TRAF2

gene
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Also known as TRAP3RNF117

Summary

TRAF2 (TNF receptor associated factor 2, HGNC:12032) is a protein-coding gene on chromosome 9q34.3, encoding TNF receptor-associated factor 2 (Q12933). E3 ubiquitin-protein ligase that regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis.

The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from members of the TNF receptor superfamily. This protein directly interacts with TNF receptors, and forms a heterodimeric complex with TRAF1. This protein is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-kappaB. The protein complex formed by this protein and TRAF1 interacts with the inhibitor-of-apoptosis proteins (IAPs), and functions as a mediator of the anti-apoptotic signals from TNF receptors. The interaction of this protein with TRADD, a TNF receptor associated apoptotic signal transducer, ensures the recruitment of IAPs for the direct inhibition of caspase activation. BIRC2/c-IAP1, an apoptosis inhibitor possessing ubiquitin ligase activity, can unbiquitinate and induce the degradation of this protein, and thus potentiate TNF-induced apoptosis. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of only one transcript has been determined.

Source: NCBI Gene 7186 — RefSeq curated summary.

At a glance

  • Clinical variants (ClinVar): 85 total
  • Druggable target: yes
  • MANE Select transcript: NM_021138

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:12032
Approved symbolTRAF2
NameTNF receptor associated factor 2
Location9q34.3
Locus typegene with protein product
StatusApproved
AliasesTRAP3, RNF117
Ensembl geneENSG00000127191
Ensembl biotypeprotein_coding
OMIM601895
Entrez7186

Gene structure

Transcript identifiers

Ensembl transcripts: 61 — 57 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000247668, ENST00000414589, ENST00000419057, ENST00000429509, ENST00000466107, ENST00000469701, ENST00000474950, ENST00000482854, ENST00000850853, ENST00000882552, ENST00000882553, ENST00000882554, ENST00000882555, ENST00000882556, ENST00000882557, ENST00000882558, ENST00000882559, ENST00000882560, ENST00000882561, ENST00000882562, ENST00000882563, ENST00000882564, ENST00000882565, ENST00000882566, ENST00000882567, ENST00000882568, ENST00000882569, ENST00000882570, ENST00000882571, ENST00000882572, ENST00000882573, ENST00000882574, ENST00000882575, ENST00000882576, ENST00000882577, ENST00000882578, ENST00000936013, ENST00000936014, ENST00000936015, ENST00000936016, ENST00000936017, ENST00000936018, ENST00000936019, ENST00000936020, ENST00000936021, ENST00000936022, ENST00000936023, ENST00000936024, ENST00000936025, ENST00000936026, ENST00000943528, ENST00000943529, ENST00000943530, ENST00000943531, ENST00000943532, ENST00000943533, ENST00000943534, ENST00000943535, ENST00000943536, ENST00000943537, ENST00000943538

RefSeq mRNA: 1 — MANE Select: NM_021138 NM_021138

CCDS: CCDS7013

Canonical transcript exons

ENST00000247668 — 11 exons

ExonStartEnd
ENSE00000870770136920234136920515
ENSE00000870771136921038136921215
ENSE00000985052136923852136924000
ENSE00001042880136899594136899672
ENSE00001095643136900422136900520
ENSE00001307288136886516136886541
ENSE00001556395136925683136926607
ENSE00002394952136898713136898928
ENSE00003461184136909920136909994
ENSE00003570672136916541136916615
ENSE00003628449136908070136908231

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 90.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.4597 / max 73.7123, expressed in 1748 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter IDTPM avgSamples expressed
995807.45971748

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
lower esophagus mucosaUBERON:003583490.38gold quality
endometrium epitheliumUBERON:000481189.14silver quality
mucosa of transverse colonUBERON:000499187.43gold quality
olfactory bulbUBERON:000226486.60gold quality
type B pancreatic cellCL:000016986.21gold quality
lymph nodeUBERON:000002985.96gold quality
right testisUBERON:000453485.33gold quality
cerebellar hemisphereUBERON:000224585.29gold quality
right hemisphere of cerebellumUBERON:001489085.24gold quality
cerebellar cortexUBERON:000212985.20gold quality
granulocyteCL:000009484.95gold quality
left testisUBERON:000453384.88gold quality
ganglionic eminenceUBERON:000402384.08gold quality
cerebellumUBERON:000203783.92gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099183.91gold quality
spleenUBERON:000210683.56gold quality
apex of heartUBERON:000209883.52gold quality
esophagus mucosaUBERON:000246983.51gold quality
popliteal arteryUBERON:000225083.23gold quality
tibial arteryUBERON:000761083.22gold quality
left lobe of thyroid glandUBERON:000112083.10gold quality
triceps brachiiUBERON:000150982.94gold quality
right lobe of thyroid glandUBERON:000111982.68gold quality
ventricular zoneUBERON:000305382.26gold quality
right lobe of liverUBERON:000111482.22gold quality
tongue squamous epitheliumUBERON:000691982.21gold quality
thyroid glandUBERON:000204682.07gold quality
testisUBERON:000047381.93gold quality
endocervixUBERON:000045881.91gold quality
transverse colonUBERON:000115781.81gold quality

Single-cell (SCXA)

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

ExperimentMarker?Max mean expression
E-ANND-3yes2.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting TRAF2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-448799.9664.581252
HSA-MIR-4756-3P99.6266.301319
HSA-MIR-4753-5P99.5468.511356
HSA-MIR-532-3P99.3465.761195
HSA-MIR-797499.2465.481137
HSA-MIR-593-3P99.2267.281327
HSA-MIR-361-3P99.1966.451381
HSA-MIR-146A-3P99.1368.991881
HSA-MIR-140-3P99.0467.691324
HSA-MIR-320A-5P98.8866.751248
HSA-MIR-3190-5P98.8764.891345
HSA-MIR-5088-3P98.2966.631310
HSA-MIR-4436B-3P98.2565.261494
HSA-MIR-6735-5P98.2465.361488
HSA-MIR-6867-3P98.1266.071305
HSA-MIR-7843-5P98.1265.261421
HSA-MIR-4632-5P97.8265.381470
HSA-MIR-6879-5P97.7765.521521
HSA-MIR-428797.5567.241247
HSA-MIR-4685-3P97.5567.351255
HSA-MIR-15A-3P97.4765.08527
HSA-MIR-214-5P97.3466.50617
HSA-MIR-4790-3P96.6367.08806
HSA-MIR-342-3P96.4467.481344

Literature-anchored findings (GeneRIF, showing 40)

  • These findings show a role for SphK in the signal transduction by TRAF2 specifically leading to activation of NF-kappa B and antiapoptosis. (PMID:11777919)
  • TNF-RII and c-IAP1 mediate its ubiquination (PMID:11907583)
  • TRAF2, TRAF3, cIAP1, Smac, and lymphotoxin beta receptor associate and are involved in apoptosis (PMID:12571250)
  • TNF signaling leads to oligomerization, ubiquitination, and activation of GCKR and activation of the SAPK pathway in a manner that depends upon TRAF2 polyubiquitination and oligomerization and Ubc13 function (PMID:12591926)
  • TRAF2 has a role in TNF-alpha induced IKK phosphorylation of NF-kappaB p65 (PMID:12842894)
  • stoichiometry of TRAF1-TRAF2 heteromeric complexes ((TRAF2)2-TRAF1 versus TRAF2-(TRAF1)2) determines their capability to mediate CD40 signaling but has no major effect on TNF signaling (PMID:14557256)
  • TRAF2 plays an important role as regulator of IAP nucleocytoplasmic localization, by preventing nuclear translocation of cIAP1 and cIAP2. (PMID:15265700)
  • AIP1 is a novel transducer in TNF-induced TRAF2-dependent activation of ASK1 that mediates a balance between JNK versus NF-kappaB signaling (PMID:15310755)
  • there is a novel association between TRAF2 and TRAF3 that is mediated by unique portions of each protein and that specifically regulates activation of NF-kappaB, but not AP-1 (PMID:15383523)
  • TNF receptor-associated factor 2 (TRAF2) overexpression does not only block apoptosis induction by CD95 antigen but also converts this death receptor into a mediator of invasiveness in pancreatic adenocarcinoma (PMID:15670977)
  • TRAF3 specifically blocked the NF-kappaB activation via TRAF2/5. (PMID:15708970)
  • TRAF2 colocalizes with eIF4GI in insoluble stress granules during cellular exposure to stress conditions. (PMID:15743837)
  • In contrast with its effects on signaling triggered by other TNF receptors, functional studies reveal that TRAF2 plays a novel inhibitory role in glucocorticoid-induced TNF receptor (GITR)-triggered NF-kappa B activation. (PMID:15944293)
  • Results for the first time place tumor necrosis factor receptor-associated factor-2 (TRAF2), previously shown to function in TNF signaling, within the interferon signal transduction pathway (PMID:16009713)
  • TRAF2-dependent CD40 signal transduction requires TRAF6 in nonhemopoietic cells (PMID:16260598)
  • a single cIAP can direct its E3 ligase activity toward different substrates and can alter the cellular functions of different protein targets, including TRAF2 and SMAC, in accordance with differences in the specificity of individual BIR domains (PMID:16282325)
  • A constitutive expression of TRAF1, TRAF2, and TANK/I-TRAF in human gliomas was documented (PMID:16304992)
  • These data indicate that vFLIP uses TRAF2 and TRAF3 for signalling to NF-kappaB, which is crucial for KSHV-associated lymphomagenesis (PMID:16311516)
  • an LMP1-associated complex containing TRAF6, TAB2, and TAK1 plays an essential role in the activation of JNK (PMID:16446357)
  • GSTP1-1 plays an important regulatory role in TNF-alpha-induced signaling by forming ligand-binding interactions with TRAF2, which provides insight for analysing the protective effects of GSTP1-1 in tumor cells. (PMID:16636664)
  • the t(11, 18)(q21;q21) translocation creating the c-IAP2.MALT1 fusion protein activates NF-kappaB independently of TRAF1 AND TRAF2 and contributes to human malignancy in the absence of signaling adaptors that might otherwise regulate its activity (PMID:16891304)
  • JAB1 regulates ubiquitination of TRAF2 (PMID:16936264)
  • IHPK2-TRAF2 binding leads to attenuation of TAK1- and NF-kappaB-mediated signaling and is partially responsible for the apoptotic activity of IHPK2. (PMID:17379600)
  • TNF-induced TRAF2-RIP1-AIP1-ASK1 complex formation and for the activation of ASK1-JNK/p38 apoptotic signaling. (PMID:17389591)
  • These data together uncovers a new signaling pathway regulating APE/Ref-1 nuclear translocation involving CD40-crosslinking, TRAF2 and p38. (PMID:17599408)
  • Dominant-negative forms of TRAF2 and TRAF3 inhibited but did not fully block LMP1-mediated transformation. (PMID:17626074)
  • These findings demonstrate that Trx, TRAF2, and TRAF6 regulate ASK1 activity by modulating N-terminal homophilic interaction of ASK1. (PMID:17724081)
  • There was a positive correlation between TRAF2 and cyclin D1 expressions and the expression NF-kappaBp65 in the epithelial cells and lymphocytes in oral lichen planus. (PMID:18024283)
  • Our findings suggest that the TRAF-2 pathway is involved Alzheimer disease. The mechanisms are currently unclear and need further examination. (PMID:18069092)
  • LMP2A protein controls the expression of TRAF2 mRNA, which in turn is necessary for signaling by LMP1. (PMID:18230756)
  • TNF-R2 mediates TNF-alpha signaling in chromaffin cells via activation of nuclear factor (NF)-kappaB. (PMID:18292192)
  • TRAF2 might be involved in activation of NF-kappaB in a subset of ABC-like primary nodal diffuse large B-cell lymphomas indicating a poor outcome. (PMID:18312353)
  • place TRAF2 directly in the signaling pathway transduced through the IFNAR1 subunit of the IFN receptor (PMID:18362156)
  • These results suggest an important role for Smurf2 binding to TRAF2 in determining specific signalling outputs of TNF-R2. (PMID:18671942)
  • TRAF2 expression and subsequent degradation are required for the differentiation of monocytes into fully functional macrophages (PMID:18827186)
  • results unveil a new, finely tuned mechanism for TNF-alpha-induced IKK activation modulated by TRAF2 phosphorylation and suggest that TRAF2 phosphorylation contributes to elevated levels of basal NF-kappaB activity in certain human cancers (PMID:18981220)
  • TRAF2 plays a critical role in TNF signaling by directing the IKK complex to the membrane, promoting TRAF2 K63-linked ubiquitination, and positioning the IKKalpha and IKKbeta chains with the TAK1/TAB kinase. (PMID:19150425)
  • glomerular and tubular expression of TNF-alpha, (TNF receptor-associated death domain protein)TRADD, RIP(receptor-interacting protein) and TRAF-2 (TNF receptor-associated factor-) was significantly up-regulated in Lupus nephritis (PMID:19151112)
  • TRAF2 interaction is critical for c-IAP2/MALT1-mediated increases in the NF-kappaB activity, increased expression of endogenous NF-kappaB target genes and resistance to apoptosis. (PMID:19234489)
  • c-IAP1 can be targeted for degradation by two distinct processes,through degradation of the TRAF2-c-IAP1 heterodimer or through induced autoubiquitination of c-IAP1 by IAP antagonists, releasing TRAF2 (PMID:19243308)

Cross-species orthologs

6 orthologs

OrganismSymbolGene ID
danio_reriotraf2aENSDARG00000030173
danio_reriounm_sa808ENSDARG00000078378
mus_musculusTraf2ENSMUSG00000026942
rattus_norvegicusTraf2ENSRNOG00000006238
caenorhabditis_elegansWBGENE00006612
caenorhabditis_eleganstrf-2WBGENE00022454

Paralogs (5): TRAF1 (ENSG00000056558), TRAF4 (ENSG00000076604), TRAF5 (ENSG00000082512), TRAF3 (ENSG00000131323), TRAF6 (ENSG00000175104)

Protein

Protein identifiers

TNF receptor-associated factor 2Q12933 (reviewed: Q12933)

Alternative names: E3 ubiquitin-protein ligase TRAF2, RING-type E3 ubiquitin transferase TRAF2, Tumor necrosis factor type 2 receptor-associated protein 3

All UniProt accessions (4): Q12933, B1AMX7, B1AMX8, B1AMY1

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis. Catalyzes ‘Lys-63’-linked ubiquitination of target proteins, such as BIRC3, IKBKE, MLST8, RIPK1 and TICAM1. Is an essential constituent of several E3 ubiquitin-protein ligase complexes, where it promotes the ubiquitination of target proteins by bringing them into contact with other E3 ubiquitin ligases. Regulates BIRC2 and BIRC3 protein levels by inhibiting their autoubiquitination and subsequent degradation; this does not depend on the TRAF2 RING-type zinc finger domain. Plays a role in mediating activation of NF-kappa-B by EIF2AK2/PKR. In complex with BIRC2 or BIRC3, promotes ubiquitination of IKBKE. Acts as a regulator of mTORC1 and mTORC2 assembly by mediating ‘Lys-63’-linked ubiquitination of MLST8, thereby inhibiting formation of the mTORC2 complex, while facilitating assembly of the mTORC1 complex. Required for normal antibody isotype switching from IgM to IgG.

Subunit / interactions. Homotrimer. Heterotrimer with TRAF1. Heterotrimer with TRAF3 (via TRAF domain). The domain containing the RING-type and the first TRAF-type zinc finger can also form homodimers (in vitro). Interacts with TNFRSF1B/TNFR2. Interacts with TNFRSF5/CD40. Interacts with TNFRSF4, TNFRSF7/CD27, TNFRSF8/CD30, TNFRSF9/CD137, TNFRSF11A/RANK, TNFRSF13B/TACI, TNFRSF14, TNFRSF16/NGFR, TNFRSF17/BCMA, TNFRSF18/AITR, TNFRSF19/TROY, TNFRSF19L/RELT and EDAR. Stimulation of TNF receptor TNFRSF1A leads to the formation of two distinct signaling complexes. Plasma membrane-bound complex I is composed of TNFRSF1A, TRADD, RIPK1, TRAF2 and BIRC2/c-IAP1 or BIRC3 which interacts with CHUCK/IKK-alpha, IKBKB/IKK-beta and IKBKG/IKK-gamma promoting cell survival. Subsequently, TRADD, RIPK1 and TRAF2 dissociate from TNFRSF1A and form cytoplasmic complex II with FADD and caspase CASP8 promoting cell apoptosis. Interacts with TRADD. Identified in a complex with TNFRSF1A, RIPK1 and IKBKB/IKK-beta. Interacts with RIPK2. Interacts with BIRC2 and BIRC3 N-terminus; a single BIRC2 or BIRC3 molecule interacts with a heterotrimer formed by TRAF1 and TRAF2, or a TRAF2 homotrimer. Identified in a complex composed of TRAF2, TRAF3, BIRC2 and BIRC3. Interacts with BIRC2; the interaction promotes BIRC2 stability. Interaction with BIRC2 and/or BIRC3 is essential for ubiquitination of IKBKE, degradation of NFKBIA and activation of NF-kappa-B. Within complex I, phosphorylated TRAF2 interacts (via ‘Lys-63’-linked polyubiquitin chains) with CHUCK/IKK-alpha, IKBKB/IKK-beta, IKBKG/IKK-gamma TAB2, TAB3 and TAK1 in response to TNF stimulation. Within complex I, interacts with UXT isoform 1 (via TPQE motif); the interaction prevents the recruitment of FADD and CASP8/caspase 8 to complex I. Forms a complex composed of TNFRSF8/CD30 or TNFRSF1B/TNFR2, and TRAF1, TRAF2 and E3 ligase TRAIP. Within the complex, interacts with TRAIP; the interaction inhibits TRAF2-mediated NF-kappa B activation. Component of a complex composed of TANK and TBK1. Interacts with TRPC4AP. Interacts with MAP3K1/MEKK1, MAP3K5/ASK1 and MAP3K11/MLK3 in response to TNF stimulation; the interaction leads to JNK activation and interaction with MAP3K5 is inhibited by PRMT1. Component of a complex composed of MAP3K14/NIK BIRC3 and TRAF3; the interaction leads to BIRC2/3-mediated ubiquitination of TRAF3 upon CD40 engagement in a TRAF2-dependent manner. Interacts with MAP3K14/NIK in response to TNF stimulation; the interaction leads to NF-kappa B activation. Interacts with PEG3; the interaction may promote TRAF2-mediated NF-kappa B activation. Interacts with HIVEP3; the interaction may inhibit TNF-TRAF2-mediated NF-kappa B and JNK activation. Interacts with TANK/ITRAF; the interaction prevents interaction between TNFRSF1B/TNFR2 and TRAF2. Interacts with deubiquitinating enzyme CYLD; the interaction results in the deubiquitination and inactivation of TRAF2. Interacts with SIAH2; the interaction leads to TRAF2 ubiquitination and degradation. Interacts with E2 conjugating enzyme UBE2N/Ubc13, E3 ligase ITCH and RNF11 in response to TNF stimulation. Interacts with ubiquitin-editing enzyme TNFAIP3/A20 in response to TNF stimulation; the interaction promotes TRAF2 dissociation from UBE2N/Ubc13, ITCH, RNF11 and TAX1BP1 and prevents prolonged TRAF-2 ubiquitination. Interacts with TAX1BP1 in response to TNF stimulation; the interaction promotes TRAF2 dissociation from UBE2N/Ubc13 and TNFAIP3/A20, and prevents prolonged TRAF-2 ubiquitination. Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain). Interacts with deubiquitinating enzyme USP48. Interacts with PTPN2; probably involved in TNF-mediated signaling. Interacts with Toll-like receptor TLR4/3 adapter TICAM1/TRIF; the interaction may promote TICAM1 ubiquitination. Interacts with kinase/endoribonuclease ERN1/IRE1 and DAB2IP in response to ER stress; the interaction requires DAB2IP. Interacts with ERN1/IRE1 and TAOK3 in response to ER stress; the interaction may promote TRAF2 phosphorylation. Interacts (via zinc fingers) with DAB2IP (via C-terminus PER domain)in response to TNF stimulation. Interacts with CASP8AP2/FLASH. Interacts with NFATC2IP; the interaction may repress IL-4 production in T cells. Interacts with kinase CDK9. Interacts with sphingosine kinase 1 SPHK1. Interacts with kinase TNIK. Interacts with TRAFD1. Interacts with DNA phosphodiesterase TDP2. Interacts with MAVS/IPS1. Interacts with CARD14. Interacts with Epstein-Barr virus LMP1/BNFL1. Interacts with GPS2. Interacts with XPNPEP3. Interacts with RIPK3. Interacts with RELL2. Interacts with LRRC19. Interacts with GAPDH; promoting TRAF2 ubiquitination.

Subcellular location. Cytoplasm.

Post-translational modifications. Phosphorylated at several serine residues within the first 128 amino acid residues. Phosphorylated at Thr-117 in response to signaling via TNF and TNFRSF1A. Phosphorylation at Thr-117 is required for ‘Lys-63’-linked polyubiquitination, but not for ‘Lys-48’-linked polyubiquitination. Phosphorylation at Thr-117 is important for interaction with IKKA and IKKB, activation of IKK and subsequent activation of NF-kappa-B. Undergoes both ‘Lys-48’-linked and ‘Lys-63’-linked polyubiquitination. Polyubiquitinated via ‘Lys-63’-linked ubiquitin in response to TNF signaling; this requires prior phosphorylation at Thr-117. ‘Lys-63’-linked polyubiquitination promotes TRAF2-mediated activation of NF-kappa-B. Can be polyubiquitinated at several Lys residues via ‘Lys-48’-linked ubiquitin chains in response to TNF signaling, leading to proteasomal degradation. Autoubiquitinated, leading to its subsequent proteasomal degradation. Polyubiquitinated by BIRC2 and SIAH2, leading to its subsequent proteasomal degradation. Deubiquitinated by CYLD, a protease that specifically cleaves ‘Lys-63’-linked polyubiquitin chains. Ubiquitination is inhibited by LRRC19; inhibits proteasomal degradation. Ubiquitinated at Lys-320 by the SCF(FBXL2) complex, leading to its degradation by the proteasome. Ubiquitinated by E3 ubiquitin-protein ligase complex containing FBXO7; leading to repression of NF-kappa-B signaling.

Activity regulation. Has very low E3 ubiquitin ligase activity in the absence of sphingosine-1-phosphate. E3 ubiquitin ligase activity is strongly activated by cytoplasmic sphingosine-1-phosphate.

Domain organisation. The coiled coil domain mediates homo- and hetero-oligomerization. The MATH/TRAF domain binds to receptor cytoplasmic domains. The RING-type zinc finger domain is essential for E3 ubiquitin-protein ligase activity. It is not essential for the stabilization of BIRC2, or for the ubiquitination of RIPK1 in response to TNFR1 signaling.

Pathway. Protein modification; protein ubiquitination.

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

Isoforms (4)

UniProt IDNamesCanonical?
Q12933-11yes
Q12933-22
Q12933-33
Q12933-44

RefSeq proteins (1): NP_066961* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR001293Znf_TRAFDomain
IPR001841Znf_RINGDomain
IPR002083MATH/TRAF_domDomain
IPR008974TRAF-likeHomologous_superfamily
IPR012227TNF_rcpt-assoc_TRAF_metFamily
IPR013083Znf_RING/FYVE/PHDHomologous_superfamily
IPR017907Znf_RING_CSConserved_site
IPR018957Znf_C3HC4_RING-typeDomain
IPR027133TRAF2_RING-HCDomain
IPR032070TRAF_BIRC3-bdDomain
IPR037305TRAF2_MATHDomain
IPR049342TRAF1-6_MATH_domDomain
IPR049441TRAF2_ZnfDomain

Pfam: PF00097, PF02176, PF16673, PF21341, PF21355

UniProt features (64 total): helix 17, strand 15, mutagenesis site 7, modified residue 6, turn 4, splice variant 3, zinc finger region 3, cross-link 2, sequence conflict 2, initiator methionine 1, chain 1, domain 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

15 structures.

PDBMethodResolution (Å)
3KNVX-RAY DIFFRACTION1.9
8T5QX-RAY DIFFRACTION1.9
1CZYX-RAY DIFFRACTION2
1D00X-RAY DIFFRACTION2
1D01X-RAY DIFFRACTION2
1D0AX-RAY DIFFRACTION2
1F3VX-RAY DIFFRACTION2
1CA4X-RAY DIFFRACTION2.2
1CA9X-RAY DIFFRACTION2.3
1QSCX-RAY DIFFRACTION2.4
1D0JX-RAY DIFFRACTION2.5
3M0AX-RAY DIFFRACTION2.61
3M06X-RAY DIFFRACTION2.67
1CZZX-RAY DIFFRACTION2.7
3M0DX-RAY DIFFRACTION2.8

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q12933-F190.730.76

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 (8): 7, 11, 22, 117, 31, 320, 2, 5

Mutagenesis-validated functional residues (7):

PositionPhenotype
11reduces global phosphorylation. partial reduction of tnf-dependent activation of nf-kappa-b and activation of jnk.
11slight increase of tnf-dependent activation of nf-kappa-b and activation of jnk.
31abolishes ’lys-63’-linked polyubiquitination.
117loss of phosphorylation site. abolishes activation of nf-kappa-b.
285strongly reduced interaction with birc3.
288strongly reduced interaction with birc3.
292strongly reduced interaction with birc3.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

IDPathway
R-HSA-140534Caspase activation via Death Receptors in the presence of ligand
R-HSA-3371378Regulation by c-FLIP
R-HSA-5213460RIPK1-mediated regulated necrosis
R-HSA-5218900CASP8 activity is inhibited
R-HSA-5357786TNFR1-induced proapoptotic signaling
R-HSA-5357905Regulation of TNFR1 signaling
R-HSA-5357956TNFR1-induced NF-kappa-B signaling pathway
R-HSA-5668541TNFR2 non-canonical NF-kB pathway
R-HSA-5675482Regulation of necroptotic cell death
R-HSA-5676594TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway
R-HSA-5689880Ub-specific processing proteases
R-HSA-69416Dimerization of procaspase-8
R-HSA-75893TNF signaling
R-HSA-933541TRAF6 mediated IRF7 activation
R-HSA-933542TRAF6 mediated NF-kB activation
R-HSA-9693928Defective RIPK1-mediated regulated necrosis
R-HSA-9758274Regulation of NF-kappa B signaling

MSigDB gene sets: 420 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, BIOCARTA_TNFR2_PATHWAY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS

GO Biological Process (45): toll-like receptor signaling pathway (GO:0002224), regulation of immunoglobulin production (GO:0002637), positive regulation of T cell cytokine production (GO:0002726), signal transduction (GO:0007165), canonical NF-kappaB signal transduction (GO:0007249), signal transduction involved in regulation of gene expression (GO:0023019), CD40 signaling pathway (GO:0023035), protein catabolic process (GO:0030163), positive regulation of interleukin-2 production (GO:0032743), tumor necrosis factor-mediated signaling pathway (GO:0033209), negative regulation of glial cell apoptotic process (GO:0034351), response to endoplasmic reticulum stress (GO:0034976), non-canonical NF-kappaB signal transduction (GO:0038061), T cell activation (GO:0042110), regulation of apoptotic process (GO:0042981), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), regulation of protein-containing complex assembly (GO:0043254), positive regulation of JUN kinase activity (GO:0043507), regulation of JNK cascade (GO:0046328), mRNA stabilization (GO:0048255), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), protein autoubiquitination (GO:0051865), protein-containing complex assembly (GO:0065003), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), protein K63-linked ubiquitination (GO:0070534), cellular response to nitric oxide (GO:0071732), programmed necrotic cell death (GO:0097300), interleukin-17-mediated signaling pathway (GO:0097400), CD27 signaling pathway (GO:0160162), positive regulation of tumor necrosis factor-mediated signaling pathway (GO:1903265), TORC1 complex assembly (GO:1905669), TORC2 complex disassembly (GO:1905670), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), protein polyubiquitination (GO:0000209), regulation of production of molecular mediator of immune response (GO:0002700), apoptotic process (GO:0006915), activation of NF-kappaB-inducing kinase activity (GO:0007250), positive regulation of gene expression (GO:0010628), programmed cell death (GO:0012501)

GO Molecular Function (22): ubiquitin-protein transferase activity (GO:0004842), tumor necrosis factor receptor binding (GO:0005164), CD40 receptor binding (GO:0005174), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), protein phosphatase binding (GO:0019903), protein-macromolecule adaptor activity (GO:0030674), mitogen-activated protein kinase kinase kinase binding (GO:0031435), ubiquitin protein ligase binding (GO:0031625), thioesterase binding (GO:0031996), signaling adaptor activity (GO:0035591), identical protein binding (GO:0042802), tumor necrosis factor binding (GO:0043120), protein-containing complex binding (GO:0044877), sphingolipid binding (GO:0046625), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), lipid binding (GO:0008289), transferase activity (GO:0016740), tumor necrosis factor receptor superfamily binding (GO:0032813), metal ion binding (GO:0046872)

GO Cellular Component (14): ubiquitin ligase complex (GO:0000151), tumor necrosis factor receptor superfamily complex (GO:0002947), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cell cortex (GO:0005938), cytoplasmic side of plasma membrane (GO:0009898), vesicle membrane (GO:0012506), CD40 receptor complex (GO:0035631), membrane raft (GO:0045121), TRAF2-GSTP1 complex (GO:0097057), IRE1-TRAF2-ASK1 complex (GO:1990604), protein-containing complex (GO:0032991), signaling receptor complex (GO:0043235)

Reactome top-level categories

Rollup of top-13 pathways:

CategoryPathways
TNF signaling3
Caspase activation via Death Receptors in the presence of ligand2
DDX58/IFIH1-mediated induction of interferon-alpha/beta2
Caspase activation via extrinsic apoptotic signalling pathway1
Regulated Necrosis1
Regulation of necroptotic cell death1
Cytokine Signaling in Immune system1
RIPK1-mediated regulated necrosis1
TNFR2 non-canonical NF-kB pathway1
Deubiquitination1
Death Receptor Signaling1
Diseases of programmed cell death1
TAK1-dependent IKK and NF-kappa-B activation1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
protein binding3
binding3
cellular anatomical structure3
intracellular signaling cassette2
canonical NF-kappaB signal transduction2
regulation of canonical NF-kappaB signal transduction2
tumor necrosis factor receptor superfamily binding2
cytoplasm2
protein-containing complex2
pattern recognition receptor signaling pathway1
immunoglobulin production1
regulation of production of molecular mediator of immune response1
T cell cytokine production1
positive regulation of T cell mediated immunity1
positive regulation of cytokine production involved in immune response1
regulation of T cell cytokine production1
cell communication1
cellular process1
signaling1
regulation of cellular process1
cellular response to stimulus1
signal transduction1
regulation of gene expression1
cell surface receptor signaling pathway1
macromolecule catabolic process1
protein metabolic process1
positive regulation of cytokine production1
interleukin-2 production1
regulation of interleukin-2 production1
cytokine-mediated signaling pathway1
cellular response to tumor necrosis factor1
glial cell apoptotic process1
regulation of glial cell apoptotic process1
negative regulation of apoptotic process1
cellular response to stress1
lymphocyte activation1
apoptotic process1
regulation of programmed cell death1
positive regulation of intracellular signal transduction1
negative regulation of intracellular signal transduction1

Protein interactions and networks

STRING

2016 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
TRAF2TRADDQ15628996
TRAF2RIPK1Q13546994
TRAF2MAP3K5Q99683994
TRAF2ERN1O75460993
TRAF2BIRC2Q13490993
TRAF2TNFRSF1AP19438992
TRAF2BIRC3Q13489990
TRAF2FADDQ13158982
TRAF2TRAF5O00463970
TRAF2IKBKGQ9Y6K9958
TRAF2CASP8Q14790941
TRAF2SPHK1Q9NYA1941
TRAF2TRAF3Q13114921
TRAF2TNFP01375918
TRAF2TAB2Q9NYJ8797

IntAct

1573 interactions, top by confidence:

ABTypeScore
CD40TRAF2psi-mi:“MI:0915”(physical association)0.960
TRAF2CD40psi-mi:“MI:0915”(physical association)0.960
TRAF2TRADDpsi-mi:“MI:0407”(direct interaction)0.940
TRAF2TRAF6psi-mi:“MI:0915”(physical association)0.900
RIPK1TRAF2psi-mi:“MI:0915”(physical association)0.880
TNFAIP3TRAF2psi-mi:“MI:0915”(physical association)0.870
RAD23ATRAF2psi-mi:“MI:0915”(physical association)0.870
GORASP2TRAF2psi-mi:“MI:0915”(physical association)0.870
TRAF2TNFAIP3psi-mi:“MI:0915”(physical association)0.870
TRAF2RAD23Apsi-mi:“MI:0915”(physical association)0.870
TRAF2GORASP2psi-mi:“MI:0915”(physical association)0.870
ATXN1TRAF2psi-mi:“MI:0915”(physical association)0.860
EFEMP1TRAF2psi-mi:“MI:0915”(physical association)0.860
TRAF2BCL10psi-mi:“MI:0915”(physical association)0.850
TIFATRAF2psi-mi:“MI:0915”(physical association)0.840
TRAF2TIFApsi-mi:“MI:0915”(physical association)0.840
TRAF2PRKAB2psi-mi:“MI:0915”(physical association)0.830
THAP7TRAF2psi-mi:“MI:0915”(physical association)0.830
SPG21TRAF2psi-mi:“MI:0915”(physical association)0.830
PRKAB2TRAF2psi-mi:“MI:0915”(physical association)0.830
TRAF2SPG21psi-mi:“MI:0915”(physical association)0.830
USP2TRAF2psi-mi:“MI:0915”(physical association)0.780
NEBLTRAF2psi-mi:“MI:0915”(physical association)0.780
TRAF2GABPB1psi-mi:“MI:0915”(physical association)0.780
TRAF2PIN1psi-mi:“MI:0915”(physical association)0.780

BioGRID (2201): TRAF2 (Co-crystal Structure), TRAF2 (Affinity Capture-Western), PPP4R1 (Two-hybrid), TRAF2 (Affinity Capture-Western), TRAF2 (Affinity Capture-Western), TRAF2 (Affinity Capture-Western), TRAF2 (Affinity Capture-MS), TRAF2 (Affinity Capture-Western), ELAVL1 (Affinity Capture-Western), TRAF2 (Two-hybrid), TRAF2 (Two-hybrid), TRAF2 (Two-hybrid), TRAF2 (Two-hybrid), TRAF2 (Two-hybrid), TRAF2 (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: O00463, P39428, P39429, P68907, P70191, Q12933, Q13077, Q13114, Q60803, Q69ZS0, Q9UPQ7, A0A0C5PRQ1, A8Q2D1, B3EWZ5, B3EWZ6, C9D7R3, D2KBH9, D5FM34, D5FM37, D5FM38, K7Z9Q9, O16977, O19045, O43897, O57382, O57460, O62243, P07584, P0DJJ2, P0DM61, P0DM62, P13497, P28825, P28826, P31579, P31580, P31581, P42662, P42664, P42674

SIGNOR signaling

48 interactions.

AEffectBMechanism
CYLD“down-regulates activity”TRAF2deubiquitination
UBE2N“up-regulates activity”TRAF2ubiquitination
TRAF2“up-regulates activity”MAP3K7ubiquitination
TRAF2up-regulatesBIRC3binding
BIRC2“down-regulates quantity by destabilization”TRAF2ubiquitination
TRAF2“down-regulates quantity by destabilization”MAP3K14ubiquitination
TRAF2“up-regulates activity”BIRC2binding
TRAF2“up-regulates activity”RIPK1ubiquitination
CD40“up-regulates activity”TRAF2binding
TRAF2up-regulatesMAP3K1binding
TRAF2“up-regulates activity”UBE2Nbinding
BIRC3“down-regulates quantity by destabilization”TRAF2ubiquitination
PRKCZunknownTRAF2phosphorylation
TNFRSF1Aup-regulatesTRAF2
TRAF2up-regulatesRIPK1
Ub:E2“up-regulates activity”TRAF2ubiquitination
TRAF2up-regulatesTICAM1polyubiquitination
IKBKE“up-regulates activity”TRAF2phosphorylation
MAP4K4“down-regulates quantity”TRAF2phosphorylation
TNFRSF1B“up-regulates activity”TRAF2binding
TRAF1up-regulatesTRAF2binding
TRAF2up-regulatesTRAF1binding
TRADD“up-regulates activity”TRAF2binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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:

PathwayPartnersFoldFDR
TNFR1-induced proapoptotic signaling543.1×2e-05
Regulation of TNFR1 signaling521.9×4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance63
Likely benign3
Benign3

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3299 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
9:136898840:T:CC34R1.000
9:136898878:G:CQ46H1.000
9:136898878:G:TQ46H1.000
9:136900425:T:CF91L1.000
9:136900427:C:AF91L1.000
9:136900427:C:GF91L1.000
9:136900431:G:CD93H1.000
9:136923905:G:CG398R1.000
9:136923906:G:AG398D1.000
9:136923906:G:TG398V1.000
9:136923936:C:TS408F1.000
9:136923941:T:CF410L1.000
9:136923943:C:AF410L1.000
9:136923943:C:GF410L1.000
9:136923983:T:AW424R1.000
9:136923983:T:CW424R1.000
9:136923985:G:CW424C1.000
9:136923985:G:TW424C1.000
9:136925696:T:CL434P1.000
9:136925734:T:CF447L1.000
9:136925735:T:CF447S1.000
9:136925736:C:AF447L1.000
9:136925736:C:GF447L1.000
9:136925761:T:AF456I1.000
9:136925761:T:CF456L1.000
9:136925762:T:CF456S1.000
9:136925763:T:AF456L1.000
9:136925763:T:GF456L1.000
9:136925771:C:AP459Q1.000
9:136925792:C:AA466E1.000

dbSNP variants (sampled 300 via entrez): RS1000042028 (9:136917399 G>T), RS1000065492 (9:136901904 C>A), RS1000120872 (9:136881044 G>A,C,T), RS1000120925 (9:136887870 TTTTA>T), RS1000127897 (9:136891824 C>T), RS1000158896 (9:136892043 A>G), RS1000220433 (9:136923503 C>G,T), RS1000319904 (9:136897189 C>G,T), RS1000376099 (9:136926223 G>A,T), RS1000399161 (9:136926918 AGGCTCCACCGAGCATCCT>A), RS1000411701 (9:136909291 G>A), RS1000412442 (9:136914230 G>A,C), RS1000462357 (9:136883851 C>T), RS1000462852 (9:136890512 A>G,T), RS1000467458 (9:136914038 C>T)

Disease associations

OMIM: gene MIM:601895 | 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: yes

ChEMBL targets (1): CHEMBL6067211 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
6.25Kd565.7nMCHEMBL5653589
6.17ED50680nMCHEMBL5653589
5.59Kd2585nMCHEMBL3752910
5.51ED503107nMCHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2149651: Binding affinity to human TRAF2 incubated for 45 mins by Kinobead based pull down assaykd0.5657uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2149651: Binding affinity to human TRAF2 incubated for 45 mins by Kinobead based pull down assaykd2.5852uM

CTD chemical–gene interactions

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

ChemicalActions (top 5)PubMed papers
sodium arseniteaffects methylation, decreases expression, increases expression4
Acetaminophenaffects cotreatment, increases expression2
Benzo(a)pyrenedecreases methylation, affects methylation2
Cisplatinaffects response to substance, decreases expression, increases reaction, affects reaction, increases cleavage (+2 more)2
6-methoxyflavonedecreases expression1
parthenolidedecreases reaction, increases expression, decreases expression1
2-anisidinedecreases expression1
naringeninaffects cotreatment, increases expression1
bisphenol Aaffects cotreatment, increases expression1
VX-agentincreases expression1
coumarinincreases phosphorylation1
1’-acetoxychavicol acetatedecreases reaction, increases expression1
harringtoninincreases expression1
di-n-butylphosphoric acidaffects expression1
perfluorooctane sulfonic aciddecreases expression1
anacardic aciddecreases activity1
zerumboneaffects binding, decreases reaction, increases activity1
2-hydroxyursolic aciddecreases expression1
obeticholic aciddecreases expression1
abrineincreases expression1
xinfengincreases expression, decreases expression, decreases reaction1
jinfukangdecreases expression, increases reaction1
ibrutinibdecreases response to substance1
NSC 689534decreases expression, affects binding1
PCI 5002affects cotreatment, increases expression1
ceritinibdecreases expression1
Resveratroldecreases expression1
Zoledronic Acidincreases expression1
Arsenic Trioxidedecreases expression1
Vorinostatdecreases reaction, increases activity1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL5652693BindingBinding affinity to human TRAF2 incubated for 45 mins by Kinobead based pull down assayNVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

CellosaurusNameCategorySex
CVCL_B077Z-138Cancer cell lineMale
CVCL_D8CYUbigene A-549 TRAF2 KOCancer cell lineMale
CVCL_D8XKUbigene HCT 116 TRAF2 KOCancer cell lineMale
CVCL_D9UTUbigene HEK293 TRAF2 KOTransformed cell lineFemale
CVCL_E0S0Ubigene HeLa TRAF2 KOCancer cell lineFemale
CVCL_TT54HAP1 TRAF2 (-) 1Cancer cell lineMale
CVCL_TT55HAP1 TRAF2 (-) 2Cancer cell lineMale

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.