Читать книгу Human Developmental Biology - Danton Inc. O'Day - Страница 24

Alternatively, surface receptors can be activated by specific ligands that bind to “death receptors” (i.e., “Extrinsic Pathway”). Death receptors are members of the tumor necrosis factor (TNF)/nerve growth factor (NGF) receptor superfamily. They make up a subfamily characterized by the intracellular death domain (DD). The extrinsic pathway is typically mediated by immune cells to initiate intracellular signaling and the downstream activation of relevant caspases. Some work suggests both intrinsic and extrinsic pathways mediate apoptosis during oogenesis and likely of aging eggs after fertilization.

The diagram presented in Figure 3.12 shows some of the signaling events that are initiated when tumor necrosis factor alpha (TNFα) leads to apoptosis. It should be noted that TNFα also mediates other signaling pathways involved in normal cellular functions. For TNF-mediated apoptosis the acronym TRAIL (tumor-necrosis factor-related apoptosis inducing ligand) is used to specify this function versus the factor’s other roles.

Figure 3.12. The signaling events initiated by TNFα binding.

The binding of TNFα to its receptor (TNF-receptor or TNFR) makes the receptor’s intracellular death domain available for binding to TRADD (TNFR-associated death domain). TRADD is an adaptor that in turn directs the binding of FADD (Fas-associated death domain), another adaptor that mediates the binding of pro-caspase-8 to this multiprotein complex. This leads to the proteolytic processing of the inactive pro-caspase-8 into the active caspase-8 enzyme. Caspase-8 is an initiator caspase that in turn proteolytically activates several other caspases. The activated caspases-3,6 and 7 are effector caspases that proteolytically digest a number of target proteins, ultimately leading to apoptosis. There are a number of other apoptosis-specific pathways, each of which involves unique sets of adaptor proteins and caspases and each of which is designed to direct apoptosis at a specific place or time in human development or other aspects of cell function.