negative regulation of extrinsic apoptotic signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of extrinsic apoptotic signaling pathway. [GOC:mtg_apoptosis]

Negative regulation of extrinsic apoptotic signaling pathway involves a complex interplay of cellular mechanisms that actively suppress the activation of the death receptor pathway, preventing the initiation of programmed cell death. This intricate process involves the following key steps:

1. **Ligand Binding and Receptor Clustering:** The extrinsic apoptotic signaling pathway is initiated by the binding of death ligands, such as TNF-α, FasL, and TRAIL, to their corresponding death receptors (TNFR1, Fas, and TRAIL-R1/2, respectively). This binding event triggers receptor trimerization and the formation of a death-inducing signaling complex (DISC).
2. **Recruitment of Adaptor Proteins:** The DISC serves as a platform for the recruitment of adaptor proteins, including FADD (Fas-associated death domain) and TRADD (TNF receptor-associated death domain). These adaptor proteins possess death domains that mediate interactions with other proteins involved in the apoptotic cascade.
3. **Activation of Caspases:** FADD and TRADD, once recruited to the DISC, bind and activate caspase-8, an initiator caspase. Caspase-8 is a proteolytic enzyme that cleaves and activates downstream effector caspases, such as caspase-3 and caspase-7.
4. **Negative Regulation by Anti-Apoptotic Proteins:** To prevent uncontrolled apoptosis, cells employ a variety of anti-apoptotic proteins that act to inhibit the extrinsic pathway. These proteins include:
* **FLIP (FLICE-inhibitory protein):** FLIP is a caspase-8 homolog that lacks proteolytic activity. It competes with caspase-8 for binding to FADD, preventing the formation of an active DISC and caspase-8 activation.
* **c-FLIP:** c-FLIP is another anti-apoptotic protein that inhibits caspase-8 activation by forming inactive complexes with FADD and caspase-8.
* **NF-κB (nuclear factor kappa B):** NF-κB is a transcription factor that is activated by TNF-α and other stimuli. NF-κB induces the expression of anti-apoptotic genes, including c-FLIP, Bcl-2, and IAPs (inhibitor of apoptosis proteins), thereby promoting cell survival.
* **IAPs (inhibitor of apoptosis proteins):** IAPs directly bind to and inhibit caspase-3 and caspase-7, preventing the execution of apoptosis.
5. **Regulation by Cellular Context:** The decision to activate or suppress the extrinsic apoptotic pathway is influenced by a variety of cellular factors, including the type and concentration of the death ligand, the expression levels of death receptors and anti-apoptotic proteins, and the overall cellular stress status.

In summary, negative regulation of the extrinsic apoptotic signaling pathway involves a delicate balance between pro- and anti-apoptotic signals. This complex interplay ensures that apoptosis is triggered only when necessary, preventing uncontrolled cell death and maintaining cellular homeostasis.'
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Proteins (16)

Compounds (598)