Death Receptors

Peter H Krammer, German Cancer Research Center, Heidelberg, Germany
Inna N Lavrik, German Cancer Research Center, Heidelberg, Germany

Published online: September 2009

DOI: 10.1002/9780470015902.a0021571

Apoptosis or programmed cell death is a common property of all multicellular organisms. It can be triggered by a number of factors including ultraviolet (UV) or -irradiation, chemotherapeutic drugs or growth factor withdrawal. A death signal can either be induced by death receptors (extrinsic pathway) or via the mitochondria (intrinsic pathway). The death receptor (DR) family is the subfamily of the tumour necrosis factor receptor (TNFR) superfamily. Stimulation of the death receptors results in the transduction of either apoptotic or survival signals. Here we present a general overview of death receptor signalling and describe the main mechanisms leading to activation of death receptor signalling pathways.

Key concepts:

  • Stimulation of the death receptors (DR) leads to apoptosis.
  • All DR are distinguished by the presence of the death domain.
  • Crosslinking of DR with death ligands results in formation of the death-inducing signalling complex (DISC).
  • Caspases play the central role in the transduction of death receptor apoptotic signal.
  • As a result of DISC formation procaspase-8 is activated with the formation of the active caspase-8 heterotetramer, which then triggers apoptotic signal.
  • c-FLIP proteins block caspase-8 activation at the DISC and thereby death receptor-induced apoptosis.
  • There are two types of apoptotic signalling: Type I and Type II cells.
  • Stimulation of DR also might lead to the induction of nonapoptotic pathways.

Keywords: death receptors; caspase; death domain; apoptosis

Figure 1. Death receptors. Death receptors and corresponding death ligands are shown. Death domains (DD) are shown in red. DR-death receptors. DcR-decoy receptors.
Figure 2. CD95 death-inducing signaling complex (DISC). The DISC consists of CD95, (depicted in yellow), FAS-associated death domain, FADD, (depicted in light blue), procaspase-8/procaspase-10, (depicted in green) and cellular FLICE-inhibitory proteins, c-FLIP, (depicted in violet). The interactions between the molecules at the DISC are based on homotypic contacts. The death domain (DD) of CD95 interacts with the DD of FADD, whereas the death effector domain (DED) of FADD interacts with the N-terminal tandem DEDs of procaspase-8, procaspase-10 and c-FLIP. DD are shown in red; DED are shown in light yellow.
Figure 3. CD95 signaling pathways. Stimulation with ligand (CD95L/FasL/APO-1L) leads to formation of the CD95 death-inducing signaling complex (DISC), where activation of caspase-8 and caspase-10 takes place. Caspase-8-mediated apoptosis can occur in two ways according to the Type I/Type II model. 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 caspase-3, caspase-6 and caspase-7. In Type II cells, there are lower levels of CD95 DISC formation and, thus, lower levels of active caspase-8. 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 initiator procaspase-9, which in turn cleaves downstream effector caspases. Type II CD95 signaling might be blocked by Bcl-2 family members such as Bcl-2 and Bcl-xL.
Figure 4. Scheme of c-FLIP isoforms. The scheme represents three isoforms of c-FLIP: c-FLIPLong (c-FLIPL), c-FLIPShort (c-FLIPS) and c-FLIPRaji (c-FLIPR). Death effector domain (DED) is presented in light yellow. Catalytically inactive caspase-like domains of c-FLIPL: p20 and p12 are indicated.
close
 References
    Ashkenazi A and Dixit VM (1998) Death receptors: signaling and modulation. Science 281: 1305–1308.
    Ashkenazi A and Dixit VM (1999) Apoptosis control by death and decoy receptors. Current Opinion in Cell Biology 11: 255–260.
    Bentele M, Lavrik I, Ulrich M et al. (2004) Mathematical modeling reveals threshold mechanism in CD95-induced apoptosis. Journal of Cell Biology 166: 839–851.
    Boatright KM, Renatus M, Scott FL et al. (2003) A unified model for apical caspase activation. Molecular Cell 11: 529–541.
    Bodmer JL, Schneider P and Tschopp J (2002) The molecular architecture of the TNF superfamily. Trends in Biochemical Sciences 27: 19–26.
    Chang DW, Xing Z, Pan Y et al. (2002) c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO Journal 21: 3704–3714.
    Feig C, Tchikov V, Schutze S and Peter ME (2007) Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling. EMBO Journal 26: 221–231.
    Fuentes-Prior P and Salvesen GS (2004) The protein structures that shape caspase activity, specificity, activation and inhibition. Biochemical Journal 384: 201–232.
    Golks A, Brenner D, Fritsch C, Krammer PH and Lavrik IN (2005) c-FLIPR, a new regulator of death receptor-induced apoptosis. Journal of Biological Chemistry 280: 14507–14513.
    Hofmann K, Bucher P and Tschopp J (1997) The CARD domain: a new apoptotic signalling motif. Trends in Biochemical Sciences 22: 155–156.
    Kischkel FC, Hellbardt S, Behrmann I et al. (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO Journal 14: 5579–5588.
    Krammer PH (2000) CD95's deadly mission in the immune system. Nature 407: 789–795.
    Krammer PH, Arnold R and Lavrik IN (2007) Life and death in peripheral T cells. Nature Reviews Immunology 7: 532–542.
    Krueger A, Baumann S, Krammer PH and Kirchhoff S (2001a) FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Molecular and Cellular Biology 21: 8247–8254.
    Krueger A, Schmitz I, Baumann S, Krammer PH and Kirchhoff S (2001b) Cellular flice-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the cd95 death-inducing signaling complex. Journal of Biological Chemistry 276: 20633–20640.
    Lavrik I, Golks A and Krammer PH (2005a) Death receptor signaling. Journal of Cell Science 118: 265–267.
    Lavrik IN, Golks A and Krammer PH (2005b) Caspases: pharmacological manipulation of cell death. Journal of Clinical Investigation 115: 2665–2672.
    Lavrik IN, Mock T, Golks A et al. (2008) CD95 stimulation results in the formation of a novel death effector domain protein-containing complex. Journal of Biological Chemistry 283: 26401–26408.
    Lee KH, Feig C, Tchikov V et al. (2006) The role of receptor internalization in CD95 signaling. EMBO Journal 25: 1009–1023.
    Micheau O, Thome M, Schneider P et al. (2002) The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. Journal of Biological Chemistry 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.
    Muzio M, Chinnaiyan AM, Kischkel FC et al. (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85: 817–827.
    Peter ME, Budd RC, Desbarats J et al. (2007) The CD95 receptor: apoptosis revisited. Cell 129: 447–450.
    Peter ME and Krammer PH (2003) The CD95(APO-1/Fas) DISC and beyond. Cell Death and Differentiation 10: 26–35.
    Salvesen GS (2002) Caspases: opening the boxes and interpreting the arrows. Cell Death and Differentiation 9: 3–5.
    Scaffidi C, Fulda S, Srinivasan A et al. (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO Journal 17: 1675–1687.
    Scaffidi C, Schmitz I, Krammer PH and Peter ME (1999) The role of c-FLIP in modulation of CD95-induced apoptosis. Journal of Biological Chemistry 274: 1541–1548.
    Sprick MR, Rieser E, Stahl H et al. (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 Journal 21: 4520–4530.
    Sprick MR, Weigand MA, Rieser E et al. (2000) FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12: 599–609.
    Thornberry NA and Lazebnik Y (1998) Caspases: enemies within. Science 281: 1312–1316.
    Trauth BC, Klas C, Peters AM et al. (1989) Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245: 301–305.
    Varfolomeev EE, Schuchmann M, Luria V et al. (1998) Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9: 267–276.
    Walczak H and Krammer PH (2000) The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Experimental Cell Research 256: 58–66.
    Yeh WC, Itie A, Elia AJ et al. (2000) Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 12: 633–642.
    Yeh WC, Pompa JL, McCurrach ME et al. (1998) FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279: 1954–1958.
 Further Reading
    Kischkel FC, Lawrence DA, Tinel A et al. (2001) Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. Journal of Biological Chemistry 2: 2.
    Suda T, Takahashi T, Golstein P and Nagata S (1993) Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75: 1169–1178.

Related Sub-Topics:

Cell Membranes | Intracellular and Extracellular Signalling | Cell Biology of Cancer | Cell Death and Cellular Senescence | Membrane Proteins | Signal Transduction | Posttranslational Modification | Protein Degradation | Mechanisms of Cell Death, Senescence and Metabolism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Death Receptors
 
How to Cite close
Krammer, Peter H, and Lavrik, Inna N(Sep 2009) Death Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021571]