membrane as a pre-formed homotrimer. FasL expression on the other hand is cell restricted and highly regulated. Like the other ligands in the superfamily, FasL is membrane-bound and subject to cleavage by metalloproteases. However, unlike other ligands, the soluble form of FasL does not appear to be functional and may even inhibit the membrane-bound FasL mediated apoptosis (soluble, trimeric Tfn triggers trimerization of the receptor; membrane-bound or soluble Trail are biologically active molecules that homotrimerize). It is thought that redistribution of Fas within membrane domains such as lipid rafts may induce an apoptotic signal independent of FasL; however FasL (or agonistic antibodies) has been shown to trigger apoptosis. The ligand-receptor interaction may involve multimerization and formation of an active DISC (death-inducing signaling complex) via DD mediated interaction with Fadd requires oligomerization and clustering. Via its second functional domain DED (death effector domain), Fadd recruits the initiator caspase Casp8 to the DISC where it is activated. While in human cells and in some cell lines Casp10 may also be recruited, Casp8 is the main initiator caspase which once activated, will in turn activate the effector/executioner caspases or the BH3-only protein Bid. Direct activation of effector/executioner caspases is characteristic of the so-called type I cells. Additional amplification via the intrinsic, mitochondrial, intrinsic apoptosis mediated through the activation of Bid is a feature of type II cells. However, the distinction between type I cells such as lymphocytes and type II such as hepatocytes in the FasL/Fas induced apoptosis is not clear. Cflar protein (known as Flip) can also be recruited to the DISC where it antagonizes the activation of Casp8. DED-DED interactions mediate the recruitment; the inhibition is thought to be due to competition for Fadd binding. There are several Cflar variants resulting from alternative mRNA splicing of which three are expressed at the protein level. Generally, Cflar has an anti-apoptotic effect. However, under certain circumstances one of the variants appears to actually promote FasL/Fas dependent apoptosis. FasL is mostly expressed in lymphocytes and the apoptotic pathway it promotes plays important roles in the immune system. To see the ontology report for annotations GViewer and download click here
[click to see related KEGG map - map04210 and associated entry at Reactome - REACT_900.1]...(less)