RNF181

Summary

RNF181 (ring finger protein 181, HGNC:28037) is a protein-coding gene on chromosome 2p11.2, encoding E3 ubiquitin-protein ligase RNF181 (Q9P0P0). E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.

RNF181 binds the integrin alpha-IIb (ITGA2B; MIM 607759)/beta-3 (ITGB3; MIM 173470) complex and has E3 ubiquitin ligase activity (Brophy et al., 2008 [PubMed 18331836]).

Source: NCBI Gene 51255 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 24 total
• MANE Select transcript: NM_016494

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28037
Approved symbol	RNF181
Name	ring finger protein 181
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Aliases	HSPC238
Ensembl gene	ENSG00000168894
Ensembl biotype	protein_coding
OMIM	612490
Entrez	51255

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000306368, ENST00000414390, ENST00000441634, ENST00000443647, ENST00000456023, ENST00000461845, ENST00000867201, ENST00000923726, ENST00000923727, ENST00000923728, ENST00000923729, ENST00000923730

RefSeq mRNA: 1 — MANE Select: NM_016494 NM_016494

CCDS: CCDS1981

Canonical transcript exons

ENST00000306368 — 5 exons

Exon	Start	End
ENSE00001135451	85596822	85596931
ENSE00001135456	85596519	85596649
ENSE00001154971	85597445	85597708
ENSE00001934446	85595745	85595849
ENSE00003653200	85597104	85597178

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 98.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 74.1655 / max 265.9175, expressed in 1826 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21224	62.2714	1826
21223	11.8941	1801

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	98.63	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.46	gold quality
tibialis anterior	UBERON:0001385	98.14	gold quality
body of pancreas	UBERON:0001150	98.06	gold quality
left ventricle myocardium	UBERON:0006566	97.89	gold quality
upper arm skin	UBERON:0004263	97.76	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.71	gold quality
descending thoracic aorta	UBERON:0002345	97.64	gold quality
cartilage tissue	UBERON:0002418	97.60	gold quality
pancreas	UBERON:0001264	97.58	gold quality
right adrenal gland	UBERON:0001233	97.52	gold quality
islet of Langerhans	UBERON:0000006	97.49	gold quality
metanephros cortex	UBERON:0010533	97.49	gold quality
thoracic aorta	UBERON:0001515	97.46	gold quality
left coronary artery	UBERON:0001626	97.45	gold quality
ascending aorta	UBERON:0001496	97.44	gold quality
left adrenal gland	UBERON:0001234	97.41	gold quality
spinal cord	UBERON:0002240	97.41	gold quality
body of stomach	UBERON:0001161	97.40	gold quality
coronary artery	UBERON:0001621	97.39	gold quality
left adrenal gland cortex	UBERON:0035825	97.39	gold quality
aorta	UBERON:0000947	97.38	gold quality
adult mammalian kidney	UBERON:0000082	97.37	gold quality
popliteal artery	UBERON:0002250	97.37	gold quality
tibial artery	UBERON:0007610	97.37	gold quality
granulocyte	CL:0000094	97.34	gold quality
right coronary artery	UBERON:0001625	97.30	gold quality
right adrenal gland cortex	UBERON:0035827	97.30	gold quality
mucosa of transverse colon	UBERON:0004991	97.25	gold quality
decidua	UBERON:0002450	97.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-75367	no	141.50
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting RNF181, 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-4534	99.99	66.58	1907
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-6793-3P	97.66	65.78	1084

Literature-anchored findings (GeneRIF, showing 8)

• The presence of RN181 in human platelets was established; RN181 has ubiquitin E3 ligase activity. (PMID:18331836)
• Data show LOC51255 (RNF181) protein located in the cytoplasm of HePG2 cell line. (PMID:19426595)
• RN181 suppresses the tumorigenesis of hepatocellular carcinoma through the inhibition of ERK/MAPK signaling in the liver. (PMID:21391225)
• The identification and validation of proteins interacting with HSP238 may lead to the discovery of novel mechanisms through which HSPC238 suppresses tumorigenesis in human hepatocellular carcinoma (PMID:26398855)
• RNF181 limits the proliferation of human diffuse large B cell lymphoma cells that depend upon aberrant CARD11 signaling to NF-kappaB for growth and survival in culture. (PMID:26711259)
• RN181 functions as a tumour suppressor in gastric cancer by regulation of the ERK/MAPK-cyclin D1/CDK4 pathway, controlling cell proliferation and tumor volume. (PMID:30714150)
• The ubiquitin ligase RNF181 stabilizes ERalpha and modulates breast cancer progression. (PMID:32973333)
• RN181 regulates the biological behaviors of oral squamous cell carcinoma cells via mediating ERK/MAPK signaling pathway. (PMID:34052676)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf181	ENSDARG00000023958
rattus_norvegicus	Rnf181	ENSRNOG00000012035
drosophila_melanogaster	CG7694	FBGN0038627
caenorhabditis_elegans	rnf-126	WBGENE00021842

Paralogs (2): RNF126 (ENSG00000070423), RNF115 (ENSG00000265491)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF181 — Q9P0P0 (reviewed: Q9P0P0)

Alternative names: RING finger protein 181

All UniProt accessions (5): Q9P0P0, C9J1C6, C9J391, F8WBU5, H7C426

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Catalyzes monoubiquitination of 26S proteasome subunit PSMC2/RPT1.

Subunit / interactions. Directly interacts with ITGA2B and, as a result, with integrin ITGA2B/ITGB3. There is no evidence that integrin ITGA2B/ITGB3 is an endogenous substrate for RNF181-directed ubiquitination.

Tissue specificity. Widely expressed, with highest levels in liver and heart and lowest levels in brain and skeletal muscle. Expressed in platelets (at protein level).

Post-translational modifications. Autoubiquitinated as part of the enzymatic reaction.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the RNF181 family.

RefSeq proteins (1): NP_057578* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily

Pfam: PF13639

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 (5 total): chain 1, zinc finger region 1, region of interest 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P0P0-F1	84.68	0.54

Functional residue map

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

Post-translational modifications (1): 153

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-8852135	Protein ubiquitination

MSigDB gene sets: 150 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, WANG_LMO4_TARGETS_DN, GOBP_PROTEIN_AUTOUBIQUITINATION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, NKX25_01, GFI1_01, chr2p11, USF_02, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, GINESTIER_BREAST_CANCER_ZNF217_AMPLIFIED_DN

GO Biological Process (2): protein ubiquitination (GO:0016567), protein autoubiquitination (GO:0051865)

GO Molecular Function (6): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (1): cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Protein ubiquitination	1
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification by small protein conjugation	1
protein ubiquitination	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

958 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF181	ITGA2B	P08514	674
RNF181	UBR4	Q5T4S7	617
RNF181	ITGB3	P05106	600
RNF181	UBR7	Q8N806	575
RNF181	UBE3A	P78355	560
RNF181	HUWE1	Q7Z6Z7	559
RNF181	USP39	Q53GS9	527
RNF181	DCTN4	Q9UJW0	520
RNF181	UBE3C	Q15386	509
RNF181	ACTR1B	P42025	506
RNF181	TMEM72	A0PK05	476
RNF181	VAMP5	O95183	461
RNF181	TMEM150A	Q86TG1	429
RNF181	NTM	Q9P121	426
RNF181	MAT2A	P31153	421

IntAct

69 interactions, top by confidence:

A	B	Type	Score
FBXO7	SKP1	psi-mi:“MI:0914”(association)	0.900
UBE2D1	RNF181	psi-mi:“MI:0915”(physical association)	0.670
UBE2D4	RNF181	psi-mi:“MI:0915”(physical association)	0.670
RNF181	UBE2D4	psi-mi:“MI:0915”(physical association)	0.670
PSMB3	PSMD11	psi-mi:“MI:0914”(association)	0.640
CDA	LIN7A	psi-mi:“MI:0914”(association)	0.640
PSMB9	PSMD11	psi-mi:“MI:0914”(association)	0.530
SLC44A5	NME2P1	psi-mi:“MI:0914”(association)	0.530
SLC32A1	NPLOC4	psi-mi:“MI:0914”(association)	0.530
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
SEM1	PSMC2	psi-mi:“MI:0914”(association)	0.530
SLC9A4	RNF181	psi-mi:“MI:0915”(physical association)	0.400
GDPD4	RNF181	psi-mi:“MI:0915”(physical association)	0.400
SLC44A3	RNF181	psi-mi:“MI:0915”(physical association)	0.400
RNF181	UBE2D2	psi-mi:“MI:0915”(physical association)	0.370
UBE2D3	RNF181	psi-mi:“MI:0915”(physical association)	0.370
UBE2E1	RNF181	psi-mi:“MI:0915”(physical association)	0.370
RNF181	UBE2E3	psi-mi:“MI:0915”(physical association)	0.370
RNF181	UBE2U	psi-mi:“MI:0915”(physical association)	0.370
BTG1	RNF181	psi-mi:“MI:0915”(physical association)	0.370
NPY5R	RNF181	psi-mi:“MI:0915”(physical association)	0.370
RNF181	PEG10	psi-mi:“MI:0915”(physical association)	0.370
RNF181	ZMYND10	psi-mi:“MI:0915”(physical association)	0.370
RNF181	CLK4	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (172): RNF181 (Biochemical Activity), UBE2D1 (Reconstituted Complex), RNF181 (Affinity Capture-MS), RNF181 (Affinity Capture-MS), RNF181 (FRET), CARD11 (Affinity Capture-Western), UBC (Biochemical Activity), UBE2D1 (Reconstituted Complex), UBE2D2 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2E1 (Reconstituted Complex), UBE2N (Reconstituted Complex), BCL10 (Biochemical Activity), RNF181 (Affinity Capture-MS), RNF181 (Affinity Capture-MS)

ESM2 similar proteins: A0JP89, A7YY07, B3M1F2, B4KCG1, B4M686, B4N8G7, J9VG42, O13731, O13786, O45595, O74975, P30631, P34470, P38239, P49583, P50536, Q06651, Q06834, Q11076, Q12157, Q197D9, Q3T0W3, Q5M974, Q6AXU4, Q6C435, Q6FQ33, Q6GMD3, Q6GPV5, Q757W2, Q75CC8, Q7ZW78, Q8GUU2, Q8L9T5, Q8LBA0, Q8RXD3, Q93Z92, Q95Y41, Q9C919, Q9CY62, Q9HGN5

Diamond homologs: A5WWA0, E9QAU8, O22197, O43567, O49500, O54965, O64763, O80927, P0CH02, P0CH30, P0DPR2, Q06003, Q07G42, Q08CG8, Q08D68, Q0V9R0, Q0VD51, Q0WPW5, Q3T0W3, Q3U2C5, Q3UHJ8, Q4KLR8, Q4V7B8, Q566M8, Q5DTZ6, Q5M974, Q5NCP0, Q5R476, Q5RCV8, Q5SSZ7, Q5XIL0, Q641J8, Q66HG0, Q66J97, Q67YI6, Q68DV7, Q69U49, Q6AVN2, Q6AXU4, Q6GPV5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RNF181	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	7	23.0×	4e-06
Regulation of TNFR1 signaling	6	22.4×	2e-05
Vpu mediated degradation of CD4	5	22.1×	7e-05
Degradation of CRY and PER proteins	6	22.0×	2e-05
Cross-presentation of soluble exogenous antigens (endosomes)	5	21.1×	8e-05
AUF1 (hnRNP D0) binds and destabilizes mRNA	5	20.7×	8e-05
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	5	20.7×	8e-05
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	5	20.7×	8e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein K48-linked ubiquitination	9	21.7×	7e-08
protein polyubiquitination	9	14.8×	1e-06
negative regulation of canonical NF-kappaB signal transduction	5	12.3×	3e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	16	11.9×	1e-10
ubiquitin-dependent protein catabolic process	11	11.7×	3e-07
protein ubiquitination	9	5.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

754 predictions. Top by Δscore:

Variant	Effect	Δscore
2:85595845:GCAAG:G	donor_gain	1.0000
2:85595846:CAAG:C	donor_loss	1.0000
2:85595847:AAG:A	donor_loss	1.0000
2:85596518:GGTCA:G	acceptor_gain	1.0000
2:85596645:GGCTG:G	donor_gain	1.0000
2:85596646:GCTG:G	donor_gain	1.0000
2:85596646:GCTGG:G	donor_gain	1.0000
2:85595850:GTGG:G	donor_gain	0.9900
2:85596517:A:AG	acceptor_gain	0.9900
2:85596517:AG:A	acceptor_gain	0.9900
2:85596518:G:GG	acceptor_gain	0.9900
2:85596518:G:GT	acceptor_loss	0.9900
2:85596518:GG:G	acceptor_gain	0.9900
2:85596518:GGT:G	acceptor_gain	0.9900
2:85596518:GGTC:G	acceptor_gain	0.9900
2:85596647:C:T	donor_gain	0.9900
2:85596647:CTGG:C	donor_loss	0.9900
2:85596648:TGGT:T	donor_loss	0.9900
2:85596650:GTG:G	donor_loss	0.9900
2:85596651:T:TG	donor_loss	0.9900
2:85596652:G:GG	donor_loss	0.9900
2:85596821:G:C	acceptor_gain	0.9900
2:85596846:T:TA	acceptor_gain	0.9900
2:85597102:A:AG	acceptor_gain	0.9900
2:85597103:G:GG	acceptor_gain	0.9900
2:85597103:GACAA:G	acceptor_gain	0.9900
2:85597174:A:G	donor_gain	0.9900
2:85597174:ATAAG:A	donor_loss	0.9900
2:85597175:TAAG:T	donor_loss	0.9900
2:85597176:AAGG:A	donor_loss	0.9900

AlphaMissense

1013 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:85596593:C:A	A54D	0.999
2:85596830:T:C	C76R	0.999
2:85596839:T:C	C79R	0.999
2:85596896:T:C	F98L	0.999
2:85596898:C:A	F98L	0.999
2:85596898:C:G	F98L	0.999
2:85596909:G:A	C102Y	0.999
2:85596922:G:C	W106C	0.999
2:85596922:G:T	W106C	0.999
2:85597113:T:C	C113R	0.999
2:85597122:T:C	C116R	0.999
2:85596830:T:A	C76S	0.998
2:85596831:G:C	C76S	0.998
2:85596839:T:A	C79S	0.998
2:85596840:G:A	C79Y	0.998
2:85596840:G:C	C79S	0.998
2:85596841:T:G	C79W	0.998
2:85596897:T:C	F98S	0.998
2:85596908:T:A	C102S	0.998
2:85596908:T:C	C102R	0.998
2:85596909:G:C	C102S	0.998
2:85596909:G:T	C102F	0.998
2:85596910:C:G	C102W	0.998
2:85596920:T:A	W106R	0.998
2:85596920:T:C	W106R	0.998
2:85596924:T:C	L107P	0.998
2:85597113:T:A	C113S	0.998
2:85597114:G:A	C113Y	0.998
2:85597114:G:C	C113S	0.998
2:85597115:T:G	C113W	0.998

dbSNP variants (sampled 300 via entrez): RS1001470386 (2:85593881 G>A), RS1001611639 (2:85594965 C>T), RS1001642708 (2:85595343 C>G), RS1002619365 (2:85596424 T>C), RS1002648958 (2:85596853 TGAG>T,TGAGGAG), RS1005328244 (2:85598180 C>T), RS1006849859 (2:85595904 C>A,G), RS1007123116 (2:85597918 C>T), RS1007778671 (2:85597312 G>A), RS1007855356 (2:85597647 G>A), RS1009119311 (2:85594923 G>A), RS1009762680 (2:85593927 C>T), RS1010356469 (2:85595601 G>A,C,T), RS1010902145 (2:85597561 A>G,T), RS1011156789 (2:85596350 T>C)

Disease associations

OMIM: gene MIM:612490 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001148_4	Prostate cancer	3.000000e-15

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Tunicamycin	increases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects methylation	1
glycidyl methacrylate	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
cupric chloride	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
chloropicrin	increases expression	1
abrine	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
DDT	decreases expression	1
Diazinon	increases methylation	1
Estradiol	decreases expression	1
Hydrogen Peroxide	affects expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Smoke	decreases expression	1
Dronabinol	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases expression	1
Antirheumatic Agents	decreases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3G5	Abcam HEK293T RNF181 KO	Transformed cell line	Female
CVCL_D9QT	Ubigene HEK293 RNF181 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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