Molecular Determinants of Kinase Pathway Activation by Apo2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand

Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) mainly activates programmed cell death through caspases. By contrast, TNF primarily induces gene transcription through the inhibitor of κB kinase (IKK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. Apo2L/TRAIL also can stimulate these kinases, albeit less strongly; however, the underlying mechanisms of this stimulation and its relation to apoptosis are not well understood. Here we show that Apo2L/TRAIL activates kinase pathways by promoting the association of a secondary signaling complex, subsequent to assembly of a primary, death-inducing signaling complex (DISC). The secondary complex retained the DISC components FADD and caspase-8, but recruited several factors involved in kinase activation by TNF, namely, RIP1, TRAF2, and NEMO/IKKγ. Secondary complex formation required Fas-associated death domain (FADD), as well as caspase-8 activity. Apo2L/TRAIL stimulation of JNK and p38 further depended on RIP1 and TRAF2, whereas IKK activation required NEMO. Apo2L/TRAIL induced secretion of interleukin-8 and monocyte chemoattractant protein-1, augmenting macrophage migration. Thus, Apo2L/TRAIL and TNF organize common molecular determinants in distinct signaling complexes to stimulate similar kinase pathways. One function of kinase stimulation by Apo2L/TRAIL may be to promote phagocytic engulfment of apoptotic cells. Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) mainly activates programmed cell death through caspases. By contrast, TNF primarily induces gene transcription through the inhibitor of κB kinase (IKK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. Apo2L/TRAIL also can stimulate these kinases, albeit less strongly; however, the underlying mechanisms of this stimulation and its relation to apoptosis are not well understood. Here we show that Apo2L/TRAIL activates kinase pathways by promoting the association of a secondary signaling complex, subsequent to assembly of a primary, death-inducing signaling complex (DISC). The secondary complex retained the DISC components FADD and caspase-8, but recruited several factors involved in kinase activation by TNF, namely, RIP1, TRAF2, and NEMO/IKKγ. Secondary complex formation required Fas-associated death domain (FADD), as well as caspase-8 activity. Apo2L/TRAIL stimulation of JNK and p38 further depended on RIP1 and TRAF2, whereas IKK activation required NEMO. Apo2L/TRAIL induced secretion of interleukin-8 and monocyte chemoattractant protein-1, augmenting macrophage migration. Thus, Apo2L/TRAIL and TNF organize common molecular determinants in distinct signaling complexes to stimulate similar kinase pathways. One function of kinase stimulation by Apo2L/TRAIL may be to promote phagocytic engulfment of apoptotic cells. Members of the tumor necrosis factor (TNF) 2The abbreviations used are: TNFtumor necrosis factorTNFRTNF receptorAbantibodyApo2LApo2L ligandcIAPcellular inhibitor of apoptosis proteinDISCdeath-inducing signaling complexFADDFas-associated protein with death domainFasLFas ligandFBSfetal bovine serumGSTglutathione S-transferaseFLIPcellular FLICE inhibitory proteinIκBinhibitor of nuclear factor-κBJNKc-Jun amino-terminal kinaseNF-κBnuclear factor-κBRPMIRoswell Park Memorial InstitutesiRNAsmall interfering RNARIPreceptor interacting proteinTRADDTNF receptor-associated death domainTRAFTNF receptor-associated factorTRAILtumor necrosis factor-related apoptosis-inducing ligandzVADbenzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketoneIKKinhibitor of κB kinaseMAPKmitogen-activated protein kinaseMEFmouse embryo fibroblastSAPKstress-activated protein kinase; CHIIL-8interleukin-8IBimmunoblotMCP-1monocyte chemoattractant protein-1. superfamily regulate many physiological and pathological aspects of immune system development and function (reviewed in Refs. 1Smith C.A. Farrah T. Goodwin R.G. Cell. 1994; 76: 959-962Abstract Full Text PDF PubMed Scopus (1838) Google Scholar, 2Ashkenazi A. Dixit V.M. Science. 1998; 281: 1305-1308Crossref PubMed Scopus (5154) Google Scholar, 3Wallach D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1125) Google Scholar, 4Idriss H.T. Naismith J.H. Microsc. Res. Tech. 2000; 50: 184-195Crossref PubMed Scopus (662) Google Scholar, 5Locksley R.M. Killeen N. Lenardo M.J. Cell. 2001; 104: 487-501Abstract Full Text Full Text PDF PubMed Scopus (3018) Google Scholar). The TNF ligand superfamily is defined by structural similarity and ability to recognize corresponding TNF receptor (TNFR) superfamily members, which share homology in their extracellular, cysteine-rich domains. The intracellular domains of TNFRs are devoid of enzymatic activity: The majority contain an amino acid sequence motif that mediates interaction with TNFR-associated factors (TRAFs). Conversely, a minority of TNFRs share an intracellular “death domain” motif, which interacts with adaptor molecules that contain related death domains. The signaling activities and biological functions of the death-domain-containing TNFR subgroup are diverse. A key signaling activity of Fas, which binds to Fas ligand (FasL), and of DR4 and DR5, which bind to Apo2L/TRAIL, is apoptosis induction. On the other hand, TNFR1, which binds TNF and LT-α, primarily regulates transcription of pro-inflammatory and immunomodulatory genes and contributes to cell death signaling only in unique situations. tumor necrosis factor TNF receptor antibody Apo2L ligand cellular inhibitor of apoptosis protein death-inducing signaling complex Fas-associated protein with death domain Fas ligand fetal bovine serum glutathione S-transferase cellular FLICE inhibitory protein inhibitor of nuclear factor-κB c-Jun amino-terminal kinase nuclear factor-κB Roswell Park Memorial Institute small interfering RNA receptor interacting protein TNF receptor-associated death domain TNF receptor-associated factor tumor necrosis factor-related apoptosis-inducing ligand benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone inhibitor of κB kinase mitogen-activated protein kinase mouse embryo fibroblast stress-activated protein kinase; CHI interleukin-8 immunoblot monocyte chemoattractant protein-1. The apoptosis-signaling events that the death-inducing ligands FasL and Apo2L/TRAIL trigger are relatively well defined (reviewed in Refs. 6Ashkenazi A. Nat. Rev. Cancer. 2002; 2: 420-430Crossref PubMed Scopus (1108) Google Scholar, 7Peter M.E. Krammer P.H. Cell Death Differ. 2003; 10: 26-35Crossref PubMed Scopus (894) Google Scholar, 8LeBlanc H.N. Ashkenazi A. Cell Death Differ. 2003; 10: 66-75Crossref PubMed Scopus (755) Google Scholar). Binding of Fas, DR4, or DR5 by cognate ligand leads to conformational changes that promote interaction between the death domain of the receptor and the homologous region of the adaptor molecule Fas-associated death domain (FADD). FADD also contains a “death effector domain,” which mediates recruitment of two death effector domain-containing apical proteases: caspase-8 and caspase-10. This primary signaling complex, consisting of ligand, receptor, FADD, and apical caspase(s), is dubbed the death-inducing signaling complex (DISC) (9Kischkel F.C. Hellbardt S. Behrmann I. Germer M. Pawlita M. Krammer P.H. Peter M.E. EMBO J. 1995; 14: 5579-5588Crossref PubMed Scopus (1787) Google Scholar). Caspase-8 and -10 belong to the cysteine protease family, which plays a crucial role in programmed cell death. In living cells, caspase-8 and -10 are expressed as inactive precursors; in the DISC, these caspases become activated by oligomerization. Once activated, caspase-8 and -10 undergo proteolytic self-processing, in turn cleaving and activating downstream effector caspases, such as caspase-3, -6, and -7, which mediate the execution phase of apoptotic cell death R.M. C.A. J. Cell 1999; PubMed Scopus Google Scholar, J. Cell Death Differ. 2002; PubMed Scopus Google Scholar). In cell death receptor stimulation of caspase-8 and -10 effector activation to the cell to apoptotic death. In death further of the apoptosis This can be by of the The of activates the and which trigger of factors that promote activation of the apical protease In further effector of the cell death A cellular factor FLICE inhibitory protein which structural similarity to caspase-8 and -10 but can death apoptosis signaling J. M. M. Immunol. 1998; 10: PubMed Scopus Google Scholar). in and can apical recruitment to the DISC, whereas also can the of caspase-8 and In to the events by of FasL and Apo2L/TRAIL to their corresponding death TNF to leads to activation of the and p38 mitogen-activated protein kinase signaling pathways Science. 2002; PubMed Scopus Google Scholar). binds through its death domain to the adaptor molecule TNFR-associated death domain in turn binds two other RIP1, which also contains a death domain and mediates activation of the IKK and p38 and TRAF2, which activation of IKK and activates the by formation of the complex, in which the protein and two kinases, and are key components Kovalenko A. D. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). IKK activation in of the inhibitor of which in binds to and in the of to to the can promote gene two cellular inhibitor of apoptosis and to the complex, but the role of these in signaling In cellular TNF activates the and p38 kinase pathways but not apoptotic pathways. of several genes by TNF, and apoptosis however, such as of protein or of TNF can stimulate a (reviewed in Refs. J. M.J. 2003; PubMed Scopus Google and E.E. Ashkenazi A. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). by TNF on the formation of a secondary intracellular signaling complex, of RIP1, and TRAF2, as well as FADD and caspase-8 J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the signaling activity of FasL and Apo2L/TRAIL is apoptosis in cells, is the ability of these ligands to the and p38 pathways (reviewed in Refs. P.H. 2000; PubMed Scopus Google Scholar, A. Ashkenazi A. Rev. 2003; 14: PubMed Scopus Google Scholar, M. Krammer P.H. Immunol. 2003; PubMed Scopus Google Scholar, Ashkenazi A. PubMed Scopus Google Scholar, F.C. Cell Res. 14: PubMed Scopus Google Scholar, M. D. A. Full Text Full Text PDF PubMed Scopus Google Scholar). stimulation by FasL and Apo2L/TRAIL is of of the activity of this transcription a between activity and to death-inducing in cell of activity by molecular to cell death signaling by FasL and Apo2L/TRAIL (reviewed in Refs. J. M.J. 2003; PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar). the biological role and of kinase activation in the of apoptosis signaling by FasL and Apo2L/TRAIL are not well understood. in to the events stimulation by these the molecular determinants underlying their function with FADD or caspase-8 on apoptosis signaling and not kinase activation in M.E. A. M. A. Science. 1998; PubMed Scopus Google Scholar, E.E. M. N. D. V.M. T. D. T. T. D. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). of FADD or caspase-8 not with activation of or JNK by TNF, or Apo2L/TRAIL T. M. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In contrast, of cell with in FADD or caspase-8 an of these apoptosis as well as kinase activation by death receptor ligands J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Cell Differ. 1999; 10: Google Scholar, S. M. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, S. D. D. M. M. J. Cell PubMed Scopus Google Scholar). gene the of FADD and caspase-8 kinase activation by Apo2L/TRAIL not N. M. M. N. T. T. J. Full Text Full Text PDF PubMed Scopus Google Scholar). or a of and RIP1 in activation of JNK and by FasL and Apo2L/TRAIL S. D. D. M. M. J. Cell PubMed Scopus Google Scholar, N. M. M. N. T. T. J. Full Text Full Text PDF PubMed Scopus Google Scholar, J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, A. A. M. S. Cell 2000; PubMed Scopus Google Scholar). kinase activation by FasL and Apo2L/TRAIL to we in this to further of the molecular components and events that mediate this as to such as and RIP1 to with the Apo2L/TRAIL DR4 and DR5 in (reviewed in 2Ashkenazi A. Dixit V.M. Science. 1998; 281: 1305-1308Crossref PubMed Scopus (5154) Google Scholar). In and cells, RIP1 is with DR4 and DR5, in ligand and N. A. M. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). that between cellular components not recruitment of RIP1, or to the Apo2L/TRAIL DISC F.C. Cell Res. 14: PubMed Scopus Google Scholar, N. S. J. J. Nat. Cell 2000; 2: PubMed Scopus Google Scholar, F.C. A. Ashkenazi A. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Krammer P.H. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). we the formation of a secondary signaling complex subsequent to assembly of the Apo2L/TRAIL DISC and several components of this complex that are crucial kinase In we that kinase stimulation by Apo2L/TRAIL is with and macrophage that role of kinase activation by this ligand may be to promote the recruitment of to the of Cell and cells, cells, cells, cells, and cells, and the and mouse embryo by and by cell in and with and cell in Apo2L/TRAIL in or and as Ashkenazi A. J. Full Text Full Text PDF PubMed Scopus Google TNF the and and immunoblot the and DISC Cell and the secondary the and c-Jun protein Cell DISC, and Secondary with by and and the DISC as F.C. A. Ashkenazi A. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the of the secondary signaling complex, of the DISC, cell to of or by of FADD, caspase-8, or of by the and The used gene FADD, and RIP1, and and and and caspase-8, and and and TRAF2, and and and and and as Ashkenazi A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of p38 and and in the of gene as with and the by On the the with and in of In the gene with of Apo2L/TRAIL or In other with the ligand in the with a kinase inhibitor and by by immunoblot or and In and to the immunoblot and in kinase as Cell 17: PubMed Scopus Google Scholar). by by in of the and with Apo2L/TRAIL, or TNF used in the as in the Cell by as PubMed Scopus Google Scholar). of RNA Apo2L/TRAIL FasL or TNF by in a of of and and of and an the The of to in the The changes of stimulation as a of the to the by and in of of the with Apo2L/TRAIL or FasL or TNF in of the of the and the of and by a and a and a in and to the of to the with fetal serum a or with the or in the or with Apo2L/TRAIL in to the by that with apoptosis to Apo2L/TRAIL of its kinase activation this we several cell to death by Apo2L/TRAIL, or TNF the protein inhibitor The cell to of the whereas other cell these with the of as a system TNF signaling S. D. D. M. M. J. Cell PubMed Scopus Google Scholar, Cell. 2003; Full Text Full Text PDF PubMed Scopus Google we this cell further key in other cell by the and of kinase activation by death receptor ligands JNK activation by of and of its ability to p38 activation by immunoblot of cellular and activation by of and Apo2L/TRAIL or FasL of induced a of JNK with c-Jun activity and or TNF a activation of by and by Apo2L/TRAIL and FasL also activated p38 by or whereas TNF induced p38 activation by Apo2L/TRAIL and FasL also and protein By contrast, TNF induced and with of protein by its through that stimulation of p38 and required to Apo2L/TRAIL or FasL as with TNF of JNK activation a similar in not a of kinase we the of the gene Apo2L/TRAIL induced of as with of by TNF these show that Apo2L/TRAIL is of the and IKK kinase albeit less and less Apo2L/TRAIL of a Secondary by and J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google a primary complex that kinase TNF a secondary signaling complex that mediates apoptotic that Apo2L/TRAIL may in a DISC that activates caspases, and a secondary complex that activates kinase pathways. the that Apo2L/TRAIL induces assembly of a secondary signaling complex, we an of the DISC of through the ligand and these to an this to FADD, RIP1, TRAF2, or NEMO. with in N. S. J. J. Nat. Cell 2000; 2: PubMed Scopus Google Scholar, F.C. A. Ashkenazi A. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Krammer P.H. 2000; Full Text Full Text PDF PubMed Scopus Google of to cells, Apo2L/TRAIL the assembly of a DISC DR5 is not expressed in these FADD, and caspase-8, but not RIP1 RIP1, and also the DISC not of the with DR5 antibody the of DR5, DISC in the FADD of association of FADD with caspase-8 and RIP1 of RIP1 to FADD and interaction of with FADD, caspase-8, and association with and interaction with FADD and association with caspase-8 and RIP1 of these of Apo2L/TRAIL association with FADD, which a The interaction of RIP1 with FADD whereas the association of RIP1 with to of of or of TRAF2, or not that Apo2L/TRAIL induces the formation of a secondary signaling complex which DR5, but FADD and caspase-8, and RIP1, TRAF2, NEMO. of FADD, RIP1, and in by the of the secondary complex kinase we used to signaling FADD the of p38 and and of by Apo2L/TRAIL, but not by TNF A and of in a of the cell that not FADD J. Cell Differ. 1999; 10: Google further the of FADD activation by Apo2L/TRAIL but not by TNF In FADD but not FADD of cell death by Apo2L/TRAIL or TNF but not by the an and FADD as a adaptor kinase activation by TNF J. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar). is of with TNFR1, as well as with RIP1, TRAF2, and FADD, which bind to to in and other cell by mouse not the of this we to the of this adaptor in kinase activation by to the of RIP1 and in RIP1 is a death domain kinase that binds to in a and is activation of the and p38 pathways A. EMBO 2003; PubMed Scopus Google Scholar, S. J. N. Cell 2003; PubMed Scopus Google Scholar). that RIP1 contributes also to JNK activation by TNF A. EMBO 2003; PubMed Scopus Google Scholar). is also RIP1 in kinase activation by Apo2L/TRAIL or FasL S. D. D. M. M. J. Cell PubMed Scopus Google Scholar, A. A. M. S. Cell 2000; PubMed Scopus Google Scholar). RIP1 in not Apo2L/TRAIL stimulation of but of p38 and and RIP1 kinase activation by TNF, of p38 and and of RIP1 by Apo2L/TRAIL and TNF RIP1 also cell death by Apo2L/TRAIL or TNF, but not by Thus, RIP1 is p38 and IKK but JNK stimulation by binds to through and as a adaptor JNK activation by TNF A. D. J. A. D. N. M. Full Text Full Text PDF PubMed Scopus Google Scholar). is also stimulation by TNF, with T. S. T. S. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). with mouse embryo JNK activation by c-Jun by Apo2L/TRAIL, or TNF In to this of to of and in and in or A and the and molecular in the and as or with not or cell death in to Apo2L/TRAIL, or TNF and with the in cell a in Apo2L/TRAIL activation of caspase-8 and JNK signaling plays an role in the of cell death E.E. Ashkenazi A. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). that a signaling whereas plays an inhibitory role in apoptosis activation by TNF A. M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. Cell PubMed Scopus Google Scholar). with these of in cell whereas of not In contrast, of or or not cell death Thus, whereas JNK activity cell death by TNF but not by Apo2L/TRAIL, to the of of not the of to death by TNF or Apo2L/TRAIL that cell death by may be of and by JNK activity. Caspase-8 by with E.E. M. N. D. V.M. T. D. T. T. D. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Krammer P.H. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, H.N. S. Res. 2000; PubMed Scopus Google Scholar, A. EMBO J. 2002; PubMed Scopus Google of caspase-8 death by Apo2L/TRAIL or TNF, but not kinase activation A and of and and of caspase-8 less in or cells, these cell a less or in kinase activation a cell or in to Apo2L/TRAIL, whereas Caspase-8 in by Apo2L/TRAIL with a structural enzymatic caspase-8 activation of JNK and by FasL and Apo2L/TRAIL S. D. D. M. M. J. Cell PubMed Scopus Google Scholar). further the of enzymatic caspase-8 activity kinase stimulation by Apo2L/TRAIL, we used the inhibitor (OMe)-fluoromethyl ketone and of by the activation of caspase-8 by Apo2L/TRAIL of with Apo2L/TRAIL activation of JNK and p38 TNF stimulation of these and not in to Apo2L/TRAIL and TNF of these events and of the of on DISC assembly and association between DR5 and FADD that of activity by the In to its on the DISC, and formation of the secondary complex that caspase-8 activity is complex formation and kinase activation by further the of caspase-8 activity complex we of the that the molecule functions as an inhibitor of caspase-8 activation by Apo2L/TRAIL Ashkenazi A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). the of of on ligand activation of the in cells. with Apo2L/TRAIL of DISC recruitment and of caspase-8 in the Apo2L/TRAIL DISC cell death not also the of and by Apo2L/TRAIL, but on stimulation of these events by TNF of by Apo2L/TRAIL further to the that enzymatic caspase-8 activity is in the of contributes to the formation of a secondary signaling complex that mediates kinase activation by A by of activation by TNF is the of genes that can the apoptosis-inducing activity of TNF, the of TNF pro-inflammatory function E.E. Ashkenazi A. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). in activation by Apo2L/TRAIL the activity of this however, the of caspase-8 Apo2L/TRAIL stimulation of kinase pathways of this this we with TNF to stimulate kinase pathways and the ability of Apo2L/TRAIL to trigger cell death. TNF or of cell death by Apo2L/TRAIL in or cells, and Apo2L/TRAIL and that cell death by Apo2L/TRAIL the of kinase activation by these we that the stimulation of kinase pathways by Apo2L/TRAIL to to the apoptotic by this with this Apo2L/TRAIL induced of the and in in contrast, on of these in cells, which are to apoptosis by Apo2L/TRAIL TNF induced of of in cell with of in further the biological of the induced by Apo2L/TRAIL, we the activity of in a cell induced a in the of as with cells, whereas not macrophage that kinase activation by Apo2L/TRAIL secretion and macrophage the ability of the death-inducing ligands FasL and Apo2L/TRAIL to stimulate the and p38 pathways. of the this activity namely, in the of death receptor or cell death D. Varfolomeev E.E. Malinin N.L. Goltsev Y.V. Kovalenko A.V. Boldin M.P. Annu. Rev. Immunol. 1999; 17: 331-367Crossref PubMed Scopus (1125) Google Scholar, R.M. A. M. D. Ashkenazi A. Science. PubMed Scopus Google Scholar, M. T. N. J. Full Text Full Text PDF PubMed Scopus Google Scholar, D. T. T. N. 2001; PubMed Scopus Google Scholar). In the we used as a primary these are only to and to physiological of kinase Apo2L/TRAIL of induced not only cell death but also activation of and as in several other cell activation by Apo2L/TRAIL and stimulation by TNF, that the molecular determinants of kinase activation by these ligands or that the two ligands similar which organize in distinct signaling with the we that Apo2L/TRAIL not only a receptor-associated DISC, but also a secondary intracellular signaling complex molecules that are involved also in kinase activation by of DR5 by Apo2L/TRAIL to recruitment of FADD and caspase-8 to the receptor, a The Apo2L/TRAIL DISC not contain RIP1, TRAF2, or NEMO. of secondary intracellular by of the primary DISC of a complex that the ligand and receptor, but FADD, caspase-8, RIP1, TRAF2, and NEMO. also may be involved in this secondary complex, but we to this of immunoblot and Thus, TNF and Apo2L/TRAIL to trigger two related of intracellular TNF a primary complex that kinase activation and a secondary intracellular complex FADD and caspase-8 that apoptosis J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Apo2L/TRAIL, on the other hand, a primary complex that apoptosis and a secondary intracellular complex that kinase In association of the secondary complex on formation of the primary complex and of the primary complex the The secondary complex by Apo2L/TRAIL may complexes distinct The in and of the between FADD, RIP1, and in to Apo2L/TRAIL the of but this further that Apo2L/TRAIL FADD cell death and kinase of p38 and IKK by Apo2L/TRAIL depended on RIP1, whereas stimulation of JNK RIP1 with a to cell death. One this is that activation of p38 and IKK by Apo2L/TRAIL regulates cell death induction. TNF, which activates p38 and IKK not cell death by Apo2L/TRAIL, that RIP1 apoptosis of its in kinase RIP1 may apoptosis by the secondary Apo2L/TRAIL signaling complex, through interaction with J. Full Text Full Text PDF PubMed Scopus Google Scholar). caspase-8 activation by Apo2L/TRAIL Apo2L/TRAIL stimulation of p38 and IKK not In to p38 and IKK JNK enzymatic activity in this in JNK the and of and in the of in of the cell that c-Jun and activation of and whereas these by activity and c-Jun A. M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. Cell PubMed Scopus Google Scholar). Thus, the in activity in may of by to death by Apo2L/TRAIL, as well as This with in and in the of which that is not involved in of apoptosis signaling by Apo2L/TRAIL and FasL A. A. M. S. Cell 2000; PubMed Scopus Google Scholar). of promote apoptosis is well that activation by TNF the ability of TNF to cell death A. 2003; PubMed Scopus Google Scholar, S. M. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). with and with the inhibitory of on cell whereas this of or not the to TNF by that the of death signaling by not TNF, is a of JNK to apoptosis by Apo2L/TRAIL and of or not cell the to this ligand by these that to death apoptosis of JNK activation TNF of cell not the activity of In with J. J. 1998; Full Text Full Text PDF PubMed Scopus Google we that Apo2L/TRAIL caspase-8 not only of cell but also kinase a function or the enzymatic activity of caspase-8 to kinase of with an inactive caspase-8 to by FasL N. M. M. N. T. T. J. Full Text Full Text PDF PubMed Scopus Google a of caspase-8 enzymatic activity. Conversely, a inactive caspase-8 by death FADD, or caspase-8 A. A. 2000; PubMed Scopus Google a enzymatic activity. that of to which caspases, caspase-8, the Apo2L/TRAIL DISC, and assembly of the secondary or kinase activation by In of a molecule that recruitment and activation of caspase-8 the DISC Ashkenazi A. J. Full Text Full Text PDF PubMed Scopus Google kinase activation by that the enzymatic activity of caspase-8 is not only apoptosis but also kinase activation by not the that role of caspase-8 also may to kinase that FADD is retained in the secondary complex, is that caspase-8 activity of FADD the receptor, but this further stimulation by the TNF secondary signaling complex of activation by the TNF primary signaling complex J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). show by that activation by the primary signaling complex of Apo2L/TRAIL the formation of a secondary complex, which in turn leads to kinase One function of the secondary complex may be to the of activation by Apo2L/TRAIL through an activity of kinase activation is not a inhibitory and in cell may in apoptosis by In show that Apo2L/TRAIL induces kinase activation downstream of DISC assembly and caspase-8 activation by Apo2L/TRAIL is with of the and and with macrophage migration. the a Apo2L/TRAIL activates kinase pathways in with activation to promote of apoptotic Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). and the with