TRAIL-R1, DR4 (Homo sapiens)

Description [+]

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

References [+]

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.)

Source	Domain Name	Start	End
PFAM A	TNFR_c6	148	188
PFAM A	TNFR_c6	190	229
PFAM A	Death	366	448

Protein sequence [+]

Structure links:

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

Evolution [+]

Name	Relationship	Species
TNFRSF10A	orthology	Chimpanzee
TNFRSF10A	orthology	Gorilla
E_caballus_ENSECAP00000022015	orthology	Horse
TNFRSF10A	orthology	Macaca
Tnfrsf10b	orthology	Mouse
TNFRSF10A	orthology	Orangutan
Tnfrsf10b	orthology	Rat
NP_001025950.1	paralogy	Chicken
NM_204115.1	paralogy	Chicken
NP_989717.1	paralogy	Chicken
TNFRSF10B	paralogy	Chimpanzee
TNFRSF10D	paralogy	Chimpanzee
P_troglodytes_ENSPTRP00000034372	paralogy	Chimpanzee
T_rubripes_ENSTRUP00000013812	paralogy	Fugu
G_aculeatus_ENSGACP00000020911	paralogy	Gasterosteus
G_aculeatus_ENSGACP00000007142	paralogy	Gasterosteus
G_gorilla_ENSGGOP00000010787	paralogy	Gorilla
TNFRSF10B	paralogy	Gorilla
TNFRSF10D	paralogy	Gorilla
TRAIL-R4, TNFRSF10D	paralogy	Human
TRAIL-R2, TNFRSF10B	paralogy	Human
TNFRSF10D	paralogy	Macaca
O_latipes_ENSORLP00000020293	paralogy	Medaka
O_latipes_ENSORLP00000003602	paralogy	Medaka
M_domestica_ENSMODP00000011508	paralogy	Monodelphis
Tnfrsf14	paralogy	Mouse
TNFRSF10B	paralogy	Orangutan
TNFRSF10D	paralogy	Orangutan
O_anatinus_ENSOANP00000021880	paralogy	Ornithorhynchus
O_anatinus_ENSOANP00000029006	paralogy	Ornithorhynchus
Tnfrsf14	paralogy	Rat
TNFRSF10D	paralogy	Tetraodon
BC075302.1	paralogy	Xenopus
TNFRSF1A	paralogy	Zebra finch
hdr	paralogy	Zebrafish

Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0007165	signal transduction	biological_proccess	TAS
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:0006915	apoptosis	biological_proccess	IEA
GO:0006955	immune response	biological_proccess	IEA
GO:0005035	death receptor activity	mollecular_function	TAS
GO:0045569	TRAIL binding	mollecular_function	NAS
GO:0008656	caspase activator activity	mollecular_function	NAS
GO:0004872	receptor activity	mollecular_function	NAS
GO:0008134	transcription factor binding	mollecular_function	IPI
GO:0005515	protein binding	mollecular_function	IEA
GO:0004888	transmembrane receptor activity	mollecular_function	IEA
GO:0016020	membrane	cell_component	IEA
GO:0016021	integral to membrane	cell_component	IC

Check GO Evidence Codes here

KEGG Pathways [+]

Curated Isoforms [+]

Transcript	Translation
OTTHUMT00000215133 *	OTTHUMP00000123526 *

Information from other databases [+]

Gene related links:

Gene info from HGNC [?] :11904
Gene related info from GeneCards [?] : TRAIL-R1, DR4
Ensembl genome browser [?] : ENSG00000104689
Expression info from Arrayexpress [?] : ENSG00000104689
Protein expression from Protein Atlas: [?] ENSG00000104689
Community gene edition from Wikigenes: [?] 8797

Protein related links:

Uniprot protein info: O00220
PIR protein info: O00220
Protein interactions from IntAct: O00220

Gene and disease information from OMIM: (For a full disease description table, click here.)

OMIM gene information: 603611
OMIM disease information:

Other links

entrezgene: 8797
refseq_dna: NM_003844
refseq_peptide: NP_003835

Click on [?] for more information.