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.
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. 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 Baxtranslocation is necessary for the apoptosis triggered by DR6, but through an unknown pathway instead of the traditional pathways of intrinsic versus extrinsic. 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. This pathway is essentially "hi-jacked" in the aging brain.
^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. PMID9714541.
^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. PMID21463639.
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. PMID9714541.Cite uses deprecated parameter |author-separator= (help)
Liu J; Na S; Glasebrook A et al. (2001). "Enhanced CD4+ T cell proliferation and Th2 cytokine production in DR6-deficient mice". Immunity15 (1): 23–34. doi:10.1016/S1074-7613(01)00162-5. PMID11485735.Cite uses deprecated parameter |author-separator= (help)
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". Oncogene20 (55): 7965–7975. doi:10.1038/sj.onc.1204985. PMID11753679.Cite uses deprecated parameter |author-separator= (help)
Mungall AJ; Palmer SA; Sims SK et al. (2003). "The DNA sequence and analysis of human chromosome 6". Nature425 (6960): 805–811. doi:10.1038/nature02055. PMID14574404.Cite uses deprecated parameter |author-separator= (help)
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. PMID14702039.Cite uses deprecated parameter |author-separator= (help)
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. PMID15623156.Cite uses deprecated parameter |author-separator= (help)