Q62073 (M3K7_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	579 AA.
Sequence status	Complete.
Protein existence	Evidence 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 By similarity. Ref.1 Ref.2 Ref.4
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium By similarity.
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.
Subunit structure	Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 By similarity. Identified in the TRIKA2 complex composed of MAP3K7, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 By similarity. Interacts with PPM1L. Interaction with PP2A and PPP6C leads to its repressed activity By similarity. Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling By similarity. Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation By similarity. Interacts with WDR34 (via WD domains) By similarity. Interacts with RBCK1 By similarity. Interacts with TGFBR1; induces MAP3K7 activation by TRAF6 By similarity. Interacts with CYLD. Interacts with MAPK8IP1, SMAD6 and VRK2. Interacts with TRIM5 By similarity. Ref.2 Ref.3 Ref.5 Ref.6
Subcellular location	Cytoplasm By similarity. Cell membrane; Peripheral membrane protein; Cytoplasmic side By similarity. 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 By similarity.
Post-translational modification	Association with TAB1/MAP3K7IP1 promotes autophosphorylation 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 Thr-187 by PP2A and PPP6C leads to inactivation By similarity. Ubiquitinated, leading 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. Ref.4 Ref.5
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 process	Apoptosis Stress response Transcription Transcription regulation
Cellular component	Cell membrane Cytoplasm Membrane
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	I-kappaB phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB angiogenesis Inferred from mutant phenotype PubMed 16556914. Source: MGI apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of apoptotic process Inferred from mutant phenotype PubMed 16260493. Source: MGI negative regulation of necroptosis Inferred from mutant phenotype PubMed 21052097. Source: UniProtKB negative regulation of reactive oxygen species metabolic process Inferred from mutant phenotype PubMed 21052097. Source: UniProtKB neural tube formation Inferred from mutant phenotype PubMed 16260493. Source: MGI positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from genetic interaction PubMed 16260493. Source: MGI positive regulation of JNK cascade Inferred from genetic interaction PubMed 16260493. Source: MGI positive regulation of JUN kinase activity Inferred from sequence or structural similarity. Source: UniProtKB regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW response to stress Inferred from electronic annotation. Source: UniProtKB-KW transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW transforming growth factor beta receptor signaling pathway Inferred from mutant phenotype PubMed 16145668. Source: MGI
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase kinase activity Inferred from direct assay PubMed 12464436. Source: MGI MAP kinase kinase kinase activity Inferred from sequence or structural similarity. Source: UniProtKB magnesium ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Mapk8ip1	Q9WVI9-2	4	EBI-1775345,EBI-288464
Tab2	Q99K90	5	EBI-1775345,EBI-1775124
TAB3	Q8N5C8	2	EBI-1775345,EBI-359964	From a different organism.
VRK2	Q86Y07-1	3	EBI-1775345,EBI-1207633	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 579	579	Mitogen-activated protein kinase kinase kinase 7		PRO_0000086253
Regions
	Domain	36 – 291	256	Protein kinase
	Nucleotide binding	42 – 50	9	ATP By similarity
	Region	1 – 300	300	Interaction with MAPK8IP1
	Compositional bias	8 – 16	9	Poly-Ser
Sites
	Active site	156	1	Proton acceptor By similarity
	Binding site	63	1	ATP By similarity
Amino acid modifications
	Modified residue	184	1	Phosphothreonine; by autocatalysis By similarity
	Modified residue	187	1	Phosphothreonine; by autocatalysis By similarity
	Modified residue	192	1	Phosphoserine; by autocatalysis By similarity
	Modified residue	389	1	Phosphoserine Ref.9
	Modified residue	412	1	Phosphoserine Ref.7 Ref.8 Ref.9

Sequences

	Sequence		Length	Mass (Da)
	Q62073 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 97C8F6F3C8E283EE	FASTA	579	64,228
	10 20 30 40 50 60 MSTASAASSS SSSSASEMIE 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 DMSEIEARIV ATAGNGQPRR RSIQDLTVTG 430 440 450 460 470 480 TEPGQVSSRS SSPSVRMITT SGPTSEKPAR SHPWTPDDST DTNGSDNSIP MAYLTLDHQL 490 500 510 520 530 540 QPLAPCPNSK ESMAVFEQHC KMAQEYMKVQ TEIALLLQRK QELVAELDQD EKDQQNTSRL 550 560 570 VQEHKKLLDE NKSLSTYYQQ CKKQLEVIRS QQQKRQGTS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction." Yamaguchi K., Shirakabe K., Shibuya H., Irie K., Ohishi I., Ueno N., Taniguchi T., Nishida E., Matsumoto K. Science 270:2008-2011(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[2]	"BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6." Kimura N., Matsuo R., Shibuya H., Nakashima K., Taga T. J. Biol. Chem. 275:17647-17652(2000) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH SMAD6.
[3]	"Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon)." Li M.G., Katsura K., Nomiyama H., Komaki K., Ninomiya-Tsuji J., Matsumoto K., Kobayashi T., Tamura S. J. Biol. Chem. 278:12013-12021(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PPM1L.
[4]	"X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase 1 (JNK1) activation by transforming growth factor beta1 (TGF-beta1) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (TAK1)." Kaur S., Wang F., Venkatraman M., Arsura M. J. Biol. Chem. 280:38599-38608(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, UBIQUITINATION, PROTEASOMAL DEGRADATION.
[5]	"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.
[6]	"Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1." Blanco S., Santos C., Lazo P.A. Mol. Cell. Biol. 27:7273-7283(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH VRK2 AND MAPK8IP1.
[7]	"Qualitative and quantitative analyses of protein phosphorylation in naive and stimulated mouse synaptosomal preparations." Munton R.P., Tweedie-Cullen R., Livingstone-Zatchej M., Weinandy F., Waidelich M., Longo D., Gehrig P., Potthast F., Rutishauser D., Gerrits B., Panse C., Schlapbach R., Mansuy I.M. Mol. Cell. Proteomics 6:283-293(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-412, MASS SPECTROMETRY. Tissue: Brain cortex.
[8]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-412, MASS SPECTROMETRY. Tissue: Liver.
[9]	"The phagosomal proteome in interferon-gamma-activated macrophages." Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P. Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389 AND SER-412, MASS SPECTROMETRY. Tissue: Macrophage.
[10]	"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.
[11]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	D76446 mRNA. Translation: BAA11184.1.
IPI	IPI00121080.
RefSeq	NP_766276.1. NM_172688.3.
UniGene	Mm.258589.
3D structure databases
ProteinModelPortal	Q62073.
SMR	Q62073. Positions 2-305.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-40666N.
IntAct	Q62073. 7 interactions.
PTM databases
PhosphoSite	Q62073.
Proteomic databases
PaxDb	Q62073.
PRIDE	Q62073.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000080933; ENSMUSP00000079734; ENSMUSG00000028284.
GeneID	26409.
KEGG	mmu:26409.
Organism-specific databases
CTD	6885.
MGI	MGI:1346877. Map3k7.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00690000101754.
HOGENOM	HOG000231735.
HOVERGEN	HBG003485.
KO	K04427.
Gene expression databases
ArrayExpress	Q62073.
Bgee	Q62073.
CleanEx	MM_MAP3K7.
Genevestigator	Q62073.
GermOnline	ENSMUSG00000028284. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR017421. MAPKKK7. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF07714. Pkinase_Tyr. 1 hit. [Graphical view]
PIRSF	PIRSF038168. MAPKKK7. 1 hit.
PRINTS	PR00109. TYRKINASE.
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	MAP3K7. mouse.
NextBio	304393.
SOURCE	Search...

Entry information

Entry name

M3K7_MOUSE

Accession

Primary (citable) accession number: Q62073

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	November 1, 1996
Last modified:	May 1, 2013
This is version 122 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program