TRAIL-R1, DR4 (Homo sapiens)
- Synonyms: TRAIL-R1, DR4, TNFRSF10A, DR4, CD261
- Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
- Short gene description: Tumor necrosis factor receptor superfamily member 10A Precursor (Death receptor 4)(TNF-related apoptosis-inducing ligand receptor 1)(TRAIL receptor 1)(TRAIL-R1)(CD261 antigen) [Source:UniProtKB/Swiss-Prot;Acc:O00220]
- Family: Death receptor
- Process: apoptosis,
- Pathways: extrinsic pathway,
- Criteria: manually curated
- Curator comment:
- Mouse ortholog(s): Tnfrsf10b
- WIKI: TRAIL-R1, DR4-H_sapiens
- The receptor for the cytotoxic ligand TRAIL.
- Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM
- TRAIL (also known as Apo-2L) is a member of the tumor necrosis factor (TNF) ligand family that rapidly induces apoptosis in a variety of transformed cell lines. The human receptor for TRAIL was found to be an undescribed member of the TNF-receptor family (designated death receptor-4, DR4) that contains a cytoplasmic "death domain" capable of engaging the cell suicide apparatus but not the nuclear factor kappa B pathway in the system studied. Unlike Fas, TNFR-1, and DR3, DR4 could not use FADD to transmit the death signal, suggesting the use of distinct proximal signaling machinery. Thus, the DR4-TRAIL axis defines another receptor-ligand pair involved in regulating cell suicide and tissue homeostasis. Science. 1997 Apr 4;276(5309):111-3.
- 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-R1, DR4 | Homo sapiens | 9606 | length:468
- 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: O00220
- PFAM domain and domain family information: O00220
View protein alignment and tree with Jalview:
Explore tree at phylomeDB:   Click here.
Homologs list [+]
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Gene Ontology [+]
|GO id||Name||Ontology type||Evidence|
|GO:0007250||activation of NF-kappaB-inducing kinase activity||biological_proccess||NAS|
|GO:0006917||induction of apoptosis||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:0005035||death receptor activity||mollecular_function||TAS|
|GO:0008656||caspase activator activity||mollecular_function||NAS|
|GO:0008134||transcription factor binding||mollecular_function||IPI|
|GO:0004888||transmembrane receptor activity||mollecular_function||IEA|
|GO:0016021||integral to membrane||cell_component||IC|
Check GO Evidence Codes here
KEGG Pathways [+]
Curated Isoforms [+]
Information from other databases [+]
- OMIM gene information: 603611
- OMIM disease information:
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