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. 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. 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. 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. Belongs to the TNF receptor-associated factor family. A subfamily. 4 isoforms of the human protein are produced by alternative splicing. Note: This description may include information from UniProtKB.
Protein type: EC 6.3.2.-; Ligase; Ubiquitin ligase; Autophagy; Ubiquitin conjugating system
Chromosomal Location of Human Ortholog: 9q34
Cellular Component: internal side of plasma membrane; cytoplasm; cell cortex; cytosol; lipid raft
Molecular Function: identical protein binding; sphingolipid binding; zinc ion binding; ubiquitin-protein ligase activity; CD40 receptor binding; mitogen-activated protein kinase kinase kinase binding; tumor necrosis factor receptor binding; protein phosphatase binding; protein binding; signal transducer activity; enzyme binding; thioesterase binding; ubiquitin protein ligase binding; protein complex binding; ligase activity
Biological Process: caspase activation; positive regulation of JNK activity; protein autoubiquitination; protein heterooligomerization; apoptosis; activation of NF-kappaB-inducing kinase; positive regulation of T cell cytokine production; signal transduction; activation of NF-kappaB transcription factor; regulation of apoptosis; cellular protein complex assembly; tumor necrosis factor-mediated signaling pathway; positive regulation of interleukin-2 production; innate immune response; protein catabolic process; protein complex assembly; positive regulation of transcription factor activity; positive regulation of T cell activation; regulation of immunoglobulin secretion
SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.