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.

Keywords: B-cell lymphoma; TNF receptor associated factor 2 (TRAF2); apoptosis; autophagy; cellular inhibitor of apoptosis 1/2 (cIAP1/2); necroptosis; nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NFκB); tumor necrosis factor (TNF).

Figure 1

Domain architecture of TRAF2. A sequence of 501 amino acids prescribes the molecular structure of full-length TRAF2. It is essentially composed of a RING domain (aa 32–79), five zinc fingers (Zf) and a TRAF domain comprising a coiled-coil N-TRAF domain with a cIAP1/2 binding site (aa 283–294) [3,4] and a C-TRAF domain. Phosphorylation and ubiquitination sites of known relevance for TRAF2 function are indicated and comprise serine S11 and S55 [5,6,7], lysine K31 and K63 [8,9], and threonine T117 [10].

Figure 2

TRAF2 and the cIAPs in receptor-induced activation of the classical and alternative NFκB pathway. The activities of TRAF2 and the cIAPs have opposing qualities in the classical (left panel) and alternative (right panel) NFκB signaling pathway. In the classical NFκB pathway TRAF2 and the cIAPs enable signaling, while in the alternative NFκB pathway they act as inhibitors. Importantly, TNFR-induced recruitment of TRAF2 and the cIAPs, which triggers the classical NFκB pathway, is linked with an “inhibitory” relocation of these molecules away from their cytosolic substrate NIK in the alternative NFκB pathway. Therefore, TNFRs eventually stimulate both NFκB signaling pathways despite the opposing quality they have in these pathways. For more details, refer to main text.

Figure 3

TRAF2 in RIG1 signaling. Binding of dsRNA by RIG1, results in conformational change, K63-ubiquitination, and filament formation. RIG1 filaments in turn instruct filament formation of mitochondria-associated MAVS. The MAVS filaments enable recruitment of TRAF2 and IRF3, but also other TRAF proteins not indicated here. TRAF2 and the other TRAF proteins mediate the recruitment of the IKK complex and TANK-binding kinase 1 (TBK1)/IKKε enabling activation of the classical NFκB pathway and IRF3 by the mechanisms described in detail in the text. Please note, TRAF2 acts independently here from cIAP1 and cIAP2 [74]. For more details refer to main text.

Figure 4

TRAF2 in IER1 signaling. After ER stress-induced dimerization IREα triggers production of the transcription factor XBP1 by its endonuclease activity engages splicing and recruits TRAF2 to trigger ASK1/JNK signaling but also, by still poorly studied mechanisms, classical NFκB signaling and apoptosis. The IRE1α/TRAF2/ASK/JNK axis is also connected with autophagy by the JNK-mediated phosphorylation of the Beclin inhibitory Bcl-2 protein. Interestingly, TRAF2 in concert with cIAP1/2 can further contribute to autophagy by K63-ubiquitination of Beclin. For more details refer to main text.