View source for Death receptor 6

{{redirect|DR6|the highway in the [[Dominican Republic]]|DR-6|the debug register|DR6 register}}
{{Infobox_gene}}
'''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.<ref name="pmid9714541">{{cite journal | vauthors = Pan G, Bauer JH, Haridas V, Wang S, Liu D, Yu G, Vincenz C, Aggarwal BB, Ni J, Dixit VM | title = Identification and functional characterization of DR6, a novel death domain-containing TNF receptor | journal = FEBS Letters | volume = 431 | issue = 3 | pages = 351–6 | date = July 1998 | pmid = 9714541 | doi = 10.1016/S0014-5793(98)00791-1 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/116991/1/feb2s0014579398007911.pdf }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TNFRSF21 tumor necrosis factor receptor superfamily, member 21| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=27242| accessdate = }}</ref> It is mostly expressed in the [[thymus]], [[spleen]] and [[white blood cells]].<ref>{{cite book|last1=Salido|first1=Ginés María|last2=Rosado|first2=Juan Antonio|title=Apoptosis: Involvement of Oxidative Stress and Intracellular Ca2+ Homeostasis|date=2009|publisher=[[Springer Science+Business Media|Springer]]|location=Heidelberg, Germany|page=37|url=https://books.google.co.uk/books?id=eF-sII0kHhsC&pg=PA37}}</ref> 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 aspargenines at the 82, 141, 252, 257, 278, and 289 amino acid locations.<ref name = "Mungall_2003"/>

== Function ==

The protein encoded by this gene is a member of the [[tumor necrosis factor receptor|TNF-receptor]] superfamily. This receptor has been shown to activate [[NF-κB]] and [[MAPK8]]/[[c-Jun N-terminal kinases|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. [[Gene knockout|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.<ref name="entrez" /> 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.<ref name="pmid11455969">{{cite journal | vauthors = Daniel PT, Wieder T, Sturm I, Schulze-Osthoff K | title = The kiss of death: promises and failures of death receptors and ligands in cancer therapy | journal = Leukemia | volume = 15 | issue = 7 | pages = 1022–32 | year = 2001 | pmid = 11455969 | doi = 10.1038/sj.leu.2402169| url = }}</ref> It is also expressed in endothelial cells. Tumor cells can induce, through exposition of amyloid precursor protein (APP), DR6-mediated endothelial cell [[necroptosis]] allowing tumors metastasis.

== Clinical significance ==

The free serum levels of this DR6 are heightened with anti-cell death factors in patients that have later stage ovarian cancer.<ref name="pmid21617380">{{cite journal | vauthors = Sasaroli D, Gimotty PA, Pathak HB, Hammond R, Kougioumtzidou E, Katsaros D, Buckanovich R, Devarajan K, Sandaltzopoulos R, Godwin AK, Scholler N, Coukos G | title = Novel surface targets and serum biomarkers from the ovarian cancer vasculature | journal = Cancer Biology & Therapy | volume = 12 | issue = 3 | pages = 169–80 | year = 2011 | pmid = 21617380 | pmc = 3230481 | doi = 10.4161/cbt.12.3.16260}}</ref>

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.<ref name="pmid21463639">{{cite journal | vauthors = Kuester M, Kemmerzehl S, Dahms SO, Roeser D, Than ME | title = The crystal structure of death receptor 6 (DR6): a potential receptor of the amyloid precursor protein (APP) | journal = Journal of Molecular Biology | volume = 409 | issue = 2 | pages = 189–201 | date = June 2011 | pmid = 21463639 | doi = 10.1016/j.jmb.2011.03.048 }}</ref> 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 [[Bcl-2-associated X protein|Bax]] [[Protein targeting#Protein translocation|translocation]] is necessary for the apoptosis triggered by DR6, but through an unknown pathway instead of the traditional pathways of intrinsic versus extrinsic.<ref>{{cite journal | vauthors = Cetin F |title=Role of oxidative stress in Aβ animal model of Alzheimer’s disease: Vicious circle of apoptosis, nitric oxide and age | year = 2012 | journal = INTECH | url = http://www.intechopen.com/books//role-of-oxidative-stress-in-a-animal-model-of-alzheimer-s-disease-vicious-circle-of-apoptosis-nitric }}</ref>  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.<ref name=Osherovich>{{cite journal | vauthors = Osherovich L | title = Genentech's new parADigm | journal = Science-Business eXchange | year=2009 | volume = 2 | issue = 8 | pages = 1–5 | doi = 10.1038/scibx.2009.300 }}</ref>   This pathway is essentially "hi-jacked" in the aging brain.

== References ==
{{reflist|33em|refs =

<ref name = "Mungall_2003">{{cite journal | vauthors = Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, Wilming L, Jones MC, Horton R, Hunt SE, Scott CE, Gilbert JG, Clamp ME, Bethel G, Milne S, Ainscough R, Almeida JP, Ambrose KD, Andrews TD, Ashwell RI, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Barker DJ, Barlow KF, Bates K, Beare DM, Beasley H, Beasley O, Bird CP, Blakey S, Bray-Allen S, Brook J, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Carder C, Carter NP, Chapman JC, Clark SY, Clark G, Clee CM, Clegg S, Cobley V, Collier RE, Collins JE, Colman LK, Corby NR, Coville GJ, Culley KM, Dhami P, Davies J, Dunn M, Earthrowl ME, Ellington AE, Evans KA, Faulkner L, Francis MD, Frankish A, Frankland J, French L, Garner P, Garnett J, Ghori MJ, Gilby LM, Gillson CJ, Glithero RJ, Grafham DV, Grant M, Gribble S, Griffiths C, Griffiths M, Hall R, Halls KS, Hammond S, Harley JL, Hart EA, Heath PD, Heathcott R, Holmes SJ, Howden PJ, Howe KL, Howell GR, Huckle E, Humphray SJ, Humphries MD, Hunt AR, Johnson CM, Joy AA, Kay M, Keenan SJ, Kimberley AM, King A, Laird GK, Langford C, Lawlor S, Leongamornlert DA, Leversha M, Lloyd CR, Lloyd DM, Loveland JE, Lovell J, Martin S, Mashreghi-Mohammadi M, Maslen GL, Matthews L, McCann OT, McLaren SJ, McLay K, McMurray A, Moore MJ, Mullikin JC, Niblett D, Nickerson T, Novik KL, Oliver K, Overton-Larty EK, Parker A, Patel R, Pearce AV, Peck AI, Phillimore B, Phillips S, Plumb RW, Porter KM, Ramsey Y, Ranby SA, Rice CM, Ross MT, Searle SM, Sehra HK, Sheridan E, Skuce CD, Smith S, Smith M, Spraggon L, Squares SL, Steward CA, Sycamore N, Tamlyn-Hall G, Tester J, Theaker AJ, Thomas DW, Thorpe A, Tracey A, Tromans A, Tubby B, Wall M, Wallis JM, West AP, White SS, Whitehead SL, Whittaker H, Wild A, Willey DJ, Wilmer TE, Wood JM, Wray PW, Wyatt JC, Young L, Younger RM, Bentley DR, Coulson A, Durbin R, Hubbard T, Sulston JE, Dunham I, Rogers J, Beck S | display-authors = 6  | title = The DNA sequence and analysis of human chromosome 6 | journal = Nature | volume = 425 | issue = 6960 | pages = 805–11 | date = October 2003 | pmid = 14574404 | doi = 10.1038/nature02055 }}
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== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Pan G, Bauer JH, Haridas V, Wang S, Liu D, Yu G, Vincenz C, Aggarwal BB, Ni J, Dixit VM | title = Identification and functional characterization of DR6, a novel death domain-containing TNF receptor | journal = FEBS Letters | volume = 431 | issue = 3 | pages = 351–6 | date = July 1998 | pmid = 9714541 | doi = 10.1016/S0014-5793(98)00791-1 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/116991/1/feb2s0014579398007911.pdf }}
* {{cite journal | vauthors = Liu J, Na S, Glasebrook A, Fox N, Solenberg PJ, Zhang Q, Song HY, Yang DD | title = Enhanced CD4+ T cell proliferation and Th2 cytokine production in DR6-deficient mice | journal = Immunity | volume = 15 | issue = 1 | pages = 23–34 | date = July 2001 | pmid = 11485735 | doi = 10.1016/S1074-7613(01)00162-5 }}
* {{cite journal | vauthors = Zhao H, Yan M, Wang H, Erickson S, Grewal IS, Dixit VM | title = Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice | journal = The Journal of Experimental Medicine | volume = 194 | issue = 10 | pages = 1441–8 | date = November 2001 | pmid = 11714751 | pmc = 2193683 | doi = 10.1084/jem.194.10.1441 }}
* {{cite journal | vauthors = Kasof GM, Lu JJ, Liu D, Speer B, Mongan KN, Gomes BC, Lorenzi MV | title = Tumor necrosis factor-alpha induces the expression of DR6, a member of the TNF receptor family, through activation of NF-kappaB | journal = Oncogene | volume = 20 | issue = 55 | pages = 7965–75 | date = November 2001 | pmid = 11753679 | doi = 10.1038/sj.onc.1204985 }}
* {{cite journal | vauthors = Mai T, Wang X, Zhang Z, Xin D, Na Y, Guo Y | title = Androgen receptor coregulator ARA267-alpha interacts with death receptor-6 revealed by the yeast two-hybrid | journal = Science in China Series C: Life Sciences | volume = 47 | issue = 5 | pages = 442–8 | date = October 2004 | pmid = 15623156 | doi = 10.1360/03yc0214 }}
* {{cite journal | vauthors = Klíma M, Zájedová J, Doubravská L, Andera L | title = Functional analysis of the posttranslational modifications of the death receptor 6 | journal = Biochimica et Biophysica Acta | volume = 1793 | issue = 10 | pages = 1579–87 | date = October 2009 | pmid = 19654028 | doi = 10.1016/j.bbamcr.2009.07.008 }}
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{{NLM content}}
{{PDB Gallery|geneid=27242}}
{{Tumor necrosis factor receptor superfamily}}
{{Cytokine receptor modulators}}

[[Category:TNF receptor family]]


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