regulation of extrinsic apoptotic signaling pathway

Definition

Target type: biologicalprocess

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

The extrinsic apoptotic signaling pathway, also known as the death receptor pathway, is triggered by external stimuli, primarily by the binding of specific ligands to death receptors on the cell surface. This pathway plays a crucial role in eliminating cells that are damaged, infected, or no longer needed, contributing to normal development and tissue homeostasis. Here's a detailed breakdown of the process:

1. **Ligand Binding and Receptor Trimerization:** The pathway is initiated when death receptor ligands, such as tumor necrosis factor alpha (TNFα), Fas ligand (FasL), or TRAIL (TNF-related apoptosis-inducing ligand), bind to their corresponding death receptors. These receptors belong to the tumor necrosis factor receptor (TNFR) superfamily, which includes TNFR1, Fas (CD95), and TRAIL receptors (DR4 and DR5). Ligand binding triggers the assembly of three death receptor molecules into a trimer, forming a death-inducing signaling complex (DISC).

2. **Recruitment of Adaptor Proteins:** The DISC serves as a platform for recruiting adaptor proteins, such as FADD (Fas-associated death domain) and TRADD (TNF receptor-associated death domain). These adaptor proteins contain death domains that interact with the death domains of both the death receptor and caspase-8.

3. **Caspase-8 Activation:** The recruitment of caspase-8 to the DISC leads to its activation. Caspase-8 is an initiator caspase, meaning it initiates the caspase cascade, a series of proteolytic events that ultimately lead to apoptosis. Caspase-8 activation can occur in two ways:
- **Direct activation:** In some cases, caspase-8 is directly activated within the DISC by autocatalytic cleavage.
- **Indirect activation:** In other cases, caspase-8 forms a complex with caspase-10, another initiator caspase, and this complex is then activated through autocatalytic cleavage.

4. **Activation of Executioner Caspases:** Once activated, caspase-8 cleaves and activates downstream executioner caspases, such as caspase-3, caspase-6, and caspase-7. These executioner caspases are responsible for the execution phase of apoptosis, triggering the dismantling of the cell.

5. **Apoptosis Execution:** Executioner caspases cleave a variety of cellular substrates, including proteins involved in DNA repair, cell cycle regulation, cytoskeleton integrity, and nuclear lamins. These cleavages lead to characteristic apoptotic features such as:
- **DNA fragmentation:** Caspase-activated DNase (CAD) is activated by executioner caspases, leading to cleavage of DNA into fragments of 180-200 base pairs.
- **Cell shrinkage and blebbing:** Caspases cleave cytoskeletal proteins, causing cell shrinkage and formation of blebs, small membrane-bound vesicles that detach from the cell.
- **Apoptotic body formation:** The cell eventually fragments into apoptotic bodies, which are engulfed by neighboring phagocytes, removing the cell without triggering inflammation.

6. **Regulation of Extrinsic Apoptotic Signaling:** The extrinsic apoptotic pathway is tightly regulated to prevent unwanted cell death and ensure appropriate elimination of damaged or unwanted cells. Several mechanisms contribute to this regulation:
- **Expression and localization of death receptors and ligands:** The expression and localization of both death receptors and their ligands are carefully controlled, limiting the activation of the pathway to specific cell types and contexts.
- **Inhibitory proteins:** Several inhibitory proteins can bind to death receptors, preventing ligand binding and blocking DISC formation. Examples include FLIP (FLICE-inhibitory protein), c-FLIP, and IAP (inhibitor of apoptosis protein) family members.
- **Cellular signaling pathways:** Various cellular signaling pathways can modulate the extrinsic apoptotic pathway, including NF-κB, MAPK, and PI3K/Akt pathways. These pathways can either promote or inhibit apoptosis, depending on the specific context.

7. **Therapeutic Implications:** The extrinsic apoptotic pathway is a major target for cancer therapy. TRAIL agonists, for example, can trigger apoptosis in tumor cells without affecting normal cells, demonstrating the therapeutic potential of targeting this pathway.

In summary, the extrinsic apoptotic signaling pathway is a highly regulated process that plays a critical role in maintaining cellular homeostasis and eliminating unwanted cells. The pathway is activated by the binding of specific ligands to death receptors, leading to a caspase cascade that culminates in apoptosis. Understanding the intricate mechanisms involved in the regulation of this pathway has significant implications for therapeutic interventions in various diseases, particularly cancer.'
"

Proteins (1)

Compounds (7)