Apo2L/TRAIL-Dependent Recruitment of Endogenous FADD and Caspase-8 to Death Receptors 4 and 5
Open accessAbstract
Fas (APO-1/CD95) and tumor necrosis factor receptor 1 (TNFR1) trigger apoptosis by recruiting the apoptosis initiator caspase-8 through the adaptor FADD. Fas binds FADD directly, whereas TNFR1 binds FADD indirectly, through TRADD. TRADD alternatively recruits the NF-kappaB-inducing adaptor RIP. The TNF homolog Apo2L/TRAIL triggers apoptosis through two distinct death receptors, DR4 and DR5; however, receptor over-expression studies have yielded conflicting results on the ligand's signaling mechanism. Apo2L/TRAIL induced homomeric and heteromeric complexes of DR4 and DR5 and stimulated recruitment of FADD and caspase-8 and caspase-8 activation in nontransfected cells. TRADD and RIP, which bound TNFR1, did not bind DR4 and DR5. Thus, Apo2L/TRAIL and FasL initiate apoptosis through similar mechanisms, and FADD may be a universal adaptor for death receptors.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
FAS and TRAILR ligands stabilize preformed receptor homotrimers to induce a conformational change enabling DD-dependent FADD association.
“In the case of FAS and TRAILRs, the cognate ligands—namely, FAS ligand (FASLG; also known as CD95L or APO-1L) and TNF superfamily member 10 (TNFSF10; best known as TRAIL), respectively—stabilize preformed receptor homotrimers to induce a conformational change at their intracellular tails that enables the death domain (DD)-dependent association of the adapter Fas associated via death domain (FADD)”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [279]
Cites
Thornberry, N. A., & Lazebnik, Y. A. (1998) · Science · doi:10.1126/science.281.5381.1312 · Cited by 6,857 · see citing works
Death Receptors: Signaling and Modulation
Ashkenazi, A., & Dixit, V. M. (1998) · Science · doi:10.1126/science.281.5381.1305 · Cited by 5,866 · see citing works
Self-citationNagata, S. (1997) · Cell · doi:10.1016/s0092-8674(00)81874-7 · Cited by 4,908 · see citing works
Nicoletti, I., Migliorati, G., Pagliacci, M. C., Grignani, F., & Riccardi, C. (1991) · Journal of Immunological Methods · doi:10.1016/0022-1759(91)90198-o · Cited by 4,580 · see citing works
Identification and characterization of a new member of the TNF family that induces apoptosis
Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C.-P., Nicholl, J. K., Sutherland, G. R., Smith, T. D., Rauch, C., Smith, C. A., et al. (1995) · Immunity · doi:10.1016/1074-7613(95)90057-8 · Cited by 2,900 · see citing works
Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo.
Walczak, H., Miller, R. E., Ariail, K., Gliniak, B., Griffith, T. S., Kubin, M., Chin, W., Jones, J., Woodward, A., Le, T., et al. (1999) · Nature Medicine · doi:10.1038/5517 · Cited by 2,497 · see citing works
Safety and antitumor activity of recombinant soluble Apo2 ligand
Ashkenazi, A., Pai, R. C., Fong, S., Leung, S., Lawrence, D. A., Marsters, S. A., Blackie, C., Chang, L., McMurtrey, A. E., Hebert, A., et al. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6926 · Cited by 2,213 · see citing works
Self-citationKischkel, F. C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P. H., & Peter, M. E. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00245.x · Cited by 2,181 · see citing works
Self-citationInduction of Apoptosis by Apo-2 Ligand, a New Member of the Tumor Necrosis Factor Cytokine Family
Pitti, R. M., Marsters, S. A., Ruppert, S., Donahue, C. J., Moore, A., & Ashkenazi, A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.22.12687 · Cited by 1,777 · see citing works
Self-citationThe Receptor for the Cytotoxic Ligand TRAIL
Pan, G., O’Rourke, K. M., Chinnaiyan, A. M., Gentz, R., Ebner, R., Ni, J., & Dixit, V. M. (1997) · Science · doi:10.1126/science.276.5309.111 · Cited by 1,755 · see citing works
Control of TRAIL-Induced Apoptosis by a Family of Signaling and Decoy Receptors
Sheridan, J. P., Marsters, S. A., Pitti, R. M., Gurney, A. L., Skubatch, M., Baldwin, D. T., Ramakrishnan, L., Gray, C. L., Baker, K. P., Wood, W. I., et al. (1997) · Science · doi:10.1126/science.277.5327.818 · Cited by 1,664 · see citing works
Self-citationAn Antagonist Decoy Receptor and a Death Domain-Containing Receptor for TRAIL
Pan, G., Ni, J., Wei, Y.-F., Yu, G.-L., Gentz, R., & Dixit, V. M. (1997) · Science · doi:10.1126/science.277.5327.815 · Cited by 1,486 · see citing works
Varfolomeev, E., Schuchmann, M., Luria, V., Chiannilkulchai, N., Beckmann, J., Mett, I., Rebrikov, D., Brodianski, V. M., Kemper, O., Kollet, O., et al. (1998) · Immunity · doi:10.1016/s1074-7613(00)80609-3 · Cited by 1,332 · see citing works
TUMOR NECROSIS FACTOR RECEPTOR AND Fas SIGNALING MECHANISMS
Wallach, D., Varfolomeev, E. E., Malinin, N. L., Goltsev, Y. V., Kovalenko, A. V., & Boldin, M. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.331 · Cited by 1,299 · see citing works
Apoptosis control by death and decoy receptors
Ashkenazi, A., & Dixit, V. M. (1999) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(99)80034-9 · Cited by 1,281 · see citing works
Self-citationFLICE is activated by association with the CD95 death‐inducing signaling complex (DISC)
Medema, J. P., Scaffidi, C., Kischkel, F. C., Shevchenko, A., Mann, M., Krammer, P. H., & Peter, M. E. (1997) · The EMBO Journal · doi:10.1093/emboj/16.10.2794 · Cited by 1,189 · see citing works
Self-citationOsteoprotegerin Is a Receptor for the Cytotoxic Ligand TRAIL
Emery, J. G., McDonnell, P., Burke, M. B., Deen, K. C., Lyn, S. D., Silverman, C., Dul, E., Appelbaum, E. R., Eichman, C., DiPrinzio, R., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.23.14363 · Cited by 1,183 · see citing works
TRAIL‐R2: a novel apoptosis‐mediating receptor for TRAIL
Walczak, H., Degli‐Esposti, M. A., Johnson, R. S., Smolak, P. J., Waugh, J. Y., Boiani, N., Timour, M. S., Gerhart, M. J., Schooley, K. A., Smith, C. A., et al. (1997) · The EMBO Journal · doi:10.1093/emboj/16.17.5386 · Cited by 1,130 · see citing works
KILLER/DR5 is a DNA damage–inducible p53–regulated death receptor gene
Wu, G. S., Burns, T. F., McDonald, E. R., Jiang, W., Meng, R., Krantz, I. D., Kao, G., Gan, D.-D., Zhou, J.-Y., Muschel, R. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1097-141 · Cited by 1,081 · see citing works
FADD: Essential for Embryo Development and Signaling from Some, But Not All, Inducers of Apoptosis
Yeh, W., de la Pompa, J. L., McCurrach, M. E., Shu, H., Elia, A., Shahinian, A., Ng, M. S. W., Wakeham, A. C., Khoo, W., Mitchell, K., et al. (1998) · Science · doi:10.1126/science.279.5358.1954 · Cited by 886 · see citing works
Daxx, a Novel Fas-Binding Protein That Activates JNK and Apoptosis
Yang, X., Khosravi‐Far, R., Chang, H. Y., & Baltimore, D. (1997) · Cell · doi:10.1016/s0092-8674(00)80294-9 · Cited by 830 · see citing works
The Role of c-FLIP in Modulation of CD95-induced Apoptosis
Scaffidi, C., Schmitz, I., Krammer, P. H., & Peter, M. E. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.3.1541 · Cited by 819 · see citing works
Degli‐Esposti, M. A., Dougall, W. C., Smolak, P. J., Waugh, J. Y., Smith, C. A., & Goodwin, R. G. (1997) · Immunity · doi:10.1016/s1074-7613(00)80399-4 · Cited by 815 · see citing works
Zhang, J., Cado, D., Chen, A., Kabra, N., & Winoto, A. (1998) · Nature · doi:10.1038/32681 · Cited by 792 · see citing works
Chaudhary, P. M., Eby, M. T., Jasmin, A., Bookwalter, A., Murray, J. M., & Hood, L. (1997) · Immunity · doi:10.1016/s1074-7613(00)80400-8 · Cited by 712 · see citing works
TRAIL Receptors 1 (DR4) and 2 (DR5) Signal FADD-Dependent Apoptosis and Activate NF-κB
Schneider, P., Thome, M., Burns, K., Bodmer, J.-L., Hofmann, K., Kataoka, T., Holler, N., & Tschopp, J. (1997) · Immunity · doi:10.1016/s1074-7613(00)80401-x · Cited by 697 · see citing works
Downregulation of Fas ligand by shedding
Tanaka, M., Itai, T., Adachi, M., & Nagata, S. (1998) · Nature Medicine · doi:10.1038/nm0198-031 · Cited by 666 · see citing works
Intracellular Regulation of TRAIL-Induced Apoptosis in Human Melanoma Cells
Griffith, T. S., Chin, W. A., Jackson, G. C., Lynch, D. H., & Kubin, M. Z. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.6.2833 · Cited by 663 · see citing works
A novel receptor for Apo2L/TRAIL contains a truncated death domain
Marsters, S. A., Sheridan, J. P., Pitti, R. M., Huang, A. J. Y., Skubatch, M., Baldwin, D. T., Yuan, J., Gurney, A. L., Goddard, A. D., Godowski, P. J., et al. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00422-2 · Cited by 654 · see citing works
Self-citationWang, J., Zheng, L., Lobito, A. A., Chan, F. K.-M., Dale, J. K., Sneller, M. C., Xu, Y., Puck, J. M., Straus, S. E., & Lenardo, M. J. (1999) · Cell · doi:10.1016/s0092-8674(00)80605-4 · Cited by 639 · see citing works
Cloning and Characterization of TRAIL-R3, a Novel Member of the Emerging TRAIL Receptor Family
Degli‐Esposti, M. A., Smolak, P. J., Walczak, H., Waugh, J. Y., Huang, C.-P., DuBose, R. F., Goodwin, R. G., & Smith, C. A. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.7.1165 · Cited by 630 · see citing works
Identification and Molecular Cloning of Two Novel Receptors for the Cytotoxic Ligand TRAIL
MacFarlane, M., Ahmad, M., Srinivasula, S. M., Fernandes‐Alnemri, T., Cohen, G. M., & Alnemri, E. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.41.25417 · Cited by 558 · see citing works
Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade
Juo, P., Kuo, C. J., Yuan, J., & Blenis, J. (1998) · Current Biology · doi:10.1016/s0960-9822(07)00420-4 · Cited by 524 · see citing works
Newton, K., Harris, A. W., Bath, M. L., Smith, K. G. C., & Strasser, A. (1998) · The EMBO Journal · doi:10.1093/emboj/17.3.706 · Cited by 499 · see citing works
Monocyte-mediated Tumoricidal Activity via the Tumor Necrosis Factor–related Cytokine, TRAIL
Griffith, T. S., Wiley, S. R., Kubin, M. Z., Sedger, L. M., Maliszewski, C. R., & Fanger, N. A. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.189.8.1343 · Cited by 477 · see citing works
Tumor necrosis factor ligand superfamily: involvement in the pathology of malignant lymphomas
Gruss, H., & Dower, S. (1995) · Blood · doi:10.1182/blood.v85.12.3378.bloodjournal85123378 · Cited by 457 · see citing works
Hymowitz, S. G., Christinger, H. W., Fuh, G., Ultsch, M. H., O'Connell, M., Kelley, R. F., Ashkenazi, A., & de Vos, A. M. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80207-5 · Cited by 434 · see citing works
Self-citationFLICE Is Predominantly Expressed as Two Functionally Active Isoforms, Caspase-8/a and Caspase-8/b
Scaffidi, C., Medema, J. P., Krammer, P. H., & Peter, M. E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.43.26953 · Cited by 391 · see citing works
TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL
Screaton, G. R., Mongkolsapaya, J., Xu, X., Cowper, A. E., McMichael, A. J., & Bell, J. I. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00297-1 · Cited by 325 · see citing works
TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling
Pan, G., Ni, J., Yu, G., Wei, Y.-F., & Dixit, V. M. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)00135-5 · Cited by 316 · see citing works
Huang, D. C. S., Hahne, M., Schroeter, M., Frei, K., Fontana, A., Villunger, A., Newton, K., Tschopp, J. F., & Strasser, A. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.14871 · Cited by 300 · see citing works
A Unique Zinc-Binding Site Revealed by a High-Resolution X-ray Structure of Homotrimeric Apo2L/TRAIL
Hymowitz, S. G., O'Connell, M. P., Ultsch, M. H., et al. (2000) · Biochemistry · doi:10.1021/bi992242l · Cited by 264 · see citing works
Jones, E. Y., Mongkolsapaya, J., Grimes, J. M., Chen, N., Xu, X., Stuart, D. I., & Screaton, G. R. (1999) · Nature Structural Biology · doi:10.1038/14935 · Cited by 253 · see citing works
Scaffidi, C., Volkland, J., Blomberg, I., Hoffmann, I., Krammer, P. H., & Peter, M. E. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.3.1236 · Cited by 153 · see citing works
Mühlenbeck, F., Haas, E., Schwenzer, R., Schubert, G., Grell, M., Smith, C. W., Scheurich, P., & Wajant, H. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.49.33091 · Cited by 141 · see citing works
Mongkolsapaya, J., Cowper, A., Xu, X., Morris, G. M., McMichael, A. J., Bell, J. I., & Screaton, G. R. (1998) · PubMed · Cited by 140 · see citing works
p53-dependent impairment of T-cell proliferation in FADD dominant-negative transgenic mice
Zörnig, M., Hueber, A., & Evan, G. I. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70182-4 · Cited by 120 · see citing works
Mongkolsapaya, J., Cowper, A. E., Xu, X., Morris, G. M., McMichael, A. J., Bell, J. I., & Screaton, G. R. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.1.3 · Cited by 116 · see citing works
Wallach, D. (1997) · Nature · doi:10.1038/40516 · Cited by 101 · see citing works
Molecular Cloning and Characterization of Two Novel Pro-apoptotic Isoforms of Caspase-10
Ng, P. W. P., Porter, A. G., & Jänicke, R. U. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.15.10301 · Cited by 83 · see citing works
REGULATION OF APO-2 LIGAND/TRAIL EXPRESSION IN NK CELLS—INVOLVEMENT IN NK CELL-MEDIATED CYTOTOXICITY
Johnsen, A., Haux, J., Steinkjer, B., Nonstad, U., Egeberg, K. W., Sundan, A., Ashkenazi, A., & Espevik, T. (1999) · Cytokine · doi:10.1006/cyto.1999.0489 · Cited by 83 · see citing works
Self-citationThe V410I (G1228A) variant of the caspase-10 gene is a common polymorphism in the Danish population
Grønbæk, K., Dalby, T., Zeuthen, J., et al. (2000) · Blood · doi:10.1182/blood.v95.6.2184.2184 · Cited by 40 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Signalling pathways of the TNF superfamily: a double-edged sword
Aggarwal, B. B. (2003) · Nature Reviews Immunology · doi:10.1038/nri1184 · Cited by 2,793 · see citing works
Festjens, N., Vanden Berghe, T., & Vandenabeele, P. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.06.014 · Cited by 710 · see citing works
Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy
von Karstedt, S., Montinaro, A., & Walczak, H. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.28 · Cited by 556 · see citing works
Barnhart, B. C., Alappat, E. C., & Peter, M. E. (2003) · Seminars in Immunology · doi:10.1016/s1044-5323(03)00031-9 · Cited by 419 · see citing works
Altucci, L., Rossin, A., Raffelsberger, W., Reitmair, A., Chomienne, C., & Gronemeyer, H. (2001) · Nature Medicine · doi:10.1038/89050 · Cited by 340 · see citing works
Henry, C. M., & Martin, S. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.022 · Cited by 267 · see citing works
The ‘complexities’ of life and death: Death receptor signalling platforms
Dickens, L. S., Powley, I. R., Hughes, M. A., & MacFarlane, M. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2012.04.005 · Cited by 208 · see citing works
The linear ubiquitin chain assembly complex regulates TRAIL‐induced gene activation and cell death
Lafont, E., Kantari‐Mimoun, C., Draber, P., De Miguel, D., Hartwig, T., Reichert, M., Kupka, S., Shimizu, Y., Taraborrelli, L., Spit, M., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201695699 · Cited by 114 · see citing works
Bellail, A. C., Olson, J. J., Yang, X., Chen, Z. J., & Hao, C. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0172 · Cited by 113 · see citing works
Nazim, U. M., Moon, J.-H., Lee, J.-H., Lee, Y.-J., Seol, J.-W., Eo, S.-K., Lee, J.-H., & Park, S.-Y. (2016) · Oncotarget · doi:10.18632/oncotarget.8048 · Cited by 58 · see citing works
- Authors
- Kischkel, F. C., Lawrence, D. A., Chuntharapai, A., Schow, P., Kim, K. J., & Ashkenazi, A.
- Affiliations
- Genentech (US)
- Corresponding author
- Ashkenazi, Avi
- ORCID
- Lawrence, David A
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2000-06
- Volume
- 12
- Issue
- 6
- Pages
- 611-620
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2009085926
- Cited by
- 975
- References
- 52
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 15 · 2023: 22 · 2022: 13 · 2021: 21 · 2020: 30 · 2019: 22 · 2018: 29 · 2017: 36 · 2016: 28 · 2015: 34 · 2014: 37 · 2013: 38 · 2012: 43
- FWCI
- 26.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Social Sciences › Anthropology › Death, Funerary Practices, and Mourning
- Keywords
- Apo2L/TRAIL, death receptor 4, DR5, FADD, caspase-8, TRADD, RIP, Fas, TNF receptor 1, adaptor proteins, apoptosis signaling, caspase-8 activation
- MeSH terms
- Carrier Proteins, Extracellular Space, Humans, Ligands, Membrane Glycoproteins, Proteins, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Signal Transduction, Lymphoma, B-Cell, Apoptosis, Receptors, Tumor Necrosis Factor, Models, Immunological, fas Receptor, Caspases, Macromolecular Substances, TNF Receptor-Associated Factor 1, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, Caspase 8, Fas-Associated Death Domain Protein, Receptors, TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand, Receptor-Interacting Protein Serine-Threonine Kinases, Caspase 9
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
