Reviewed, UniProtKB/Swiss-Prot O43318 (M3K7_HUMAN)

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

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

General annotation (Comments)

Function	Component of a protein kinase signal transduction cascade. Mediator of TGF-beta signal transduction. Stimulates NF-kappa-B activation and the p38 MAPK pathway. Ref.9
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Subunit structure	Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with MAP3K7IP1 and MAP3K7IP2. Interacts with PPM1L. Interaction with PP2A and PPP6C leads to its' repressed activity. Ref.9 Ref.5 Ref.6 Ref.7 Ref.8 Ref.11
Post-translational modification	Association with MAP3K7IP1 promotes autophosphorylation and subsequent activation. Dephosphorylation at Thr-187 by PP2A and PPP6C leads to inactivation.
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
Coding sequence diversity	Alternative splicing
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	T cell receptor signaling pathway Non-traceable author statement. Source: UniProtKB activation of NF-kappaB-inducing kinase activity Inferred from mutant phenotype. Source: UniProtKB positive regulation of T cell activation Inferred by curator. Source: UniProtKB positive regulation of T cell cytokine production Inferred from mutant phenotype. Source: UniProtKB positive regulation of interleukin-2 production Inferred from mutant phenotype. Source: UniProtKB protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro transforming growth factor beta receptor signaling pathway Traceable author statement. Source: ProtInc
Cellular component	cytosol Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro MAP kinase kinase kinase activity Traceable author statement. Source: ProtInc magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Ref.8 Inferred from physical interaction. Source: UniProtKB protein tyrosine kinase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
IKBKAP	O95163	1	EBI-358684,EBI-347559
MAP3K14	Q99558	1	EBI-358704,EBI-358011
MAP3K7IP2	Q9NYJ8	1	EBI-358684,EBI-358708
PELI3	Q8N2H9-1	1	EBI-358684,EBI-448466
PELI3	Q8N2H9-2	1	EBI-358684,EBI-448472
STAT3	P40763	1	EBI-358684,EBI-518675
Stat3	P42227	1	EBI-358684,EBI-602878	From a different organism.

Alternative products

This entry describes 3 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.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 606

606

Mitogen-activated protein kinase kinase kinase 7

PRO_0000086252

Regions

Domain

36 – 291

256

Protein kinase

Nucleotide binding

42 – 50

9

ATP By similarity

Compositional bias

8 – 14

7

Poly-Ser

Sites

Active site

156

1

Proton acceptor By similarity

Binding site

63

1

ATP

Amino acid modifications

Modified residue

184

1

Phosphothreonine; by autocatalysis Probable

Modified residue

187

1

Phosphothreonine; by autocatalysis Probable

Modified residue

192

1

Phosphoserine; by autocatalysis Probable

Modified residue

389

1

Phosphoserine Ref.14

Modified residue

439

1

Phosphoserine Ref.14 Ref.10 Ref.12 Ref.13

Natural variations

Alternative sequence

404 – 430

27

Missing in isoform 1A.

VSP_004886

Alternative sequence

509 – 518

10

PLAPCPNSKE → ARTSCRTGPG in isoform 1C.

VSP_004887

Alternative sequence

519 – 606

88

Missing in isoform 1C.

VSP_004888

Experimental info

Mutagenesis

63

1

K → W: Loss of kinase activity Ref.9

Secondary structure

1

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606

Helix Strand Turn

Details...

Helix

33 – 35

3

Beta strand

36 – 43

8

Beta strand

46 – 55

10

Beta strand

58 – 64

7

Helix

70 – 83

14

Beta strand

92 – 95

4

Turn

97 – 100

4

Beta strand

101 – 105

5

Helix

112 – 117

6

Beta strand

119 – 123

5

Helix

127 – 145

19

Beta strand

148 – 150

3

Helix

159 – 161

3

Beta strand

162 – 165

4

Turn

166 – 169

4

Beta strand

170 – 173

4

Helix

198 – 201

4

Helix

209 – 224

16

Turn

228 – 232

5

Helix

236 – 244

9

Helix

257 – 266

10

Helix

271 – 273

3

Helix

277 – 287

11

Helix

288 – 290

3

Beta strand

312 – 314

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1B [UniParc]. Last modified June 1, 1998. Version 1. Checksum: 3D8F8147CD174013	FASTA	606	67,196
	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
	Isoform 1A. Checksum: 40EDE237BBB568EE		579	64,230
	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 ATTGNGQPRR RSIQDLTVTG 430 440 450 460 470 480 TEPGQVSSRS SSPSVRMITT SGPTSEKPTR SHPWTPDDST DTNGSDNSIP MAYLTLDHQL 490 500 510 520 530 540 QPLAPCPNSK ESMAVFEQHC KMAQEYMKVQ TEIALLLQRK QELVAELDQD EKDQQNTSRL 550 560 570 VQEHKKLLDE NKSLSTYYQQ CKKQLEVIRS QQQKRQGTS
	Isoform 1C. Checksum: A92C927A8621AF90		518	56,706
	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 WTPDDSTDTN GSDNSIPMAY LTLDHQLQAR TSCRTGPG

References

	« Hide 'large scale' referencesShow '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: 9480845] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1A; 1B AND 1C). Tissue: Lung.
[2]	NHLBI resequencing and genotyping service (RS&G) Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"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. , 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: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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 1A). Tissue: Uterus.
[5]	"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: 8638164] [Abstract] Cited for: INTERACTION WITH MAP3K7IP1.
[6]	"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: 10838074] [Abstract] Cited for: INTERACTION WITH MAP3K7IP1, PHOSPHORYLATION AT THR-184; THR-187 AND SER-192, ACTIVATION.
[7]	"Pellino2 activates the mitogen activated protein kinase pathway." Jensen L.E., Whitehead A.S. FEBS Lett. 545:199-202(2003) [PubMed: 12804775] [Abstract] Cited for: INTERACTION WITH PELI1 AND PELI2.
[8]	"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: 12874243] [Abstract] Cited for: INTERACTION WITH PELI3.
[9]	"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: 12589052] [Abstract] Cited for: FUNCTION, INTERACTION WITH SMAD7; MAP2K3 AND P38 KINASE, MUTAGENESIS OF LYS-63.
[10]	"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: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, MASS SPECTROMETRY. Tissue: Epithelium.
[11]	"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: 17079228] [Abstract] Cited for: INTERACTION WITH PP2A AND PPP6C, DEPHOSPHORYLATION AT THR-187 BY PP2A AND PPP6C.
[12]	"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: 18088087] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, MASS SPECTROMETRY. Tissue: Platelet.
[13]	"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: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, MASS SPECTROMETRY.
[14]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J.,