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Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis.
J Biol Chem 2003; 278(28):25534-41JB

Abstract

Death receptors are a subfamily of the tumor necrosis factor (TNF) receptor subfamily. They are characterized by a death domain (DD) motif within their intracellular domain, which is required for the induction of apoptosis. Fas-associated death domain protein (FADD) is reported to be the universal adaptor used by death receptors to recruit and activate the initiator caspase-8. CD95, TNF-related apoptosis-inducing ligand (TRAIL-R1), and TRAIL-R2 bind FADD directly, whereas recruitment to TNF-R1 is indirect through another adaptor TNF receptor-associated death domain protein (TRADD). TRADD also binds two other adaptors receptor-interacting protein (RIP) and TNF-receptor-associated factor 2 (TRAF2), which are required for TNF-induced NF-kappaB and c-Jun N-terminal kinase activation, respectively. Analysis of the native TNF signaling complex revealed the recruitment of RIP, TRADD, and TRAF2 but not FADD or caspase-8. TNF failed to induce apoptosis in FADD- and caspase-8-deficient Jurkat cells, indicating that these apoptotic mediators were required for TNF-induced apoptosis. In an in vitro binding assay, the intracellular domain of TNF-R1 bound TRADD, RIP, and TRAF2 but did not bind FADD or caspase-8. Under the same conditions, the intracellular domain of both CD95 and TRAIL-R2 bound both FADD and caspase-8. Taken together these results suggest that apoptosis signaling by TNF is distinct from that induced by CD95 and TRAIL. Although caspase-8 and FADD are obligatory for TNF-mediated apoptosis, they are not recruited to a TNF-induced membrane-bound receptor signaling complex as occurs during CD95 or TRAIL signaling, but instead must be activated elsewhere within the cell.

Authors+Show Affiliations

Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, P.O. Box 138, Lancaster Road, Leicester, LE1 9HN, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12721308

Citation

Harper, Nicholas, et al. "Fas-associated Death Domain Protein and Caspase-8 Are Not Recruited to the Tumor Necrosis Factor Receptor 1 Signaling Complex During Tumor Necrosis Factor-induced Apoptosis." The Journal of Biological Chemistry, vol. 278, no. 28, 2003, pp. 25534-41.
Harper N, Hughes M, MacFarlane M, et al. Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. J Biol Chem. 2003;278(28):25534-41.
Harper, N., Hughes, M., MacFarlane, M., & Cohen, G. M. (2003). Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. The Journal of Biological Chemistry, 278(28), pp. 25534-41.
Harper N, et al. Fas-associated Death Domain Protein and Caspase-8 Are Not Recruited to the Tumor Necrosis Factor Receptor 1 Signaling Complex During Tumor Necrosis Factor-induced Apoptosis. J Biol Chem. 2003 Jul 11;278(28):25534-41. PubMed PMID: 12721308.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. AU - Harper,Nicholas, AU - Hughes,Michelle, AU - MacFarlane,Marion, AU - Cohen,Gerald M, Y1 - 2003/04/29/ PY - 2003/5/2/pubmed PY - 2003/8/15/medline PY - 2003/5/2/entrez SP - 25534 EP - 41 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 278 IS - 28 N2 - Death receptors are a subfamily of the tumor necrosis factor (TNF) receptor subfamily. They are characterized by a death domain (DD) motif within their intracellular domain, which is required for the induction of apoptosis. Fas-associated death domain protein (FADD) is reported to be the universal adaptor used by death receptors to recruit and activate the initiator caspase-8. CD95, TNF-related apoptosis-inducing ligand (TRAIL-R1), and TRAIL-R2 bind FADD directly, whereas recruitment to TNF-R1 is indirect through another adaptor TNF receptor-associated death domain protein (TRADD). TRADD also binds two other adaptors receptor-interacting protein (RIP) and TNF-receptor-associated factor 2 (TRAF2), which are required for TNF-induced NF-kappaB and c-Jun N-terminal kinase activation, respectively. Analysis of the native TNF signaling complex revealed the recruitment of RIP, TRADD, and TRAF2 but not FADD or caspase-8. TNF failed to induce apoptosis in FADD- and caspase-8-deficient Jurkat cells, indicating that these apoptotic mediators were required for TNF-induced apoptosis. In an in vitro binding assay, the intracellular domain of TNF-R1 bound TRADD, RIP, and TRAF2 but did not bind FADD or caspase-8. Under the same conditions, the intracellular domain of both CD95 and TRAIL-R2 bound both FADD and caspase-8. Taken together these results suggest that apoptosis signaling by TNF is distinct from that induced by CD95 and TRAIL. Although caspase-8 and FADD are obligatory for TNF-mediated apoptosis, they are not recruited to a TNF-induced membrane-bound receptor signaling complex as occurs during CD95 or TRAIL signaling, but instead must be activated elsewhere within the cell. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/12721308/Fas_associated_death_domain_protein_and_caspase_8_are_not_recruited_to_the_tumor_necrosis_factor_receptor_1_signaling_complex_during_tumor_necrosis_factor_induced_apoptosis_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12721308 DB - PRIME DP - Unbound Medicine ER -