View source for MAP3K8

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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Mitogen-activated protein kinase kinase kinase 8''' is an [[enzyme]] that in humans is encoded by the ''MAP3K8'' [[gene]].<ref name="pmid2072910">{{cite journal | vauthors = Miyoshi J, Higashi T, Mukai H, Ohuchi T, Kakunaga T | title = Structure and transforming potential of the human cot oncogene encoding a putative protein kinase | journal = Molecular and Cellular Biology | volume = 11 | issue = 8 | pages = 4088–96 | date = Aug 1991 | pmid = 2072910 | pmc = 361219 | doi =  10.1128/mcb.11.8.4088}}</ref><ref name="pmid8479752">{{cite journal | vauthors = Chan AM, Chedid M, McGovern ES, Popescu NC, Miki T, Aaronson SA | title = Expression cDNA cloning of a serine kinase transforming gene | journal = Oncogene | volume = 8 | issue = 5 | pages = 1329–33 | date = May 1993 | pmid = 8479752 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: MAP3K8 mitogen-activated protein kinase kinase kinase 8| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1326}}</ref>
== Function ==
The gene was identified by its oncogenic transforming activity in cells. The encoded protein is a member of the [[serine/threonine-specific protein kinase]] family. This kinase can activate [[ERK1]], [[ERK2]] and [[p38 MAP kinases]].<ref name=pmid23954936>{{cite journal | vauthors = Arthur JS, Ley SC | title = Mitogen-activated protein kinases in innate immunity. |  journal = Nature Reviews Immunology | volume = 13| issue = 9 | pages = 679–92 | date = Sep 2013 | pmid = 23954936 |doi=10.1038/nri3495 | s2cid = 12049695 }}</ref><ref name=pmid27402796>{{cite journal | vauthors = Pattison MJ, Mitchell O, Flynn HR, Chen CS, Yang HT, Ben-Addi H, Boeing S, Snijders AP, Ley SC | title = TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase. | journal = Biochemical Journal | volume = 473 | issue = 18 | pages = 2845–61 | date = Sep 2016 | pmid = 27402796 |doi=10.1042/BCJ20160502 | pmc=5095906}}</ref> This kinase was shown to activate [[IkappaB kinase]]s, and thus induce the nuclear production of [[NF-kappaB]]. This kinase was also found to promote the production of TNF-alpha and IL-2 during T lymphocyte activation. Studies of a similar gene in rat suggested the direct involvement of this kinase in the proteolysis of NF-kappaB1, p105 (NFKB1). This gene may also start transcription at a downstream in-frame translation start codon, and thus produce an isoform containing a shorter N-terminus. The shorter isoform has been shown to display weaker transforming activity.<ref name="entrez" /> In mice, the gene is known as '''TPL2''' and is a tumor-suppressor gene whose absence contributes to the development and progression of cancer.<ref>{{cite journal|last=DeCicco-Skinner|first=Kathleen|title=Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis|pmc=3460638|pmid=20935675|doi=10.1038/onc.2010.447|volume=30|issue=4|year=2011|journal=Oncogene|pages=389–97}}</ref> However, it functions in other organs as a oncogene, promoting cancer.<ref>{{cite journal|last=DeCicco-Skinner|first=Kathleen|title=Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis|pmc=3460638|pmid=20935675|doi=10.1038/onc.2010.447|volume=30|issue=4|year=2011|journal=Oncogene|pages=389–97}}</ref>
== Interactions ==
MAP3K8 has been shown to [[Protein-protein interaction|interact]] with [[AKT1]],<ref name=pmid12138205>{{cite journal | vauthors = Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A | title = Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription | journal = Molecular and Cellular Biology | volume = 22 | issue = 16 | pages = 5962–74 | date = Aug 2002 | pmid = 12138205 | pmc = 133991 | doi = 10.1128/MCB.22.16.5962-5974.2002 }}</ref> [[CHUK]],<ref name=pmid10072079>{{cite journal | vauthors = Lin X, Cunningham ET, Mu Y, Geleziunas R, Greene WC | title = The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases | journal = Immunity | volume = 10 | issue = 2 | pages = 271–80 | date = Feb 1999 | pmid = 10072079 | doi = 10.1016/S1074-7613(00)80027-8 | doi-access = free }}</ref> [[NFKB2]],<ref name=pmid14743216>{{cite journal | vauthors = Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G | title = A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway | journal = Nature Cell Biology | volume = 6 | issue = 2 | pages = 97–105 | date = Feb 2004 | pmid = 14743216 | doi = 10.1038/ncb1086 | s2cid = 11683986 }}</ref> [[NFKB1]],<ref name=pmid14743216/><ref name=pmid9950430>{{cite journal | vauthors = Belich MP, Salmerón A, Johnston LH, Ley SC | title = TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105 | journal = Nature | volume = 397 | issue = 6717 | pages = 363–8 | date = Jan 1999 | pmid = 9950430 | doi = 10.1038/16946 | bibcode = 1999Natur.397..363B | s2cid = 4391108 }}</ref> [[C22orf25]]<ref>{{cite web|title=Molecular Interaction Database|url=http://mint.bio.uniroma2.it/mint/Welcome.do|access-date=2012-05-08|archive-url=https://web.archive.org/web/20060506110418/http://mint.bio.uniroma2.it/mint/Welcome.do|archive-date=2006-05-06|url-status=dead}}</ref> and [[TNIP2]].<ref name=pmid15169888>{{cite journal | vauthors = Lang V, Symons A, Watton SJ, Janzen J, Soneji Y, Beinke S, Howell S, Ley SC | title = ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability | journal = Molecular and Cellular Biology | volume = 24 | issue = 12 | pages = 5235–48 | date = Jun 2004 | pmid = 15169888 | doi = 10.1128/MCB.24.12.5235-5248.2004 | pmc=419892}}</ref>
== References ==
{{reflist}}
== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Aoki M, Akiyama T, Miyoshi J, Toyoshima K | title = Identification and characterization of protein products of the cot oncogene with serine kinase activity | journal = Oncogene | volume = 6 | issue = 9 | pages = 1515–9 | date = Sep 1991 | pmid = 1833717 }}
* {{cite journal | vauthors = Aoki M, Hamada F, Sugimoto T, Sumida S, Akiyama T, Toyoshima K | title = The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation | journal = The Journal of Biological Chemistry | volume = 268 | issue = 30 | pages = 22723–32 | date = Oct 1993 | doi = 10.1016/S0021-9258(18)41587-6 | pmid = 8226782 | doi-access = free }}
* {{cite journal | vauthors = Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC | title = Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase | journal = The EMBO Journal | volume = 15 | issue = 4 | pages = 817–26 | date = Feb 1996 | pmid = 8631303 | pmc = 450280 | doi =  10.1002/j.1460-2075.1996.tb00417.x}}
* {{cite journal | vauthors = Ballester A, Tobeña R, Lisbona C, Calvo V, Alemany S | title = Cot kinase regulation of IL-2 production in Jurkat T cells | journal = Journal of Immunology | volume = 159 | issue = 4 | pages = 1613–8 | date = Aug 1997 | doi = 10.4049/jimmunol.159.4.1613 | pmid = 9257820 | doi-access = free }}
* {{cite journal | vauthors = Ballester A, Velasco A, Tobeña R, Alemany S | title = Cot kinase activates tumor necrosis factor-alpha gene expression in a cyclosporin A-resistant manner | journal = The Journal of Biological Chemistry | volume = 273 | issue = 23 | pages = 14099–106 | date = Jun 1998 | pmid = 9603908 | doi = 10.1074/jbc.273.23.14099 | doi-access = free }}
* {{cite journal | vauthors = Lin X, Mu Y, Cunningham ET, Marcu KB, Geleziunas R, Greene WC | title = Molecular determinants of NF-kappaB-inducing kinase action | journal = Molecular and Cellular Biology | volume = 18 | issue = 10 | pages = 5899–907 | date = Oct 1998 | pmid = 9742107 | pmc = 109176 | doi =  10.1128/mcb.18.10.5899}}
* {{cite journal | vauthors = Belich MP, Salmerón A, Johnston LH, Ley SC | title = TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105 | journal = Nature | volume = 397 | issue = 6717 | pages = 363–8 | date = Jan 1999 | pmid = 9950430 | doi = 10.1038/16946 | bibcode = 1999Natur.397..363B | s2cid = 4391108 }}
* {{cite journal | vauthors = Lin X, Cunningham ET, Mu Y, Geleziunas R, Greene WC | title = The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases | journal = Immunity | volume = 10 | issue = 2 | pages = 271–80 | date = Feb 1999 | pmid = 10072079 | doi = 10.1016/S1074-7613(00)80027-8 | doi-access = free }}
* {{cite journal | vauthors = Chiariello M, Marinissen MJ, Gutkind JS | title = Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation | journal = Molecular and Cellular Biology | volume = 20 | issue = 5 | pages = 1747–58 | date = Mar 2000 | pmid = 10669751 | pmc = 85357 | doi = 10.1128/MCB.20.5.1747-1758.2000 }}
* {{cite journal | vauthors = Sánchez-Góngora E, Lisbona C, de Gregorio R, Ballester A, Calvo V, Pérez-Jurado L, Alemany S | title = COT kinase proto-oncogene expression in T cells: implication of the JNK/SAPK signal transduction pathway in COT promoter activation | journal = The Journal of Biological Chemistry | volume = 275 | issue = 40 | pages = 31379–86 | date = Oct 2000 | pmid = 10896655 | doi = 10.1074/jbc.M000382200 | doi-access = free }}
* {{cite journal | vauthors = Luftig MA, Cahir-McFarland E, Mosialos G, Kieff E | title = Effects of the NIK aly mutation on NF-kappaB activation by the Epstein-Barr virus latent infection membrane protein, lymphotoxin beta receptor, and CD40 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 18 | pages = 14602–6 | date = May 2001 | pmid = 11278268 | doi = 10.1074/jbc.C100103200 | doi-access = free }}
* {{cite journal | vauthors = Eliopoulos AG, Davies C, Blake SS, Murray P, Najafipour S, Tsichlis PN, Young LS | title = The oncogenic protein kinase Tpl-2/Cot contributes to Epstein-Barr virus-encoded latent infection membrane protein 1-induced NF-kappaB signaling downstream of TRAF2 | journal = Journal of Virology | volume = 76 | issue = 9 | pages = 4567–79 | date = May 2002 | pmid = 11932422 | pmc = 155061 | doi = 10.1128/JVI.76.9.4567-4579.2002 }}
* {{cite journal | vauthors = Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A | title = Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription | journal = Molecular and Cellular Biology | volume = 22 | issue = 16 | pages = 5962–74 | date = Aug 2002 | pmid = 12138205 | pmc = 133991 | doi = 10.1128/MCB.22.16.5962-5974.2002 }}
* {{cite journal | vauthors = Waterfield MR, Zhang M, Norman LP, Sun SC | title = NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase | journal = Molecular Cell | volume = 11 | issue = 3 | pages = 685–94 | date = Mar 2003 | pmid = 12667451 | doi = 10.1016/S1097-2765(03)00070-4 | doi-access = free }}
* {{cite journal | vauthors = Channavajhala PL, Wu L, Cuozzo JW, Hall JP, Liu W, Lin LL, Zhang Y | title = Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling | journal = The Journal of Biological Chemistry | volume = 278 | issue = 47 | pages = 47089–97 | date = Nov 2003 | pmid = 12975377 | doi = 10.1074/jbc.M306002200 | doi-access = free }}
* {{cite journal | vauthors = Gándara ML, López P, Hernando R, Castaño JG, Alemany S | title = The COOH-terminal domain of wild-type Cot regulates its stability and kinase specific activity | journal = Molecular and Cellular Biology | volume = 23 | issue = 20 | pages = 7377–90 | date = Oct 2003 | pmid = 14517305 | pmc = 230324 | doi = 10.1128/MCB.23.20.7377-7390.2003 }}
* {{cite journal | vauthors = Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G | title = A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway | journal = Nature Cell Biology | volume = 6 | issue = 2 | pages = 97–105 | date = Feb 2004 | pmid = 14743216 | doi = 10.1038/ncb1086 | s2cid = 11683986 }}
{{refend}}
{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
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[[Category:EC 2.7.11]]