Repair
R-HSA-74160	Gene expression (Transcription)
R-HSA-9006936	Signaling by TGFB family members
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 192 (showing top): REACTOME_FORMATION_OF_INCISION_COMPLEX_IN_GG_NER, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, NKX25_02, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, ACTGCAG_MIR173P, CAGCTG_AP4_Q5, GOBP_POSITIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA_STIMULUS, GOBP_NUCLEOTIDE_EXCISION_REPAIR, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY

GO Biological Process (9): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), pattern specification process (GO:0007389), protein ubiquitination (GO:0016567), positive regulation of transforming growth factor beta receptor signaling pathway (GO:0030511), positive regulation of protein ubiquitination (GO:0031398), global genome nucleotide-excision repair (GO:0070911), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (7): zinc ion binding (GO:0008270), SUMO polymer binding (GO:0032184), SMAD binding (GO:0046332), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), PML body (GO:0016605), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	2
Global Genome Nucleotide Excision Repair (GG-NER)	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Signaling by TGFB family members	1
RNA Polymerase II Transcription	1
Signaling by TGF-beta Receptor Complex	1
Generic Transcription Pathway	1
DNA Repair	1
Nucleotide Excision Repair	1
Gene expression (Transcription)	1
Signal Transduction	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	3
cellular anatomical structure	3
modification-dependent protein catabolic process	1
multicellular organism development	1
multicellular organismal process	1
protein modification by small protein conjugation	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
positive regulation of cellular response to transforming growth factor beta stimulus	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
nucleotide-excision repair	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
transition metal ion binding	1
SUMO binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nuclear body	1
cellular_component	1

Protein interactions and networks

STRING

1892 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF111	SMAD7	O15105	924
RNF111	AXIN1	O15169	910
RNF111	SKIL	P12756	817
RNF111	AXIN2	Q9Y2T1	810
RNF111	SMAD3	P84022	783
RNF111	FOXA2	Q9Y261	750
RNF111	SMURF2	Q9HAU4	743
RNF111	RNF4	P78317	697
RNF111	SMAD2	Q15796	663
RNF111	SUMO1	P55856	640
RNF111	SUMO2	P55855	628
RNF111	RNF168	Q8IYW5	617
RNF111	ESRP2	Q9H6T0	564
RNF111	SMURF1	Q9HCE7	553
RNF111	SIMC1	Q8NDZ2	541

IntAct

96 interactions, top by confidence:

A	B	Type	Score
CSNK2A1	RNF111	psi-mi:“MI:0915”(physical association)	0.850
RNF111	CSNK2A1	psi-mi:“MI:0915”(physical association)	0.850
CSNK2A2	EIF3J	psi-mi:“MI:0914”(association)	0.790
UBE2D1	RNF111	psi-mi:“MI:0915”(physical association)	0.740
RNF111	UBE2D3	psi-mi:“MI:0915”(physical association)	0.740
UBE2I	RNF111	psi-mi:“MI:0915”(physical association)	0.740
KRTAP5-9	RNF111	psi-mi:“MI:0915”(physical association)	0.740
RNF111	UBE2I	psi-mi:“MI:0915”(physical association)	0.740
RNF111	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.740
RNF111	UBE2D1	psi-mi:“MI:0915”(physical association)	0.740
UBE2D3	RNF111	psi-mi:“MI:0915”(physical association)	0.740
CSNK2B	RPS6KA5	psi-mi:“MI:0914”(association)	0.660
CSNK2B	NMT2	psi-mi:“MI:0914”(association)	0.660
CSNK2B	RPS6KA4	psi-mi:“MI:0914”(association)	0.640
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
CSNK2A2	PES1	psi-mi:“MI:0914”(association)	0.640

BioGRID (210): RNF111 (Two-hybrid), RNF111 (Two-hybrid), RNF111 (Two-hybrid), RNF111 (Two-hybrid), RNF111 (Two-hybrid), RNF111 (Two-hybrid), RNF111 (Two-hybrid), EDARADD (Two-hybrid), LCE4A (Two-hybrid), RNF111 (Biochemical Activity), RNF111 (Reconstituted Complex), RNF111 (Reconstituted Complex), SMAD2 (Affinity Capture-Western), SMAD3 (Affinity Capture-Western), RNF111 (Affinity Capture-MS)

ESM2 similar proteins: A2AFE9, A2X0Q6, A3A2Z8, A5PJK7, B1ATL7, C7IW64, O65685, O94602, P03413, P11821, P38128, P80074, Q01196, Q03347, Q08775, Q0V9R0, Q10108, Q13761, Q2HRB6, Q5R476, Q5UQP5, Q63046, Q66J97, Q6AWY2, Q6F2E2, Q6NRV8, Q6PF39, Q6ZNA4, Q7L0R7, Q84JP1, Q8CFA7, Q8LFU0, Q8VY64, Q90ZT7, Q93ZH2, Q945M9, Q99ML9, Q9D1Z2, Q9E6P2, Q9FGD6

Diamond homologs: A6H619, C4QVX6, E9QAU8, Q0V9R0, Q2HJ46, Q5R476, Q66J97, Q6NRV8, Q6ZNA4, Q6ZSG1, Q7ZWF4, Q90ZT7, Q940T5, Q95Y82, Q99ML9, Q9C1X4, Q9FMM4, Q9P1Y6, Q9VE61, A5WWA0, O22197, O43567, O49500, O54965, O64763, O80927, P0CH02, P0CH30, P0DPR2, Q06003, Q07G42, Q08CG8, Q08D68, Q0VD51, Q0WPW5, Q3T0W3, Q3U2C5, Q3UHJ8, Q4KLR8, Q4V7B8

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
AXIN1	up-regulates	RNF111	binding
RNF111	down-regulates	SMAD7	binding
RNF111	down-regulates	SMAD7	ubiquitination
TGFB1	“down-regulates quantity by repression”	RNF111	“transcriptional regulation”
RNF111	down-regulates	SKIL	ubiquitination
RNF111	up-regulates	AP2M1	ubiquitination
RNF111	down-regulates	SKI	ubiquitination
Ub:E2	“up-regulates activity”	RNF111	ubiquitination
RNF111	“down-regulates quantity by destabilization”	SUMO2	polyubiquitination
RNF111	“down-regulates quantity by destabilization”	PML	polyubiquitination
RNF111	“down-regulates quantity by destabilization”	SKIL	polyubiquitination
RNF111	“up-regulates activity”	ESRP2	ubiquitination
RNF111	“down-regulates activity”	SMAD3	ubiquitination
RNF111	“down-regulates activity”	SMAD2	ubiquitination
RNF111	“down-regulates quantity by destabilization”	SMAD2	ubiquitination
RNF111	down-regulates	SMAD3	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 73 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	8	50.8×	3e-10
Antigen processing: Ubiquitination & Proteasome degradation	19	12.2×	1e-13
KEAP1-NFE2L2 pathway	5	10.4×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein monoubiquitination	7	37.0×	8e-08
protein K11-linked ubiquitination	6	36.2×	1e-06
protein K48-linked ubiquitination	12	31.1×	1e-12
protein K63-linked ubiquitination	6	24.7×	1e-05
protein autoubiquitination	6	21.6×	2e-05
protein polyubiquitination	10	17.8×	3e-08
ubiquitin-dependent protein catabolic process	12	13.7×	1e-08
regulation of cell cycle	7	8.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

151 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	130
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

7197 predictions. Top by Δscore:

Variant	Effect	Δscore
15:58880108:C:CC	acceptor_gain	1.0000
15:58883621:TTTA:T	donor_loss	1.0000
15:58883622:TTAC:T	donor_loss	1.0000
15:58883623:TA:T	donor_loss	1.0000
15:58883625:C:CT	donor_loss	1.0000
15:58883782:TAGTG:T	acceptor_gain	1.0000
15:58883783:AGTG:A	acceptor_gain	1.0000
15:58883784:GTG:G	acceptor_gain	1.0000
15:58883784:GTGC:G	acceptor_loss	1.0000
15:58883785:TG:T	acceptor_gain	1.0000
15:58883785:TGC:T	acceptor_loss	1.0000
15:58883786:GC:G	acceptor_loss	1.0000
15:58883787:C:A	acceptor_loss	1.0000
15:58883787:C:CC	acceptor_gain	1.0000
15:58883788:T:G	acceptor_loss	1.0000
15:58886971:TTA:T	donor_loss	1.0000
15:58886973:A:AC	donor_gain	1.0000
15:58886973:AC:A	donor_gain	1.0000
15:58886974:C:CA	donor_loss	1.0000
15:58886974:C:CC	donor_gain	1.0000
15:58886974:CC:C	donor_gain	1.0000
15:58886974:CCT:C	donor_gain	1.0000
15:58887115:CAACT:C	acceptor_gain	1.0000
15:58887116:AACT:A	acceptor_gain	1.0000
15:58887117:ACT:A	acceptor_gain	1.0000
15:58887118:CT:C	acceptor_gain	1.0000
15:58887118:CTC:C	acceptor_gain	1.0000
15:58887119:TCT:T	acceptor_gain	1.0000
15:58887119:TCTGT:T	acceptor_loss	1.0000
15:58887120:C:CC	acceptor_gain	1.0000

AlphaMissense

6483 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:59052407:T:G	I328S	1.000
15:59055828:T:C	L385P	1.000
15:59091120:T:A	I902N	1.000
15:59091140:C:G	H909D	1.000
15:59091146:T:C	Y911H	1.000
15:59091146:T:G	Y911D	1.000
15:59091147:A:G	Y911C	1.000
15:59092597:T:A	C942S	1.000
15:59092597:T:C	C942R	1.000
15:59092598:G:A	C942Y	1.000
15:59092598:G:C	C942S	1.000
15:59092598:G:T	C942F	1.000
15:59092599:T:G	C942W	1.000
15:59092604:T:A	I944N	1.000
15:59092604:T:C	I944T	1.000
15:59092604:T:G	I944S	1.000
15:59092606:T:A	C945S	1.000
15:59092606:T:C	C945R	1.000
15:59092606:T:G	C945G	1.000
15:59092607:G:A	C945Y	1.000
15:59092607:G:C	C945S	1.000
15:59092607:G:T	C945F	1.000
15:59092608:T:G	C945W	1.000
15:59092610:T:C	L946S	1.000
15:59092612:T:C	S947P	1.000
15:59092619:T:C	L949S	1.000
15:59092640:G:C	R956T	1.000
15:59094783:A:C	R956S	1.000
15:59094783:A:T	R956S	1.000
15:59094788:T:A	L958H	1.000

dbSNP variants (sampled 300 via entrez): RS1000027195 (15:59050285 G>C), RS1000028856 (15:59086441 A>G), RS1000088480 (15:59056061 C>G), RS1000094341 (15:59049391 A>C,G,T), RS1000124563 (15:59019207 G>A), RS1000132149 (15:59069188 C>T), RS1000171414 (15:58997155 G>A), RS1000224533 (15:59061329 T>G), RS1000418744 (15:59014372 T>C), RS1000489453 (15:59092942 G>T), RS1000495088 (15:58994669 G>A), RS1000558569 (15:59071706 T>A,C), RS1000584161 (15:59034593 A>G,T), RS1000642123 (15:59040017 A>G), RS1000674122 (15:59076789 A>G)

Disease associations

OMIM: gene MIM:605840 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000904_2	Asperger disorder	7.000000e-06
GCST001639_9	Metabolite levels	1.000000e-10
GCST002194_4	Social communication problems	1.000000e-07
GCST002844_5	Atopic dermatitis	1.000000e-07
GCST004069_6	Cerebrospinal fluid AB1-42 levels	6.000000e-06
GCST010241_244	Apolipoprotein A1 levels	4.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0005427	social communication impairment
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0004614	apolipoprotein A 1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cisplatin	decreases expression, affects cotreatment	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Nickel	decreases expression	1
Phthalic Acids	increases methylation	1
Ribonucleotides	affects binding	1
Selenium	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7ZG	Ubigene A-549 RNF111 KO	Cancer cell line	Male
CVCL_TJ23	HAP1 RNF111 (-) 1	Cancer cell line	Male
CVCL_TJ24	HAP1 RNF111 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.