TRAIL-R2, TNFRSF10B (Homo sapiens)

Description [+]

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

References [+]

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.)

Source	Domain Name	Start	End
PFAM A	TNFR_c6	97	137
PFAM A	Death	340	422

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: O14763
PFAM domain and domain family information: O14763
Protein 3D structures from PDB: 1ZA3 1DU3 1D0G 1D4V 2H9G

Evolution [+]

Name	Relationship	Species
TNFRSF10B	orthology	Chimpanzee
TNFRSF10B	orthology	Gorilla
E_caballus_ENSECAP00000022015	orthology	Horse
TNFRSF10B	orthology	Macaca
M_domestica_ENSMODP00000011508	orthology	Monodelphis
Tnfrsf10b	orthology	Mouse
TNFRSF10B	orthology	Orangutan
O_anatinus_ENSOANP00000021880	orthology	Ornithorhynchus
Tnfrsf10b	orthology	Rat
NM_204115.1	paralogy	Chicken
NP_001025950.1	paralogy	Chicken
NP_989717.1	paralogy	Chicken
TNFRSF10A	paralogy	Chimpanzee
TNFRSF10D	paralogy	Chimpanzee
TNFRSF10C	paralogy	Chimpanzee
P_troglodytes_ENSPTRP00000034372	paralogy	Chimpanzee
TNFRSF1A	paralogy	Chimpanzee
TNR1A_BOVIN	paralogy	Cow
LTBR	paralogy	Dog
TNFRSF25	paralogy	Fugu
T_rubripes_ENSTRUP00000013812	paralogy	Fugu
T_rubripes_ENSTRUP00000010129	paralogy	Fugu
G_aculeatus_ENSGACP00000007142	paralogy	Gasterosteus
G_aculeatus_ENSGACP00000011439	paralogy	Gasterosteus
G_aculeatus_ENSGACP00000020911	paralogy	Gasterosteus
TNFRSF25	paralogy	Gasterosteus
TNFRSF10D	paralogy	Gorilla
TNFRSF10A	paralogy	Gorilla
TNFRSF10C	paralogy	Gorilla
G_gorilla_ENSGGOP00000010787	paralogy	Gorilla
TNFRSF1A	paralogy	Horse
TRAIL-R3 / TNFSF10C	paralogy	Human
TRAIL-R1, DR4	paralogy	Human
TRAIL-R4, TNFRSF10D	paralogy	Human
TNFRSF10D	paralogy	Macaca
TNFRSF11B	paralogy	Macaca
TNFRSF10A	paralogy	Macaca
O_latipes_ENSORLP00000003602	paralogy	Medaka
O_latipes_ENSORLP00000020293	paralogy	Medaka
LTBR	paralogy	Monodelphis
TNFRSF1A	paralogy	Monodelphis
TNFRSF25	paralogy	Monodelphis
TNFRSF10D	paralogy	Orangutan
TNFRSF10C	paralogy	Orangutan
TNFRSF10A	paralogy	Orangutan
O_anatinus_ENSOANP00000007822	paralogy	Ornithorhynchus
TNFRSF10D	paralogy	Tetraodon
TNFRSF1A	paralogy	Zebra finch
hdr	paralogy	Zebrafish
tnfrsfa	paralogy	Zebrafish

Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0007165	signal transduction	biological_proccess	IEA
GO:0006915	apoptosis	biological_proccess	IEA
GO:0006955	immune response	biological_proccess	IEA
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:0005515	protein binding	mollecular_function	IEA
GO:0004872	receptor activity	mollecular_function	IEA
GO:0004888	transmembrane receptor activity	mollecular_function	IEA
GO:0004872	receptor activity	mollecular_function	NAS
GO:0008656	caspase activator activity	mollecular_function	NAS
GO:0045569	TRAIL binding	mollecular_function	NAS
GO:0016020	membrane	cell_component	IEA
GO:0005886	plasma membrane	cell_component	EXP
GO:0016021	integral to membrane	cell_component	IC

Check GO Evidence Codes here

KEGG Pathways [+]

Curated Isoforms [+]

Transcript	Translation
OTTHUMT00000215099 *	OTTHUMP00000123492 *
OTTHUMT00000215100	OTTHUMP00000123493

Information from other databases [+]

Gene related links:

Gene info from HGNC [?] :11905
Gene related info from GeneCards [?] : TRAIL-R2, TNFRSF10B
Ensembl genome browser [?] : ENSG00000120889
Expression info from Arrayexpress [?] : ENSG00000120889
Protein expression from Protein Atlas: [?] ENSG00000120889
Community gene edition from Wikigenes: [?] 8795

Protein related links:

Uniprot protein info: O14763
PIR protein info: O14763
Protein interactions from IntAct: O14763

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

OMIM gene information: 603612
OMIM disease information: 275355

Other links

entrezgene: 8795
refseq_dna: NM_003842
refseq_dna: NM_147187
refseq_peptide: NP_003833
refseq_peptide: NP_671716

Click on [?] for more information.