Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed DR (Death Receptors), on their surface, which detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery. Death Receptors belong to the TNF (Tumour Necrosis Factor) gene superfamily and generally can have several functions other than initiating apoptosis. Eight members of the Death Receptor family have been characterized so far: TNFR1 (Tumor Necrosis Factor Receptor-1) also known as DR1, CD120a, p55 and p60, Fas (also known as DR2, APO1 and CD95), DR3 (Death Receptor-3) (also known as APO-3, LARD, TRAMP and WSL1), TRAILR1 (TNF-Related Apoptosis-Inducing Ligand Receptor-1) also known as DR4 and APO-2, TRAILR2 (also known as DR5, KILLER and TRICK2), DR6, EDAR (Ectodysplasin-A Receptor) and NGFR (Nerve Growth Factor Receptor). These are distinguished by a cytoplasmic region of approximately 80 residues termed the DD (Death Domain). When these receptors are triggered by corresponding ligands, a number of molecules are recruited to the DD and subsequently a signaling cascade is activated. Death ligands also interact with DcRs (Decoy Receptors) that do not possess DDs and so cannot form signaling complexes. Decoy receptors are members of the TNFR superfamily that are capable of competing with signaling receptors for ligand binding, thereby inhibiting their function. TRAILR3 (also known as DcR1) and TRAILR4 (also known as DcR2) compete with DR4 and DR5 for binding of APO2L/TRAIL. DcR3 competes with Fas for binding of FasL and with DR3 for binding of TL1A. Two types of DR signaling complexes can be distinguished. The first group comprises the DISCs (Death-Inducing Signaling Complexes) that are formed at the Fas receptor, TRAILR1 or TRAILR2. All three receptors recruit DISCs with similar compositions. DISC formation results in the activation of Caspase8, which plays the central role in transduction of the apoptotic signal. The second group comprises the TNFR1, DR3, DR6 and EDAR. These recruit a different set of molecules, which transduce both apoptotic and survival signals (Ref.1 & 2). |