extrinsic apoptotic signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals in which a signal is conveyed from the cell surface to trigger the apoptotic death of a cell. The pathway starts with either a ligand binding to a cell surface receptor, or a ligand being withdrawn from a cell surface receptor (e.g. in the case of signaling by dependence receptors), and ends when the execution phase of apoptosis is triggered. [GOC:mtg_apoptosis, GOC:yaf, PMID:17340152]

The extrinsic apoptotic signaling pathway, also known as the death receptor pathway, is a major mechanism of programmed cell death. It is triggered by external stimuli, such as the binding of death ligands to death receptors on the cell surface. These ligands include: TNF-alpha (tumor necrosis factor-alpha), FasL (Fas ligand), and TRAIL (TNF-related apoptosis-inducing ligand).

Upon ligand binding, death receptors trimerize and recruit adaptor proteins such as FADD (Fas-associated protein with death domain) and TRADD (TNF receptor-associated death domain). These adaptor proteins, in turn, recruit caspase-8, an initiator caspase, through their death domains. The recruitment of caspase-8 forms a death-inducing signaling complex (DISC), which activates caspase-8 by proteolytic cleavage.

Activated caspase-8 then triggers a caspase cascade, activating downstream effector caspases such as caspase-3, -6, and -7. These effector caspases cleave a variety of cellular substrates, leading to the dismantling of the cell and the formation of apoptotic bodies.

Here's a detailed breakdown of the steps involved:

1. **Ligand Binding:** The process begins with the binding of death ligands to their respective death receptors. This binding event initiates the formation of the death-inducing signaling complex (DISC).
2. **DISC Formation:** Death receptor trimerization brings together FADD and TRADD, which then recruit pro-caspase-8.
3. **Caspase-8 Activation:** Within the DISC, caspase-8 is activated by proteolytic cleavage. This activation is essential for the pathway's progression.
4. **Caspase Cascade:** Activated caspase-8 triggers a cascade of caspase activation, activating effector caspases like caspase-3, -6, and -7.
5. **Apoptotic Execution:** The activated effector caspases dismantle the cell through cleavage of various cellular substrates. This process includes DNA fragmentation, nuclear breakdown, and cytoskeletal dismantling.
6. **Formation of Apoptotic Bodies:** The cell breaks down into membrane-bound vesicles called apoptotic bodies, which are then engulfed by phagocytes, preventing inflammation.

The extrinsic apoptotic signaling pathway plays a crucial role in various physiological processes, including:

* **Immune system regulation:** It eliminates self-reactive immune cells, preventing autoimmune diseases.
* **Development:** It eliminates unnecessary cells during embryonic development and tissue remodeling.
* **Tumor suppression:** It eliminates pre-cancerous cells, acting as a barrier against tumor growth.

Dysregulation of the extrinsic apoptotic pathway can contribute to various diseases, including:

* **Cancer:** Defective apoptosis pathways can allow cancer cells to escape programmed cell death and proliferate unchecked.
* **Autoimmune diseases:** Inappropriate activation of the pathway can lead to the destruction of healthy cells by the immune system.
* **Neurodegenerative diseases:** Increased apoptosis in the brain can contribute to the loss of neurons observed in conditions like Alzheimer's disease.

Overall, the extrinsic apoptotic signaling pathway is a tightly regulated process that plays a vital role in maintaining cellular homeostasis and organismal health.'
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Proteins (16)

Compounds (494)