Tumor Necrosis Factor Receptors: Pleiotropic Signaling Complexes and Their Differential Effects

Abstract

Since its discovery in 1975, TNFα has been a subject of intense study as it plays significant roles in both immunity and cancer. Such attention is well deserved as TNFα is unique in its engagement of pleiotropic signaling via its two receptors: TNFR1 and TNFR2. Extensive research has yielded mechanistic insights into how a single cytokine can provoke a disparate range of cellular responses, from proliferation and survival to apoptosis and necrosis. Understanding the intracellular signaling pathways induced by this single cytokine via its two receptors is key to further revelation of its exact functions in the many disease states and immune responses in which it plays a role. In this review, we describe the signaling complexes formed by TNFR1 and TNFR2 that lead to each potential cellular response, namely, canonical and non-canonical NF-κB activation, apoptosis and necrosis. This is followed by a discussion of data from in vivo mouse and human studies to examine the differential impacts of TNFR1 versus TNFR2 signaling.

Keywords: NF-kappa B; TNF; TNF blockade; TNF receptor; epithelial to mesenchymal transition; signaling/signaling pathways.

Figure 1

Overview of TNFR1 activation pathway. Flow diagram for TNFR1 activation contrasting the outcomes of inflammatory cytokine production versus cell death. The top panels depict formation of the core signaling complex with recruitment and assembly of TRAF2/5, cIAP 1/2 and RIPK1 at the death domain of TNFR1, and subsequent recruitment of LUBAC. The middle and lower panels show the divergence of potential pathways from formation of the core complex. On the left, complete ubiquitination of RIPK1 results in formation of Complex I, which leads to recruitment of NEMO and TAK1 that activate NFκB and JNK, respectively. On the right, incomplete ubiquitination of RIPK1 leads to formation of complex IIa or IIb, with assembly of FLIP_L, FADD and pro-caspase 8 or 10, leading apoptosis via activation of the latter. Below this, the formation of Complex IIc in the absence of sufficient caspases leads to necroptosis via activation of MLKL via the necrosome formed by assembly of RIPK1 and RIPK3. Stars indicate phosphorylation, blue bursts represent ubiquitination, purple bursts represent M1 ubiquitination.

Figure 2

Overview of TNFR2 activation pathway. Flow diagram for TNFR2 activation contrasting the non-canonical versus canonical pathways. The top panels show recruitment of TRAF proteins, cIAP1/2 and NIK to TNFR2 upon binding ligand (mTNFα). On the left, this assembly leads to non-canonical NFκB activation via accumulation of NIK. On the right, the pathway of canonical NFκB activation is shown, the details of which are unknown but presumably result from K63 and M1 polyubiquitin chains mediating the recruitment of TAK1 and NEMO. Stars indicate phosphorylation, blue bursts represent ubiquitination, purple burst represent M1 ubiquitination. Question mark in canonical pathways indicate the target of ubiquitination is unknown.