FAS signaling pathway

The Fas receptor (CD95) mediates apoptotic signaling by Fas-ligand (CD95L) expressed on the surface of other cells. It is one of the death receptors (DRs) which are members of the tumor necrosis factor (TNF) receptor superfamily that possesses a cytoplasmic death domain (DD). Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells express the proapoptotic death receptor, CD95 (Fas Receptor), as part of their armamentarium against infected or transformed cells. The apoptosis pathway induced by these DR ligands (Fas-ligands) is called the cell-extrinsic pathway. The Fas-FasL interaction plays an important role in the immune system and lack of this system leads to autoimmunity, indicating that Fas-mediated apoptosis removes self-reactive lymphocytes. Fas signaling is also involved in immune surveillance to remove transformed cells and virus infected cells.

Binding of the cognate homotrimeric receptors drives DR clustering and binding of DR to signaling adaptors including Fas-associated death domain (FADD) and Death-domain associated protein (DAXX), and then recruits caspase-8 and caspase-10, closely related apical proteases, to form the death-inducing signaling complex (DISC). The DISC mediates autocatalytic processing of caspases 8 and 10 and releases active enzyme into the cytoplasm. Active caspases 8 and 10 stimulate the executioner caspases 3, 6 and 7, which in turn cleave many cellular substrates, culminating in apoptotic cell death. In B cells, apoptosis requires further amplification by means of caspase-8-mediated processing of the Bcl-2–family protein Bid, which engages the cell-intrinsic mitochondrial pathway. Activation of JNK kinase, activation of Jun, and production of ceramide may also play roles in Fas-mediated apoptosis. The cellular FLICE inhibitory protein (c-FLIP) inhibit DR-mediated apoptosis by competing with caspase-8 for binding to FADD. Viruses and tumors may escape immune surveillance in part through suppression of fas-mediated apoptosis using similar mechanisms.

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Data source: KEGG, BioCarta