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Death Receptor-Ligand System

Representative Targets in Death Receptor-Ligand System Full List of Targets in Death Receptor-Ligand System Tested Data-Supported Products Targeting Death Receptor-Ligand System

The death receptor-ligand system is a critical component of the extrinsic pathway of apoptosis, involving specific cell surface receptors that bind to corresponding ligands to initiate programmed cell death. This system is essential for maintaining cellular homeostasis and plays a pivotal role in immune regulation, development, and the elimination of cancer cells.

Death receptors are a subset of the tumor necrosis factor receptor (TNFR) superfamily that includes TNFR1, Fas (CD95), and the TRAIL receptors (DR4 and DR5). These receptors share a common feature known as the death domain (DD), a cytoplasmic motif essential for transmitting apoptotic signals from the bound receptor to intracellular signaling pathways. Upon ligand binding, these receptors oligomerize and recruit adaptor proteins through their death domains, forming a signaling complex that initiates apoptosis.

The ligands for these receptors, such as Fas ligand (FasL), TNF-alpha, and TRAIL, are typically produced by immune cells but can also be expressed by other cell types under certain conditions. FasL, for instance, binds to the Fas receptor, leading to the recruitment of the adaptor molecule FADD (Fas-associated death domain). FADD then recruits procaspase-8, forming the death-inducing signaling complex (DISC). The aggregation of procaspase-8 at the DISC facilitates its auto-cleavage and activation. The active caspase-8 initiates a cascade of downstream caspase activation, ultimately leading to cell death. In some cells, caspase-8 cleaves Bid, a BH3-only protein, linking the extrinsic pathway to the intrinsic mitochondrial pathway, thus amplifying the apoptotic signal.

The death receptor-ligand system is regulated by various mechanisms to prevent inappropriate activation that could lead to diseases such as autoimmune disorders, or, conversely, insufficient activation which can contribute to cancer progression. For example, the expression of decoy receptors (DcRs) for TRAIL, which bind the ligand but do not transduce a death signal, serves as a regulatory mechanism to modulate this pathway. Additionally, cellular FLICE-like inhibitory proteins (c-FLIPs) can compete with procaspase-8 for binding to FADD, inhibiting DISC formation and thus preventing apoptosis.

Figure 1 Figure 1 Death receptors and their ligands. (Walczak, 2013) Figure 1 Death receptors and their ligands. (Walczak, 2013)

Representative Targets in Death Receptor-Ligand System

FAS

FAS, also known as CD95 or Apo-1, is a member of the tumor necrosis factor receptor (TNFR) superfamily and plays a pivotal role in the regulation of programmed cell death, or apoptosis. FAS is best known for its involvement in the extrinsic apoptosis pathway, which is crucial for maintaining cellular homeostasis and immune system function. The FAS receptor is activated upon binding with its ligand, FASL (FAS Ligand), leading to the trimerization of the receptor on the cell surface. This trimerization prompts the recruitment of the adaptor molecule FADD (Fas-associated death domain) to the death domain of FAS. FADD, in turn, recruits and activates pro-caspase-8, forming the death-inducing signaling complex (DISC). The activation of caspase-8 is a critical step in the cascade, leading to the activation of downstream effector caspases such as caspase-3, which execute the apoptotic program resulting in cell death. FAS plays a vital role in the immune system, particularly in the elimination of activated lymphocytes and the prevention of autoimmune reactions. Defective FAS signaling can lead to disorders characterized by the uncontrolled proliferation of lymphocytes and the accumulation of self-reactive immune cells, as seen in autoimmune lymphoproliferative syndrome (ALPS). The FAS/FASL system is also implicated in a variety of other pathological conditions, including cancer, where resistance to FAS-mediated apoptosis can contribute to tumor growth and immune evasion. Conversely, inappropriate activation of FAS can lead to excessive cell death, contributing to tissue damage in diseases such as hepatitis, HIV infection, and certain neurodegenerative conditions.

Recommended Rabbit Anti-FAS mAb (CAT#: ZG-0664J)
Figure 2 Rabbit Anti-FAS Antibody (ZG-0664J) in IHC
Figure 2 Rabbit Anti-FAS Antibody (ZG-0664J) in IHC. IHC image of this product diluted at 1:100 and staining in paraffin-embedded human tonsil tissue performed on a Leica BondTM system. After dewaxing and hydration, antigen retrieval was mediated by high pressure in a citrate buffer (pH 6.0). Section was blocked with 10% normal goat serum 30min at RT. Then primary antibody (1% BSA) was incubated at 4°C overnight. The primary is detected by a Goat anti-rabbit IgG polymer labeled by HRP and visualized using 0.05% DAB.

TNFRSF1A

TNFRSF1A, commonly known as TNF Receptor 1 (TNFR1), is a critical member of the tumor necrosis factor receptor superfamily that primarily mediates the biological effects of tumor necrosis factor-alpha (TNF-α), a potent cytokine involved in inflammatory and immune responses. TNFR1 is ubiquitously expressed on the surface of most cell types and is activated by binding TNF-α, which leads to several downstream signaling pathways influencing inflammation, cell proliferation, differentiation, and death. Upon TNF-α engagement, TNFR1 undergoes trimerization, which facilitates the recruitment of several adaptor proteins to its cytoplasmic death domain. This assembly leads to the formation of a complex known as the TNFR1 signaling complex. This complex initiates various signaling cascades, including the activation of NF-κB and MAP kinases, which are crucial for regulating immune responses and cell survival. Additionally, this complex can initiate the extrinsic pathway of apoptosis through the recruitment and activation of caspase-8, highlighting the dual role of TNFR1 in both survival and cell death mechanisms. TNFR1's ability to induce apoptosis is regulated by the context of the signaling environment and the presence of other molecular adapters that can shift the balance toward survival or death. The receptor’s role in apoptosis and necroptosis—a form of programmed necrosis—is particularly important in conditions where controlled cell death is necessary to maintain tissue homeostasis or respond to cellular stress. Dysregulation of TNFR1 signaling is implicated in various pathological conditions, including chronic inflammatory diseases such as rheumatoid arthritis, Crohn’s disease, and psoriasis, as well as in autoimmune disorders and sepsis. Given its central role in inflammation and cell death, TNFR1 is a target for therapeutic intervention. Biological drugs that inhibit TNF-α or block its interaction with TNFR1 have been successfully used to treat inflammatory diseases by reducing inflammation and halting disease progression.

Recommended Human Anti-TNFRSF1A Single Domain Antibody (CAT#: HPAB-J0307-YC)
Figure 3 Anti-TNFRSF1A Single Domain Antibody (HPAB-J0307-YC) [Biotin] in ELISA
Figure 3 Anti-TNFRSF1A Single Domain Antibody (HPAB-J0307-YC) [Biotin] in ELISA. ELISA analysis of HPAB-J0307-YC-Biotin was performed by coating with Recombinant Human TNFRSF1A Protein, Fc Tag. Incubation: Antigen, 1 µg/mL, 100 µl/well. The secondary antibody: SA-HRP 1:2000.

TNFRSF10B

TNFRSF10B, commonly known as Death Receptor 5 (DR5) or TRAIL receptor 2 (TRAIL-R2), is a member of the tumor necrosis factor receptor superfamily that plays a crucial role in mediating apoptosis through the extrinsic pathway. This receptor is specifically activated by its ligand TRAIL (TNF-related apoptosis-inducing ligand), a cytokine that selectively induces apoptosis in cancer cells while generally sparing normal cells, making it a valuable target for cancer therapy. Upon binding with TRAIL, TNFRSF10B undergoes trimerization, leading to the recruitment of the adaptor protein FADD (Fas-associated protein with death domain) and pro-caspase-8, forming the death-inducing signaling complex (DISC). This assembly triggers the activation of pro-caspase-8 to caspase-8, which then initiates a cascade of further caspase activations, ultimately leading to apoptosis. Caspase-8 can also cleave and activate other downstream effector caspases, such as caspase-3, enhancing the apoptotic process. TNFRSF10B is predominantly expressed in cancerous tissues and is minimally expressed in most normal tissues, which allows TRAIL-mediated therapy to target tumor cells preferentially. The role of TNFRSF10B in cancer apoptosis has spurred significant interest in developing TRAIL or DR5 agonists as anticancer therapeutics. These agents aim to exploit the natural tumor-selective killing mechanism of TRAIL, offering a strategy to induce cancer cell death with minimal side effects. However, resistance to TRAIL-induced apoptosis is a challenge in some cancer types, which has led to ongoing research efforts to understand the mechanisms of resistance and to develop combination therapies that sensitize tumor cells to TRAIL. In addition to cancer, the role of TNFRSF10B and TRAIL signaling is being investigated in other pathological conditions, such as immune disorders and inflammatory diseases, where modulating apoptosis can be beneficial.

Recommended Human Anti-TNFRSF10B mAb (CAT#: TAB-203)
Figure 4 Anti-Human DR5 Recombinant Antibody (TAB-203) in WB
Figure 4 Anti-Human DR5 Recombinant Antibody (TAB-203) in WB. Western blot analysis of TAB-203 was performed with DR5/TRAIL R2 Protein, Human, Recombinant (His Tag). TAB-203 incubation concentration: 2ng/μL. The secondary antibody: HRP-Anti-Human IgG (H+L). Lane 1: Reducing Antigen (0.1μg). Lane 2: Reducing Antigen (0.3μg). Lane 3: Reducing Antigen (0.6μg).
Recommended Mouse Anti-TNFRSF10B mAb (CAT#: ZG-0484F)
Figure 5 Mouse Anti-TNFRSF10B Recombinant Antibody (ZG-0484F) in WB
Figure 5 Mouse Anti-TNFRSF10B Recombinant Antibody (ZG-0484F) in WB. Western blot detection of DR5 in MCF-7 and T47D cell lysates was performed using DR5 mouse mAb (1:2000 dilution). Predicted band size: 40/48KDa. Observed band size: 40/48KDa.
Recommended Mouse Anti-TNFRSF10B mAb (CAT#: ZG-0485F)
Figure 6 Mouse Anti-TNFRSF10B Recombinant Antibody (ZG-0485F) in ICC
Figure 6 Mouse Anti-TNFRSF10B Recombinant Antibody (ZG-0485F) in ICC. DR5 mouse mAb diluted 1:100 was used to perform immunocytochemistry on HeLa cells fixed with paraformaldehyde.

Full List of Targets in Death Receptor-Ligand System

Biomarker Alternative Names Gene ID UniProt ID Roles
DR4ATDR4; drought-repressed 4; T9L24.45; T9L24-45843668Q39091This gene encodes a plant-specific protease inhibitor-like protein whose transcript level in root disappears in response to progressive drought stress. The decrease in transcript level is independent from abscisic acid level.
DR5DR5; CD262; KILLER; TRICK2; TRICKB; ZTNFR9; TRAILR2; TRICK2A; TRICK2B; TRAIL-R2; KILLER/DR58795O14763The protein encoded by this gene is a member of the TNF-receptor superfamily, and contains an intracellular death domain. This receptor can be activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL/APO-2L), and transduces an apoptosis signal. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for this gene.
DR6TNFRSF21; CD358; BM-01827242O75509TNFRSF21 (death receptor-6, DR6) is an orphan TNF receptor superfamily member and belongs to a subgroup of receptors called death receptors. This type I transmembrane receptor possesses four extracellular cysteine-rich motifs and a cytoplasmic death domain. DR6 is an extensively posttranslationally modified transmembrane protein and that N-and O-glycosylations of amino acids in its extracellular part. DR6 interacts with the adaptor protein TRADD and mediates signal transduction through its death domain, and expression of DR6 in mammalian cells induces activation of both NF-kappaB and JNK and cell apoptosis. DR6 knockout mice have enhanced CD4+ T cell proliferation and Th2 cytokine production, suggested that DR6 serves as an important regulatory molecule in T-helper cell activation, and is involved in inflammation and immune regulation. DR6 is expressed ubiquitously with high expression in lymphoid organs, heart, brain and pancreas. Some tumor cells overexpress DR6, typically in conjunction with elevated anti-apoptosis molecules. DR6 may also be involved in tumor cell survival and immune evasion, which is subject to future investigations.
FASFas Cell Surface Death Receptor; Tumor Necrosis Factor Receptor Superfamily, Member 6; Fas (TNF Receptor Superfamily, Member 6); Apoptosis-Mediating Surface Antigen FAS; TNF Receptor Superfamily Member 6; FASLG Receptor; CD95 Antigen; TNFRSF6; APT1; FAS1; Mutant Tumor Necrosis Receptor Superfamily Member 6355P25445The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]
FaslFasl; Fas ligand (TNF superfamily, member 6); gld; CD178; CD95L; Fas-L; Faslg; CD95-L; Tnfsf6; Tnlg1a; APT1LG114103P41047This gene is a member of the tumor necrosis factor superfamily. The primary function of the encoded transmembrane protein is the induction of apoptosis triggered by binding to FAS. The FAS/FASLG signaling pathway is essential for immune system regulation, including activation-induced cell death (AICD) of T cells and cytotoxic T lymphocyte induced cell death. It has also been implicated in the progression of several cancers. Defects in this gene may be related to some cases of systemic lupus erythematosus (SLE). Alternatively spliced transcript variants have been described.
TNF-alphaAPC1 protein; Cachectin; Cachetin; DIF; TNF; TNF, monocyte-derived; TNFA; TNF-A; TNFalpha; TNF-alpha; TNF-alphacachectin; TNFATNF, macrophage-derived; TNFG1F; TNFSF1A; TNFSF2; TNFSF2TNF superfamily, member 2; tumor necrosis factor (TNF superfamily, member 2); tumor necrosis factor alpha; Tumor necrosis factor ligand superfamily member 2; tumor necrosis factor; tumor necrosis factor-alpha; TNF-a; tumor necrosis factor ligand 1F100009088P04924Tumor necrosis factor (TNF-alpha ), also known as cachectin and TNFSF2, is the prototypic ligand of the TNF superfamily and family. The 26 kDa type II transmembrane protein is assembled intracellularly to form a noncovalently linked homotrimer. Rabbit TNF-alpha is 235 amino acids (aa) in length and contains a 35 aa cytoplasmic domain, a 21 aa transmembrane region, and a 179 extracellular domain (ECD). TNF-alpha is produced by several lymphoid cells as well as by astrocytes, endothelial cells, and smooth muscle cells.
TNFRSF10ADR4; APO2; CD261; TRAILR1; TRAILR-1; tumor necrosis factor receptor superfamily member 10A; TNF-related apoptosis-inducing ligand receptor 1; TRAIL receptor 1; TRAIL-R1; cytotoxic TRAIL receptor; death receptor 4; tumor necrosis factor receptor superfamily member 10a variant 2; tumor necrosis factor receptor superfamily, member 10a8797O00220TNFRSF10A is a member of the TNF-receptor superfamily. This receptor is activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL), and thus transduces cell death signal and induces cell apoptosis. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by TNFRSF10A.
TNFRSF10BTNFRSF10B; TRAILR2; TRAIL-R2; CD262; DR5; KILLER; TRICK2; ZTNFR9; TRICKB8795O14763The protein encoded by this gene is a member of the TNF-receptor superfamily, and contains an intracellular death domain. This receptor can be activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL/APO-2L), and transduces an apoptosis signal. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for this gene.
TNFRSF1ATNF Receptor Superfamily Member 1A; TNF-R1; TNF-RI; TNFR-I; TNFR1; TNFAR; P60; P55; Tumor Necrosis Factor Receptor Superfamily, Member 1A; Tumor Necrosis Factor Receptor Superfamily Member 1A; Tumor Necrosis Factor Receptor 1A Isoform Beta; Tumor Necrosis Factor Binding Protein 1; Tumor Necrosis Factor Receptor Type 1; Tumor Necrosis Factor Receptor Type I7132P19438This gene encodes a member of the TNF receptor superfamily of proteins. The encoded receptor is found in membrane-bound and soluble forms that interact with membrane-bound and soluble forms, respectively, of its ligand, tumor necrosis factor alpha. Binding of membrane-bound tumor necrosis factor alpha to the membrane-bound receptor induces receptor trimerization and activation, which plays a role in cell survival, apoptosis, and inflammation. Proteolytic processing of the encoded receptor results in release of the soluble form of the receptor, which can interact with free tumor necrosis factor alpha to inhibit inflammation. Mutations in this gene underlie tumor necrosis factor receptor-associated periodic syndrome (TRAPS), characterized by fever, abdominal pain and other features. Mutations in this gene may also be associated with multiple sclerosis in human patients.
TNFRSF25TNF Receptor Superfamily Member 25; Tumor Necrosis Factor Receptor Superfamily, Member 12 (Translocating Chain-Association Membrane Protein); Lymphocyte-Associated Receptor Of Death; Apoptosis-Mediating Receptor TRAMP; Apoptosis-Mediating Receptor DR3; Apoptosis-Inducing Receptor AIR; Protein WSL-1; TNFRSF12; APO-3; DDR3; LARD; DR3; Tumor Necrosis Factor Receptor Superfamily, Member 25; Tumor Necrosis Factor Receptor Superfamily Member 258718Q93038The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed preferentially in the tissues enriched in lymphocytes, and it may play a role in regulating lymphocyte homeostasis. This receptor has been shown to stimulate NF-kappa B activity and regulate cell apoptosis. The signal transduction of this receptor is mediated by various death domain containing adaptor proteins. Knockout studies in mice suggested the role of this gene in the removal of self-reactive T cells in the thymus. Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported, most of which are potentially secreted molecules. The alternative splicing of this gene in B and T cells encounters a programmed change upon T-cell activation, which predominantly produces full-length, membrane bound isoforms, and is thought to be involved in controlling lymphocyte proliferation induced by T-cell activation.
TNFSF10TL2; APO2L; CD253; TANCR; TRAIL; Apo-2L; TNLG6A8743P50591The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein preferentially induces apoptosis in transformed and tumor cells, but does not appear to kill normal cells although it is expressed at a significant level in most normal tissues. This protein binds to several members of TNF receptor superfamily including TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and possibly also to TNFRSF11B/OPG. The activity of this protein may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and TNFRSF11B/OPG that cannot induce apoptosis. The binding of this protein to its receptors has been shown to trigger the activation of MAPK8/JNK, caspase 8, and caspase 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.
TNFSF15TL1; VEGI9966O95150The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is abundantly expressed in endothelial cells, but is not expressed in either B or T cells. The expression of this protein is inducible by TNF and IL-1 alpha. This cytokine is a ligand for receptor TNFRSF25 and decoy receptor TNFRSF21/DR6. It can activate NF-kappaB and MAP kinases, and acts as an autocrine factor to induce apoptosis in endothelial cells. This cytokine is also found to inhibit endothelial cell proliferation, and thus may function as an angiogenesis inhibitor. Two transcript variants encoding different isoforms have been found for this gene.
TRAILTRAIL receptor; TRAIL8743P50591TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.

Tested Data-Supported Products Targeting Death Receptor-Ligand System

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Reference
  1. Walczak, Henning. "Death receptor–ligand systems in cancer, cell death, and inflammation." Cold Spring Harbor perspectives in biology 5.5 (2013): a008698.

For research use only. Not intended for any clinical use.

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