href="http://pfam.janelia.org/family/PF02754">cysteine-rich domain) characteristic of the receptor superfamily. Two other receptors, while homologous to the apoptosis-inducing ones, lack a functional intracellular DD; a decoy function for these receptors has only been shown in overexpression studies. The fifth receptor is the secreted osteoprotegerin with low affinity for Tnfsf10; the role of this interaction, if any, remains to be determined. Tnfsf10 is a type II transmembrane protein which can be cleaved by metalloproteases. Both the soluble and the membrane-bound protein are biologically active molecules that homotrimerize. Binding to the R1 and R2 receptors, known as Dr4 and 5, (official symbols TNFSR10A and B, rodents only express B), results in conformational changes leading to recruitment of Fadd adapter protein and formation of DISC (death-inducing signaling complex). The two receptors appear to exist as preassembled oligomers but ligand-induced trimerization has also been reported. Fadd interacts with the receptors via its own DD domain; a second functional domain DED (death effector domain) mediates the recruitment of the initiator caspase Casp8 and when present, Casp10 to the DISC where they are activated. The molecular mechanism of caspase activation at the DISC is not well understood; three models currently attempt to explain it. Activated Casp8 can then activate the effector/executioner caspases; this is the case in type I cells. In type II cells, amplification via the intrinsic, mitochondrial pathway is necessary for full activation of the executioner caspases. In this case, activated Casp8 cleaves Bid to the active t-Bid form. Bid is a member of the pro-apoptotic BH3-only group of the Bcl family. 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. Differential expression of Trail, its receptors and/or regulatory proteins such as Cflar has been associated with resistance to Trail mediated apoptosis in certain cancers. Mutations within the death domain of the receptors or deletions within the region containing the receptor genes have also been reported for certain lymphomas. Unlike other death receptor ligands, Trail mediated apoptosis has anti-tumor activity while leaving normal cells unaffected. Soluble recombinant human Trail and agonistic monoclonal antibodies for the two receptors have been produced; some are subjects of phase I and II clinical trials. 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_402.1]...(less)