id: PW:0000682 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000682 title: trail mediated signaling pathway description_xrefs: - KEGG:map04210 description: Trail mediated signaling is one of the major extrinsic apoptotic pathways engaging the death receptors. Trail, also known as Apo2L (official symbol Tnfsf10) and its receptors belong to the tumor necrosis superfamily (TNF) of ligands and receptors. Of the five receptors that can bind Tnfsf10, only two can induce apoptosis; they both contain the DD domain ( death domain ) in their cytoplasmic part while the extracellular part contains the CCG (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. diagram_image: https://rgd.mcw.edu/pathway/PW0000682/Trail%20mediated%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000682/Trail%20mediated%20signaling%20pathway/Trail%20mediated%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000104 label: intrinsic apoptotic pathway diagram_gene_links: - id: RGD:620160 label: Bid - id: RGD:2275 label: Casp3 - id: RGD:620944 label: Casp7 - id: RGD:620945 label: Casp8 - id: RGD:620847 label: Cflar - id: RGD:628700 label: Fadd - id: RGD:1308041 label: Tnfrsf10b - id: RGD:628734 label: Tnfsf10 diagram_chemicals: [] diagram_edges: - source: Casp3 relation: positively_affects target: caspase targets - source: Casp7 relation: positively_affects target: caspase targets - source: Casp8 relation: associated_with target: Fadd - source: Casp8 relation: positively_affects target: Bid - source: Casp8 relation: positively_affects target: Casp3 - source: Casp8 relation: positively_affects target: Casp7 - source: Cflar relation: associated_with target: Fadd - source: Cflar relation: negatively_affects target: Casp8 - source: Fadd relation: associated_with target: TNFRSF10A - source: Fadd relation: associated_with target: Tnfrsf10b - source: TNFRSF10A relation: associated_with target: Tnfsf10 - source: Tnfrsf10b relation: associated_with target: Tnfsf10 diagram_labels: - Casp8 --+> Bid - Casp8 --+> Casp3 - Casp8 --+> Casp7 diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/caspase-targets label: caspase targets references: - id: RGD:4143170 citation: Falschlehner C, etal., Int J Biochem Cell Biol. 2007;39(7-8):1462-75. Epub 2007 Feb 14. - id: RGD:4143171 citation: Pennarun B, etal., Biochim Biophys Acta. 2010 Apr;1805(2):123-40. Epub 2009 Dec 2. - id: RGD:5129731 citation: Fesik SW Cell. 2000 Oct 13;103(2):273-82. - id: RGD:5129769 citation: Fischer U, etal., Cell Death Differ. 2003 Jan;10(1):76-100. - id: RGD:5129784 citation: Danial NN and Korsmeyer SJ, Cell. 2004 Jan 23;116(2):205-19. - id: RGD:5129806 citation: Jin Z and El-Deiry WS, Cancer Biol Ther. 2005 Feb;4(2):139-63. Epub 2005 Feb 27. - id: RGD:5129909 citation: Luthi AU and Martin SJ, Cell Death Differ. 2007 Apr;14(4):641-50. Epub 2007 Feb 2. - id: RGD:5129929 citation: Thorburn A J Thorac Oncol. 2007 Jun;2(6):461-5. - id: RGD:5129980 citation: Yang JK Yonsei Med J. 2008 Feb 29;49(1):19-27. - id: RGD:5130017 citation: Johnstone RW, etal., Nat Rev Cancer. 2008 Oct;8(10):782-98. - id: RGD:5130043 citation: Guicciardi ME and Gores GJ, FASEB J. 2009 Jun;23(6):1625-37. Epub 2009 Jan 13. - id: RGD:5130114 citation: Testa U J Cell Biochem. 2010 May;110(1):21-34. - id: RGD:5130125 citation: Tourneur L and Chiocchia G, Trends Immunol. 2010 Jul;31(7):260-9. Epub 2010 Jun 25.