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Pathway Description
Apoptosis Signaling
Homo sapiens
Signaling Pathway
Created: 2025-03-11
Last Updated: 2025-08-28
Apoptosis is a highly regulated process of programmed cell death that is critical for maintaining tissue homeostasis and removing damaged or unwanted cells. It is triggered by both extrinsic and intrinsic signals, which converge on a central pathway involving a cascade of proteases, particularly caspases. In the extrinsic pathway, the process begins when Fas ligand (TNF superfamily member 6) binds to the Fas receptor (TNF receptor superfamily member 6) on the cell surface. This binding activates the Fas-associated death domain (FADD), which in turn activates Caspase-8. Caspase-8 then initiates the downstream caspase cascade by activating Caspase-3 and Caspase-7, leading to the execution of apoptosis. Similarly, TNF-related apoptosis-inducing ligand (TRAIL) also activates Fas receptor and triggers the same cascade, emphasizing the critical role of death receptors in the extrinsic pathway. The intrinsic pathway is activated by internal signals such as DNA damage, oxidative stress, or mitochondrial dysfunction. In this pathway, pro-apoptotic proteins like BAX and BAK1 are activated and translocate to the mitochondrial membrane, where they promote the release of cytochrome c into the cytosol. Cytochrome c binds to Apaf-1, forming the apoptosome complex, which activates Caspase-9. Activated Caspase-9 then triggers Caspase-3 and Caspase-7, leading to cellular degradation. Moreover, the anti-apoptotic proteins Bcl-2 and Bcl-XL normally inhibit BAX and BAK1, preventing mitochondrial membrane permeabilization. Under stress conditions, these inhibitors are neutralized, allowing apoptosis to proceed. Calcium ions play an essential role in apoptosis by activating various proteases. Calcium activates calpain-1, which further contributes to apoptosis by cleaving important substrates like Caspase-12, linking calcium signaling with endoplasmic reticulum stress. Additionally, calcium triggers the activation of BH3-interacting domain death agonist (BID), which enhances mitochondrial membrane permeabilization and facilitates cytochrome c release. This connects the intrinsic and extrinsic pathways, as BID is also cleaved by Caspase-8 in the extrinsic pathway, acting as a link between the two. The release of mitochondrial proteins such as cytochrome c and SMAC/DIABLO into the cytosol is a crucial step in both pathways. SMAC/DIABLO binds to and neutralizes inhibitors of apoptosis proteins (IAPs), such as baculoviral IAP repeat-containing 2 (BIRC2), facilitating the activation of caspases. Proteins like Granzyme B, released by cytotoxic T-cells, also promote apoptosis by directly activating Caspase-3 and Caspase-7. Furthermore, in the execution phase, Caspase-3 and Caspase-7 cleave structural components like Actin, Spectrin, and Lamin, causing cellular disintegration. Caspase-3 also cleaves Poly(ADP-ribose) polymerase (PARP), which is involved in DNA repair; its cleavage by Caspase-3 impairs DNA repair, promoting DNA fragmentation. This fragmentation is mediated by the DNA fragmentation factor (DFF), which translocates to the nucleus and cleaves DNA into oligonucleosome fragments, marking the final stages of apoptosis. Apoptosis is further regulated by several signaling molecules such as NF-kB, which can inhibit apoptosis by promoting cell survival pathways. However, under certain conditions, NF-kB can also contribute to pro-apoptotic signaling by activating caspases or promoting cytokine receptor signaling, which eventually leads to cell death. The translocation of various proteins such as BAX, BAK1, and Cytochrome c from the cytosol or mitochondria to the nucleus and other cellular compartments orchestrates the timing and execution of the apoptotic process.
References
Apoptosis Signaling References
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