Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed DR (Death Receptors), on their surface which detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery. Death Receptors belong to the TNF (Tumor Necrosis Factor) gene superfamily and generally can have several functions other than initiating apoptosis. Eight members of the Death Receptor family have been characterized so far:

  • TNFR1 (Tumor Necrosis Factor Receptor-1) also known as DR1, CD120a, p55 and p60
  • Fas also known as DR2, APO1 and CD95
  • DR3 (Death Receptor-3) also known as APO-3, LARD, TRAMP and WSL1
  • TRAILR1 (TNF-Related Apoptosis-Inducing Ligand Receptor-1) also known as DR4 and APO-2
  • TRAILR2 also known as DR5, KILLER and TRICK2
  • DR6
  • EDAR (Ectodysplasin-A Receptor)
  • NGFR (Nerve Growth Factor Receptor)

These proteins are distinguished by a cytoplasmic region of approximately 80 residues termed the DD (Death Domain). When these receptors are triggered by corresponding ligands, a number of molecules are recruited to the DD and a subsequent signaling cascade is activated. Death ligands also interact with DcRs (Decoy Receptors) that do not possess DDs and so cannot form signaling complexes. Decoy receptors are members of the TNFR superfamily that are capable of competing with signalling receptors for ligand binding, thereby inhibiting their function. TRAILR3 (also known as DcR1) and TRAILR4 (also known as DcR2) compete with DR4 and DR5 for binding of APO2L/TRAIL. DcR3 competes with Fas for binding of FasL and with DR3 for binding of TL1A.

Two types of DR signaling complex can be distinguished:

  • The first group comprises the DISCs (Death-Inducing Signaling Complexes) that are formed at the Fas receptor, TRAILR1 or TRAILR2. All three receptors recruit DISCs with similar compositions. DISC formation results in the activation of Caspase8, 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 (Ref. 1 & 2).

Fas, a member of the TNFR family, typifies the classical view of DR function. The Fas receptor, upon binding to the FasL, trimerizes and induces apoptosis through a cytoplasmic domain called DD (Death Domain) that interacts with signaling adaptors like FAF-1 (Fas-Associated Factor-1), FADD (Fas-Associated Death Domain), Daxx, FAP1 (Fas-Associated Protein-Tyrosine Phosphatase-1), Flash and RIP (Receptor-Interacting Protein). FADD carries a DED (Death Effector Domain) and by homologous interaction it recruits the DED containing Procaspase-8 protein which is in an inactive state. Procaspase-8 is proteolytically activated by Caspase-8. FLIP (FLICE-Inhibitory Protein) inhibits activation of Procaspase-8 at the DISC by blocking its processing. FLIPL also facilitates the cleavage of Procaspase-8 at the DISC by forming FLIPL-Procaspase-8 heterodimers. FADD also helps in the activation of Caspase-10. Caspase-8 can cleave the BH3-only protein BID (BH3 Interacting Domain Death Agonist), and the resulting tBID (Truncated BID) can inactivate Bcl2 (B-Cell CLL/Lymphoma-2) in the mitochondrial membrane. This allows the escape of CytoC (Cytochrome-C), which clusters with APAF1 (Apoptotic Protease Activating Factor-1) and Caspase-9 in the presence of dATP to activate Caspase-9. SMAC (Second Mitochondria-Derived Activator of Caspase)/DIABLO and HTRA2 (High Temperature Requirement Protein-A2) are also released from the mitochondria and inactivate IAPs (Inhibitors of Apoptosis), which further inhibits Caspase-3. Active Caspase-9 can cleave and activate Procaspase-3, leading to the breakdown of several cytoskeletal and nuclear proteins (structural, signaling proteins or kinases) like GDID4 (GDP-Dissociation Inhibitor-D4), PARP (Poly ADP-Ribose Polymerase), Alpha-Fodrin, GAS2 (Growth Arrest Specific-2) and Lamin-A, thus inducing apoptosis, and degradation of the ICAD (Inhibitor of Caspase-Activated DNase). Besides Fas, TRAILR1 and TRAILR2 also lead to apoptosis by formation of DISCs. TRAILR1 and TRAILR2 are activated by binding to the ligand TRAIL. DISCs also consist of oligomerized, probably trimerized, receptors, the DD-containing adaptor molecule FADD, two isoforms of Procaspase-8 (Procaspase-8/a and Procaspase-8/b), Procaspase-10 and the cellular FLIPL/S. Signaling downstream of TRAILR1/R2 receptors is similar to Fas signaling (Ref. 3 & 4).

TNFR1 signaling differs from Fas receptor or TRAILR1/R2-induced apoptosis. TNFR1 is an integral membrane protein with its receptor domain exposed at the surface of the cell binding the complementary death activator, which transmits a signal to the cytoplasm that leads to activation of downstream products. TNFR1, after binding to its ligand TNF-alpha, recruits TRADD (TNFR-Associated Death Domain) as a platform adaptor, and, in turn, assembles alternative signaling complexes through secondary adaptors. One type of complex is a DISC that involves FADD and Caspase-8 (and probably Caspase-10) and triggers apoptosis in a manner similar to the other DR. Another complex involves RIP, TRADD, TRAF1/2 (TNFR-Associated Factor), and probably other, as-yet-unidentified molecules. It is proposed to trigger the NF-KappaB signaling pathway through recruitment of the IKK (I-KappaB Kinase) complex and activates JNK1 (c-Jun Kinase) through a TRAF2 and NIK (NF-KappaB-Inducing Kinase) dependent mechanism. ASK1 (Apoptosis signal-regulating Kinase-1), a MAP Kinase, is also required for TNF-mediated JNK activation. TNFR1 is also able to mediate apoptosis through the recruitment of an adapter molecule called RAIDD (RIP-associated ICH-1/CED-3 homologous protein with a death domain). RAIDD associates with RIP through interactions between death domains and can recruit Caspase-2 through an interaction with a motif, similar to the death effector domain, known as CARD (caspase recruitment domain). Recruitment of Caspase-2 leads to induction of apoptosis. Another kinase, which is believed to be involved in TNF-alpha induced apoptosis is DAPK (Death-Associated Protein Kinase). DAPK is a calcium/calmodulin-regulated serine/threonine kinase that carries ankyrin repeats, a death domain, and is localized to the cytoskeleton (Ref. 5 & 6).

The DR3 and DR6 signaling pathways are less well characterized. The ligand for DR3 is TWEAK (TNF-Related Weak Inducer of Apoptosis)/TL1A while the ligand for DR6 remains undiscovered. RIP and TRADD are recruited to the receptor complex, and DR3 and DR6 promote activation of NF-KappaB that leads to the expression of survival genes. Another death receptor, which plays an important role in the nervous system is p75(NTR). p75(NTR) is a member of the TNFR (Tumor Necrosis Factor) receptor superfamily, having no tyrosine kinase domain. When NGF binds selectively to p75(NTR), it causes the activation of the pro-apoptotic JNK cascade. MEKKs (MAP/ERK Kinase Kinases) and SEK (SAPK/ERK Kinase) are the upstream regulators of JNK. JNKs, in turn, upregulate p53 and the pro-apoptotic member of the Bcl2 family: BAX (Bcl2 Associated-X Protein) in a sequential manner, which causes apoptosis of neuronal cells. Our current understanding of DR signaling has opened up possibilities for the design of new therapeutic strategies for targeting death receptor pathways. This may allow the treatment of a number of diseases potentially associated with defects in DR signaling, such as multiple sclerosis and Alzheimer's disease. In tumors that retain some responsiveness to conventional therapy, death receptor engagement in combination with chemotherapy or irradiation might lead to synergistic apoptosis activation, and reduce the probability that tumor cells resistant to either type of agent will emerge. In tumors that have lost p53 function, death receptor targeting might help to circumvent resistance to chemotherapy and radiotherapy (Ref. 7, 8 & 9).


Pathway


Apoptosis through Death Receptors

Key

Pathway Key

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References
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  4. Regulating TRAIL receptor-induced cell death at the membrane : a deadly discussion. Shirley S, Morizot A, Micheau O. Recent Pat Anticancer Drug Discov. 2011 Sep;6(3):311-23. doi: 10.2174/157489211796957757.
  5. Regulation of death receptor signaling by the ubiquitin system. Wertz IE, Dixit VM. Cell Death Differ. 2010 Jan;17(1):14-24.
  6. Caspase-2: the orphan caspase. Bouchier-Hayes L, Green DR. Cell Death Differ. 2012 Jan;19(1):51-7. doi: 10.1038/cdd.2011.157. Epub 2011 Nov 11.
  7. The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Meylan F, Davidson TS, Kahle E, Kinder M, Acharya K, Jankovic D, Bundoc V, Hodges M, Shevach EM, Keane-Myers A, Wang EC, Siegel RM. Immunity. 2008 Jul 18;29(1):79-89. Epub 2008 Jun 19.
  8. TL1A and DR3, a TNF family ligand-receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation. Meylan F, Richard AC, Siegel RM. Immunol Rev. 2011 Nov;244(1):188-96. doi: 10.1111/j.1600-065X.2011.01068.x.
  9. p53 modulates acquired resistance to EGFR inhibitors and radiation. Huang S, Benavente S, Armstrong EA, Li C, Wheeler DL, Harari PM. Cancer Res. 2011 Nov 15;71(22):7071-9. Epub 2011 Nov 8.