37.4:
The Extrinsic Apoptotic Pathway
The extrinsic apoptotic pathway is activated through extracellular death signals from immune cells.
These immune cells recognize dangerous cells, such as diseased ones, through homotrimeric ligands that bind to death receptors on the target cell membrane.
The death receptors belong to the tumor necrosis factor or TNF superfamily, which includes TNF receptor 1 and the Fas receptor.
In the Fas signaling pathway, the Fas ligand expressed on the surface of immune cells binds to Fas receptor on the target cell, causing activation of the receptor death domain.
The activated death domain recruits an adaptor protein, Fas-associated death domain, which then binds to initiator procaspase-8 to form the death-inducing signaling complex or DISC.
Inside DISC, procaspase-8 molecules dimerize and self-cleave to form active caspase-8, which is released into the cytosol.
Caspase-8 activates executioner procaspase-3 to form caspase-3 that cleaves cellular proteins, resulting in apoptosis.
37.4:
The Extrinsic Apoptotic Pathway
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate their apoptotic pathway. The extrinsic apoptotic pathway is vital in removing cancerous cells or virus-infected cells.
Another example of external apoptotic signaling occurs during T-cell development in the thymus to eliminate self-reactive T-cells. T-cells are immune cells that bind foreign macromolecules and particles and target them for destruction by the immune system. In order to prevent the immune system from attacking the body's own cells, T-cells do not target “self” proteins (proteins of the same individual). Immature T-cells, or thymocytes, undergo a screening process to determine whether or not they bind self-proteins. If the T-cell binds to self-proteins, it is signaled for apoptosis, thus preventing an autoimmune response.
Inhibiting Apoptosis
Anti-apoptotic regulators are proteins that can inhibit the extrinsic apoptotic pathway in cells. The FLICE inhibitory protein, or c-FLIP is one of the master anti-apoptotic regulators that binds to FADD (Fas-associated death domain protein), and caspases such as caspase-8. This binding prevents the formation of the death-inducing signaling complex (DISC), thus preventing the apoptotic pathway.
Some portion of this text is adapted from Openstax, Biology 2e, Section: 9.3