MAP3K8

Mitogen-activated protein kinase kinase kinase 8
Identifiers
Symbols	MAP3K8; COT; EST; ESTF; FLJ10486; MEKK8; TPL2; Tpl-2; c-COT
External IDs	OMIM: 191195 MGI: 1346878 HomoloGene: 3812 GeneCards: MAP3K8 Gene
EC number	2.7.11.25
Gene Ontology Molecular function • nucleotide binding • magnesium ion binding • protein serine/threonine kinase activity • MAP kinase kinase kinase activity • protein binding • ATP binding Cellular component • cytoplasm • cytosol • cytosol Biological process • protein phosphorylation • cell cycle • signal transduction • T cell costimulation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1326	26410
Ensembl	ENSG00000107968	ENSMUSG00000024235
UniProt	P41279	Q3T9M0
RefSeq (mRNA)	NM_005204	NM_007746.2
RefSeq (protein)	NP_005195	NP_031772.1
Location (UCSC)	Chr 10: 30.72 – 30.75 Mb	Chr 18: 4.33 – 4.35 Mb
PubMed search	[1]	[2]

Mitogen-activated protein kinase 8 is an enzyme that in humans is encoded by the MAP3K8 gene.

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 MAP kinase and JNK kinase pathways. 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 utilize 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.

Interactions

MAP3K8 has been shown to interact with AKT1, CHUK, NFKB2 and NFKB1.

Further reading

• Aoki M, Akiyama T, Miyoshi J, Toyoshima K (1991). "Identification and characterization of protein products of the cot oncogene with serine kinase activity". Oncogene 6 (9): 1515–9. PMID 1833717. 
• Aoki M, Hamada F, Sugimoto T, et al. (1993). "The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation". J. Biol. Chem. 268 (30): 22723–32. PMID 8226782. 
• Salmeron A, Ahmad TB, Carlile GW, et al. (1996). "Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase". EMBO J. 15 (4): 817–26. PMC 450280. PMID 8631303. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=450280. 
• Ballester A, Tobeña R, Lisbona C, et al. (1997). "Cot kinase regulation of IL-2 production in Jurkat T cells". J. Immunol. 159 (4): 1613–8. PMID 9257820. 
• Ballester A, Velasco A, Tobeña R, Alemany S (1998). "Cot kinase activates tumor necrosis factor-alpha gene expression in a cyclosporin A-resistant manner". J. Biol. Chem. 273 (23): 14099–106. doi:10.1074/jbc.273.23.14099. PMID 9603908. 
• Lin X, Mu Y, Cunningham ET, et al. (1998). "Molecular determinants of NF-kappaB-inducing kinase action". Mol. Cell. Biol. 18 (10): 5899–907. PMC 109176. PMID 9742107. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=109176. 
• Belich MP, Salmerón A, Johnston LH, Ley SC (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. PMID 9950430. 
• Lin X, Cunningham ET, Mu Y, et al. (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. PMID 10072079. 
• Chiariello M, Marinissen MJ, Gutkind JS (2000). "Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation". Mol. Cell. Biol. 20 (5): 1747–58. doi:10.1128/MCB.20.5.1747-1758.2000. PMC 85357. PMID 10669751. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=85357. 
• Sánchez-Góngora E, Lisbona C, de Gregorio R, et al. (2000). "COT kinase proto-oncogene expression in T cells: implication of the JNK/SAPK signal transduction pathway in COT promoter activation". J. Biol. Chem. 275 (40): 31379–86. doi:10.1074/jbc.M000382200. PMID 10896655. 
• Luftig MA, Cahir-McFarland E, Mosialos G, Kieff E (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". J. Biol. Chem. 276 (18): 14602–6. doi:10.1074/jbc.C100103200. PMID 11278268. 
• Eliopoulos AG, Davies C, Blake SS, et al. (2002). "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". J. Virol. 76 (9): 4567–79. doi:10.1128/JVI.76.9.4567-4579.2002. PMC 155061. PMID 11932422. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=155061. 
• Kane LP, Mollenauer MN, Xu Z, et al. (2002). "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription". Mol. Cell. Biol. 22 (16): 5962–74. doi:10.1128/MCB.22.16.5962-5974.2002. PMC 133991. PMID 12138205. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=133991. 
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241. 
• Waterfield MR, Zhang M, Norman LP, Sun SC (2003). "NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase". Mol. Cell 11 (3): 685–94. doi:10.1016/S1097-2765(03)00070-4. PMID 12667451. 
• Channavajhala PL, Wu L, Cuozzo JW, et al. (2004). "Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling". J. Biol. Chem. 278 (47): 47089–97. doi:10.1074/jbc.M306002200. PMID 12975377. 
• Gándara ML, López P, Hernando R, et al. (2003). "The COOH-terminal domain of wild-type Cot regulates its stability and kinase specific activity". Mol. Cell. Biol. 23 (20): 7377–90. doi:10.1128/MCB.23.20.7377-7390.2003. PMC 230324. PMID 14517305. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=230324. 
• Bouwmeester T, Bauch A, Ruffner H, et al. (2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216.