TRAF4

Summary

TRAF4 (TNF receptor associated factor 4, HGNC:12034) is a protein-coding gene on chromosome 17q11.2, encoding TNF receptor-associated factor 4 (Q9BUZ4). Adapter protein with E3 ligase activity that is involved in many diverse biological processes including cell proliferation, migration, differentiation, DNA repair, platelet activation or apoptosis.

This gene encodes a member of the TNF receptor associated factor (TRAF) family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF receptor superfamily. The encoded protein has been shown to interact with neurotrophin receptor, p75 (NTR/NTSR1), and negatively regulate NTR induced cell death and NF-kappa B activation. This protein has been found to bind to p47phox, a cytosolic regulatory factor included in a multi-protein complex known as NAD(P)H oxidase. This protein thus, is thought to be involved in the oxidative activation of MAPK8/JNK. Alternatively spliced transcript variants have been observed but the full-length nature of only one has been determined.

Source: NCBI Gene 9618 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 59 total
• MANE Select transcript: NM_004295

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12034
Approved symbol	TRAF4
Name	TNF receptor associated factor 4
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	CART1, MLN62, RNF83
Ensembl gene	ENSG00000076604
Ensembl biotype	protein_coding
OMIM	602464
Entrez	9618

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 6 protein_coding, 6 retained_intron, 4 nonsense_mediated_decay

ENST00000262395, ENST00000262396, ENST00000394925, ENST00000422344, ENST00000444415, ENST00000454852, ENST00000461195, ENST00000469529, ENST00000473421, ENST00000475329, ENST00000478021, ENST00000498540, ENST00000578917, ENST00000580073, ENST00000584944, ENST00000586813

RefSeq mRNA: 1 — MANE Select: NM_004295 NM_004295

CCDS: CCDS11243

Canonical transcript exons

ENST00000262395 — 7 exons

Exon	Start	End
ENSE00001176118	28748945	28750956
ENSE00002729975	28744011	28744255
ENSE00003504041	28747213	28747264
ENSE00003559874	28747843	28747947
ENSE00003669967	28748017	28748178
ENSE00003687497	28748511	28748666
ENSE00003789970	28748262	28748423

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.6699 / max 659.0263, expressed in 1782 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160068	36.6605	1782
208112	0.0094	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	97.62	gold quality
right uterine tube	UBERON:0001302	97.46	gold quality
metanephros cortex	UBERON:0010533	97.41	gold quality
mucosa of transverse colon	UBERON:0004991	97.03	gold quality
right lobe of thyroid gland	UBERON:0001119	96.80	gold quality
minor salivary gland	UBERON:0001830	96.61	gold quality
left lobe of thyroid gland	UBERON:0001120	96.44	gold quality
right lobe of liver	UBERON:0001114	96.14	gold quality
saliva-secreting gland	UBERON:0001044	95.74	gold quality
ganglionic eminence	UBERON:0004023	95.66	gold quality
cortical plate	UBERON:0005343	95.64	gold quality
thyroid gland	UBERON:0002046	95.34	gold quality
gall bladder	UBERON:0002110	95.16	gold quality
rectum	UBERON:0001052	95.09	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.03	gold quality
body of pancreas	UBERON:0001150	94.95	gold quality
body of stomach	UBERON:0001161	94.54	gold quality
mouth mucosa	UBERON:0003729	94.32	gold quality
upper lobe of left lung	UBERON:0008952	94.05	gold quality
transverse colon	UBERON:0001157	93.74	gold quality
esophagus mucosa	UBERON:0002469	93.53	gold quality
small intestine	UBERON:0002108	93.44	gold quality
stomach	UBERON:0000945	93.20	gold quality
stromal cell of endometrium	CL:0002255	93.10	gold quality
upper lobe of lung	UBERON:0008948	92.68	gold quality
pancreas	UBERON:0001264	92.41	gold quality
nasal cavity mucosa	UBERON:0001826	92.13	gold quality
left uterine tube	UBERON:0001303	92.05	gold quality
right lung	UBERON:0002167	92.01	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.01	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	18.27
E-MTAB-9467	yes	16.27
E-ANND-3	yes	13.94
E-MTAB-8498	yes	11.67
E-GEOD-93593	yes	3.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ALX1, TP53, TP63

Literature-anchored findings (GeneRIF, showing 40)

• Involvement in oxidative activation of c-Jun N-terminal kinase (PMID:12023963)
• activation of the NF-kappaB pathway is involved in up-regulation of TRAF4 in T-cells (PMID:12354113)
• TRAF4 may play a role in p53-mediated proapoptotic signaling in the response to cellular stress (PMID:12788948)
• TNF-receptor activation leads to activation of the p70S6K; TRAF4 is a mediator in this TNF-induced signaling pathway; and TRAF4 inhibits Fas-induced apoptosis (PMID:12801526)
• MEKK4 is the MAPK kinase kinase for TRAF4 regulation of the JNK pathway (PMID:16157600)
• TRAF4 gene amplification is one of the mechanisms responsible for TRAF4 protein overexpression in human cancers (PMID:16799635)
• The nuclear expression of TRAF4 in breast carcinoma is suppressed, and correlated to the invasive ability of breast cancer. (PMID:17927880)
• Disrupting endogenous p63 expression downregulated TRAF4 mRNA & protein in SCCHN cells. Endogenous p63 bound the TRAF4 promoter in vivo. TAp63 is the most active transactivator of TRAF4. TRAF4 is associated with differentiation of SCCHN cells. (PMID:18087216)
• Apart from being a well replicated risk factor for RA, TRAF1/C5 also appears to be a risk factor for the rheumatoid factor-negative polyarthritis subtype of JIA and seems to be associated with subtypes of JIA characterised by a polyarticular course. (PMID:18593758)
• TRAF4 is one of the emerging TJ-dependent signaling pathways that responds to cell polarity by regulating the cell proliferation/differentiation balance, and subsequently epithelium homeostasis. (PMID:18953416)
• Identify TRAF4 as a novel binding partner for GPIb-IX-V and GPVI in human platelets. (PMID:20946164)
• A novel motif in the Crohn’s disease susceptibility protein, NOD2, allows TRAF4 to down-regulate innate immune responses. (PMID:21097508)
• Like IKKalpha, TRAF4 is atypical within its family because it is the only TRAF family member to negatively regulate innate immune signaling. IKKalpha’s phosphorylation of serine-426 on TRAF4 was required for this negative regulation. (PMID:22547678)
• Primary cells from TRAF4-deficient mice display markedly enhanced IL-17-activated signaling pathways and induction of chemokine mRNA/ (PMID:22649194)
• The results indicate that TRAF4 and TRAF6 are overexpressed in IBD. TRAF4 and TRAF6 play different roles in the pathogenesis of IBD (PMID:23431243)
• Data iindicate that TRAF2 affects the localization and function of TRAF4 in breast cancer cell lines. (PMID:23743189)
• Data indicate that Smad ubiquitin regulatory factor Smurf1 regulates cell migration through ubiquitination of tumor necrosis factor receptor-associated factor 4 (TRAF4). (PMID:23760265)
• The short form of the TRAF4 TRAF domain was purified to homogeneity and crystallized. (PMID:23908043)
• TRAF4 regulates the TGF-beta pathway and is a key determinant in breast cancer pathogenesis. (PMID:23973329)
• Determined the crystal structure of TRAF domain of TRAF4 (residues 292-466) at 2.60 A resolution by X-ray crystallography method. The trimericly assembled TRAF4 resembles a mushroom shape, containing a super helical “stalk” which is made of three right-handed intertwined alpha helixes and a C-terminal “cap”, which is divided at residue L302 as a boundary. (PMID:23982741)
• our results suggest that the tumor suppressor microRNA, miR-29a, is one of the regulators of expression in metastatic prostate cancer. (PMID:24100420)
• TRAF4 attenuation impaired glucose metabolism by inhibiting expression of Glut1 and HK2 mediated by the Akt pathway. (PMID:24154876)
• possesses a novel phosphoinositide (PIP)-binding domain crucial for its recruitment to tight junctions (PMID:24311986)
• As a first step towards elucidating the molecular mechanisms of the TRAF4-mediated signalling pathway, the first crystal structure of the human TRAF4 TRAF domain with a coiled-coil domain is reported at 2.3 A resolution. (PMID:24419373)
• Results identified beta-catenin as a TRAF4-binding protein, TRF4 enhanced expression of beta-catenin, and mediated its translocation from the cytoplasm to the nucleus, thereby facilitating activation of the Wnt signaling pathway in breast cancer. (PMID:24990246)
• Data indicate that TRAF4 is specifically overexpressed in human breast cancer cells and plays an important role in tumorigenesis of breast cancer through direct interaction and activation of Akt. (PMID:24993240)
• review highlights TGF-beta-induced SMAD-dependent signaling and non-SMAD signaling as the major pathways regulated by TRAF4 involved in breast cancer metastasis (PMID:25249198)
• Data indicate that tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) regulated osteosarcoma cell growth in vitro and in vivo, suggesting a candidate molecular target for osteosarcoma prevention and therapy. (PMID:25270078)
• Expression of tumor necrosis factor receptor-assicated factor 4 correlates with expression of Girdin and promotes nuclear translocation of Girdin in breast cancer (PMID:25591657)
• promotes tumorigenesis in osteosarcoma cell lines via Akt signaling (PMID:25700355)
• TRAF4 upregulated PRMT5 expression, which occurred predominantly in the nucleus, on which TRAF4 promotion of cell proliferation in breast cancer is mainly dependent. (PMID:25704480)
• p70s6k/S6 signaling pathway played an important role in the promoting function of TRAF4 on cell proliferation. This work suggests a new direction for understanding the oncogenic function of TRAF4 in breast cancer. (PMID:25738361)
• Recent data implicates TRAF4 in carcinogenesis. The molecular mechanism addressing TRAF4 to tight junctions involves lipid binding by the TRAF domain. Review. (PMID:25840457)
• these results suggest that TRAF4 promoted colon cancer cell growth and invasion (PMID:25973026)
• Data showed that TRAF4 was highly expressed in non-small cell lung cancer (NSCLC) cells, and miR-370 overexpression significantly inhibited its expression. These results suggest that TRAF4 serves as an oncogene in NSCLC. (PMID:25976502)
• There was a significant positive correlation between TRAF2 and TRAF4 expression levels in malignant pleural effusion cells (PMID:26331901)
• The TRAF4-ERK5 is a dominant pathway in human skin squamous cell carcinoma. (PMID:26347473)
• TRAF4 may promote oral squamous carcinoma cell growth, invasion and migration by Wnt/beta-catenin pathway. (PMID:26617938)
• TRAF4 expression is higher in mastocytosis patients with food hypersensitivity in their medical history, while B3GAT1 expression is lower in mastocytosis patients with insect venom allergy in history (PMID:27086366)
• miR-4443 acts in a tumor-suppressive manner by down-regulating TRAF4 and NCOA1 downstream of MEK-C/EBP-mediated leptin and insulin signaling, and that insulin and/or leptin resistance (e.g. in obesity) may suppress this pathway and increase the risk of metastatic CRC. (PMID:27842582)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	traf4a	ENSDARG00000003963
danio_rerio	traf4b	ENSDARG00000038964
mus_musculus	Traf4	ENSMUSG00000017386
rattus_norvegicus	Traf4	ENSRNOG00000013169
drosophila_melanogaster	Traf4	FBGN0026319

Paralogs (5): TRAF1 (ENSG00000056558), TRAF5 (ENSG00000082512), TRAF2 (ENSG00000127191), TRAF3 (ENSG00000131323), TRAF6 (ENSG00000175104)

Protein

Protein identifiers

TNF receptor-associated factor 4 — Q9BUZ4 (reviewed: Q9BUZ4)

Alternative names: Cysteine-rich domain associated with RING and Traf domains protein 1, Metastatic lymph node gene 62 protein, RING finger protein 83

All UniProt accessions (10): Q9BUZ4, A0A0C4DFM9, C9JJ10, F6SA91, J3QR87, J3QS94, J9JIG0, K7EJG7, K7EM06, K7ER49

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein with E3 ligase activity that is involved in many diverse biological processes including cell proliferation, migration, differentiation, DNA repair, platelet activation or apoptosis. Promotes EGFR-mediated signaling by facilitating the dimerization of EGFR and downstream AKT activation thereby promoting cell proliferation. Ubiquitinates SMURF2 through ‘Lys-48’-linked ubiquitin chain leading to SMURF2 degradation through the proteasome and subsequently osteogenic differentiation. Promotes ‘Lys-63’-mediated ubiquitination of CHK1 which in turn activates cell cycle arrest and activation of DNA repair. In addition, promotes an atypical ‘Lys-29’-linked ubiquitination at the C-terminal end of IRS1 which is crucial for insulin-like growth factor (IGF) signal transduction. Regulates activation of NF-kappa-B in response to signaling through Toll-like receptors. Required for normal skeleton development, and for normal development of the respiratory tract. Required for activation of RPS6KB1 in response to TNF signaling. Modulates TRAF6 functions. Inhibits adipogenic differentiation by activating pyruvate kinase PKM activity and subsequently the beta-catenin signaling pathway.

Subunit / interactions. Homotrimer. Interacts with LTBR/TNFRSF3, NGFR/TNFRSF16, RPS6KB1 and TGFB1I1. Interacts with SMURF1. Interacts (via TRAF domain) with MAP3K4 (via kinase domain). Interacts with NCF1, TICAM1, IRAK1 and TRAF6, and is probably part of a complex containing TRAF4, NCF1, TICAM1, IRAK1 and TRAF6. Interacts (via MATH domain) with GP6 and GP1BB. Interacts with EGFR (via C-terminal region); this interaction promotes the formation of EGFR asymmetric dimers. Interacts with PKM; this interaction promotes PKM kinase activity.

Subcellular location. Cytoplasm. Nucleus. Perinuclear region. Cell junction. Tight junction. Cell membrane. Cytoskeleton.

Tissue specificity. Expressed in epithelial cells of thymus, dendritic cells of lymph node, and in the basal cell layer of epithelia such as epidermis, nasopharynx, respiratory tract, salivary gland, and esophagus.

Post-translational modifications. Polyubiquitinated, leading to its proteasomal degradation. Ubiquitinated at Lys-263 by the SCF(FBXL2) complex, leading to its degradation by the proteasome.

Domain organisation. The coiled coil domain mediates homo- and hetero-oligomerization. The MATH/TRAF domain binds to receptor cytoplasmic domains.

Induction. Up-regulated by bacterial lipopolysaccharides (LPS) and by single-stranded CpG oligodeoxynucleotide.

Pathway. Protein degradation; proteasomal ubiquitin-dependent pathway.

Similarity. Belongs to the TNF receptor-associated factor family. B subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BUZ4-1	1	yes
Q9BUZ4-2	2, TRAF4 variant 5

RefSeq proteins (1): NP_004286* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001293	Znf_TRAF	Domain
IPR001841	Znf_RING	Domain
IPR002083	MATH/TRAF_dom	Domain
IPR008974	TRAF-like	Homologous_superfamily
IPR012227	TNF_rcpt-assoc_TRAF_met	Family
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR018957	Znf_C3HC4_RING-type	Domain
IPR037307	TRAF4_MATH	Domain
IPR049342	TRAF1-6_MATH_dom	Domain

Pfam: PF00097, PF02176, PF21355

UniProt features (45 total): strand 16, helix 10, turn 6, zinc finger region 4, sequence variant 2, chain 1, domain 1, mutagenesis site 1, coiled-coil region 1, modified residue 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3ZJB	X-RAY DIFFRACTION	1.84
4K8U	X-RAY DIFFRACTION	2.3
5YC1	X-RAY DIFFRACTION	2.51
4M4E	X-RAY DIFFRACTION	2.6
9OLB	X-RAY DIFFRACTION	2.62
9OGV	X-RAY DIFFRACTION	2.8
2EOD	SOLUTION NMR
2YUC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BUZ4-F1	91.46	0.77

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 (2): 426, 263

Mutagenesis-validated functional residues (1):

Position	Phenotype
18	complete loss of e3 ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 320 (showing top): ATF_B, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, CREL_01, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_REGULATION_OF_PHOSPHORYLATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, HSIAO_HOUSEKEEPING_GENES, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, AP4_Q6

GO Biological Process (13): apoptotic process (GO:0006915), cell surface receptor signaling pathway (GO:0007166), respiratory gaseous exchange by respiratory system (GO:0007585), respiratory tube development (GO:0030323), regulation of apoptotic process (GO:0042981), regulation of canonical NF-kappaB signal transduction (GO:0043122), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), innate immune response (GO:0045087), positive regulation of protein kinase activity (GO:0045860), positive regulation of JNK cascade (GO:0046330), immune system process (GO:0002376), signal transduction (GO:0007165), activation of NF-kappaB-inducing kinase activity (GO:0007250)

GO Molecular Function (13): tumor necrosis factor receptor binding (GO:0005164), zinc ion binding (GO:0008270), protein kinase binding (GO:0019901), ubiquitin protein ligase binding (GO:0031625), thioesterase binding (GO:0031996), signaling adaptor activity (GO:0035591), identical protein binding (GO:0042802), WW domain binding (GO:0050699), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), enzyme binding (GO:0019899), metal ion binding (GO:0046872)

GO Cellular Component (11): fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), bicellular tight junction (GO:0005923), perinuclear region of cytoplasm (GO:0048471), membrane (GO:0016020), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein binding	2
cytoplasm	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
signal transduction	1
multicellular organismal process	1
tube development	1
animal organ development	1
apoptotic process	1
regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1
regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
immune response	1
defense response to symbiont	1
positive regulation of protein phosphorylation	1
protein kinase activity	1
positive regulation of kinase activity	1
regulation of protein kinase activity	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
biological_process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
activation of protein kinase activity	1
non-canonical NF-kappaB signal transduction	1
tumor necrosis factor receptor superfamily binding	1
transition metal ion binding	1
kinase binding	1
ubiquitin-like protein ligase binding	1
enzyme binding	1
protein-macromolecule adaptor activity	1
protein domain specific binding	1

Protein interactions and networks

STRING

1603 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRAF4	NCF1	P14598	916
TRAF4	TGFB1I1	O43294	825
TRAF4	NOD2	Q9HC29	793
TRAF4	MTO1	Q9Y2Z2	786
TRAF4	IL17RA	Q96F46	772
TRAF4	GP1BB	P13224	762
TRAF4	LASP1	Q14847	737
TRAF4	MLLT6	P55198	711
TRAF4	MAP3K3	Q99759	689
TRAF4	FNBP1	Q96RU3	647
TRAF4	MAP2K5	Q13163	645
TRAF4	RIPK2	O43353	612
TRAF4	IL17RC	Q8NAC3	596
TRAF4	KIF11	P52732	588
TRAF4	TNFRSF1A	P19438	581

IntAct

446 interactions, top by confidence:

A	B	Type	Score
TRAF4	TBC1D7	psi-mi:“MI:0915”(physical association)	0.840
TBC1D7	TRAF4	psi-mi:“MI:0915”(physical association)	0.840
TRAF4	BYSL	psi-mi:“MI:0915”(physical association)	0.780
BYSL	TRAF4	psi-mi:“MI:0915”(physical association)	0.780
UBL4B	TRAF4	psi-mi:“MI:0915”(physical association)	0.780
TRAF4	WWP2	psi-mi:“MI:0915”(physical association)	0.780
TRAF4	KRT40	psi-mi:“MI:0915”(physical association)	0.780
TRAF4	UBL4B	psi-mi:“MI:0915”(physical association)	0.780
WWP2	TRAF4	psi-mi:“MI:0915”(physical association)	0.780
KRT40	TRAF4	psi-mi:“MI:0915”(physical association)	0.780
TRAF4	TRAF4	psi-mi:“MI:0915”(physical association)	0.760
TRAF4	ATOSB	psi-mi:“MI:0915”(physical association)	0.740
TRAF4	UBL4A	psi-mi:“MI:0915”(physical association)	0.720
ZNF3	TRAF4	psi-mi:“MI:0915”(physical association)	0.720
TRAF4	QARS1	psi-mi:“MI:0915”(physical association)	0.720
TRAF4	BAHD1	psi-mi:“MI:0915”(physical association)	0.720
KRT31	TRAF4	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (337): TRAF4 (Two-hybrid), TRAF4 (Two-hybrid), TRAF4 (Two-hybrid), TRAF4 (Two-hybrid), TRAF4 (Two-hybrid), TRAF4 (Two-hybrid), TRAF4 (Two-hybrid), TRAF4 (Two-hybrid), TRAF4 (Two-hybrid), NOS1AP (Two-hybrid), MRPL28 (Two-hybrid), WWP1 (Two-hybrid), WWP2 (Two-hybrid), BAHD1 (Two-hybrid), EXOC7 (Two-hybrid)

ESM2 similar proteins: A0A974CYQ5, A5WW08, A7XUJ6, B5DF45, B6CJY4, B6CJY5, O00463, O15344, O70583, P0DW87, P0DW89, P39429, P53351, P70191, P70196, P82457, P82458, Q08CH8, Q12933, Q13114, Q28DL4, Q29RQ5, Q2TAD9, Q3KPU8, Q3MV19, Q3U9F6, Q3ZCC3, Q5FWP4, Q5R4L1, Q60803, Q61382, Q6DJN2, Q6GNX1, Q6IWL4, Q6J1I7, Q6P256, Q80WG7, Q8N2W9, Q91ZY8, Q969K3

Diamond homologs: B5DF45, B6CJY4, B6CJY5, O00463, P39428, P39429, P70191, P70196, Q12933, Q13077, Q13114, Q28DL4, Q3MV19, Q3ZCC3, Q60803, Q61382, Q6DJN2, Q6IWL4, Q9BUZ4, P28825, P28826, Q16820, Q61847, A7XUJ6, Q9Y4K3, E7FDW2, O60106, O70263, P68907, Q28GL3, Q5FWL3, Q5M7Z0, Q5R7T5, Q5RAG4, Q69ZS0, Q6NTV1, Q6NZ21, Q7ZW16, Q8BH75, Q8TBB1

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CHUK	down-regulates	TRAF4	phosphorylation
Ub:E2	“up-regulates activity”	TRAF4	ubiquitination
TRAF4	“down-regulates quantity by destabilization”	SMURF2	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1689 predictions. Top by Δscore:

Variant	Effect	Δscore
17:28744178:G:T	donor_gain	1.0000
17:28747206:A:AG	acceptor_gain	1.0000
17:28747207:T:G	acceptor_gain	1.0000
17:28747211:A:AG	acceptor_gain	1.0000
17:28747211:AGT:A	acceptor_gain	1.0000
17:28747212:G:GA	acceptor_gain	1.0000
17:28747212:GT:G	acceptor_gain	1.0000
17:28747212:GTG:G	acceptor_gain	1.0000
17:28747212:GTGA:G	acceptor_gain	1.0000
17:28747212:GTGAA:G	acceptor_gain	1.0000
17:28747261:CAAGG:C	donor_loss	1.0000
17:28747265:GTGA:G	donor_loss	1.0000
17:28747266:T:A	donor_loss	1.0000
17:28747841:A:AG	acceptor_gain	1.0000
17:28747842:G:GG	acceptor_gain	1.0000
17:28748059:A:AG	acceptor_gain	1.0000
17:28748254:A:AG	acceptor_gain	1.0000
17:28748255:T:G	acceptor_gain	1.0000
17:28748260:A:AG	acceptor_gain	1.0000
17:28748261:G:GC	acceptor_gain	1.0000
17:28748261:GA:G	acceptor_gain	1.0000
17:28748261:GAGC:G	acceptor_gain	1.0000
17:28748261:GAGCC:G	acceptor_gain	1.0000
17:28748420:CCAGG:C	donor_loss	1.0000
17:28748423:GGTGA:G	donor_loss	1.0000
17:28748424:G:GG	donor_gain	1.0000
17:28748425:T:G	donor_loss	1.0000
17:28748500:T:TA	acceptor_gain	1.0000
17:28748502:T:TA	acceptor_gain	1.0000
17:28748503:G:A	acceptor_gain	1.0000

AlphaMissense

3092 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:28744164:T:C	C18R	1.000
17:28744165:G:A	C18Y	1.000
17:28744166:C:G	C18W	1.000
17:28744173:T:C	C21R	1.000
17:28744174:G:A	C21Y	1.000
17:28744212:T:C	C34R	1.000
17:28744213:G:A	C34Y	1.000
17:28744218:C:G	H36D	1.000
17:28744224:T:C	F38L	1.000
17:28744226:C:A	F38L	1.000
17:28744226:C:G	F38L	1.000
17:28744227:T:A	C39S	1.000
17:28744227:T:C	C39R	1.000
17:28744228:G:A	C39Y	1.000
17:28744228:G:C	C39S	1.000
17:28744228:G:T	C39F	1.000
17:28744229:C:G	C39W	1.000
17:28744236:T:C	C42R	1.000
17:28744237:G:A	C42Y	1.000
17:28744238:C:G	C42W	1.000
17:28744240:T:C	L43P	1.000
17:28747223:T:C	F52L	1.000
17:28747225:C:A	F52L	1.000
17:28747225:C:G	F52L	1.000
17:28747229:T:A	C54S	1.000
17:28747229:T:C	C54R	1.000
17:28747230:G:A	C54Y	1.000
17:28747230:G:C	C54S	1.000
17:28747231:C:G	C54W	1.000
17:28747251:T:A	L61Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000288379 (17:28744405 A>G,T), RS1000635095 (17:28743262 G>A), RS1000673362 (17:28743273 C>G), RS1000689570 (17:28750246 G>A,C), RS1000739876 (17:28750031 C>T), RS1001086505 (17:28742904 C>G), RS1001625340 (17:28750290 G>A,T), RS1002394627 (17:28749709 C>A,G,T), RS1002456556 (17:28749941 A>C,G), RS1002485556 (17:28744432 C>A,G), RS1002626425 (17:28743677 C>G), RS1002702824 (17:28747012 C>G), RS1002753555 (17:28746721 C>G), RS1003223764 (17:28745046 CG>C), RS1003290967 (17:28751443 G>C)

Disease associations

OMIM: gene MIM:602464 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

54 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, affects expression, decreases expression, affects cotreatment	3
Benzo(a)pyrene	increases expression, increases methylation	3
Cisplatin	affects cotreatment, increases expression	3
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
2-anisidine	affects expression	1
bufotalin	decreases expression	1
methylmercuric chloride	increases expression	1
VX-agent	increases expression	1
3,3’-diindolylmethane	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
hydroquinone	decreases expression	1
vanadium pentoxide	decreases expression	1
clothianidin	increases expression	1
abrine	increases expression	1
perfluorobutanesulfonic acid	decreases expression	1
jinfukang	increases expression, affects cotreatment	1
(+)-JQ1 compound	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Glyphosate	increases expression	1
Ethanol	increases expression	1
Allergens	affects cotreatment, decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Vehicle Emissions	affects cotreatment, decreases expression	1
Calcitriol	increases expression	1
Cannabinoids	affects methylation, increases abundance	1
Capsaicin	increases expression	1

Cellosaurus cell lines

5 cell lines: 3 embryonic stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7P4	SEES3-1V human TRAF4, clone1	Embryonic stem cell	Male
CVCL_A7P5	SEES3-1V human TRAF4, clone2	Embryonic stem cell	Male
CVCL_A7P6	SEES3-1V human TRAF4, clone3	Embryonic stem cell	Male
CVCL_D8XM	Ubigene HCT 116 TRAF4 KO	Cancer cell line	Male
CVCL_E1MF	HyCyte PC-3 KO-hTRAF4	Cancer cell line	Male

Clinical trials (associated diseases)

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