Reviewed, UniProtKB/Swiss-Prot P41279 (M3K8_HUMAN)

Names and origin

Protein names

Recommended name:
    Mitogen-activated protein kinase kinase kinase 8
    EC=2.7.11.25
Alternative name(s):
    COT proto-oncogene serine/threonine-protein kinase
    Cancer Osaka thyroid oncogene
      Short name=C-COT
    Tumor progression locus 2
      Short name=TPL-2

Gene names

Name:	MAP3K8
Synonyms:	COT, ESTF

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	467 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Required for TLR4 activation of the MEK/ERK pathway. Able to activate NF-kappa-B 1 by stimulating proteasome-mediated proteolysis of NF-kappa-B 1/p105. Plays a role in the cell cycle. The longer form has some transforming activity, although it is much weaker than the activated cot oncoprotein. Ref.8 Ref.9
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Subunit structure	Forms a ternary complex with NFKB1 and TNIP2.
Subcellular location	Cytoplasm. Ref.8 Ref.2
Tissue specificity	Expressed in several normal tissues and human tumor-derived cell lines.
Developmental stage	Isoform 1 is activated specifically during the S and G2/M phases of the cell cycle.
Post-translational modification	Autophosphorylated. Isoform 1 undergoes phosphorylation mainly on Ser residues, and isoform 2 on both Ser and Thr residues. Ref.8 Ref.10
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Alternative initiation Polymorphism
Disease	Proto-oncogene
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	cell cycle Inferred from electronic annotation. Source: InterPro protein amino acid phosphorylation Ref.1 Traceable author statement. Source: ProtInc signal transduction Inferred from electronic annotation. Source: InterPro
Cellular component	cytosol Ref.2 Traceable author statement. Source: ProtInc
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase kinase kinase activity Inferred from electronic annotation. Source: EC magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Ref.9 Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MAP2K1	P29678	1	EBI-354900,EBI-1631983	From a different organism.
TNIP2	Q8NFZ5	3	EBI-354900,EBI-359372

Alternative products

This entry describes 2 isoforms produced by alternative initiation. [Align] [Select]

Isoform 1 (identifier: P41279-1)

Also known as: 58 kDa;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P41279-2)

Also known as: 52 kDa;

The sequence of this isoform differs from the canonical sequence as follows:
     1-29: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 467	467	Mitogen-activated protein kinase kinase kinase 8		PRO_0000024350
Regions
	Domain	138 – 388	251	Protein kinase
	Nucleotide binding	144 – 152	9	ATP By similarity
Sites
	Active site	253	1	Proton acceptor By similarity
	Binding site	167	1	ATP By similarity
Amino acid modifications
	Modified residue	141	1	Phosphoserine Ref.10
Natural variations
	Alternative sequence	1 – 29	29	Missing in isoform 2.		VSP_018843
	Natural variant	214	1	S → F: dbSNP rs3087944.		VAR_051638
	Natural variant	398 – 415	18	CQSLD…LLSRK → GHQVIHEGSSTNDPNNSC in oncogenic form.		VAR_006198
	Natural variant	416 – 467	52	Missing in oncogenic form.		VAR_006199
Experimental info
	Sequence conflict	399	1	Q → T in BAA03387. Ref.1
	Sequence conflict	399	1	Q → T Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (58 kDa) [UniParc]. Last modified July 19, 2004. Version 2. Checksum: 7728969EA3E4E8EC	FASTA	467	52,925
	10 20 30 40 50 60 MEYMSTGSDN KEEIDLLIKH LNVSDVIDIM ENLYASEEPA VYEPSLMTMC QDSNQNDERS 70 80 90 100 110 120 KSLLLSGQEV PWLSSVRYGT VEDLLAFANH ISNTAKHFYG QRPQESGILL NMVITPQNGR 130 140 150 160 170 180 YQIDSDVLLI PWKLTYRNIG SDFIPRGAFG KVYLAQDIKT KKRMACKLIP VDQFKPSDVE 190 200 210 220 230 240 IQACFRHENI AELYGAVLWG ETVHLFMEAG EGGSVLEKLE SCGPMREFEI IWVTKHVLKG 250 260 270 280 290 300 LDFLHSKKVI HHDIKPSNIV FMSTKAVLVD FGLSVQMTED VYFPKDLRGT EIYMSPEVIL 310 320 330 340 350 360 CRGHSTKADI YSLGATLIHM QTGTPPWVKR YPRSAYPSYL YIIHKQAPPL EDIADDCSPG 370 380 390 400 410 420 MRELIEASLE RNPNHRPRAA DLLKHEALNP PREDQPRCQS LDSALLERKR LLSRKELELP 430 440 450 460 ENIADSSCTG STEESEMLKR QRSLYIDLGA LAGYFNLVRG PPTLEYG
	Isoform 2 (52 kDa). Checksum: 2121FEF4658882FD	FASTA	438	49,620
	10 20 30 40 50 60 MENLYASEEP AVYEPSLMTM CQDSNQNDER SKSLLLSGQE VPWLSSVRYG TVEDLLAFAN 70 80 90 100 110 120 HISNTAKHFY GQRPQESGIL LNMVITPQNG RYQIDSDVLL IPWKLTYRNI GSDFIPRGAF 130 140 150 160 170 180 GKVYLAQDIK TKKRMACKLI PVDQFKPSDV EIQACFRHEN IAELYGAVLW GETVHLFMEA 190 200 210 220 230 240 GEGGSVLEKL ESCGPMREFE IIWVTKHVLK GLDFLHSKKV IHHDIKPSNI VFMSTKAVLV 250 260 270 280 290 300 DFGLSVQMTE DVYFPKDLRG TEIYMSPEVI LCRGHSTKAD IYSLGATLIH MQTGTPPWVK 310 320 330 340 350 360 RYPRSAYPSY LYIIHKQAPP LEDIADDCSP GMRELIEASL ERNPNHRPRA ADLLKHEALN 370 380 390 400 410 420 PPREDQPRCQ SLDSALLERK RLLSRKELEL PENIADSSCT GSTEESEMLK RQRSLYIDLG 430 ALAGYFNLVR GPPTLEYG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Structure and transforming potential of the human cot oncogene encoding a putative protein kinase." Miyoshi J., Higashi T., Mukai H., Ohuchi T., Kakunaga T. Mol. Cell. Biol. 11:4088-4096(1991) [PubMed: 2072910] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation." Aoki M., Sugimoto T., Sumida S., Hamada F., Akiyama T., Toyoshima K. J. Biol. Chem. 268:22723-22732(1993) [PubMed: 8226782] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION.
[3]	"Expression cDNA cloning of a serine kinase transforming gene." Chan A.M., Chedid M., McGovern E.S., Popescu N.C., Miki T., Aaronson S.A. Oncogene 8:1329-1333(1993) [PubMed: 8479752] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Bone.
[4]	SeattleSNPs variation discovery resource Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed: 15164054] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Brain.
[7]	"COT kinase proto-oncogene expression in T cells: implication of the JNK/SAPK signal transduction pathway in COT promoter activation." Sanchez-Gongora E., Lisbona C., de Gregorio R., Ballester A., Calvo V., Perez-Jurado L., Alemany S. J. Biol. Chem. 275:31379-31386(2000) [PubMed: 10896655] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-112. Tissue: T-cell.
[8]	"Identification and characterization of protein products of the cot oncogene with serine kinase activity." Aoki M., Akiyama T., Miyoshi J., Toyoshima K. Oncogene 6:1515-1519(1991) [PubMed: 1833717] [Abstract] Cited for: ALTERNATIVE INITIATION, FUNCTION, SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION.
[9]	"ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability." Lang V., Symons A., Watton S.J., Janzen J., Soneji Y., Beinke S., Howell S., Ley S.C. Mol. Cell. Biol. 24:5235-5248(2004) [PubMed: 15169888] [Abstract] Cited for: FUNCTION, INTERACTION WITH NFKB1 AND TNIP2.
[10]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-141, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

Cross-references

Sequence databases
EMBLGenBankDDBJ	D14497 mRNA. Translation: BAA03387.1. Z14138 mRNA. Translation: CAA78512.1. AY309013 Genomic DNA. Translation: AAP45053.1. AL161651 Genomic DNA. Translation: CAI14227.1. BC104833 mRNA. Translation: AAI04834.1. BC113566 mRNA. Translation: AAI13567.1. AF133211 Genomic DNA. Translation: AAG13454.1.
IPI	IPI00298726. IPI00759772.
PIR	A48713.
RefSeq	NP_005195.2.
UniGene	Hs.432453
3D structure databases
HSSP	HSSP built from PDB template 1F3M based on UniProtKB Q13153.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP:27534N.
IntAct	P41279. 29 interactions.
PTM databases
PhosphoSite	P41279.
Proteomic databases
PRIDE	P41279.
Genome annotation databases
Ensembl	ENSG00000107968. Homo sapiens. [Contig view]
GeneID	1326.
KEGG	hsa:1326.
Organism-specific databases
GeneCards	GC10P030762.
HGNC	HGNC:6860. MAP3K8.
HPA	CAB005120. HPA017962.
MIM	191195. gene.
PharmGKB	PA30606.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P41279.
HOVERGEN	P41279.
OMA	P41279. DCSPGMR.
Enzyme and pathway databases
BRENDA	2.7.11.25. 247.
Pathway_Interaction_DB	tcrjnkpathway. JNK signaling in the CD4+ TCR pathway. tcrraspathway. Ras signaling in the CD4+ TCR pathway. nfat_3pathway. Role of Calcineurin-dependent NFAT signaling in lymphocytes. tcrpathway. TCR signaling in naive CD4+ T cells. cd8tcrpathway. TCR signaling in naive CD8+ T cells.
Gene expression databases
ArrayExpress	P41279.
Bgee	P41279.
CleanEx	HS_MAP3K8.
GermOnline	ENSG00000107968. Homo sapiens.
Family and domain databases
InterPro	IPR017424. MAPKKK8. IPR000719. Prot_kinase_core. IPR017441. Protein_kinase_ATP_BS. IPR017442. Se/Thr_pkinase-rel. IPR008271. Ser_thr_pkin_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
PIRSF	PIRSF038171. MAPKKK8. 1 hit.
ProDom	PD000001. Prot_kinase. 1 hit. [Graphical view] [Entries sharing at least one domain]
PROSITE	PS00107. PROTEIN_KINASE_ATP. False negative. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	5403.
SOURCE	Search...

Entry information

Entry name

M3K8_HUMAN

Accession

Primary (citable) accession number: P41279
Secondary accession number(s): Q14275, Q5T855, Q9HC81

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	July 19, 2004
Last modified:	June 16, 2009
This is version 90 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)