The TNFR (Tumor Necrosis Factor Receptor) superfamily comprises a growing family of type I membrane bound glycoproteins, which interact with the TNF family of soluble mediators and type II transmembrane proteins. At least 23 TNFR superfamily members and 17 known ligands have been identified in mammals. These receptors trigger pleiotropic responses, ranging from apoptosis and differentiation to proliferation, and have been implicated in immune regulation, host defense and lymphoid organ development. Members of the TNFR family are characterized by the presence of varying numbers (two to six) of cysteine-rich repeats in their cytoplasmic domains. Among these molecules, a novel subgroup has been defined, termed DR (Death Receptors), as one of their most prominent functions is to induce apoptosis. DR
are characterized by an intracellular region of about 80 amino acids, designated the DD (Death Domain), because it is required for the transmission of the cytotoxic signal (Ref.1). Currently, five different such DRs are known including CD95, TNFR1 (TNF Receptor-1), DR3 and two TRAIL (TNF-Related Apoptosis-Inducing Ligand) receptors, called TRAILR1 and TRAILR2. DR
activate two main signaling cascades: (i) a cell survival-promoting cascade leading to the activation of NF-KappaB (Nuclear Factor-Kappa B) and the JNK (Jun-NH2-Terminal Kinase), and (ii) a Caspase cascade leading to apoptotic cell death (Ref.1). It is not completely clear how the downstream signaling pathways are mediated. However, the degradation of I-KappaB, an inhibitor of NF-KappaB, promotes the release of NF-KappaB from the IKKs
(I-KappaB Kinase) complex and allows NF-KappaB to freely enter the nucleus. IKK
consists of two kinase subunits, IKK-Alpha (also known as IKK1) and IKK-Beta (also known as IKK2), and a regulatory subunit called IKK-Gamma (also known as NEMO), and is itself activated by phosphorylation (Ref.2).
DR3 (also called TRAMP (TNF Receptor-Related-Apoptosis-Mediated-Protein), Ws1, Apo3, LARD, TR3, and TNFRSF25) is one of DD-containing TNFR family members and is the one most closely related to TNFR1. DR3 mediate a variety of developmental events including the regulation of cell proliferation, differentiation, and apoptosis (Ref.3). DR3 is structurally and functionally similar to TNFR1, because its overexpression leads to NF-KappaB activation and apoptosis. DR3 may bind to Apo3L (Apo3 Ligand), TL1 (TNF Ligand-Related Molecule-1) or VEGI (Vascular Endothelial Growth Inhibitor). The Apo3L is a 249 amino-acid, type II transmembrane protein. The extracellular sequence of Apo3L shows highest identity to that of TNF
(Ref.4). DR3 induced cell death is inhibited by an inhibitor of ICE-like proteases, but not by Bcl2 (B-Cell Leukemia-2). In addition, DR3 does not appear to interact with any of the known apoptosis-inducing ligands of the TNF family. DR3 transduce death signals by interaction of their DD with FADD (Fas Associated Death Domain), a DD-containing cytoplasmic protein. FADD then recruits other cytoplasmic effectors such as Caspase8, TRADD (TNFR-Associated Death Domain protein) and RIP (Receptor-Interacting Protein) that activate the apoptotic machinery. DR3 also recruits TRAF2 (TNF Receptor-Associated Factor-2) via TRADD and thus activates the transcription factor, NF-KappaB that induces the transcription of a number survival genes including IAP (Inhibitor of Apoptosis). In this respect, DR3 (like TNFR1) is capable of inducing both apoptosis and expression of survival/activation genes and is likely to have multiple functions depending on the context of its expression.
The recently identified SODD (Silencer of Death Domains) that can interact with the DDs of TNFR1 and DR3 is thought to be a first member of a class of proteins that inhibits the spontaneous self-aggregation of receptor DDs. Cross-linking of the receptors results in the release of SODD and the recruitment of intracellular adapter molecules like TRADD and FADD . The recruitment of these factors subsequently leads to the formation of multiprotein complexes that result in the activation of Caspases. Apoptosis induction through DR is a potentially promising approach for cancer therapy (Ref.5).