Fas ligand

Fas ligand (FasL or is_associated_with::CD95L) is a type-II is_associated_with::transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces is_associated_with::apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the is_associated_with::immune system and the progression of is_associated_with::cancer.

Structure
Fas ligand or FasL is a is_associated_with::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 is_associated_with::matrix metalloproteinase MMP-7.

Receptors

 * FasR: The is_associated_with::Fas receptor (is_associated_with::FasR), or is_associated_with::CD95, is the most intensely studied member of the death receptor family. The gene is situated on chromosome 10 in humans and 19 in mice. Previous reports have identified as many as eight splice variants, which are translated into seven isoforms of the protein.  Many of these isoforms are rare is_associated_with::haplotypes that are usually associated with a state of disease. Apoptosis-inducing Fas receptor is dubbed isoform 1 and is a type 1 is_associated_with::transmembrane protein. It consists of three is_associated_with::cysteine-rich pseudorepeats, a transmembrane domain, and an intracellular death domain.


 * DcR3: Decoy receptor 3 (is_associated_with::DcR3) is a recently discovered decoy receptor of the tumor necrosis factor superfamily that binds to FasL, is_associated_with::LIGHT, and is_associated_with::TLA1. DcR3 is a soluble receptor that has no is_associated_with::signal transduction capabilities (hence a "decoy") and functions to prevent is_associated_with::FasR-FasL interactions by competitively binding to membrane-bound Fas ligand and rendering them inactive.

Cell signalling
Fas forms the is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::death effector domain (DED) near its amino terminus, which facilitates binding to the DED of is_associated_with::FADD-like ICE (is_associated_with::FLICE), more commonly referred to as is_associated_with::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 is_associated_with::Bcl-2 family (namely Bcl-2 and is_associated_with::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 is_associated_with::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
is_associated_with::Apoptosis triggered by Fas-Fas ligand binding plays a fundamental role in the regulation of the is_associated_with::immune system. Its functions include:
 * is_associated_with::T-cell is_associated_with::homeostasis: the activation of is_associated_with::T-cells leads to their expression of the Fas ligand. T cells are initially resistant to Fas-mediated apoptosis during clonal expansion, but become progressively more sensitive the longer they are activated, ultimately resulting in is_associated_with::activation-induced cell death (AICD). This process is needed to prevent an excessive immune response and eliminate autoreactive T-cells. Humans and mice with deleterious mutations of Fas or Fas ligand develop an accumulation of aberrant T-cells, leading to is_associated_with::lymphadenopathy, is_associated_with::splenomegaly, and is_associated_with::lupus erythematosus.
 * is_associated_with::Cytotoxic T-cell activity: Fas-induced is_associated_with::apoptosis and the is_associated_with::perforin pathway are the two main mechanisms by which is_associated_with::cytotoxic T lymphocytes induce cell death in cells expressing foreign antigens.
 * is_associated_with::Immune privilege: Cells in immune privileged areas such as the is_associated_with::cornea or is_associated_with::testes express Fas ligand and induce the apoptosis of infiltrating is_associated_with::lymphocytes. It is one of many mechanisms the body employs in the establishment and maintenance of immune privilege.
 * Maternal tolerance: Fas ligand may be instrumental in the prevention of is_associated_with::leukocyte trafficking between the mother and the fetus, although no pregnancy defects have yet been attributed to a faulty Fas-Fas ligand system.
 * Tumor counterattack: Tumors may over-express Fas ligand and induce the is_associated_with::apoptosis of infiltrating is_associated_with::lymphocytes, allowing the tumor to escape the effects of an is_associated_with::immune response. The up-regulation of Fas ligand often occurs following is_associated_with::chemotherapy, from which the tumor cells have attained is_associated_with::apoptosis resistance.

Role in disease
Defective Fas-mediated apoptosis may lead to is_associated_with::oncogenesis as well as drug resistance in existing tumors. Germline mutation of Fas is associated with is_associated_with::autoimmune lymphoproliferative syndrome (ALPS), a childhood disorder of apoptosis.

Interactions
Fas ligand has been shown to interact with:


 * CASP8,
 * EZR,
 * is_associated_with::FADD,
 * is_associated_with::FNBP1,
 * is_associated_with::FYN,
 * FAS,
 * is_associated_with::Grb2,
 * is_associated_with::PACSIN2, and
 * is_associated_with::TNFRSF6B.