TRAIL-R2, TNFRSF10B (Homo sapiens)
- Synonyms: TRAIL-R2, TNFRSF10B, TNFRSF10B, TRAIL-R2, DR5, KILLER, TRICK2A, TRICK2B, APO-2, CD262
- Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
- Short gene description: Tumor necrosis factor receptor superfamily member 10B Precursor (Death receptor 5)(TNF-related apoptosis-inducing ligand receptor 2)(TRAIL receptor 2)(TRAIL-R2)(CD262 antigen) [Source:UniProtKB/Swiss-Prot;Acc:O14763]
- Family: Death receptor
- Process: apoptosis,
- Pathways: extrinsic pathway,
- Criteria: manually curated
- Curator comment:
- Mouse ortholog(s): Tnfrsf10b
- WIKI: TRAIL-R2, TNFRSF10B-H_sapiens
- TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL.
- Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT
- TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines and induces apoptosis in a wide variety of cells. Based on homology searching of a private database, a receptor for TRAIL (DR4 or TRAIL-R1) was recently identified. Here we report the identification of a distinct receptor for TRAIL, TRAIL-R2, by ligand-based affinity purification and subsequent molecular cloning. TRAIL-R2 was purified independently as the only receptor for TRAIL detectable on the surface of two different human cell lines that undergo apoptosis upon stimulation with TRAIL. TRAIL-R2 contains two extracellular cysteine-rich repeats, typical for TNF receptor (TNFR) family members, and a cytoplasmic death domain. TRAIL binds to recombinant cell-surface-expressed TRAIL-R2, and TRAIL-induced apoptosis is inhibited by a TRAIL-R2-Fc fusion protein. TRAIL-R2 mRNA is widely expressed and the gene encoding TRAIL-R2 is located on human chromosome 8p22-21. Like TRAIL-R1, TRAIL-R2 engages a caspase-dependent apoptotic pathway but, in contrast to TRAIL-R1, TRAIL-R2 mediates apoptosis via the intracellular adaptor molecule FADD/MORT1. The existence of two distinct receptors for the same ligand suggests an unexpected complexity to TRAIL biology, reminiscent of dual receptors for TNF, the canonical member of this family. EMBO J. 1997 Sep 1;16(17):5386-97.
- Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL.
- MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES
- A human receptor for the cytotoxic ligand TRAIL (TRAIL receptor-1, designated DR4) was identified recently as a member of the tumor necrosis factor receptor family. In this report we describe the identification of two additional human TRAIL receptors, TRAIL receptor-2 and TRAIL receptor-3, that belong to the tumor necrosis factor receptor family. Interestingly, TRAIL receptor-2 but not TRAIL receptor-3 contains a cytoplasmic "death domain" necessary for induction of apoptosis and is hence designated death receptor-5 (DR5). Like DR4, DR5 engages the apoptotic pathway independent of the adaptor molecule FADD/MORT1. Because of its lack of a death domain, TRAIL receptor-3 is not capable of inducing apoptosis. However, by competing for TRAIL, it is capable of inhibiting TRAIL-induced apoptosis. Thus, TRAIL receptor-3 may function as an antagonistic decoy receptor to attenuate the cytotoxic effect of TRAIL in most tissues that are TRAIL+, DR4+, and DR5+. J Biol Chem. 1997 Oct 10;272(41):25417-20.
- Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors.
- Sheridan JP,Marsters SA,Pitti RM,Gurney A,Skubatch M,Baldwin D,Ramakrishnan L,Gray CL,Baker K,Wood WI,Goddard AD,Godowski P,Ashkenazi A
- TRAIL (also called Apo2L) belongs to the tumor necrosis factor family, activates rapid apoptosis in tumor cells, and binds to the death-signaling receptor DR4. Two additional TRAIL receptors were identified. The receptor designated death receptor 5 (DR5) contained a cytoplasmic death domain and induced apoptosis much like DR4. The receptor designated decoy receptor 1 (DcR1) displayed properties of a glycophospholipid-anchored cell surface protein. DcR1 acted as a decoy receptor that inhibited TRAIL signaling. Thus, a cell surface mechanism exists for the regulation of cellular responsiveness to pro-apoptotic stimuli. Science. 1997 Aug 8;277(5327):818-21.
- References from Mouse ortholog(s):
- TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis.
- Finnberg N, Klein-Szanto AJ, El-Deiry WS
- Preclinical data support the potential of the death-signaling receptors for TRAIL as targets for cancer therapy. However, it is unclear whether these death-signaling receptors suppress the emergence and growth of malignant tumors in vivo. Herein we show that TNF-related apoptosis-inducing ligand receptor (TRAIL-R), the only proapoptotic death-signaling receptor for TRAIL in the mouse, suppresses inflammation and tumorigenesis. Loss of a single TRAIL-R allele on the lymphoma-prone Emu-myc genetic background significantly reduced median lymphoma-free survival. TRAIL-R-deficient lymphomas developed with equal frequency irrespective of mono- or biallelic loss of TRAIL-R, had increased metastatic potential, and showed apoptotic defects relative to WT littermates. In addition, TRAIL-R-/- mice showed decreased long-term survival following a sublethal dose of ionizing radiation. Histological evaluation of moribund irradiated TRAIL-R-/- animals showed hallmarks of bronchopneumonia as well as tumor formation with increased NF-kappaB p65 expression. TRAIL-R also suppressed diethylnitrosamine-induced (DEN-induced) hepatocarcinogenesis, as an increased number of large tumors with apoptotic defects developed in the livers of DEN-treated TRAIL-R-/- mice. Thus TRAIL-R may function as an inflammation and tumor suppressor in multiple tissues in vivo. J Clin Invest. 2008 Jan;118(1):111-23.
- Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor.
- Wu GS, Burns TF, Zhan Y, Alnemri ES, El-Deiry WS
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors are members of the tumor necrosis factor superfamily. TRAIL selectively kills cancer cells but not normal cells. We report here the cloning of the mouse homologue of the TRAIL receptor KILLER/DR5 (MK). The cDNA of MK is 1146 bp in length and encodes a protein of 381 amino acids. MK contains an extracellular cysteine-rich domain, a transmembrane domain, and a cytoplasmic death-domain characteristic of Fas, tumor necrosis factor, and human TRAIL receptors. MK is highly homologous and binds TRAIL with similar affinity as human DR4 and KILLER/DR5. MK induces apoptosis in mouse and human cells and inhibits colony growth of NIH3T3 cells. Expression of MK is p53-dependent and up-regulated by tumor suppressor p53 and by DNA damaging agents in mouse cells undergoing apoptosis. This is the first report describing a mouse TRAIL receptor gene and also demonstrating that the p53-dependent regulation of KILLER/DR5-mediated apoptosis is conserved between human and mouse. Cancer Res. 1999 Jun 15;59(12):2770-5.
- DR5 knockout mice are compromised in radiation-induced apoptosis.
- Finnberg N, Gruber JJ, Fei P, Rudolph D, Bric A, Kim SH, Burns TF, Ajuha H, Page R, Wu GS, Chen Y, McKenna WG, Bernhard E, Lowe S, Mak T, El-Deiry WS
- DR5 (also called TRAIL receptor 2 and KILLER) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called TRAIL and Apo2 ligand). DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro. However, the in vivo biology of DR5 has remained largely unexplored. To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli. Mol Cell Biol. 2005 Mar;25(5):2000-13.
Structure & Sequence [+]
Pfam domains: (Pfam is a large collection of protein families.)
Protein sequence [+]
TRAIL-R2, TNFRSF10B | Homo sapiens | 9606 | length:440
- Smartdomain prediction information: SM00208
- Smartdomain prediction information: SM00005
- Prosite motif and domain information: PS00652
- Profile motif and domain profile information: PS50017
- Profile motif and domain profile information: PS50050
- Interpro domain information: O14763
- PFAM domain and domain family information: O14763
- Protein 3D structures from PDB: 1ZA3 1DU3 1D0G 1D4V 2H9G
View protein alignment and tree with Jalview:
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Homologs list [+]
|TRAIL-R3 / TNFSF10C||paralogy||Human|
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Gene Ontology [+]
|GO id||Name||Ontology type||Evidence|
|GO:0007166||cell surface receptor linked signal transduction||biological_proccess||TAS|
|GO:0008633||activation of pro-apoptotic gene products||biological_proccess||EXP|
|GO:0007250||activation of NF-kappaB-inducing kinase activity||biological_proccess||NAS|
|GO:0008625||induction of apoptosis via death domain receptors||biological_proccess||NAS|
|GO:0006919||activation of caspase activity||biological_proccess||NAS|
|GO:0042981||regulation of apoptosis||biological_proccess||NAS|
|GO:0043123||positive regulation of I-kappaB kinase/NF-kappaB cascade||biological_proccess||IEP|
|GO:0004888||transmembrane receptor activity||mollecular_function||IEA|
|GO:0008656||caspase activator activity||mollecular_function||NAS|
|GO:0016021||integral to membrane||cell_component||IC|
Check GO Evidence Codes here
KEGG Pathways [+]
Curated Isoforms [+]
Information from other databases [+]
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