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Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the MAP3K8gene.[5][6][7]
Function
This gene was identified by its oncogenic transforming activity in cells. The encoded protein is a member of the serine/threonine protein kinase family. This kinase can activate both the ERK1/2 and p38 MAP kinases.[8][9] This kinase was shown to activate IkappaB kinases, 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.[7] In mice, this gene is known as Tpl2 and it is a tumor suppressor gene whose absence contributes to the development and progression of cancer.[10]
^Lin X, Cunningham ET, Mu Y, Geleziunas R, Greene WC (Feb 1999). "The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases". Immunity. 10 (2): 271–80. doi:10.1016/S1074-7613(00)80027-8. PMID10072079.
^ abBouwmeester 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 (Feb 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID14743216.
^Belich MP, Salmerón A, Johnston LH, Ley SC (Jan 1999). "TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105". Nature. 397 (6717): 363–8. doi:10.1038/16946. PMID9950430.
Aoki M, Akiyama T, Miyoshi J, Toyoshima K (Sep 1991). "Identification and characterization of protein products of the cot oncogene with serine kinase activity". Oncogene. 6 (9): 1515–9. PMID1833717.
Aoki M, Hamada F, Sugimoto T, Sumida S, Akiyama T, Toyoshima K (Oct 1993). "The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation". The Journal of Biological Chemistry. 268 (30): 22723–32. PMID8226782.
Ballester A, Tobeña R, Lisbona C, Calvo V, Alemany S (Aug 1997). "Cot kinase regulation of IL-2 production in Jurkat T cells". Journal of Immunology. 159 (4): 1613–8. PMID9257820.
Ballester A, Velasco A, Tobeña R, Alemany S (Jun 1998). "Cot kinase activates tumor necrosis factor-alpha gene expression in a cyclosporin A-resistant manner". The Journal of Biological Chemistry. 273 (23): 14099–106. doi:10.1074/jbc.273.23.14099. PMID9603908.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Belich MP, Salmerón A, Johnston LH, Ley SC (Jan 1999). "TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105". Nature. 397 (6717): 363–8. doi:10.1038/16946. PMID9950430.
Lin X, Cunningham ET, Mu Y, Geleziunas R, Greene WC (Feb 1999). "The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases". Immunity. 10 (2): 271–80. doi:10.1016/S1074-7613(00)80027-8. PMID10072079.
Sánchez-Góngora E, Lisbona C, de Gregorio R, Ballester A, Calvo V, Pérez-Jurado L, Alemany S (Oct 2000). "COT kinase proto-oncogene expression in T cells: implication of the JNK/SAPK signal transduction pathway in COT promoter activation". The Journal of Biological Chemistry. 275 (40): 31379–86. doi:10.1074/jbc.M000382200. PMID10896655.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Luftig MA, Cahir-McFarland E, Mosialos G, Kieff E (May 2001). "Effects of the NIK aly mutation on NF-kappaB activation by the Epstein-Barr virus latent infection membrane protein, lymphotoxin beta receptor, and CD40". The Journal of Biological Chemistry. 276 (18): 14602–6. doi:10.1074/jbc.C100103200. PMID11278268.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Waterfield MR, Zhang M, Norman LP, Sun SC (Mar 2003). "NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase". Molecular Cell. 11 (3): 685–94. doi:10.1016/S1097-2765(03)00070-4. PMID12667451.
Channavajhala PL, Wu L, Cuozzo JW, Hall JP, Liu W, Lin LL, Zhang Y (Nov 2003). "Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling". The Journal of Biological Chemistry. 278 (47): 47089–97. doi:10.1074/jbc.M306002200. PMID12975377.{{cite journal}}: CS1 maint: unflagged free DOI (link)
