Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily

Abstract

With the exception of a few signaling incompetent decoy receptors, the receptors of the tumor necrosis factor receptor superfamily (TNFRSF) are signaling competent and engage in signaling pathways resulting in inflammation, proliferation, differentiation, and cell migration and also in cell death induction. TNFRSF receptors (TNFRs) become activated by ligands of the TNF superfamily (TNFSF). TNFSF ligands (TNFLs) occur as trimeric type II transmembrane proteins but often also as soluble ligand trimers released from the membrane-bound form by proteolysis. The signaling competent TNFRs are efficiently activated by the membrane-bound TNFLs. The latter recruit three TNFR molecules, but there is growing evidence that this is not sufficient to trigger all aspects of TNFR signaling; rather, the formed trimeric TNFL–TNFR complexes have to cluster secondarily in the cell-to-cell contact zone for full TNFR activation. With respect to their response to soluble ligand trimers, the signaling competent TNFRs can be subdivided into two groups. TNFRs of one group, designated as category I TNFRs, are robustly activated by soluble ligand trimers. The receptors of a second group (category II TNFRs), however, failed to become properly activated by soluble ligand trimers despite high affinity binding. The limited responsiveness of category II TNFRs to soluble TNFLs can be overcome by physical linkage of two or more soluble ligand trimers or, alternatively, by anchoring the soluble ligand molecules to the cell surface or extracellular matrix. This suggests that category II TNFRs have a limited ability to promote clustering of trimeric TNFL–TNFR complexes outside the context of cell–cell contacts. In this review, we will focus on three aspects on the relevance of receptor oligomerization for TNFR signaling: (i) the structural factors which promote clustering of free and liganded TNFRs, (ii) the signaling pathway specificity of the receptor oligomerization requirement, and (iii) the consequences for the design and development of TNFR agonists.

Receptor Activator of NF-κB (RANK) Confers Resistance to Chemotherapy in AML and Associates with Dismal Disease Course

“…Analyses of downstream apoptotic events, i.e., treatment-induced activation of caspase-3, an effector caspase with a central role in the process of cell apoptosis, revealed that RANK signaling also reduced the cleavage of procaspase-3 into its active form upon chemotherapeutic treatment: a significant reduction of active caspase-3 levels upon RANK stimulation was observed in the presence of both doxorubicin and cytarabine ( Figure 3 D; p = 0.002 and 0.031, respectively). Similar but less pronounced results were observed in all assay systems when non-clustered trimeric soluble hRANKL (sRANKL) instead of multimeric Fc-hRANKL was used to induce signals by RANK ( Supplementary Figure S1 ), in line with data, that for TNF family members in general and RANK in particular multimerization of ligands is required to obtain optimal signaling efficacy [ 28 , 29 ]. Altogether, our findings demonstrate that in AML cells signaling via RANK confers resistance to chemotherapy.…”

Great balls of fire: activation and signalling of inflammatory caspases

“…The initiator caspases can then be further divided into whether they participate in the extrinsic or intrinsic apoptotic pathway. The extrinsic pathway involves caspase-8 and -10, which are activated by complexes like the death-inducing signalling complex (DISC) following binding of death ligands to their cognate receptors [ 14 , 15 ]. The intrinsic apoptotic pathway involves caspase-9, activated by the apoptosome following sensing of various intracellular signal like DNA-damage [ 16 , 17 ].…”

Review article: targeting the B cell activation system in autoimmune hepatitis

“…BAFF (also called BLys, TALL‐1, THANK, TNFSF13B, and CD256 145,146 ) is a type II transmembrane, homotrimeric protein that is expressed on the cell surface of myeloid cells (Table 2). 147‐149 It can also exist as a circulating soluble molecule that has been cleaved from the cell surface by a protease of the furin family 150‐154 . BAFF is a member of the tumor necrosis factor (TNF) family, 155 and its gene has been mapped to chromosome 13q32‐34 150 .…”