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 (Tumour 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) and NGFR (Nerve Growth Factor Receptor). These 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 subsequently a 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 signaling 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 complexes 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 Procaspase8 protein which is in inactive state. Procaspase8 is proteolytically activated to Caspase8. FLIP (FLICE-Inhibitory Protein) inhibits activation of Procaspase8 at the DISC by blocking its processing. FLIPL also facilitates the cleavage of Procaspase8 at the DISC by forming FLIPL-Procaspase8 heterodimers. FADD also helps in the activation of Caspase10. Caspase8 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 Caspase9 in the presence of dATP to activate Caspase9. 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 Caspase3. Active Caspase9 can cleave and activate Procaspase3 to its active form, leading to 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 Procaspase8 (Procaspase8/a and Procaspase8/b), Procaspase10 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 of 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 Caspase8 (and probably Caspase10) 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 Kinase 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 Caspase2 through an interaction with a motif similar to the death effector domain, known as CARD (caspase recruitment domain). Recruitment of Caspase2 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. 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. NGF binding selectively to p75(NTR) brings about the activation of the proapoptotic 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 proapoptotic member of the Bcl2 family: BAX (Bcl2 Associated-X Protein) in a sequential manner, which bring about apoptosis of the neuronal cells. Our current understanding of DR signaling has opened possibilities for the design of new therapeutic strategies for targeting death receptor pathways. This would allow the treatment of a number of diseases potentially associated with defects in DR signaling, such as multiple sclerosis and Alzheimer's disease. In tumours 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 that are 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).
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