MAP3K7 (mitogen-activated protein kinase kinase kinase 7)

2009-03-01   Hui Hui Tang , Kam C Yeung 

Department of Cancer Biology, Biochemistry, College of Medicine, Univeristy of Toledo, Health Science Campus, 3035 Arlington Ave., Toledo, OH 43614, USA




Atlas Image
A: The 17 exons are shown as black vertical bars. The exon numbers are shown on top of each exon. The CpG island is shown as a white box. The positions of exons in the cDNA are 1-282, 283-393, 394-459, 460-505, 506-644, 645-768, 770-898, 899-1029, 1030-1111, 1112-1242, 1243-1372, 1373-1453, 1454-1518, 1519-1624, 1625-1686, 1687-1802, and 1803-2850. The sizes (in base pairs) of intron 1 to 16 are 14956, 3073, 6891, 1407, 3451, 2913, 1278, 1499, 2290, 659, 2625, 8150, 12553, 4358, 695, and 1765, respectively.
B: MAP3K7 transcripts.


MAP3K7/TAK1 gene spans 71 kb of DNA and contains 17 exons and 16 introns. Exon 1 contains the 5 UTR of the mRNA and encodes 40 amino acid of N-terminal of the protein. Exons 2 to 8 encode the kinase domain. Exon 17 encodes the carboxyl end of the TAK1 protein and contains the 3UTR. Exon 12 and exon 16 are alternative exons.
The promoter is located between 799 bp and 1215 bp upsteam of the exon 1. The promoter has the character of housekeeping genes: the absence of TATA box, the presence of CpG island and SP1 binding sites.


Four alternatively spliced transcripts encoding 4 distinct isoforms because of the presence or absence of alternative exons 12 or/and 16 are detected.
Variant A: It lacks an in-frame coding segment, exon 12.
Variant B: This variant contains both alternative exons 12 and 16 and encodes the longest isoform.
Variant C: Variant C lacks the exon 16 resulting in a frame shift in exon 17. The resulting isoform C has a distinct and shorter C terminus when compared with variants A and B.
Variant D: Variant D lacks both exons 12 and 16.
The regulation of the TAK1 mRNA alternative splicing is tissue specific. The different variants of TAK1 may have specialized functions.


No pseudogene of MAP3K7/TAK1 was reported in human.



MAP3K7/TAK1 isoform B contains 606 amino acids (aa) and has a predicted molecular weight of 67 kDa, isoform D contains 491 aa and has a predicted molecular weight of 53.7 kDa, isoform C contains 518 aa and has a predicted molecular weight of 56.7 kDa, and isoform A contains 579 aa and has a predicted molecular weight of 64 kDa.


MAP3K7/TAK1 was first identified by screening a mouse cDNA library for clones that could act as MAPKKKs. The mouse TAK1 cDNA encodes a 579-amino acid protein. The mouse TAK1 protein contains a 300-residue COOH-terminal domain and a putative NH2-terminal protein kinase catalytic domain.
The kinase domain has approximately 30% identity to the catalytic domains of Raf-1 and MEKK1. Kondo et al. (1998) cloned human TAK1 from lung cDNA library by screening with mouse TAK1 sequence. Human TAK1 gene encodes a 579-amino-acid protein. The hTAK1 gene has 91.8% identity with the mTAK1 gene at the nucleotide level and has 99.3% to that at the amino acid level. Human TAK1 mRNA with a size of 3.0 kb was observed to express in all the tissues examined by Northern blotting. Kondo et al. (1998) found 2 isoforms of TAK1. Isoform 2 had an insertion of 27 amino acids between amino acids 403 and 404 of isoform 1 which corresponded to the mTAK1 sequence previously identified by Yamaguchi et al. (1995). The two isoforms were expressed at different ratios. Isoform 1 (Variant A) was predominantly expressed in brain, heart and spleen while the isoform 2 (Variant B) was preferentially in the kidney.
Independently, Sakurai et al. (1998) cloned hTAK1 as well as two alternatively spliced isoforms. Human TAK1a (Variant A) has 99.3% identity to murine TAK1. TAK1b (Variant B) had an insertion of 27 amino acids and TAK1c had a deletion of 39 amino acids in the carboxyl-terminal region. The catalytic domains of these three isoforms were 100% identical to that of murine TAK1. The mRNA for TAK1a and TAK1b were expressed in Hela, Jurkat and THP1 cells and TAK1a mRNA expessed predominantly in these cell lines. TAK1c mRNA (Variant C) was expressed only in Hela cells. Northern blot analysis revealed the expression of TAK1 mRNA in all the human tissues examined with the size of 3.2 and 5.7 kb. Dempsey et al. (2000) identified a fourth splice variant of TAK1 called TAK1d (Variant D). TAK1d lacked the two alternative exons and encoded a 491 amino acid protein. TAK1a and b were the most abundant forms in most tissues examined. The carboxyl-end variant TAK1 proteins were unlikely to interfere with the catalytic activity of TAK1 or its interaction with TAB1 since both of which involve the N terminus, but may affect its interaction with TAB2 which associates with the carboxyl-ends of the TAK1 proteins.


TAK1 was ubiquitously expressed in all tissues. TAK1a (variant A) was the most abundant form in heart, liver, skeletal muscle, ovary, spleen and peripheral blood mononuclear cells; TAK1b (Variant B) was more abundant in brain, kidney, prostate and small intestine; TAK1c (Variant C) is ubiquitously expressed and predominantly in prostate; and TAK1d (Variant D) existed in most tested tissues as a minor variant.


TAK1 is mostly localized in cytoplasm.


TAK1 is a member of the serine/threonine protein kinase family. It can be activated by transforming growth factor-beta (TGF-b) and TAK1 deletion mutant missing the N-terminal 22 amino acid is constitutively active. In response to TGF-b, TAK1 can phosphorylate and activate MAP kinase kinases MKK3, MKK4 and MKK6. TAK1 can activate NF-kB in the presence of TAB1. TAK1 is also involved in pro-inflammatory cytokines signaling by activating two kinase pathways. One is a MAPK cascade that leads to the activation of JNK and the other is IkB kinase cascade that causes the activation of NF-kB. It was shown that TRAF6 is a signal mediator that activates IKK and JNK in response to pro-inflammatory cytokine interleukin 1. The activation of IKK by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2. TRIKA1 is an ubiquitin-conjugating enzyme complex consisted of Ubc13 and Uev1A. TRIKA1, together with TRAF6, catalyze the formation of a Lys63-linked polyubiquitin chain that mediates IKK activation. TRIKA2 is composed of TAK1, TAB1 and TAB2.
The activation of TAK1 kinase complex is dependent on its polyubiquitination by the TRAF6-Ubc complex and phosphorylation of several residues within the kinase activation loop by yet-to-be identified kinases. The ubiquitinated TAK1 can phosphorylate IKKbeta specifically at S177 and S181. Mutation analysis revealed that a point mutation in the ATP-binding domain of TAK1 (K63W), which abolished its kinase activity, was unable to activate IKK. TAK1 was activated by auto-phosphorylation on Ser192 and dual phosphorylation of Thr-178 and Thr-184 residues within the activation loop. Mutation of a conserved serine residue (Ser192) in the activation loop between kinase domain VII and VIII abrogated the phosphorylation and activation of TAK1. TAK1 is linked to TRAFs by two adaptor proteins TAB2 and TAB3. The interaction of TAB2/TAB3 with TAK1 is essential for the activation of signaling pathway mediated by IL-1.
It was shown that protein phosphatase 2Cepsilon (PP2Cepsilon) inhibited the IL-1 and TAK1 induced activation of MKK4-JNK or MKK3-p38 signaling pathway. PP2Cepsilon inactivated TAK1 by associating with and dephosphorylating TAK1. A type-2A phosphatase, protein phosphatase 6 (PP6), was also identified as a TAK1-binding protein. PP6 repressed TAK1 activity by dephosphorylating Thr187.


Human TAK1-like (TAKL) gene encoded a 242 amino acid protein which shared a homology with human TAK1. The amino acid sequences of TAK1 were highly conserved between human and mouse.



No mutation of human MAP3K7 was reported.

Implicated in

Entity name
Breast cancer
TGF-b1 signaling is involved in tumor angiogenesis and metastasis by regulating matrix proteosis. MMP-9 is an important component of these TGF-b1 responses. TAK1 is important for TGF-b1 regulation of MMP9 and metastatic potential of breast cancer cell line MDA-MB231. Suppression of TAK1 reduces the expression of MMP9 and tumor cell invasion.
TAK1 and NFkB are required for the human MCF10A-CA1a breast cancer cells to undergo invasion in response to TGF-b. A novel TAB1:TAK1: IKKb: NFkB signaling axis forms aberrantly in breast cancer cells and enables oncogenic signaling by TGF-b.
Entity name
Lung cancer
Mutation analysis: Study on 39 lung cancer specimens and 16 lung cancer cell lines indicated that hTAK1 was not a frequent target for genetic alternations in lung cancer.

TAK1 variant D activated by siRNAs of specific sequences leads to down stream activation of p38 MAPK and JNK but not NFkB pathway. In human lung cancer cell line NCI-H460 the activation of these pathway cause cell cycle arrest and apoptosis. It suggests that TAK1 D may be a new and promising therapeutic target for the treatment of non-small cell lung cancer.
Telomeres are essential elements at the ends of chromosomes that contribute to chromosomal stability. The length of the telomere is maintained by the telomerase holoenzyme, which contains the reverse transcriptase hTERT as a major enzymatic subunit. The activity of telomerase is absent in most normal human cells because of the downregulation of the hTERT transcript resulting in the shortening of telomeres after each replicative cycle. However, in immortalized cells and cancer cells, the telomere lengths are maintained through an increase in hTERT expression. TAK1 can repress the transcription of hTERT in A549 human lung adenocarcinoma cell line and this repression is caused by recruitment of HDAC to the hTERT promoter.

Entity name
Cervical carcinoma
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of TNFa ligand family, induces apoptosis in a variety of tumor cells. TRAIL induced the delayed phosphorylation of TAK1 in human cervical carcinoma HeLa cells. TRAIL induced apoptosis was enhanced by downregulation of TAK1.
Entity name
Head and neck squamous cell carcinoma
NFkB was constitutively activated in head and neck squamous cell carcinoma (HNSCC). Constitutive activation of NFkB in HNSCC was caused by constitutive activation of IKK. Constitutive activation of NFkB is mediated through the TRADD-TRAF2-RIP-TAK1-IKK pathway.
Entity name
Exercise/joint mobility has therapeutic potency for inflammatory joint diseases such as rheumatoid and osteoarthritis. The biomechanical signals at physiological magnitudes are potent inhibitors of inflammation induced by NFkB activation in fibrochondrocytes. The biomechanical signals exert anti-inflammatory effects by inhibiting phosphorylation of TAK1.
JNK is essential for metalloproteinase (MMP) gene expression and joint destruction in inflammatory arthritis. TAK1 is an upstream kinase of JNK. TAK1 play an important role for the IL1b induced JNK activation and the JNK induced gene expression in fibroblast-like synoviocytes (FLSs). It suggests that TAK1 is a potential therapeutic target to modulate synoviocyte activation in rheumatoid arthritis (RA).
Entity name
Pro-inflammatory molecules lipopolysaccharide and Interleukin 1 trigger the activation of TAK1, which in turn activates multiple kinase JNK, p38, IKK and PKB/Akt which are important components of kinase cascades involved in inflammation. Thus TAK1 plays an important role in inflammation.
Entity name
Human airway epithelial cells
Act1/TRAF6/TAK1-mediated NF-kB activation stimulated by IL-17A regulates gene induction in human airway epithelial cells. Dominant negative TAK1 reduces IL-17A induced gene expression.


Pubmed IDLast YearTitleAuthors
171584492007TAK1-dependent signaling requires functional interaction with TAB2/TAB3.Besse A et al
171724022006Blockade of transforming growth factor-beta-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade.Choo MK et al
111186152000Alternative splicing and gene structure of the transforming growth factor beta-activated kinase 1.Dempsey CE et al
175596742007Regulation of the JNK pathway by TGF-beta activated kinase 1 in rheumatoid arthritis synoviocytes.Hammaker DR et al
77080551994TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily.Hirose T et al
169532242007Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma.Jackson-Bernitsas DG et al
170792282006Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway.Kajino T et al
158367732005TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL-1 signaling pathway.Kishida S et al
107023082000TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop.Kishimoto K et al
182307642008Sequence-specific activation of TAK1-D by short double-stranded RNAs induces apoptosis in NCI-H460 cells.Kodym R et al
94666561998Molecular cloning of human TAK1 and its mutational analysis in human lung cancer.Kondo M et al
111296602000TAK1 regulates multiple protein kinase cascades activated by bacterial lipopolysaccharide.Lee J et al
151687262004Cloning and characterization of a novel human TGF-beta activated kinase-like gene.Li J et al
125565332003Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon).Li MG et al
179477002007Biomechanical signals suppress TAK1 activation to inhibit NF-kappaB transcriptional activation in fibrochondrocytes.Madhavan S et al
183166102008Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression.Neil JR et al
178283082008TAK1 is required for TGF-beta 1-mediated regulation of matrix metalloproteinase-9 and metastasis.Safina A et al
94808451998TGF-beta-activated kinase 1 stimulates NF-kappa B activation by an NF-kappa B-inducing kinase-independent mechanism.Sakurai H et al
125471942003TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway.Takaesu G et al
114601672001TAK1 is a ubiquitin-dependent kinase of MKK and IKK.Wang C et al
85330961995Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction.Yamaguchi K et al
186175122008Phosphorylation of Thr-178 and Thr-184 in the TAK1 T-loop is required for interleukin (IL)-1-mediated optimal NFkappaB and AP-1 activation as well as IL-6 gene expression.Yu Y et al

Other Information

Locus ID:

NCBI: 6885
MIM: 602614
HGNC: 6859
Ensembl: ENSG00000135341


dbSNP: 6885
ClinVar: 6885
TCGA: ENSG00000135341


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Autophagy - animalKEGGko04140
Wnt signaling pathwayKEGGko04310
Adherens junctionKEGGko04520
Toll-like receptor signaling pathwayKEGGko04620
T cell receptor signaling pathwayKEGGko04660
MAPK signaling pathwayKEGGhsa04010
Autophagy - animalKEGGhsa04140
Wnt signaling pathwayKEGGhsa04310
Adherens junctionKEGGhsa04520
Toll-like receptor signaling pathwayKEGGhsa04620
T cell receptor signaling pathwayKEGGhsa04660
RIG-I-like receptor signaling pathwayKEGGko04622
RIG-I-like receptor signaling pathwayKEGGhsa04622
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
NF-kappa B signaling pathwayKEGGhsa04064
NF-kappa B signaling pathwayKEGGko04064
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
Toll-like receptor signalingKEGGhsa_M00686
MAPK (JNK) signalingKEGGhsa_M00688
MAPK (p38) signalingKEGGhsa_M00689
Toll-like receptor signalingKEGGM00686
MAPK (JNK) signalingKEGGM00688
MAPK (p38) signalingKEGGM00689
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
TCR signalingREACTOMER-HSA-202403
Downstream TCR signalingREACTOMER-HSA-202424
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
Activation of NF-kappaB in B cellsREACTOMER-HSA-1169091
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 10 (TLR10) CascadeREACTOMER-HSA-168142
MyD88 cascade initiated on plasma membraneREACTOMER-HSA-975871
IRAK2 mediated activation of TAK1 complexREACTOMER-HSA-937042
TAK1 activates NFkB by phosphorylation and activation of IKKs complexREACTOMER-HSA-445989
MAP kinase activation in TLR cascadeREACTOMER-HSA-450294
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1REACTOMER-HSA-450321
activated TAK1 mediates p38 MAPK activationREACTOMER-HSA-450302
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
TRAF6 mediated induction of TAK1 complexREACTOMER-HSA-937072
Toll Like Receptor 5 (TLR5) CascadeREACTOMER-HSA-168176
Toll Like Receptor 7/8 (TLR7/8) CascadeREACTOMER-HSA-168181
MyD88 dependent cascade initiated on endosomeREACTOMER-HSA-975155
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activationREACTOMER-HSA-975138
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulationREACTOMER-HSA-975163
Toll Like Receptor 9 (TLR9) CascadeREACTOMER-HSA-168138
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathwaysREACTOMER-HSA-168643
NOD1/2 Signaling PathwayREACTOMER-HSA-168638
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated NF-kB activationREACTOMER-HSA-2871837
C-type lectin receptors (CLRs)REACTOMER-HSA-5621481
CLEC7A (Dectin-1) signalingREACTOMER-HSA-5607764
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-1 signalingREACTOMER-HSA-446652
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
Beta-catenin independent WNT signalingREACTOMER-HSA-3858494
Ca2+ pathwayREACTOMER-HSA-4086398
Death Receptor SignallingREACTOMER-HSA-73887
TNF signalingREACTOMER-HSA-75893
TNFR1-induced NFkappaB signaling pathwayREACTOMER-HSA-5357956
Ub-specific processing proteasesREACTOMER-HSA-5689880
IL-17 signaling pathwayKEGGko04657
Fluid shear stress and atherosclerosisKEGGko05418
IL-17 signaling pathwayKEGGhsa04657
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
151258332004The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes.248
196755692009Direct activation of protein kinases by unanchored polyubiquitin chains.225
187584502008The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner.223
168352262006Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro.154
191972432009TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells.139
223414392012TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers.123
125471942003TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway.114
128428942003Tumor necrosis factor-alpha-induced IKK phosphorylation of NF-kappaB p65 on serine 536 is mediated through the TRAF2, TRAF5, and TAK1 signaling pathway.113
145929772003Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha.93
122422932002Interleukin-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.91


Hui Hui Tang ; Kam C Yeung

MAP3K7 (mitogen-activated protein kinase kinase kinase 7)

Atlas Genet Cytogenet Oncol Haematol. 2009-03-01

Online version: