Division of Immunogenetics, Tumorimmunology Program, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany
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Introduction |
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Death receptor family members |
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Two types of DR signaling complex can be distinguished. The first group comprises the death-inducing signaling complexes (DISCs) that are formed at the CD95 receptor, TRAILR1 or TRAILR2 (Peter and Krammer, 2003). All three receptors recruit DISCs with similar compositions. DISC formation results in the activation of caspase-8, which plays the central role in transduction of the apoptotic signal. The second group comprises the TNFR1, DR3, DR6 and EDAR. These recruit a different set of molecules, which transduce both apoptotic and survival signals.
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CD95/Fas and TRAILR signaling |
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Procaspase-10 is also activated at the DISC, forming an active heterotetramer (Sprick et al., 2002). However, whether caspase-10 can trigger cell death in absence of caspase-8 in response to CD95 or TRAILR1/R2 stimulation is controversial. Thus, the role of caspase-10 remains elusive.
FLIPL and FLIPS inhibit activation of procaspase-8 at the DISC by blocking its processing. There is increasing evidence that FLIPL also facilitates the cleavage of procaspase-8 at the DISC by forming FLIPL-procaspase-8 heterodimers (Chang et al., 2003; Micheau et al., 2002
). A detailed understanding of FLIP action at the DISC requires further studies.
Besides the above-mentioned components of the DISC, a number of molecules have been reported to be recruited to the DISC by direct interaction with DISC proteins (Daxx, FAP-1, FLASH, RIP, FAF-1 and others). The roles of many of these proteins are unclear (Peter and Krammer, 2003).
Two types of CD95 signaling have been established. Type I cells are characterized by high levels of DISC formation and increased amounts of active caspase-8. Activated caspase-8 directly leads to the activation of downstream effector caspases. In type II cells, there are lower levels of CD95 DISC formation and, thus, lower levels of active caspase-8 (Scaffidi et al., 1998). In this case, signaling requires an additional amplification loop that involves the cleavage by caspase-8 of the Bcl-2-family protein Bid to generate truncated (t) Bid and subsequent tBid-mediated release of cytochrome c (Cyt c) from mitochondria. The release of Cyt c from mitochondria results in apoptosome formation, followed by the activation of procaspase-9, which in turn cleaves downstream effector caspases (Korsmeyer et al., 2000
). Type II CD95 signaling might be blocked by Bcl-2 family members such as Bcl-2 and Bcl-xL (Willis et al., 2003
). Signaling downstream of TRAILR1/R2 receptors is similar to CD95 signaling.
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TNFR, DR3 and DR6 signaling |
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The DR3 and DR6 signaling pathways are less well characterized (Bhardwaj and Aggarwal, 2003). RIP and TRADD are recruited to the receptor complex, and DR3 and DR6 promote activation of NF-
B that leads to the expression of survival genes (Bhardwaj and Aggarwal, 2003
; Karin and Lin, 2002
).
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Modulation of Death Receptor signaling |
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Acknowledgments |
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References |
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Bhardwaj, A. and Aggarwal, B. B. (2003). Receptor-mediated choreography of life and death. J. Clin. Immunol. 23, 317-332.[CrossRef][Medline]
Chang, D. W., Xing, Z., Capacio, V. L., Peter, M. E. and Yang, X. (2003). Interdimer processing mechanism of procaspase-8 activation. EMBO J. 22, 4132-4142.
Danial, N. N. and Korsmeyer, S. J. (2004). Cell death: critical control points. Cell 116, 205-219.[CrossRef][Medline]
French, L. E. and Tschopp, J. (2003). Protein-based therapeutic approaches targeting death receptors. Cell Death Differ. 10, 117-123.[CrossRef][Medline]
Karin, M. and Lin, A. (2002). NF-kappaB at the crossroads of life and death. Nat. Immun. 3, 221-227.[CrossRef]
Korsmeyer, S. J., Wei, M. C., Saito, M., Weiler, S., Oh, K. J. and Schlesinger, P. H. (2000). Proapoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ. 7, 1166-1173.[CrossRef][Medline]
Krammer, P. H. (2000). CD95's deadly mission in the immune system. Nature 407, 789-795.[CrossRef][Medline]
Micheau, O., Thome, M., Schneider, P., Holler, N., Tschopp, J., Nicholson, D. W., Briand, C. and Grutter, M. G. (2002). The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J. Biol. Chem. 277, 45162-45171.
Micheau, O. and Tschopp, J. (2003). Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181-190.[Medline]
Peter, M. E. and Krammer, P. H. (2003). The CD95 (APO-1/Fas) DISC and beyond. Cell Death Differ. 10, 26-35.[CrossRef][Medline]
Scaffidi, C., Fulda, S., Srinivasan, A., Friesen, C., Li, F., Tomaselli, K. J., Debatin, K. M., Krammer, P. H. and Peter, M. E. (1998). Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 17, 1675-1687.
Sprick, M., Rieser, E., Stahl, H., Grosse-Wilde, A., Weigand, M. and Walczak, H. (2002). Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8. EMBO J. 21, 4520-4530.
Varfolomeev, E. E. and Ashkenazi, A. (2004). Tumor necrosis factor: an apoptosis JuNKie? Cell 116, 491-497.[CrossRef][Medline]
Wajant, H. (2003). Death receptors. Essays Biochem. 39, 53-71.[Medline]
Willis, S., Day, C. L., Hinds, M. G. and Huang, D. C. (2003). The Bcl-2-regulated apoptotic pathway. J. Cell Sci. 116, 4053-4056.