Cell death extrinsic pathway

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

C. Both extrinsic and intrinsic pathways can lead to programmed cell death (Figure 14-8). 

Figure 14-8. Overview of pathways that regulate programmed cell death. Apoptosis may occur in response to signaling through either the extrinsic pathway or the intrinsic pathway. In each case, proteolytic cleavage activates an initiator caspase, caspase 8 or 9, either of which can cleave an effector caspase such as caspase 3. Apaf-1 is part of a large complex called the apoptosome that mediates the intrinsic pathway. Binding of an extracellular death ligand to its cell-surface receptor activates the extrinsic pathway.

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

Caspase activation occurs as a late and common step in all cells undergoing apoptosis. Nevertheless, there are many initial pathways that can result in caspase activation. Probably, each distinct pathway is triggered by different apoptotic stimuli. In mammalian cells, the apoptotic response is usually mediated by the intrinsic and extrinsic pathways, depending on the origin of the death signal. The intrinsic pathway can further be divided into mitochondrial and ER stress pathways. 

The extrinsic pathway consists of a series of events initially induced by death receptors located on the cell surface. It is initiated by interaction of extracellular death ligands with their respective receptors, located on the surface of the plasma membrane. The death ligands are members of the tumor necrosis factor (TNF)/nerve growth factor (NGF) superfamily. TNF-R1, Fas (Apo-l/CD95), TRAIL-R1, TRAIL-R2, and NGF-R are examples of death receptors. They are transmembrane proteins consisting of an external domain, where the ligand associates, and a cytoplasmic domain, which contains the DD (death domain). 

Signaling for apoptosis can be initiated from outside the cell (extrinsic or death receptor pathway) or from inside the cell (intrinsic or mitochondrial pathway) [31, 32]. In both pathways, signaling results in the activation of initiator caspases. Active initiator caspases then sequentially activate downstream effector caspases such as caspase -3, -6, and -7. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair... 

Extrinsic (death receptor) pathway of caspase activation during apoptosis involves the binding of death ligands to cell surface receptors (e.g., Fas/ CD95/Apo-l or TNF receptor), recruitment of adaptor molecules Fas-associated death domain (FADD) or TNF receptor-associated death domain (TRADD) to the cytosolic end of the receptor, and formation of the death-inducing signaling complex (DISC) at the plasma membrane. DISC recruits and activates the initiator caspases, caspase-8 or -10. 

Another important mechanism for promoting programmed cell death is the binding of ligands to the death receptors, which occurs in the extrinsic pathway (8) (Fig. 1). The death receptors recruit and activate caspase-8, which in turn regulates effector caspase-3 and caspase-7. Caspase-8 processes the Bcl-2 family member Bid, which collaborates with other members of the Bcl-2 family to induce cytochrome c release from the mitochondria and thereby activates the downstream intrinsic pathway (9). 

Figure 5.2. Apoptotic processes. Various critical cellular apoptotic integrated processes are schematically shown. The extrinsic and intrinsic pathways to apoptosis are shown (see text). All organs depend on the homeodynamic balance of cell synthesis and programmed cell death (apoptosis). See insert for color representation of this figure.

Fig. 15.3 The major pathways of apoptosis. The extrinsic pathway uses extracellular death ligands (Fas ligand, tumor necrosis factor (TNF)) to activate death receptors which pass the apoptotic signal to initiator caspases (e. g. capsase 8) and to the executioner caspases (e. g. caspase 3 caspase 7). In the execution phase of apoptosis, various cellular substrates are degraded leading to cellular collapse. The intrinsic pathway uses the mitochondria as a central component for activation of apoptosis. In this pathway, a multitude of intracellular signals including various stresses, DNA damage and inappropriate cell signaling lead to activation of the pro-apoptotic protein Bax which induces release of cytochrome c from mitochindria, formation of the apoptosome and activation of the initiator caspase 9. Finally, the executioner caspases are activated and cells are destructed by proteolysis. Apoptosis via this pathway can be controlled by various antiapoptotic proteins including the Bcl-2 protein and inhibitors of apoptosis.

Apoptosis is initiated by two principal pathways. The mitochondrial pathway is intrinsic and is activated from within the cell. The other pathway (see Section 15.6) is of an extrinsic nature and is initiated by external ligands that bind to and activate transmembrane receptors called death receptors. 

The execution of apoptotic cell death is mediated by the intrinsic and extrinsic apoptotic pathways (Fig. 2). Both of these pathways eventually converge, leading to activation of caspases, cysteine-dependent aspartyl-specific proteases that represent the effector arm of apoptotic signaling [12]. The intrinsic or mitochondrial pathway is initiated by developmental cues or cellular stress signals [13]. These signals activate Bcl-2-homology 3 (BH3) proteins leading to neutralization of the anti-apoptotic proteins Bcl-2, Bcl-xL or Mcl-1, activation of pro-apoptotic proteins, Bax and Bak, and subsequent disruption of mitochondrial membrane potential. Consequent release of cytochrome c from the mitochondria into the cytoplasm leads to Apaf-1-mediated caspase-9 activation, which in turn activates effector... 

Apoptosis can be induced in mammalian cells by a number of mechanisms, but only two pathways, both for activating caspases, have been elucidated in detail [13]. The death receptor or extrinsic pathway can be induced by members of the tumor necrosis factor (TNF) family of cytokine receptors such as TNFR1 (TNF receptor-1) and Fas. The TNF family of receptors use caspase activation as a signaling mechanism, connecting ligand binding at the cell surface to the induction of apoptosis... 

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