ID:TRAF2_HUMAN DESCRIPTION: RecName: Full=TNF receptor-associated factor 2; EC=6.3.2.-; AltName: Full=E3 ubiquitin-protein ligase TRAF2; AltName: Full=Tumor necrosis factor type 2 receptor-associated protein 3; FUNCTION: Regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis. Required for normal antibody isotype switching from IgM to IgG. Has E3 ubiquitin-protein ligase activity and promotes 'Lys-63'- linked ubiquitination of target proteins, such as BIRC3, 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. ENZYME 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. PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Homotrimer, and heterotrimer with TRAF1 and 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, TNFRSF4, TNFRSF5/CD40, CD27/TNFRSF7, TNFRSF8/CD30, TNFRSF9/CD137, TNFRSF11A/RANK, TNFRSF13B/TACI, TNFRSF14, TNFRSF16/NGFR, TNFRSF17/BCMA, TNFRSF18/AITR, TNFRSF19/TROY, TNFRSF19L/RELT, XEDAR, EDAR, Epstein-Barr virus BNFL1/LMP-1 and IL15RA. Interacts with CDK9, CSK, MAP3K1, MAP3K5, MAP3K11, MAP3K14, MAP4K2, RIPK1, RIPK2, TNIK, TBK1, SPHK1, TRADD, TRAFD1, TRAIP, TANK/ITRAF, TNFAIP3, TDP2, MAVS/IPS1, TICAM1 and TRPC4AP. Interacts with CASP8AP2, NFATC2IP, PEG3 and HIVEP3 (By similarity). 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. Interaction with BIRC2 and/or BIRC3 is essential for degradation of NFKBIA and activation of NF-kappa-B. Interacts with CYLD, USP48, DAB2IP, IKKA and IKKB. Identified in a complex with TNFRSF1A, RIPK1 and IKKB. Interacts (via 'Lys-63'-linked polyubiquitin chains) with TAB2 and TAB3. Interacts with ERN1 and TAOK3. Interaction with TAOK3 is facilitated under ER stress conditions, such as treatment with tunicamycin, and may promote TRAF2 phosphorylation. INTERACTION: Self; NbExp=3; IntAct=EBI-355744, EBI-355744; P54253:ATXN1; NbExp=2; IntAct=EBI-355744, EBI-930964; Q13490:BIRC2; NbExp=8; IntAct=EBI-355744, EBI-514538; Q13489:BIRC3; NbExp=5; IntAct=EBI-355744, EBI-517709; O08736:Casp12 (xeno); NbExp=6; IntAct=EBI-355744, EBI-6140033; O75460:ERN1; NbExp=2; IntAct=EBI-355744, EBI-371750; P09211:GSTP1; NbExp=4; IntAct=EBI-355744, EBI-353467; P07174:Ngfr (xeno); NbExp=3; IntAct=EBI-355744, EBI-1038810; Q92844:TANK; NbExp=3; IntAct=EBI-355744, EBI-356349; Q9H2K8:TAOK3; NbExp=2; IntAct=EBI-355744, EBI-1384100; Q9NP84:TNFRSF12A; NbExp=3; IntAct=EBI-355744, EBI-2851995; Q92956:TNFRSF14; NbExp=4; IntAct=EBI-355760, EBI-1056653; P70191:Traf5 (xeno); NbExp=2; IntAct=EBI-355744, EBI-523899; Q6FIF0:ZFAND6; NbExp=6; IntAct=EBI-355744, EBI-724630; SUBCELLULAR LOCATION: Cytoplasm. DOMAIN: The coiled coil domain mediates homo- and hetero- oligomerization. DOMAIN: The MATH/TRAF domain binds to receptor cytoplasmic domains. DOMAIN: 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. PTM: 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. PTM: 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. SIMILARITY: Belongs to the TNF receptor-associated factor family. A subfamily. SIMILARITY: Contains 1 MATH domain. SIMILARITY: Contains 1 RING-type zinc finger. SIMILARITY: Contains 2 TRAF-type zinc fingers. WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/traf2/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q12933
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0002726 positive regulation of T cell cytokine production GO:0006915 apoptotic process GO:0006919 activation of cysteine-type endopeptidase activity involved in apoptotic process GO:0007165 signal transduction GO:0007249 I-kappaB kinase/NF-kappaB signaling GO:0007250 activation of NF-kappaB-inducing kinase activity GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway GO:0016567 protein ubiquitination GO:0016579 protein deubiquitination GO:0030163 protein catabolic process GO:0032743 positive regulation of interleukin-2 production GO:0033209 tumor necrosis factor-mediated signaling pathway GO:0034351 negative regulation of glial cell apoptotic process GO:0034622 cellular macromolecular complex assembly GO:0034976 response to endoplasmic reticulum stress GO:0042981 regulation of apoptotic process GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling GO:0043507 positive regulation of JUN kinase activity GO:0046328 regulation of JNK cascade GO:0051023 regulation of immunoglobulin secretion GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity GO:0051092 positive regulation of NF-kappaB transcription factor activity GO:0051291 protein heterooligomerization GO:0051865 protein autoubiquitination GO:0065003 macromolecular complex assembly GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress GO:0070207 protein homotrimerization GO:0070534 protein K63-linked ubiquitination GO:0071550 death-inducing signaling complex assembly GO:0071732 cellular response to nitric oxide GO:0090073 positive regulation of protein homodimerization activity GO:0097300 programmed necrotic cell death GO:1901215 negative regulation of neuron death GO:1902041 regulation of extrinsic apoptotic signaling pathway via death domain receptors GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway GO:1903721 positive regulation of I-kappaB phosphorylation GO:2001238 positive regulation of extrinsic apoptotic signaling pathway
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
