Death receptor 6

Tumor necrosis factor receptor superfamily, member 21
PDB rendering based on 2dbh.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2DBH​, 3QO4​, 3U3P​, 3U3Q​, 3U3S​, 3U3T​, 3U3V​
Identifiers
Symbols	TNFRSF21 ; BM-018; CD358; DR6
External IDs	OMIM: 605732 MGI: 2151075 HomoloGene: 8696 GeneCards: TNFRSF21 Gene
Gene ontology Molecular function • protein binding Cellular component • plasma membrane • integral component of plasma membrane • axon • intrinsic component of plasma membrane Biological process • B cell apoptotic process • adaptive immune response • apoptotic process • humoral immune response • negative regulation of B cell proliferation • negative regulation of myelination • negative regulation of T cell proliferation • myelination • cellular lipid metabolic process • small molecule metabolic process • regulation of oligodendrocyte differentiation • T cell receptor signaling pathway • neuron apoptotic process • cellular response to tumor necrosis factor • oligodendrocyte apoptotic process • negative regulation of interleukin-5 secretion • negative regulation of interleukin-13 secretion • negative regulation of interleukin-10 secretion Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	27242	94185
Ensembl	ENSG00000146072	ENSMUSG00000023915
UniProt	O75509	Q9EPU5
RefSeq (mRNA)	NM_014452	NM_178589
RefSeq (protein)	NP_055267	NP_848704
Location (UCSC)	Chr 6: 47.23 – 47.31 Mb	Chr 17: 43.02 – 43.09 Mb
PubMed search

Death receptor 6 (DR6), also known as tumor necrosis factor receptor superfamily member 21 (TNFRSF21), is a cell surface receptor of the tumor necrosis factor receptor superfamily which activates the JNK and NF-κB pathways.^[1][2] It is mostly expressed in the thymus, spleen and white blood cells.^[3]

Function

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to activate NF-κB and MAPK8/JNK, and induce cell apoptosis. Through its death domain, this receptor interacts with TRADD protein, which is known to serve as an adaptor that mediates signal transduction of TNF-receptors. Knockout studies in mice suggested that this gene plays a role in T helper cell activation, and may be involved in inflammation and immune regulation.^[2]

Clinical significance

DR6 is also thought to be involved in neurodegeneration in the brain that causes Alzheimer's disease as well as signal transduction in stress response and cellular survival.^[4] DR6 induces apoptosis when it is over expressed, however the manner in which the death signal is intracellularly transduced is currently unknown. It has been determined that Bax translocation is necessary for the apoptosis triggered by DR6, but through an unknown pathway instead of the traditional pathways of intrinsic versus extrinsic.^[5] APP (amyloid precursor protein) is the natural ligand of DR6 and is first cleaved into Aβ and N-APP. N-APP is the fragment that interacts with DR6 to trigger axonal degradation in Alzheimer's patients.^[6] This pathway is essentially "hi-jacked" in the aging brain.

References

1. Pan G, Bauer JH, Haridas V, Wang S, Liu D, Yu G, Vincenz C, Aggarwal BB, Ni J, Dixit VM (July 1998). "Identification and functional characterization of DR6, a novel death domain-containing TNF receptor". FEBS Lett. 431 (3): 351–356. doi:10.1016/S0014-5793(98)00791-1. PMID 9714541.
2. "Entrez Gene: TNFRSF21 tumor necrosis factor receptor superfamily, member 21".
3. Salido, Ginés María; Rosado, Juan Antonio (2009). Apoptosis: Involvement of Oxidative Stress and Intracellular Ca2+ Homeostasis. Heidelberg, Germany: Springer. p. 37.
4. Kuester M, Kemmerzehl S, Dahms SO, Roeser D, Than ME (June 2011). "The crystal structure of death receptor 6 (DR6): a potential receptor of the amyloid precursor protein (APP)". J. Mol. Biol. 409 (2): 189–201. doi:10.1016/j.jmb.2011.03.048. PMID 21463639.
5. Cetin F (2012). "Role of oxidative stress in Aβ animal model of Alzheimer’s disease: Vicious circle of apoptosis, nitric oxide and age". INTECH.
6. Osherovich L (2009). "Genentech's new parADigm". Science-Business eXchange 2 (8): 1–5. doi:10.1038/scibx.2009.300.

Further reading

• Pan G, Bauer JH, Haridas V, et al. (1998). "Identification and functional characterization of DR6, a novel death domain-containing TNF receptor". FEBS Lett. 431 (3): 351–356. doi:10.1016/S0014-5793(98)00791-1. PMID 9714541.
• Liu J, Na S, Glasebrook A, et al. (2001). "Enhanced CD4+ T cell proliferation and Th2 cytokine production in DR6-deficient mice". Immunity 15 (1): 23–34. doi:10.1016/S1074-7613(01)00162-5. PMID 11485735.
• Zhao H, Yan M, Wang H, et al. (2001). "Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice". J. Exp. Med. 194 (10): 1441–1448. doi:10.1084/jem.194.10.1441. PMC 2193683. PMID 11714751.
• Kasof GM, Lu JJ, Liu D, et al. (2002). "Tumor necrosis factor-alpha induces the expression of DR6, a member of the TNF receptor family, through activation of NF-kappaB". Oncogene 20 (55): 7965–7975. doi:10.1038/sj.onc.1204985. PMID 11753679.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–16903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Clark HF, Gurney AL, Abaya E, et al. (2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Res. 13 (10): 2265–2270. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
• Mungall AJ, Palmer SA, Sims SK, et al. (2003). "The DNA sequence and analysis of human chromosome 6". Nature 425 (6960): 805–811. doi:10.1038/nature02055. PMID 14574404.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–45. doi:10.1038/ng1285. PMID 14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–2127. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Mai T, Wang X, Zhang Z, et al. (2005). "Androgen receptor coregulator ARA267-alpha interacts with death receptor-6 revealed by the yeast two-hybrid". Sci. China, C, Life Sci. 47 (5): 442–8. doi:10.1360/03yc0214. PMID 15623156.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.