Death receptor 6 (DR6), also known astumor necrosis factor receptor superfamily member 21 (TNFRSF21), is acell surface receptor of thetumor necrosis factor receptor superfamily which activates theJNK andNF-κB pathways.[5][6] It is mostly expressed in thethymus,spleen andwhite blood cells.[7] The Gene for DR6 is 78,450 bases long and is found on the 6th chromosome. This is transcribed into a 655 amino acid chain weighing 71.8 kDa. Post transcriptional modifications of this protein include glycosylation on the asparagines at the 82, 141, 252, 257, 278, and 289 amino acid locations.[8]
The protein encoded by this gene is a member of theTNF-receptor superfamily. This receptor has been shown to activateNF-κB andMAPK8/JNK, and induce cellapoptosis. Through itsdeath domain, this receptor interacts withTRADD 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 inT helper cell activation, and may be involved in inflammation and immune regulation.[6] The DR6 is an alpha-helical integral membrane receptor protein that shows evidence that it has something to do with the inhibition of blood vessels forming on tumors which would allow them to grow larger. Death receptor 6 gets a chemical message and starts a signaling pathway that causes apoptosis, also known as cell death, to occur.[9] It is also expressed in endothelial cells. Tumor cells can induce, through exposition of amyloid precursor protein (APP), DR6-mediated endothelial cellnecroptosis allowing tumors metastasis.
The free serum levels of this DR6 are heightened with anti-cell death factors in patients that have later stage ovarian cancer.[10]
DR6 is also thought to be involved inneurodegeneration in the brain that causesAlzheimer's disease as well assignal transduction in stress response and cellular survival.[11] 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 thatBaxtranslocation is necessary for the apoptosis triggered by DR6, but through an unknown pathway instead of the traditional pathways of intrinsic versus extrinsic.[citation needed] APP (amyloid precursor protein) is the natural ligand of DR6 and is first cleaved intoAβ and N-APP. N-APP is the fragment that interacts with DR6 to trigger axonal degradation in Alzheimer's patients.[12] This pathway is essentially "hi-jacked" in the aging brain.
^Daniel PT, Wieder T, Sturm I, Schulze-Osthoff K (Jul 2001). "The kiss of death: promises and failures of death receptors and ligands in cancer therapy".Leukemia.15 (7):1022–1032.doi:10.1038/sj.leu.2402169.PMID11455969.S2CID24538645.
^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)".Journal of Molecular Biology.409 (2):189–201.doi:10.1016/j.jmb.2011.03.048.PMID21463639.
Kasof GM, Lu JJ, Liu D, Speer B, Mongan KN, Gomes BC, et al. (November 2001). "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.PMID11753679.S2CID25063448.
Mai T, Wang X, Zhang Z, Xin D, Na Y, Guo Y (October 2004). "Androgen receptor coregulator ARA267-alpha interacts with death receptor-6 revealed by the yeast two-hybrid".Science in China. Series C, Life Sciences.47 (5):442–448.doi:10.1360/03yc0214.PMID15623156.
Klíma M, Zájedová J, Doubravská L, Andera L (October 2009). "Functional analysis of the posttranslational modifications of the death receptor 6".Biochimica et Biophysica Acta.1793 (10):1579–1587.doi:10.1016/j.bbamcr.2009.07.008.PMID19654028.
