Apoptosis or programmed cell death can be triggered by a number of factors, including UV- or γ-irradiation, chemotherapeutic drugs or signaling by death receptors (DR). The DR family which is part of the tumor necrosis factor receptor superfamily can be triggered by death ligands to result in apoptotic or survival signals.Several members of the death receptor family have been characterized so far, including tumor necrosis factor receptor 1 (TNFR1; also known as DR1), FAS (also known as CD95), DR3, TNF-related apoptosis-inducing ligand receptor 1 (TRAILR1; also known as DR4), TRAILR2 (also known as DR5) and DR6. Two types of DR signaling complex can be distinguished. The first group comprises the death-inducing signaling complexes (DISCs) 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 caspase-8, which is primarily responsible for transduction of the apoptotic signal. The second group comprises the TNFR1, DR3 and DR6. These recruit a different set of molecules, which transduce both apoptotic and survival signals.
The DISCs associated with FAS consist of oligomerized receptors, the DD-containing adaptor protein FAS-Associated Death Domain (FADD), caspase 8/10 and FLICE-inhibitory protein (FLIP). The FAS mediated activation of caspase-8 results in the cleavage of the BCL-2-family protein BID to generate truncated (t) BID and tBID-mediated release of cytochrome c (CYTC) from mitochondria. Cytochrome c binds and activates apoptotic peptidase activating factor 1 (APAF-1) as well as procaspase-9, forming an apoptosome leading to caspase-9 activation. SMAC/DIABLO and HTRA2/OMI promote apoptosis by inhibiting inhibitors of apoptosis proteins (IAP).The activation of procaspase-9 in turn cleaves downstream effector caspases. A second pathway of FAS mediated apoptosis is via the adaptor protein DAXX, which activates the Apoptosis Signal- Regulating Kinase 1 (ASK1). ASK1 in turn activates the Janus Kinase (JNK) pathway. Activation of JNK can antagonize the anti-apoptotic action of BCL-2.
TNF-R1 signaling differs from FAS-receptor or TRAILR1/R2-induced apoptosis. TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, TNFR-associated death domain protein (TRADD), receptor-interacting protein (RIP), and TNFR-associated factor 2 (TRAF2) and rapidly signals activation of NF-kappa B (NFκB). In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NFκB is activated by complex I, complex II associates with the caspase-8 inhibitor FLIP and the cell survives. Thus, TNFR1-mediated-signal transduction results in cell death (via complex II) in instances when the initial signal from complex 1 fails to activate NFκB. In the latter case, caspase 8 in Complex II can lead to the direct activation of caspase 3, which in turn induces apoptosis.
This pathway highlights the important molecular events involved in death receptor signaling.