MAP3K8

Mitogen-activated protein kinase kinase kinase 8
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4Y83​, 4Y85​
Identifiers
Symbols	MAP3K8 ; AURA2; COT; EST; ESTF; MEKK8; TPL2; Tpl-2; c-COT
External IDs	OMIM: 191195 MGI: 1346878 HomoloGene: 3812 ChEMBL: 4899 GeneCards: MAP3K8 Gene
EC number	2.7.11.25
Gene ontology Molecular function • magnesium ion binding • protein serine/threonine kinase activity • MAP kinase kinase kinase activity • protein binding • ATP binding Cellular component • cytoplasm • cytosol Biological process • MAPK cascade • activation of MAPKK activity • protein phosphorylation • cell cycle • regulation of mitotic cell cycle • signal transduction by protein phosphorylation • stress-activated protein kinase signaling cascade • T cell costimulation • activation of protein kinase activity • regulation of apoptotic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1326	26410
Ensembl	ENSG00000107968	ENSMUSG00000024235
UniProt	P41279	Q07174
RefSeq (mRNA)	NM_001244134	NM_007746
RefSeq (protein)	NP_001231063	NP_031772
Location (UCSC)	Chr 10: 30.43 – 30.46 Mb	Chr 18: 4.33 – 4.35 Mb
PubMed search

Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the MAP3K8 gene.^[1][2][3]

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 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 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.^[3] 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.^[4]

Interactions

MAP3K8 has been shown to interact with AKT1,^[5] CHUK,^[6] NFKB2,^[7] NFKB1,^[7][8] and C22orf25.^[9]

References

1. Miyoshi J, Higashi T, Mukai H, Ohuchi T, Kakunaga T (Aug 1991). "Structure and transforming potential of the human cot oncogene encoding a putative protein kinase". Molecular and Cellular Biology 11 (8): 4088–96. doi:10.1128/mcb.11.8.4088. PMC 361219. PMID 2072910.
2. Chan AM, Chedid M, McGovern ES, Popescu NC, Miki T, Aaronson SA (May 1993). "Expression cDNA cloning of a serine kinase transforming gene". Oncogene 8 (5): 1329–33. PMID 8479752.
3. "Entrez Gene: MAP3K8 mitogen-activated protein kinase kinase kinase 8".
4. DeCicco-Skinner, Kathleen. "Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis".
5. Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A (Aug 2002). "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription". Molecular and Cellular Biology 22 (16): 5962–74. doi:10.1128/MCB.22.16.5962-5974.2002. PMC 133991. PMID 12138205.
6. 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. PMID 10072079.
7. 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 (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. PMID 14743216.
8. 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. PMID 9950430.
9. "Molecular Interaction Database".

Further reading

• 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. PMID 1833717.
• 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. PMID 8226782.
• Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC (Feb 1996). "Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase". The EMBO Journal 15 (4): 817–26. PMC 450280. PMID 8631303.
• 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. PMID 9257820.
• 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. PMID 9603908.
• Lin X, Mu Y, Cunningham ET, Marcu KB, Geleziunas R, Greene WC (Oct 1998). "Molecular determinants of NF-kappaB-inducing kinase action". Molecular and Cellular Biology 18 (10): 5899–907. doi:10.1128/mcb.18.10.5899. PMC 109176. PMID 9742107.
• 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. PMID 9950430.
• 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. PMID 10072079.
• Chiariello M, Marinissen MJ, Gutkind JS (Mar 2000). "Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation". Molecular and Cellular Biology 20 (5): 1747–58. doi:10.1128/MCB.20.5.1747-1758.2000. PMC 85357. PMID 10669751.
• 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. PMID 10896655.
• 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. PMID 11278268.
• Eliopoulos AG, Davies C, Blake SS, Murray P, Najafipour S, Tsichlis PN, Young LS (May 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". Journal of Virology 76 (9): 4567–79. doi:10.1128/JVI.76.9.4567-4579.2002. PMC 155061. PMID 11932422.
• Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A (Aug 2002). "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription". Molecular and Cellular Biology 22 (16): 5962–74. doi:10.1128/MCB.22.16.5962-5974.2002. PMC 133991. PMID 12138205.
• 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. PMID 12667451.
• 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. PMID 12975377.
• Gándara ML, López P, Hernando R, Castaño JG, Alemany S (Oct 2003). "The COOH-terminal domain of wild-type Cot regulates its stability and kinase specific activity". Molecular and Cellular Biology 23 (20): 7377–90. doi:10.1128/MCB.23.20.7377-7390.2003. PMC 230324. PMID 14517305.
• 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 (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. PMID 14743216.