Tumor necrosis factor ligand superfamily member 10 (TNFSF10), also known as TNF-related apoptosis-inducing ligand (TRAIL), Apo-2 ligand, and CD253, is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. TNFSF10 functions as a ligand that induces the process of cell death called apoptosis. TNFSF10 shows homology to other members of the tumor necrosis factor superfamily. As one member of the cluster of differentiation system, TNFSF10 is commonly used as cell markers in immunophynotyping. Different kinds of cells in the immune system can be identified through the surface CD molecules which associating with the immune function of the cell. There are more than 320 CD unique clusters and subclusters have been identified. Some of the CD molecules serve as receptors or ligands important to the cell through initiating a signal cascade which then alter the behavior of the cell. Some CD proteins do not take part in cell signal process but have other functions such as cell adhesion TNFSF10 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 TNFSF10 / TRAIL 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.
Human TNFSF10 is a type II transmembrane protein with an intracellular N-terminus and a ‘TNF homology domain’ (THD) at the extracellular C terminus. TNFSF10 can interact with several distinct receptors. Two of these receptors that belongs to TNFR superfamily, DR4 (TRAIL-R1) and DR5 (TRAIL-R2/TRICK2), are plasma membrane proteins containing intracellular death domains essential for activating apoptosis. TNFSF10 is promising for cancer therapy because it is cytotoxic and activates apoptosis in the majority of malignant cells, but not in normal cells.
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A) is also known as TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), Death receptor 4 (DR4), CD261 and APO2, which belongs to TNF superfamily. TNFRSF10A / DR4 is widely expressed and high levels are found in spleen, peripheral blood leukocytes, small intestine and thymus, but also in K-562 erythroleukemia cells, MCF-7 breast carcinoma cells and activated T-cells. APO2 / TNFRSF10A is receptor for the cytotoxic ligand TNFSF10 / TRAIL. This receptor is activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF1/TRAIL), and thus transduces cell death signal and induces cell apoptosis. TRAIL R1 can promote the activation of NF-kappa-B. TRAIL R1/CD261/TNFRSF1A induces apoptosis of many transformed cell lines but not of normal tissues, even though its death domain-containing receptor, DR4, is expressed on both cell types.
Tumor necrosis factor receptor superfamily, member 10a (TRAIL R1), also known as TRAIL receptor 1 (TRAIL R1) or CD261 antigen, 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 this protein. TRAIL R1/CD261/TNFRSF10A serves as a receptor for the cytotoxic ligand TNFSF10/TRAIL. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. TRAIL R1 can promote the activation of NF-kappa-B. TRAIL R1/CD261/TNFRSF10A induces apoptosis of many transformed cell lines but not of normal tissues, even though its death domain-containing receptor, DR4, is expressed on both cell types.
TNFRSF10B 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 apoptosis signal. The adapter molecule FADD recruits caspase-8 to the activated receptor and is required for the apoptosis mediated by TNFRSF10B. TNFRSF10B is expressed in a number of cell types; and to particularly high levels in lymphocytes and spleen. This single-pass transmembrane protein contains two cysteine-rich repeat units in its extracellular region; followed by a transmembrane segment and a cytoplasmic tail containing a typical “death domain”. TNFRSF10B expression is regulated by the tumor suppressor p53. It is also indicated that the activation of NF-kappa-B can be promoted by TNFRSF10B.
Tumor Necrosis Factor Receptor Superfamily Member 10C (TNFRSF10C) is a glycosyl-phosphatidylinositol-linked membrane protein which binds TRAIL with high affinity. TNFRSF10C has the TRAIL-binding extracellular cysteine-rich domains; lacks the intracellular signaling domain. As a result; binding of TRAIL to TRAIL R3 doesn’t transduce an apoptosis signal. The expression of TRAIL R3 gene has been shown to protect cells bearing TRAIL R1 and/or TRAIL R2 from TRAIL-induced apoptosis.
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