Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

O43318 (M3K7_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 156. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase kinase kinase 7

EC=2.7.11.25
Alternative name(s):
Transforming growth factor-beta-activated kinase 1
Short name=TGF-beta-activated kinase 1
Gene names
Name:MAP3K7
Synonyms:TAK1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length606 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. Ref.8 Ref.10 Ref.11 Ref.15 Ref.19 Ref.23 Ref.24 Ref.42

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium.

Enzyme regulation

Activated by proinflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation. Ref.10 Ref.13 Ref.15 Ref.16 Ref.24

Subunit structure

Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3. Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2. Interacts with PPM1L and PPM1B/PP2CB. Interaction with PP2A and PPP6C leads to its repressed activity. Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation. Interacts with WDR34 (via WD domains). Interacts with CYLD and RBCK1. Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6. Interacts with MAPK8IP1 and SMAD6 By similarity. Interacts with isoform 1of VRK2. Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation. Interacts with TRIM5. Ref.9 Ref.11 Ref.12 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.23 Ref.24 Ref.25 Ref.26 Ref.27 Ref.30 Ref.31 Ref.34 Ref.36 Ref.42

Subcellular location

Cytoplasm. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Note: Although the majority of MAP3K7/TAK1 is found in the cytosol, when complexed with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2, it is also localized at the cell membrane. Ref.16

Tissue specificity

Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form. Ref.2

Post-translational modification

Association with TAB1/MAP3K7IP1 promotes autophosphorylation at Ser-192 and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and PPP6C leads to inactivation.

'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation. Requires 'Lys-63'-linked polyubiquitination for autophosphorylation and subsequent activation. 'Lys-63'-linked ubiquitination does not lead to proteasomal degradation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains. Deubiquitinated by Y.enterocolitica YopP.

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
   Biological processApoptosis
Stress response
Transcription
Transcription regulation
   Cellular componentCell membrane
Cytoplasm
Membrane
   Coding sequence diversityAlternative splicing
   LigandATP-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processFc-epsilon receptor signaling pathway

Traceable author statement. Source: Reactome

I-kappaB kinase/NF-kappaB signaling

Traceable author statement. Source: Reactome

I-kappaB phosphorylation

Inferred from direct assay Ref.15. Source: UniProtKB

JNK cascade

Inferred from direct assay Ref.10. Source: UniProtKB

MyD88-dependent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

MyD88-independent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

T cell receptor signaling pathway

Non-traceable author statement PubMed 15125833. Source: UniProtKB

TRIF-dependent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

activation of MAPK activity

Inferred from direct assay Ref.10. Source: UniProtKB

activation of MAPKK activity

Inferred from direct assay Ref.8Ref.10. Source: UniProtKB

activation of NF-kappaB-inducing kinase activity

Inferred from mutant phenotype Ref.11PubMed 15125833. Source: UniProtKB

angiogenesis

Inferred from electronic annotation. Source: Ensembl

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

histone H3 acetylation

Inferred from direct assay PubMed 18838386. Source: BHF-UCL

innate immune response

Traceable author statement. Source: Reactome

negative regulation of apoptotic signaling pathway

Inferred from electronic annotation. Source: Ensembl

neural tube formation

Inferred from electronic annotation. Source: Ensembl

nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway

Traceable author statement. Source: Reactome

nucleotide-binding oligomerization domain containing signaling pathway

Traceable author statement. Source: Reactome

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from mutant phenotype PubMed 14982987. Source: UniProtKB

positive regulation of JNK cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of JUN kinase activity

Inferred from direct assay Ref.15. Source: UniProtKB

positive regulation of NF-kappaB transcription factor activity

Traceable author statement. Source: Reactome

positive regulation of T cell activation

Inferred by curator PubMed 15125833. Source: UniProtKB

positive regulation of T cell cytokine production

Inferred from mutant phenotype PubMed 15125833. Source: UniProtKB

positive regulation of interleukin-2 production

Inferred from mutant phenotype PubMed 15125833. Source: UniProtKB

stress-activated MAPK cascade

Inferred from direct assay Ref.10. Source: UniProtKB

toll-like receptor 10 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 3 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 4 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 5 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 9 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor TLR1:TLR2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor TLR6:TLR2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

transforming growth factor beta receptor signaling pathway

Traceable author statement PubMed 9466656. Source: ProtInc

   Cellular_componentAda2/Gcn5/Ada3 transcription activator complex

Inferred from direct assay PubMed 18838386. Source: BHF-UCL

cytoplasm

Inferred from direct assay. Source: HPA

cytosol

Traceable author statement. Source: Reactome

endosome membrane

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay. Source: HPA

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

MAP kinase kinase activity

Inferred from electronic annotation. Source: Ensembl

MAP kinase kinase kinase activity

Inferred from direct assay Ref.15. Source: UniProtKB

magnesium ion binding

Inferred from electronic annotation. Source: InterPro

protein kinase activity

Inferred from direct assay Ref.11. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from experiment. Source: Reactome

Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1B (identifier: O43318-1)

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 1A (identifier: O43318-2)

The sequence of this isoform differs from the canonical sequence as follows:
     404-430: Missing.
Isoform 1C (identifier: O43318-3)

The sequence of this isoform differs from the canonical sequence as follows:
     509-518: PLAPCPNSKE → ARTSCRTGPG
     519-606: Missing.
Isoform 1D (identifier: O43318-4)

The sequence of this isoform differs from the canonical sequence as follows:
     404-430: Missing.
     509-518: PLAPCPNSKE → ARTSCRTGPG
     519-606: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 606606Mitogen-activated protein kinase kinase kinase 7
PRO_0000086252

Regions

Domain36 – 291256Protein kinase
Nucleotide binding42 – 509ATP By similarity
Region1 – 300300Interaction with MAPK8IP1 By similarity
Compositional bias8 – 147Poly-Ser

Sites

Active site1561Proton acceptor By similarity
Binding site631ATP

Amino acid modifications

Modified residue1841Phosphothreonine; by autocatalysis Probable
Modified residue1871Phosphothreonine; by autocatalysis Ref.12 Ref.23 Ref.25 Ref.36 Ref.42
Modified residue1921Phosphoserine; by autocatalysis Ref.12 Ref.13
Modified residue3891Phosphoserine Ref.32 Ref.35 Ref.38 Ref.43
Modified residue4391Phosphoserine Ref.22 Ref.28 Ref.29 Ref.32 Ref.35 Ref.38 Ref.40 Ref.43
Cross-link72Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.44

Natural variations

Alternative sequence404 – 43027Missing in isoform 1A and isoform 1D.
VSP_004886
Alternative sequence509 – 51810PLAPCPNSKE → ARTSCRTGPG in isoform 1C and isoform 1D.
VSP_004887
Alternative sequence519 – 60688Missing in isoform 1C and isoform 1D.
VSP_004888

Experimental info

Mutagenesis631K → W: Loss of kinase activity. Ref.19

Secondary structure

................................................... 606
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1B [UniParc].

Last modified June 1, 1998. Version 1.
Checksum: 3D8F8147CD174013

FASTA60667,196
        10         20         30         40         50         60 
MSTASAASSS SSSSAGEMIE APSQVLNFEE IDYKEIEVEE VVGRGAFGVV CKAKWRAKDV 

        70         80         90        100        110        120 
AIKQIESESE RKAFIVELRQ LSRVNHPNIV KLYGACLNPV CLVMEYAEGG SLYNVLHGAE 

       130        140        150        160        170        180 
PLPYYTAAHA MSWCLQCSQG VAYLHSMQPK ALIHRDLKPP NLLLVAGGTV LKICDFGTAC 

       190        200        210        220        230        240 
DIQTHMTNNK GSAAWMAPEV FEGSNYSEKC DVFSWGIILW EVITRRKPFD EIGGPAFRIM 

       250        260        270        280        290        300 
WAVHNGTRPP LIKNLPKPIE SLMTRCWSKD PSQRPSMEEI VKIMTHLMRY FPGADEPLQY 

       310        320        330        340        350        360 
PCQYSDEGQS NSATSTGSFM DIASTNTSNK SDTNMEQVPA TNDTIKRLES KLLKNQAKQQ 

       370        380        390        400        410        420 
SESGRLSLGA SRGSSVESLP PTSEGKRMSA DMSEIEARIA ATTAYSKPKR GHRKTASFGN 

       430        440        450        460        470        480 
ILDVPEIVIS GNGQPRRRSI QDLTVTGTEP GQVSSRSSSP SVRMITTSGP TSEKPTRSHP 

       490        500        510        520        530        540 
WTPDDSTDTN GSDNSIPMAY LTLDHQLQPL APCPNSKESM AVFEQHCKMA QEYMKVQTEI 

       550        560        570        580        590        600 
ALLLQRKQEL VAELDQDEKD QQNTSRLVQE HKKLLDENKS LSTYYQQCKK QLEVIRSQQQ 


KRQGTS 

« Hide

Isoform 1A [UniParc].

Checksum: 40EDE237BBB568EE
Show »

FASTA57964,230
Isoform 1C [UniParc].

Checksum: A92C927A8621AF90
Show »

FASTA51856,706
Isoform 1D [UniParc].

Checksum: B7D8832E286A99C5
Show »

FASTA49153,740

References

« Hide 'large scale' references
[1]"TGF-beta-activated kinase 1 stimulates NF-kappa B activation by an NF-kappa B-inducing kinase-independent mechanism."
Sakurai H., Shigemori N., Hasegawa K., Sugita T.
Biochem. Biophys. Res. Commun. 243:545-549(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1A; 1B AND 1C).
Tissue: Lung.
[2]"Alternative splicing and gene structure of the transforming growth factor beta-activated kinase 1."
Dempsey C.E., Sakurai H., Sugita T., Guesdon F.
Biochim. Biophys. Acta 1517:46-52(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1D), TISSUE SPECIFICITY.
[3]NHLBI resequencing and genotyping service (RS&G)
Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1A).
Tissue: Trachea.
[5]"The DNA sequence and analysis of human chromosome 6."
Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.
Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1A).
Tissue: Uterus.
[8]"A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3."
Moriguchi T., Kuroyanagi N., Yamaguchi K., Gotoh Y., Irie K., Kano T., Shirakabe K., Muro Y., Shibuya H., Matsumoto K., Nishida E., Hagiwara M.
J. Biol. Chem. 271:13675-13679(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF MAP2K3/MKK3 AND MAP2K6/MKK6.
[9]"TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction."
Shibuya H., Yamaguchi K., Shirakabe K., Tonegawa A., Gotoh Y., Ueno N., Irie K., Nishida E., Matsumoto K.
Science 272:1179-1182(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TAB1/MAP3K7IP1.
[10]"TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase."
Shirakabe K., Yamaguchi K., Shibuya H., Irie K., Matsuda S., Moriguchi T., Gotoh Y., Matsumoto K., Nishida E.
J. Biol. Chem. 272:8141-8144(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION, FUNCTION.
[11]"The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway."
Ninomiya-Tsuji J., Kishimoto K., Hiyama A., Inoue J., Cao Z., Matsumoto K.
Nature 398:252-256(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TRAF6 AND TAB1/MAP3K7IP1, FUNCTION.
[12]"Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1."
Sakurai H., Miyoshi H., Mizukami J., Sugita T.
FEBS Lett. 474:141-145(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TAB1, PHOSPHORYLATION AT THR-184; THR-187 AND SER-192, ACTIVATION.
[13]"TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop."
Kishimoto K., Matsumoto K., Ninomiya-Tsuji J.
J. Biol. Chem. 275:7359-7364(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-192, ENZYME REGULATION.
[14]"Regulation of the TAK1 signaling pathway by protein phosphatase 2C."
Hanada M., Ninomiya-Tsuji J., Komaki K., Ohnishi M., Katsura K., Kanamaru R., Matsumoto K., Tamura S.
J. Biol. Chem. 276:5753-5759(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: DEPHOSPHORYLATION BY PPM1B/PP2CB, INTERACTION WITH PPM1B/PP2CB.
[15]"TAK1 is a ubiquitin-dependent kinase of MKK and IKK."
Wang C., Deng L., Hong M., Akkaraju G.R., Inoue J., Chen Z.J.
Nature 412:346-351(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION, FUNCTION, ENZYME REGULATION, INTERACTION WITH TAB1/MAP3K7IP2 AND TAB2/MAP3K7IP2, IDENTIFICATION IN THE TRIKA2 COMPLEX.
[16]"Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol."
Jiang Z., Ninomiya-Tsuji J., Qian Y., Matsumoto K., Li X.
Mol. Cell. Biol. 22:7158-7167(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH IRAK; TAB1/MAP3K7IP1; TAB2/MAP3K7IP2 AND TRAF6, PHOSPHORYLATION, ENZYME REGULATION, SUBCELLULAR LOCATION.
[17]"Pellino2 activates the mitogen activated protein kinase pathway."
Jensen L.E., Whitehead A.S.
FEBS Lett. 545:199-202(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PELI1 AND PELI2.
[18]"Pellino3, a novel member of the Pellino protein family, promotes activation of c-Jun and Elk-1 and may act as a scaffolding protein."
Jensen L.E., Whitehead A.S.
J. Immunol. 171:1500-1506(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PELI3.
[19]"Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3."
Edlund S., Bu S., Schuster N., Aspenstroem P., Heuchel R., Heldin N.E., ten Dijke P., Heldin C.H., Landstrom M.
Mol. Biol. Cell 14:529-544(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SMAD7; MAP2K3 AND P38 KINASE, MUTAGENESIS OF LYS-63.
[20]"TAB3, a new binding partner of the protein kinase TAK1."
Cheung P.C., Nebreda A.R., Cohen P.
Biochem. J. 378:27-34(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TAB3/MAP3K7IP3.
[21]"Disabled-2 (Dab2) mediates transforming growth factor beta (TGFbeta)-stimulated fibronectin synthesis through TGFbeta-activated kinase 1 and activation of the JNK pathway."
Hocevar B.A., Prunier C., Howe P.H.
J. Biol. Chem. 280:25920-25927(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DAB2.
[22]"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.
Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[23]"The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway."
Thiefes A., Wolf A., Doerrie A., Grassl G.A., Matsumoto K., Autenrieth I., Bohn E., Sakurai H., Niedenthal R., Resch K., Kracht M.
EMBO Rep. 7:838-844(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION, PHOSPHORYLATION AT THR-187 BY AUTOCATALYSIS, SUBUNIT, FUNCTION.
[24]"Osmotic stress activates the TAK1-JNK pathway while blocking TAK1-mediated NF-kappaB activation: TAO2 regulates TAK1 pathways."
Huangfu W.C., Omori E., Akira S., Matsumoto K., Ninomiya-Tsuji J.
J. Biol. Chem. 281:28802-28810(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, INTERACTION WITH TAOK1 AND TAOK2.
[25]"Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway."
Kajino T., Ren H., Iemura S., Natsume T., Stefansson B., Brautigan D.L., Matsumoto K., Ninomiya-Tsuji J.
J. Biol. Chem. 281:39891-39896(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PP2A AND PPP6C, DEPHOSPHORYLATION AT THR-187 BY PP2A AND PPP6C.
[26]"RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-kappaB activation by targeting TAB2/3 for degradation."
Tian Y., Zhang Y., Zhong B., Wang Y.Y., Diao F.C., Wang R.P., Zhang M., Chen D.Y., Zhai Z.H., Shu H.B.
J. Biol. Chem. 282:16776-16782(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RBCK1.
[27]"Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses."
Reiley W.W., Jin W., Lee A.J., Wright A., Wu X., Tewalt E.F., Leonard T.O., Norbury C.C., Fitzpatrick L., Zhang M., Sun S.C.
J. Exp. Med. 204:1475-1485(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION, INTERACTION WITH CYLD, DEUBIQUITINATION BY CYLD.
[28]"Phosphoproteome of resting human platelets."
Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A.
J. Proteome Res. 7:526-534(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Platelet.
[29]"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[30]"The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner."
Sorrentino A., Thakur N., Grimsby S., Marcusson A., von Bulow V., Schuster N., Zhang S., Heldin C.H., Landstrom M.
Nat. Cell Biol. 10:1199-1207(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TGFBR1.
[31]"Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein."
Blanco S., Sanz-Garcia M., Santos C.R., Lazo P.A.
PLoS ONE 3:E1660-E1660(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH VRK2.
[32]"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] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389 AND SER-439, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[33]"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[34]"WDR34 is a novel TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-kappaB activation pathway."
Gao D., Wang R., Li B., Yang Y., Zhai Z., Chen D.Y.
Cell. Mol. Life Sci. 66:2573-2584(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH WDR34.
[35]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389 AND SER-439, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[36]"Direct activation of protein kinases by unanchored polyubiquitin chains."
Xia Z.-P., Sun L., Chen X., Pineda G., Jiang X., Adhikari A., Zeng W., Chen Z.J.
Nature 461:114-119(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TAB2, PHOSPHORYLATION AT THR-187.
[37]"Ubiquitin-mediated activation of TAK1 and IKK."
Adhikari A., Xu M., Chen Z.J.
Oncogene 26:3214-3226(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION.
[38]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389 AND SER-439, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[39]"The TAK1-TRAF6 signalling pathway."
Landstrom M.
Int. J. Biochem. Cell Biol. 42:585-589(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.
[40]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[41]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[42]"TRIM5 is an innate immune sensor for the retrovirus capsid lattice."
Pertel T., Hausmann S., Morger D., Zueger S., Guerra J., Lascano J., Reinhard C., Santoni F.A., Uchil P.D., Chatel L., Bisiaux A., Albert M.L., Strambio-De-Castillia C., Mothes W., Pizzato M., Gruetter M.G., Luban J.
Nature 472:361-365(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TRIM5, AUTOPHOSPHORYLATION AT THR-187.
[43]"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389 AND SER-439, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[44]"Lys48-linked TAK1 polyubiquitination at lysine-72 downregulates TNFalpha-induced NF-kappaB activation via mediating TAK1 degradation."
Fan Y., Shi Y., Liu S., Mao R., An L., Zhao Y., Zhang H., Zhang F., Xu G., Qin J., Yang J.
Cell. Signal. 24:1381-1389(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION AT LYS-72.
[45]"Structural basis for the interaction of TAK1 kinase with its activating protein TAB1."
Brown K., Vial S.C., Dedi N., Long J.M., Dunster N.J., Cheetham G.M.T.
J. Mol. Biol. 354:1013-1020(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 31-328 IN COMPLEX WITH TAB1 AND ADENOSINE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB009357 mRNA. Translation: BAA25026.1.
AB009356 mRNA. Translation: BAA25025.1.
AB009358 mRNA. Translation: BAA25027.2.
AF218074 mRNA. Translation: AAF27652.1.
DQ314875 Genomic DNA. Translation: ABC40734.1.
AK315774 mRNA. Translation: BAG38124.1.
AL121964, AL121837 Genomic DNA. Translation: CAI19609.1.
AL121964, AL121837 Genomic DNA. Translation: CAI19610.1.
AL121964, AL121837 Genomic DNA. Translation: CAI19611.1.
AL121964, AL121837 Genomic DNA. Translation: CAI19612.1.
AL121837, AL121964 Genomic DNA. Translation: CAI23530.1.
AL121837, AL121964 Genomic DNA. Translation: CAI23531.1.
AL121837, AL121964 Genomic DNA. Translation: CAI23532.1.
AL121837, AL121964 Genomic DNA. Translation: CAI23533.1.
CH471051 Genomic DNA. Translation: EAW48525.1.
CH471051 Genomic DNA. Translation: EAW48526.1.
CH471051 Genomic DNA. Translation: EAW48527.1.
CH471051 Genomic DNA. Translation: EAW48529.1.
BC017715 mRNA. Translation: AAH17715.1.
PIRJC5955.
JC5956.
RefSeqNP_003179.1. NM_003188.3.
NP_663304.1. NM_145331.2.
NP_663305.1. NM_145332.2.
NP_663306.1. NM_145333.2.
UniGeneHs.594838.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2EVAX-ray2.00A31-303[»]
2YIYX-ray2.49A31-303[»]
4GS6X-ray2.20A31-303[»]
4L3PX-ray2.68A31-303[»]
4L52X-ray2.54A31-303[»]
4L53X-ray2.55A31-303[»]
ProteinModelPortalO43318.
SMRO43318. Positions 4-305.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112748. 113 interactions.
DIPDIP-27523N.
IntActO43318. 39 interactions.
MINTMINT-88554.
STRING9606.ENSP00000358335.

Chemistry

BindingDBO43318.
ChEMBLCHEMBL5776.
GuidetoPHARMACOLOGY2082.

PTM databases

PhosphoSiteO43318.

Proteomic databases

PaxDbO43318.
PRIDEO43318.

Protocols and materials databases

DNASU6885.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000369325; ENSP00000358331; ENSG00000135341. [O43318-3]
ENST00000369327; ENSP00000358333; ENSG00000135341. [O43318-4]
ENST00000369329; ENSP00000358335; ENSG00000135341. [O43318-1]
ENST00000369332; ENSP00000358338; ENSG00000135341. [O43318-2]
GeneID6885.
KEGGhsa:6885.
UCSCuc003pnz.2. human. [O43318-1]
uc003poa.2. human. [O43318-3]
uc003pob.2. human. [O43318-2]
uc003poc.2. human. [O43318-4]

Organism-specific databases

CTD6885.
GeneCardsGC06M091282.
HGNCHGNC:6859. MAP3K7.
HPAHPA007633.
MIM602614. gene.
neXtProtNX_O43318.
PharmGKBPA30603.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000231735.
HOVERGENHBG003485.
InParanoidO43318.
KOK04427.
OMACKAKWKG.
OrthoDBEOG7RBZ8D.
PhylomeDBO43318.
TreeFamTF105116.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_6782. TRAF6 Mediated Induction of proinflammatory cytokines.
REACT_6900. Immune System.
SignaLinkO43318.

Gene expression databases

ArrayExpressO43318.
BgeeO43318.
CleanExHS_MAP3K7.
GenevestigatorO43318.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR017421. MAPKKK7.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PIRSFPIRSF038168. MAPKKK7. 1 hit.
PRINTSPR00109. TYRKINASE.
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceO43318.
GeneWikiMAP3K7.
GenomeRNAi6885.
NextBio26899.
PROO43318.
SOURCESearch...

Entry information

Entry nameM3K7_HUMAN
AccessionPrimary (citable) accession number: O43318
Secondary accession number(s): B2RE27 expand/collapse secondary AC list , E1P523, O43317, O43319, Q5TDN2, Q5TDN3, Q5TDT7, Q9NTR3, Q9NZ70
Entry history
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: June 1, 1998
Last modified: April 16, 2014
This is version 156 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 6

Human chromosome 6: entries, gene names and cross-references to MIM