page_title: FADD
section_title: Extrinsic apoptosis
hierarchical_section_title: FADD / Functions / Extrinsic apoptosis
caption_attribution_description: English: Extrinsic apoptosis pathway:Extrinsic apoptosis pathway: The Fas receptor (FasR) is stimulated by Fas ligand (FasL), recruiting FADD to the FasR via an interaction between the death domains (DD) of both molecules. Procaspase 8 is recruited to FADD and interacts via the Death effector domains (DED) of both molecules. This results in the cleavage and activation of procaspase 8, forming caspase 8, which goes on to cleave and activate other caspases such as procaspase 3 to initiate the caspase cascade which leads to cell death.
context_page_description: Fas-associated protein with death domain, also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.
  FADD is an adaptor protein that bridges members of the tumor necrosis factor receptor superfamily, such as the Fas-receptor, to procaspases 8 and 10 to form the death-inducing signaling complex during apoptosis. As well as its most well known role in apoptosis, FADD has also been seen to play a role in other processes including proliferation, cell cycle regulation and development.
context_section_description: Upon stimulation by the Fas ligand, the Fas receptor trimerises. Many receptors, including Fas, contain a cytoplasmic DD and are therefore named death receptors. FADD binds to the DD of this trimeric structure via its death domain  resulting in unmasking of FADD's DED and subsequent recruitment of procaspase 8 and 10 via an interaction between the DEDs of both FADD and the procaspases. This generates a complex known as the death inducing signalling complex (DISC). Procaspase 8 and 10 are known as initiator caspases. These are inactive molecules, but when bought into close proximity with other procaspases of the same type, autocatalytic cleavage occurs at an aspartate residue within their own structures, resulting in an activated protein. This activated protein can then go on to cleave and activate further caspases, initiating the caspase cascade. The activated caspases can go on to cleave intracellular proteins such as inhibitor of caspase-activated DNase (ICAD), which ultimately leads to apoptosis of the cell.
  Binding of TRAIL to death receptors four and five (DR4 and DR5) can lead to apoptosis by the same mechanism.
  Apoptosis can also be triggered by binding of a ligand to tumor necrosis factor receptor 1 (TNFR1); however, the mechanism by which this occurs is slightly more complex. Another DD-containing adaptor protein named TRADD, along with other proteins, binds to activated TNF1R, forming what is known as complex I.  This results in activation of the NFκB pathway, which promotes cell survival. This complex is then internalised, and FADD binds to TRADD via an interaction of the DD’s of the two adapter proteins, forming what is known as complex II.  FADD again recruits procaspase 8, which initiates the caspase cascade leading to apoptosis.
caption: Extrinsic apoptosis pathway: The Fas receptor (FasR) is stimulated by Fas ligand (FasL), recruiting FADD to the FasR via an interaction between the death domains (DD) of both molecules. Procaspase 8 is recruited to FADD and interacts via the death effector domains (DED) of both molecules. This results in the cleavage and activation of procaspase 8, forming caspase 8, which goes on to cleave and activate other caspases such as procaspase 3 to initiate the caspase cascade which leads to cell death.
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