The extrinsic apoptosis signaling pathways that initiate apoptosis involve transmembrane receptor-mediated interactions. These involve death receptors that are members of the tumor necrosis factor (TNF) receptor gene superfamily.
Members of the TNF receptor family share similar cyteine-rich extracellular domains and have a cytoplasmic domain of about 80 amino acids called the “death domain”. This death domain plays a critical role in transmitting the death signal from the cell surface to the intracellular signaling pathways. To date, the best-characterized ligands and corresponding death receptors include FasL/FasR, TNF-α/TNFR1, Apo3L/DR3, Apo2L/DR4 and Apo2L/DR5.
The sequence of events that define the extrinsic phase of apoptosis are best characterized with the FasL/FasR and TNF-α/TNFR1 models. In these models, there is clustering of receptors and binding with the homologous trimeric ligand.
Upon ligand binding, cytplasmic adapter proteins are recruited which exhibit corresponding death domains that bind with the receptors.
The binding of Fas ligand to Fas receptor results in the binding of the adapter protein FADD and the binding of TNF ligand to TNF receptor results in the binding of the adapter protein TRADD with recruitment of FADD and RIP. FADD then associates with procaspase-8 via dimerization of the death effector domain. At this point, a death-inducing signaling complex (DISC) is formed, resulting in the auto-catalytic activation of procaspase-8.
Once caspase-8 is activated, the execution phase of apoptosis is triggered. Death receptor-mediated apoptosis can be inhibited by a protein called c-FLIP which will bind to FADD and caspase-8, rendering them ineffective. Another point of potential apoptosis regulation involves a protein called Toso, which has been shown to block Fas-induced apoptosis in T cells via inhibition of caspase-8 processing.