MAP3K8

MAP3K8

Available structures

Ortholog search: PDBe RCSB

List of PDB id codes
4Y83, 4Y85

Identifiers

MAP3K8, COT, EST, ESTF, MEKK8, TPL2, Tpl-2, c-COT, AURA2, mitogen-activated protein kinase kinase kinase 8, Tpl2

External IDs

OMIM: 191195; MGI: 1346878; HomoloGene: 3812; GeneCards: MAP3K8; OMA:MAP3K8 - orthologs

Gene location (Human)

Chr.	Chromosome 10 (human)^[1]

Band	10p11.23	Start	30,434,021 bp^[1]
Band	10p11.23	End	30,461,833 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 18 (mouse)^[2]

Band	18 A1\|18 2.73 cM	Start	4,331,327 bp^[2]
Band	18 A1\|18 2.73 cM	End	4,353,015 bp^[2]

RNA expression pattern

Human

Mouse (ortholog)

Top expressed in

gastric mucosa

mucosa of paranasal sinus

upper lobe of left lung

left uterine tube

germinal epithelium

monocyte

olfactory zone of nasal mucosa

Achilles tendon

tibial nerve

right lung

Top expressed in

granulocyte

saccule

lip

otic placode

skin of external ear

stroma of bone marrow

spleen

otic vesicle

hair follicle

subcutaneous adipose tissue

More reference expression data


More reference expression data

Gene ontology
Molecular function	transferase activity nucleotide binding protein kinase activity metal ion binding kinase activity protein binding ATP binding magnesium ion binding MAP kinase kinase kinase activity protein serine/threonine kinase activity
Cellular component	cytosol cytoplasm
Biological process	phosphorylation immune system process T cell costimulation stress-activated MAPK cascade cell cycle signal transduction protein phosphorylation regulation of mitotic cell cycle stress-activated protein kinase signaling cascade activation of protein kinase activity regulation of apoptotic process interleukin-1-mediated signaling pathway
Sources:Amigo / QuickGO

Species

Human

Mouse


1326


26410


ENSG00000107968


ENSMUSG00000024235


P41279


Q07174

RefSeq (mRNA)


NM_001244134 NM_005204 NM_001320961


NM_007746

RefSeq (protein)


NP_001231063 NP_001307890 NP_005195


NP_031772

Location (UCSC)

Chr 10: 30.43 – 30.46 Mb

Chr 18: 4.33 – 4.35 Mb

PubMed search

^[3]

^[4]

View/Edit Human

View/Edit Mouse

Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the MAP3K8 gene.^[5]^[6]^[7]

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.^[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, the gene is known as TPL2 and is a tumor-suppressor gene whose absence contributes to the development and progression of cancer.^[10] However, it functions in other organs as a oncogene, promoting cancer.^[11]

Interactions

MAP3K8 has been shown to interact with AKT1,^[12] CHUK,^[13] NFKB2,^[14] NFKB1,^[14]^[15] C22orf25^[16] and TNIP2.^[17]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000107968 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000024235 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ 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.
^ ^a ^b "Entrez Gene: MAP3K8 mitogen-activated protein kinase kinase kinase 8".
^ Arthur JS, Ley SC (Sep 2013). "Mitogen-activated protein kinases in innate immunity". Nature Reviews Immunology. 13 (9): 679–92. doi:10.1038/nri3495. PMID 23954936. S2CID 12049695.
^ Pattison MJ, Mitchell O, Flynn HR, Chen CS, Yang HT, Ben-Addi H, Boeing S, Snijders AP, Ley SC (Sep 2016). "TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase". Biochemical Journal. 473 (18): 2845–61. doi:10.1042/BCJ20160502. PMC 5095906. PMID 27402796.
^ DeCicco-Skinner K (2011). "Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis". Oncogene. 30 (4): 389–97. doi:10.1038/onc.2010.447. PMC 3460638. PMID 20935675.
^ DeCicco-Skinner K (2011). "Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis". Oncogene. 30 (4): 389–97. doi:10.1038/onc.2010.447. PMC 3460638. PMID 20935675.
^ 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.
^ 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.
^ ^a ^b 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. S2CID 11683986.
^ 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. Bibcode:1999Natur.397..363B. doi:10.1038/16946. PMID 9950430. S2CID 4391108.
^ "Molecular Interaction Database". Archived from the original on 2006-05-06. Retrieved 2012-05-08.
^ Lang V, Symons A, Watton SJ, Janzen J, Soneji Y, Beinke S, Howell S, Ley SC (Jun 2004). "ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability". Molecular and Cellular Biology. 24 (12): 5235–48. doi:10.1128/MCB.24.12.5235-5248.2004. PMC 419892. PMID 15169888.

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. doi:10.1016/S0021-9258(18)41587-6. 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. doi:10.1002/j.1460-2075.1996.tb00417.x. 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. doi:10.4049/jimmunol.159.4.1613. 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. Bibcode:1999Natur.397..363B. doi:10.1038/16946. PMID 9950430. S2CID 4391108.
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. S2CID 11683986.

Kinases: Serine/threonine-specific protein kinases (EC 2.7.11-12)

Serine/threonine-specific protein kinases (EC 2.7.11.1-EC 2.7.11.20)

Non-specific serine/threonine protein kinases (EC 2.7.11.1)	LATS1 LATS2 MAST1 MAST2 STK38 STK38L CIT ROCK1 SGK SGK2 SGK3 Protein kinase B AKT1 AKT2 AKT3 Ataxia telangiectasia mutated mTOR EIF-2 kinases PKR HRI EIF2AK3 EIF2AK4 Wee1 WEE1
Pyruvate dehydrogenase kinase (EC 2.7.11.2)	PDK1 PDK2 PDK3 PDK4
Dephospho-(reductase kinase) kinase (EC 2.7.11.3)	AMP-activated protein kinase α PRKAA1 PRKAA2 β PRKAB1 PRKAB2 γ PRKAG1 PRKAG2 PRKAG3
3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring) kinase (EC 2.7.11.4)	BCKDK BCKDHA BCKDHB
(isocitrate dehydrogenase (NADP+)) kinase (EC 2.7.11.5)	IDH2 IDH3A IDH3B IDH3G
(tyrosine 3-monooxygenase) kinase (EC 2.7.11.6)	STK4
Myosin-heavy-chain kinase (EC 2.7.11.7)	Aurora kinase Aurora A kinase Aurora B kinase Aurora C kinase
Fas-activated serine/threonine kinase (EC 2.7.11.8)	FASTK STK10
Goodpasture-antigen-binding protein kinase (EC 2.7.11.9)	-
IκB kinase (EC 2.7.11.10)	CHUK IKK2 TBK1 IKBKE IKBKG IKBKAP
cAMP-dependent protein kinase (EC 2.7.11.11)	Protein kinase A PRKACG PRKACB PRKACA PRKY
cGMP-dependent protein kinase (EC 2.7.11.12)	Protein kinase G PRKG1
Protein kinase C (EC 2.7.11.13)	Protein kinase C Protein kinase Cζ PKC alpha PRKCB1 PRKCD PRKCE PRKCH PRKCG PRKCI PRKCQ Protein kinase N1 PKN2 PKN3
Rhodopsin kinase (EC 2.7.11.14)	Rhodopsin kinase
Beta adrenergic receptor kinase (EC 2.7.11.15)	Beta adrenergic receptor kinase Beta adrenergic receptor kinase-2
G-protein coupled receptor kinases (EC 2.7.11.16)	GRK4 GRK5 GRK6
Ca2+/calmodulin-dependent (EC 2.7.11.17)	BRSK2 CAMK1 CAMK1A CAMK1B CAMK1D CAMK1G CAMK2 CAMK2A CAMK2B CAMK2D CAMK2G CAMK4 MLCK CASK CHEK1 CHEK2 DAPK1 DAPK2 DAPK3 STK11 MAPKAPK2 MAPKAPK3 MAPKAPK5 MARK1 MARK2 MARK3 MARK4 MELK MKNK1 MKNK2 NUAK1 NUAK2 OBSCN PASK PHKG1 PHKG2 PIM1 PIM2 PKD1 PRKD2 PRKD3 PSKH1 SNF1LK2 KIAA0999 STK40 SNF1LK SNRK SPEG TSSK2 Kalirin TRIB1 TRIB2 TRIB3 TRIO Titin DCLK1
Myosin light-chain kinase (EC 2.7.11.18)	MYLK MYLK2 MYLK3 MYLK4
Phosphorylase kinase (EC 2.7.11.19)	PHKA1 PHKA2 PHKB PHKG1 PHKG2
Elongation factor 2 kinase (EC 2.7.11.20)	EEF2K STK19
Polo kinase (EC 2.7.11.21)	PLK1 PLK2 PLK3 PLK4

Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30)

Polo kinase (EC 2.7.11.21)	PLK1 PLK2 PLK3 PLK4
Cyclin-dependent kinase (EC 2.7.11.22)	CDK1 CDK2 CDKL2 CDK3 CDK4 CDK5 CDKL5 CDK6 CDK7 CDK8 CDK9 CDK10 CDK12 CDC2L5 PCTK1 PCTK2 PCTK3 PFTK1 CDC2L1
(RNA-polymerase)-subunit kinase (EC 2.7.11.23)	RPS6KA5 RPS6KA4 P70S6 kinase P70-S6 Kinase 1 RPS6KB2 RPS6KA2 RPS6KA3 RPS6KA1 RPS6KC1
Mitogen-activated protein kinase (EC 2.7.11.24)	Extracellular signal-regulated MAPK1 MAPK3 MAPK4 MAPK6 MAPK7 MAPK12 MAPK15 C-Jun N-terminal MAPK8 MAPK9 MAPK10 P38 mitogen-activated protein MAPK11 MAPK13 MAPK14
MAP3K (EC 2.7.11.25)	MAP kinase kinase kinases MAP3K1 MAP3K2 MAP3K3 MAP3K4 MAP3K5 MAP3K6 MAP3K7 MAP3K8 RAFs ARAF BRAF KSR1 KSR2 MLKs MAP3K12 MAP3K13 MAP3K9 MAP3K10 MAP3K11 MAP3K7 ZAK CDC7 MAP3K14
Tau-protein kinase (EC 2.7.11.26)	TPK1 TTK GSK-3
(acetyl-CoA carboxylase) kinase (EC 2.7.11.27)	-
Tropomyosin kinase (EC 2.7.11.28)	-
Low-density-lipoprotein receptor kinase (EC 2.7.11.29)	-
Receptor protein serine/threonine kinase (EC 2.7.11.30)	Bone morphogenetic protein receptors BMPR1 BMPR1A BMPR1B BMPR2 ACVR1 ACVR1B ACVR1C ACVR2A ACVR2B ACVRL1 Anti-Müllerian hormone receptor

Dual-specificity kinases (EC 2.7.12)

MAP2K	MAP2K1 MAP2K2 MAP2K3 MAP2K4 MAP2K5 MAP2K6 MAP2K7

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

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2009 MuchMusic Video Awards2009 MuchMusic Video Awards LogoDateJune 21, 2009 (2009-06-21)Location299 Queen Street WestCountryCanadaHosted byJonas Brothers (co-host)WebsiteMMVA 2009 (archived)Television/radio coverageNetworkMuchMusicRuntime120 minutes ← 2008 · MMVAs · 2010 → The 2009 MuchMusic Video Awards were held in Toronto, Ontario at MuchMusic's headquarters on June 21, 2009. Along with the MuchMusic VJ's, on April 16, 2009, it was confirme...

New world order (politics)

New_world_order_(politics)

Period of history with a dramatic change in world political thought Not to be confused with New World Order (conspiracy theory). The term new world order refers to a new period of history evidencing dramatic change in world political thought and the balance of power in international relations. Despite varied interpretations of this term, it is commonly associated with the notion of world governance. The phrase new world order or similar language was used in the period toward the end of the Fi...

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圣罗莎-达塞拉Santa Rosa da Serra市镇圣罗莎-达塞拉在巴西的位置坐标：19°31′48″S 45°57′57″W / 19.53°S 45.9658°W / -19.53; -45.9658国家巴西州米纳斯吉拉斯州面积 • 总计296.342 平方公里（114.418 平方英里）人口 • 總計3,261人 • 密度11人/平方公里（28.5人/平方英里）圣罗莎-达塞拉（葡萄牙语：Santa Rosa da Serra）是巴西米纳斯吉拉斯州�...

PackBot

Cet article est une ébauche concernant les États-Unis et le domaine militaire. Vous pouvez partager vos connaissances en l’améliorant (comment ?) selon les recommandations des projets correspondants. PackBot Scout en position horizontale en mission de recherche et sauvetage au ground zero après les attentats du 11 septembre 2001 PackBot au sein de l'armée française Packbot de déminage au sein de l'US Air force en Arabie saoudite PackBot dans l'armée américaine. PackBot est un...

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Shizuoka 静岡市Kota terpilih BenderaLambangLocation of Shizuoka in Shizuoka PrefectureNegara JepangWilayahChūbuPrefekturShizuokaPemerintahan • WalikotaNobuhiro TanabeLuas • Total1,411,90 km2 (0,54.514 sq mi)Populasi (Februari 1, 2020) • Total690.013 • Kepadatan489/km2 (1,270/sq mi)Zona waktuUTC+9 (Japan Standard Time)Simbol kota • PohonCornus florida• BungaAlthaea rosea• BurungAlcedo atthisNomor ...

Dalhousie, New Brunswick

Dalhousie,_New_Brunswick

Community in Heron Bay, New Brunswick, Canada This article is about the community. For the geographic parish, former local service district, and rural census subdivision, see Dalhousie Parish, New Brunswick. Dissolved Town in New Brunswick, CanadaDalhousieDissolved TownTown of DalhousieDalhousieLocation within New Brunswick.Coordinates: 48°03′58″N 66°22′08″W / 48.066°N 66.369°W / 48.066; -66.369CountryCanadaProvinceNew BrunswickCountyRestigoucheTownHeron Ba...