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. Plays a role in mediating activation of NF-kappa-B by EIF2AK2/PKR. In complex with BIRC2 or BIRC3, promotes ubiquitination of IKBKE. (updated: Oct. 10, 2018)

Protein identification was indicated in the following studies:

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

Publication	Identification ¹	Uniprot mapping ²	Not mapped / Obsolete	TrEMBL	Swiss-Prot
Goodman (2013)	2289 (gene list)	2278	53	20599	2269
Lange (2014)	1234	1234	7	28	1224
Hegedus (2015)	2638	2622	0	235	2387
Wilson (2016)	1658	1528	170	291	1068
d'Alessandro (2017)	1826	1817	2	0	1815
Bryk (2017)	2090	2060	10	108	1942
Chu (2018)	1853	1804	55	362	1387

¹ as available in the article and/or in supplementary material
² uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Protein sequence (FASTA)

Protein coevolution profile (FreeContact)

Multiple Sequence Alignment (Muscle)

Total structural coverage: 38%

Model score: 0

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Biological Process

Activation of cysteine-type endopeptidase activity involved in apoptotic process

Activation of NF-kappaB-inducing kinase activity

Cellular protein-containing complex assembly

Cellular response to nitric oxide

Death-inducing signaling complex assembly

I-kappaB kinase/NF-kappaB signaling

Interleukin-17-mediated signaling pathway

Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress

MRNA stabilization

Negative regulation of extrinsic apoptotic signaling pathway via death domain receptors

Negative regulation of glial cell apoptotic process

Negative regulation of neuron death

Positive regulation of DNA-binding transcription factor activity

Positive regulation of extrinsic apoptotic signaling pathway

Positive regulation of I-kappaB kinase/NF-kappaB signaling

Positive regulation of I-kappaB phosphorylation

Positive regulation of interleukin-2 production

Positive regulation of JNK cascade

Positive regulation of JUN kinase activity

Positive regulation of NF-kappaB transcription factor activity

Positive regulation of T cell cytokine production

Positive regulation of tumor necrosis factor-mediated signaling pathway

Programmed necrotic cell death

Protein autoubiquitination

Protein catabolic process

Protein deubiquitination

Protein K63-linked ubiquitination

Protein-containing complex assembly

Regulation of apoptotic process

Regulation of extrinsic apoptotic signaling pathway via death domain receptors

Regulation of I-kappaB kinase/NF-kappaB signaling

Regulation of immunoglobulin production

Regulation of immunoglobulin secretion

Regulation of protein-containing complex assembly

Regulation of tumor necrosis factor-mediated signaling pathway

Response to endoplasmic reticulum stress

Signal transduction

Signal transduction involved in regulation of gene expression

Tumor necrosis factor-mediated signaling pathway

Cellular Component

CD40 receptor complex

Cell cortex

Cytoplasmic side of plasma membrane

Cytosol

IRE1-TRAF2-ASK1 complex

Membrane raft

Nucleoplasm

TRAF2-GSTP1 complex

Tumor necrosis factor receptor superfamily complex

Ubiquitin ligase complex

Vesicle membrane

Molecular Function

CD40 receptor binding

Enzyme binding

Identical protein binding

Mitogen-activated protein kinase kinase kinase binding

Protein kinase binding

Protein phosphatase binding

Protein-containing complex binding

Protein-macromolecule adaptor activity

Sphingolipid binding

Thioesterase binding

Tumor necrosis factor binding

Tumor necrosis factor receptor binding

Ubiquitin protein ligase binding

Ubiquitin-protein transferase activity

Zinc ion binding

The reference OMIM entry for this protein is 601895

Tnf receptor-associated factor 2; traf2
Tnf receptor-associated protein; trap

CLONING

The induction of the various cellular responses mediated by tumor necrosis factor (TNF; 191160) is initiated by its interaction with the TNFR1 (191190) and TNFR2 (191191) cell surface receptors. Rothe et al. (1994) used the yeast-based 2-hybrid system to detect mouse proteins that interact with the cytoplasmic domain of TNFR2. They identified and cloned 2 TNF receptor-associated factors which they termed TRAF1 (601711) and TRAF2. TRAF1 and TRAF2 share a C-terminal domain that the authors designated the TRAF domain. TRAF1 and TRAF2 can form both homo- and heterodimers. When expressed in yeast cells, a heterodimeric complex of TRAF1 and TRAF2 in which TRAF2 facilitates direct contact with the receptor was associated with the cytoplasmic domain of TNFR2. Song and Donner (1995) isolated HeLa cell cDNAs encoding the human TRAF2 homolog, which they called TRAP (TNF receptor-associated protein). The predicted 502-amino acid human protein is 87% identical to mouse TRAF2. Like TRAF3 (CD40bp; 601896), TRAP contains an N-terminal RING finger and cysteine/histidine-rich motifs. Northern blot analysis revealed TRAP expression as a 2.4-kb mRNA in all human tissues tested.

MAPPING

Gross (2014) mapped the TRAF2 gene to chromosome 9q34.3 based on an alignment of the TRAF2 sequence (GenBank GENBANK BC033810) with the genomic sequence (GRCh38).

GENE FUNCTION

TRAF2 is a common signal transducer for TNFR2 and CD40 (109535) that mediates activation of NF-kappa-B (see 164011). Rothe et al. (1996) identified ITRAF (603893), which binds to TRAF1, TRAF2, and TRAF3, and that when overexpressed inhibits TRAF2-mediated NF-kappa-B activation. They proposed that ITRAF is an inhibitor of TRAF function that regulates TRAF protein activity by sequestering TRAFs in a latent state in the cytoplasm. By in vitro binding, immunoprecipitation, immunoblot, and yeast 2-hybrid analyses, Aizawa et al. (1997) showed that TRAF2 and TRAF5 (602356) interact with overlapping but distinct sequences in the C-terminal region of CD30 (153243) and mediate the activation of NFKB. Phillips et al. (1999) showed that E2F1 (189971) can induce apoptosis by a death receptor-dependent mechanism, by downregulating TRAF2 protein levels and inhibiting activation of antiapoptotic signals such as NFKB. In this way, independent of p53 (191170), E2F1 expression can lead to the sensitization of cells to apoptosis by a number of agents. Deregulation of E2F1 activity occurs in the majority of human tumors, and the authors suggested that the ability of E2F1 to inhibit antiapoptotic signaling may contribute to the enhanced sensitivity of transformed cells to chemotherapeutic agents. Takeuchi et al. (1996) performed mutational analysis on TRAF2, including the construction of TRAF2-TRAF3 hybrid proteins. Malfolded proteins in the endoplasmic reticulum induce cellular stress and activate c-JUN amino-terminal kinases (JNKs; see 601158). Urano et al. (2000) showed that IRE1 (604033) activates chaperone genes in response to stress in the endoplasmic reticulum and also activates JNK. IRE1-alpha -/- fibroblasts were impaired in JNK activation by endoplasmic reticulum stress. Using the yeast 2-hybrid system, Urano et al. (2000) demonstrated that the cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. The dominant-negative form of TRAF2 inhibited activation of JNK by IRE1. Activation of JNK by endogenous signals init ... More on the omim web site

Subscribe to this protein entry history

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 601895 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).

TNF receptor-associated factor 2 (TRAF2)