TNF Receptor Associated Factor 2 (TRAF2) Signaling in Cancer

Abstract

Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) has been originally identified as a protein interacting with TNF receptor 2 (TNFR2) but also binds to several other receptors of the TNF receptor superfamily (TNFRSF). TRAF2, often in concert with other members of the TRAF protein family, is involved in the activation of the classical NFκB pathway and the stimulation of various mitogen-activated protein (MAP) kinase cascades by TNFRSF receptors (TNFRs), but is also required to inhibit the alternative NFκB pathway. TRAF2 has also been implicated in endoplasmic reticulum (ER) stress signaling, the regulation of autophagy, and the control of cell death programs. TRAF2 fulfills its functions by acting as a scaffold, bringing together the E3 ligase cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 with their substrates and various regulatory proteins, e.g., deubiquitinases. Furthermore, TRAF2 can act as an E3 ligase by help of its N-terminal really interesting new gene (RING) domain. The finding that TRAF2 (but also several other members of the TRAF family) interacts with the latent membrane protein 1 (LMP1) oncogene of the Epstein–Barr virus (EBV) indicated early on that TRAF2 could play a role in the oncogenesis of B-cell malignancies and EBV-associated non-keratinizing nasopharyngeal carcinoma (NPC). TRAF2 can also act as an oncogene in solid tumors, e.g., in colon cancer by promoting Wnt/β-catenin signaling. Moreover, tumor cell-expressed TRAF2 has been identified as a major factor-limiting cancer cell killing by cytotoxic T-cells after immune checkpoint blockade. However, TRAF2 can also be context-dependent as a tumor suppressor, presumably by virtue of its inhibitory effect on the alternative NFκB pathway. For example, inactivating mutations of TRAF2 have been associated with tumor development, e.g., in multiple myeloma and mantle cell lymphoma. In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes.

The multi-omics analysis identifies a novel cuproptosis-anoikis-related gene signature in prognosis and immune infiltration characterization of lung adenocarcinoma

“…Anoikis resistance of tumor cells was found to be promoted by TRAF2 interacting with the N-terminus of FAK. Similarly, down-regulation of TRAF2 and FAK was found to increase the susceptibility of human breast cancer cells to anoikis in MDA-MB-231 [ 42 , 43 ]. Most cancer types are accompanied by a decline in genetic integrity and stability, and the key function of XRCC5 is to maintain genomic stability and human ontogeny.…”

TRAF3: A novel regulator of mitochondrial physiology and metabolic pathways in B lymphocytes

“…It remains unknown whether the TRAF3-MFF interaction interferes with the TRAF3-TRAF2 interaction when TRAF3 proteins are limiting in B cells. Following viral infection, both TRAF3 and TRAF2 are recruited to the mitochondrial antiviral signaling complexes by MAVS (60)(61)(62)(63), while in response to ER stress, TRAF2 is translocated to ER via interacting with the ER stress sensor IRE1a (64,65). In addition, cIAP1/2 also binds to caspases and upon mitochondrial membrane permeabilization, cIAP1/2 binds to Smac that is released from mitochondrial intermembrane space to cytosol (66,67).…”

Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy

“…Furthermore, ER stress promotes TNF receptor-associated factor 2 (TRAF2) oligomerization via IRE1α, which activates ASK1-MKK4/7-JNK signaling, promotes survival via c-Jun-dependent Adapt78, and activates c-Jun N -terminal kinase (JNK) [ 78 ]. Inflammatory response by the IRE1α-TRAF2 complex recruits IkappaB (IκB) kinase, which contributes to the breakdown and phosphorylates IκB [ 79 ]. Thus, the translocation of NF-κB to the nucleus regulates inflammatory gene transcription.…”