Fas ligand
Fas ligand (FasL or CD95L or CD178) is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer. Structure. Fas ligand or FasL is a homotrimeric type II transmembrane protein expressed on cytotoxic T lymphocytes. It signals through trimerization of FasR, which spans the membrane of the "target" cell. This trimerization usually leads to apoptosis, or cell death. Soluble Fas ligand is generated by cleaving membrane-bound  FasL at a conserved cleavage site by the external matrix metalloproteinase MMP-7. Cell signaling. Fas forms the death-inducing signaling complex (DISC) upon ligand binding. Membrane-anchored Fas ligand trimer on the surface of an adjacent cell causes trimerization of Fas receptor. This event is also mimicked by binding of an agonistic Fas antibody, though some evidence suggests that the apoptotic signal induced by the antibody is unreliable in the study of Fas signaling. To this end, several clever ways of trimerizing the antibody for in vitro research have been employed. Upon ensuing "death domain" (DD) aggregation, the receptor complex  is internalized via the cellular endosomal machinery. This allows the adaptor molecule "Fas-associated death domain" (FADD) to bind the death domain of Fas through its own death domain. FADD also contains a "death effector domain" (DED) near its amino terminus, which facilitates binding to the DED of FADD-like ICE (FLICE), more commonly referred to as caspase-8. FLICE can then self-activate through proteolytic cleavage into p10 and p18 subunits, of which two form the active heterotetramer enzyme. Active caspase-8 is then released from the DISC into the cytosol, where it cleaves other effector caspases, eventually leading to DNA  degradation, membrane blebbing, and other hallmarks of apoptosis. Some reports have suggested that the extrinsic Fas pathway is sufficient to induce complete apoptosis in certain cell types through DISC assembly and subsequent caspase-8 activation. These cells are dubbed Type 1 cells and are characterized by the inability of anti-apoptotic members of the Bcl-2 family (namely Bcl-2 and Bcl-xL) to protect from Fas-mediated apoptosis. Characterized Type 1 cells include H9, CH1, SKW6.4, and SW480, all of which are lymphocyte lineages except the latter, which is of the colon adenocarcinoma lineage. Evidence for crosstalk between the extrinsic and intrinsic  pathways exists in the Fas signal cascade. In most cell types, caspase-8 catalyzes the cleavage of the pro-apoptotic BH3-only protein Bid into its truncated form, tBid. BH-3 only members of the Bcl-2 family engage exclusively anti-apoptotic members of the family (Bcl-2, Bcl-xL), allowing Bak and Bax to translocate to the outer mitochondrial membrane, thus permeabilizing it and facilitating release of pro-apoptotic proteins such as cytochrome c and Smac/DIABLO, an antagonist of inhibitors of apoptosis proteins (IAPs). Soluble FasL is less active than its membrane-bound counterpart and does not induce receptor trimerization and DISC  formation. Functions. Apoptosis triggered by Fas-Fas ligand binding plays a fundamental role in the regulation of the immune system. Its functions include: Role in disease. Defective Fas-mediated apoptosis may lead to oncogenesis as well as drug resistance in existing tumors. Germline mutation of Fas is associated with autoimmune lymphoproliferative syndrome (ALPS), a childhood disorder of apoptosis. Increases in Fas-mediated signaling have been implicated in the pathology of low-risk myelodysplastic syndromes (MDS) and glioblastoma. More recently, FasL-mediated apoptosis of T cells has also been suggested as an immune-evasive mechanism by which tumors can suppress T  cell infiltration similar to inhibitory immune checkpoints such as PD-1 and CTLA-4. Clinical Significance. Therapeutic rationales for the suppression of Fas signaling in the context of glioblastoma and myelodysplastic syndromes (MDS) have led to the development of the Fas fusion protein asunercept (APG101) that is currently in clinical development for these indications. Interactions. Fas ligand has been shown to interact with: