Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

MAP3K7 (mitogen-activated protein kinase kinase kinase 7)

Written2009-03Hui 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

(Note : for Links provided by Atlas : click)


Alias (NCBI)TAK1
HGNC (Hugo) MAP3K7
HGNC Alias symbMEKK7
HGNC Alias nameTGF-beta activated kinase 1
HGNC Previous nameTAK1
LocusID (NCBI) 6885
Atlas_Id 454
Location 6q15  [Link to chromosome band 6q15]
Location_base_pair Starts at 90513580 and ends at 90587072 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping MAP3K7.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
BACH2 (6q15)::MAP3K7 (6q15)MAP3K7 (6q15)::MAP3K7 (6q15)RPS8 (1p34.1)::MAP3K7 (6q15)


  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.
Description 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 3'UTR. 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.
Transcription 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.
Pseudogene No pseudogene of MAP3K7/TAK1 was reported in human.


Note 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.
Description 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.
Expression 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.
Localisation TAK1 is mostly localized in cytoplasm.
Function 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.
Homology 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.


Note No mutation of human MAP3K7 was reported.

Implicated in

Entity Breast cancer
Note 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 Lung cancer
Note 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 Cervical carcinoma
Note 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 Head and neck squamous cell carcinoma
Note 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 Arthritis
Note 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 Inflammation
Note 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 Human airway epithelial cells
Note 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.


TAK1-dependent signaling requires functional interaction with TAB2/TAB3.
Besse A, Lamothe B, Campos AD, Webster WK, Maddineni U, Lin SC, Wu H, Darnay BG.
J Biol Chem. 2007 Feb 9;282(6):3918-28. Epub 2006 Dec 8.
PMID 17158449
Blockade of transforming growth factor-beta-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade.
Choo MK, Kawasaki N, Singhirunnusorn P, Koizumi K, Sato S, Akira S, Saiki I, Sakurai H.
Mol Cancer Ther. 2006 Dec;5(12):2970-6.
PMID 17172402
Alternative splicing and gene structure of the transforming growth factor beta-activated kinase 1.
Dempsey CE, Sakurai H, Sugita T, Guesdon F.
Biochim Biophys Acta. 2000 Dec 15;1517(1):46-52.
PMID 11118615
Regulation of the JNK pathway by TGF-beta activated kinase 1 in rheumatoid arthritis synoviocytes.
Hammaker DR, Boyle DL, Inoue T, Firestein GS.
Arthritis Res Ther. 2007;9(3):R57.
PMID 17559674
TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily.
Hirose T, Fujimoto W, Tamaai T, Kim KH, Matsuura H, Jetten AM.
Mol Endocrinol. 1994 Dec;8(12):1667-80.
PMID 7708055
TAK1 mRNA expression in the tumor tissue of locally advanced head and neck Cancer Patients.
Honorato B, Alcalde J, Martinez-Monge R, Zabalegui N, Garcia-Foncillas J.
Gene Regulation and Systems Biology. 2008;2: 63-70.
Evidence 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, Ichikawa H, Takada Y, Myers JN, Lin XL, Darnay BG, Chaturvedi MM, Aggarwal BB.
Oncogene. 2007 Mar 1;26(10):1385-97. Epub 2006 Sep 4.
PMID 16953224
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 DL, Matsumoto K, Ninomiya-Tsuji J.
J Biol Chem. 2006 Dec 29;281(52):39891-6. Epub 2006 Nov 1.
PMID 17079228
TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL-1 signaling pathway.
Kishida S, Sanjo H, Akira S, Matsumoto K, Ninomiya-Tsuji J.
Genes Cells. 2005 May;10(5):447-54.
PMID 15836773
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. 2000 Mar 10;275(10):7359-64.
PMID 10702308
Sequence-specific activation of TAK1-D by short double-stranded RNAs induces apoptosis in NCI-H460 cells.
Kodym R, Kodym E, Story MD.
RNA. 2008 Mar;14(3):535-42. Epub 2008 Jan 29.
PMID 18230764
Molecular cloning of human TAK1 and its mutational analysis in human lung cancer.
Kondo M, Osada H, Uchida K, Yanagisawa K, Masuda A, Takagi K, Takahashi T, Takahashi T.
Int J Cancer. 1998 Feb 9;75(4):559-63.
PMID 9466656
TAK1 regulates multiple protein kinase cascades activated by bacterial lipopolysaccharide.
Lee J, Mira-Arbibe L, Ulevitch RJ.
J Leukoc Biol. 2000 Dec;68(6):909-15.
PMID 11129660
Cloning and characterization of a novel human TGF-beta activated kinase-like gene.
Li J, Ji C, Yang Q, Chen J, Gu S, Ying K, Xie Y, Mao Y.
Biochem Genet. 2004 Apr;42(3-4):129-37.
PMID 15168726
Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon).
Li MG, Katsura K, Nomiyama H, Komaki K, Ninomiya-Tsuji J, Matsumoto K, Kobayashi T, Tamura S.
J Biol Chem. 2003 Apr 4;278(14):12013-21. Epub 2003 Jan 28.
PMID 12556533
Biomechanical signals suppress TAK1 activation to inhibit NF-kappaB transcriptional activation in fibrochondrocytes.
Madhavan S, Anghelina M, Sjostrom D, Dossumbekova A, Guttridge DC, Agarwal S.
J Immunol. 2007 Nov 1;179(9):6246-54.
PMID 17947700
Molecular Mechanism of TAK1-Induced Repression of hTERT Transcription.
Maura M, Katakura Y, Miura T, Fujiki T, Shiraishi H, Shirahata S.
Cell Technology for Cell Products, R. Smith (ed.), 91-93. 2007 Springer.
Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression.
Neil JR, Schiemann WP.
Cancer Res. 2008 Mar 1;68(5):1462-70.
PMID 18316610
TAK1 is required for TGF-beta 1-mediated regulation of matrix metalloproteinase-9 and metastasis.
Safina A, Ren MQ, Vandette E, Bakin AV.
Oncogene. 2008 Feb 21;27(9):1198-207. Epub 2007 Sep 10.
PMID 17828308
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. 1998 Feb 13;243(2):545-9.
PMID 9480845
TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway.
Takaesu G, Surabhi RM, Park KJ, Ninomiya-Tsuji J, Matsumoto K, Gaynor RB.
J Mol Biol. 2003 Feb 7;326(1):105-15.
PMID 12547194
TAK1 is a ubiquitin-dependent kinase of MKK and IKK.
Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.
Nature. 2001 Jul 19;412(6844):346-51.
PMID 11460167
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, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K.
Science. 1995 Dec 22;270(5244):2008-11.
PMID 8533096
Phosphorylation 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, Ge N, Xie M, Sun W, Burlingame S, Pass AK, Nuchtern JG, Zhang D, Fu S, Schneider MD, Fan J, Yang J.
J Biol Chem. 2008 Sep 5;283(36):24497-505. Epub 2008 Jul 10.
PMID 18617512


This paper should be referenced as such :
Tang, HH ; Yeung, KC
MAP3K7 (mitogen-activated protein kinase kinase kinase 7)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(3):238-242.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)MAP3K7   6859
Entrez_Gene (NCBI)MAP3K7    mitogen-activated protein kinase kinase kinase 7
AliasesCSCF; FMD2; MEKK7; TAK1; 
GeneCards (Weizmann)MAP3K7
Ensembl hg19 (Hinxton)ENSG00000135341 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000135341 [Gene_View]  ENSG00000135341 [Sequence]  chr6:90513580-90587072 [Contig_View]  MAP3K7 [Vega]
ICGC DataPortalENSG00000135341
TCGA cBioPortalMAP3K7
AceView (NCBI)MAP3K7
Genatlas (Paris)MAP3K7
SOURCE (Princeton)MAP3K7
Genetics Home Reference (NIH)MAP3K7
Genomic and cartography
GoldenPath hg38 (UCSC)MAP3K7  -     chr6:90513580-90587072 -  6q15   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MAP3K7  -     6q15   [Description]    (hg19-Feb_2009)
GoldenPathMAP3K7 - 6q15 [CytoView hg19]  MAP3K7 - 6q15 [CytoView hg38]
Genome Data Viewer NCBIMAP3K7 [Mapview hg19]  
OMIM157800   602614   617137   
Gene and transcription
Genbank (Entrez)AB009356 AB009357 AB009358 AF218074 AI147171
RefSeq transcript (Entrez)NM_003188 NM_145331 NM_145332 NM_145333
Consensus coding sequences : CCDS (NCBI)MAP3K7
Gene ExpressionMAP3K7 [ NCBI-GEO ]   MAP3K7 [ EBI - ARRAY_EXPRESS ]   MAP3K7 [ SEEK ]   MAP3K7 [ MEM ]
Gene Expression Viewer (FireBrowse)MAP3K7 [ Firebrowse - Broad ]
GenevisibleExpression of MAP3K7 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6885
GTEX Portal (Tissue expression)MAP3K7
Human Protein AtlasENSG00000135341-MAP3K7 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)MAP3K7
Human Protein Atlas [tissue]ENSG00000135341-MAP3K7 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed407 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Oct 8 21:21:41 CEST 2021

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us