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Other entities represented in this entry:
HGNC Approved Gene Symbol: MAP3K7
SNOMEDCT: 720612000;
Cytogenetic location: 6q15 Genomic coordinates (GRCh38): 6:90,513,579-90,587,072 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q15 | Cardiospondylocarpofacial syndrome | 157800 | Autosomal dominant | 3 |
| Frontometaphyseal dysplasia 2 | 617137 | Autosomal dominant | 3 |
The MAP kinase (MAPK) cascades constitute functional units that couple upstream input signals to a variety of outputs through pathways that involve 3 protein kinases. MAPKKK (MAP3K; see 602448) phosphorylates MAPKK (MAP2K; see 176872), which in turn phosphorylates and activates MAPK (see 176948). MAP3K7, a member of the MAPKKK family, has been linked to interleukin-1 receptor (see IL1R1; 147810) and tumor necrosis factor receptor (see TNFRSF1A; 191190) signaling (Yamaguchi et al., 1995; Sato et al., 2005)
One MAPK pathway in S. cerevisiae controls the response to mating pheromone. Yamaguchi et al. (1995) screened a mouse cDNA library for clones that could act as MAPKKKs, suppressing a defect in the mating pheromone response pathway. They identified a cDNA that encodes a predicted 579-amino acid protein, which they named Tak1. Tak1 has a putative N-terminal protein kinase domain.
Kondo et al. (1998) identified human ESTs that were homologous to mouse Tak1 and used the resulting sequence information to clone human TAK1 from lung cDNA. The predicted 579-amino acid human TAK1 protein is 99% identical to the mouse Tak1 protein. On Northern blots, TAK1 was expressed as a 3-kb mRNA in all tissues tested. Kondo et al. (1998) found 2 isoforms of TAK1 that differed by an insertion of 27 amino acids after amino acid 403.
Independently, Sakurai et al. (1998) cloned a cDNA for TAK1 as well as 2 alternatively spliced isoforms, which they designated TAK1b (606 amino acids) and TAK1c (567 amino acids). Northern blot analysis revealed ubiquitous expression of 3.2- and 5.7-kb transcripts.
By amplifying the alternatively spliced region of TAK1, Dempsey et al. (2000) identified a fourth, shorter variant of TAK1 called TAK1d. The TAK1d variant lacks both alternative exons and encodes a 491-amino acid protein. RT-PCR analysis showed that TAK1c is ubiquitously expressed and predominates in prostate; TAK1a is the preferred form in most tissues tested; TAK1b is preferred in brain, kidney, lung, and small intestine; and TAK1d is present in most tissues as a minor variant. Dempsey et al. (2000) concluded that the variations in the C-terminal ends (in TAK1c and TAK1d) are unlikely to interfere with the catalytic activity of TAK1 or its interaction with TAB1 (602615), both of which involve the N terminus, but may change the interaction of TAK1 with the TAB2 (605101) adaptor protein.
By genomic sequence analysis, Dempsey et al. (2000) determined that the MAP3K7 gene contains 17 exons spanning 71 kb and that the alternative exons correspond to exons 12 and 16. Promoter analysis indicated the lack of a TATA box and the presence of a CpG island in a GC-rich region, suggesting that TAK1 is a housekeeping gene.
Kondo et al. (1998) used PCR of hybrid cell panels to link MAP3K7 to 2 markers that are included within a YAC from region 6q14-q21. Dempsey et al. (2000) refined the localization to 6q16.1-q16.3 by analysis of BAC clones (GenBank AL121964 and AL121837).
Yamaguchi et al. (1995) found that Tak1 regulated transcription by transforming growth factor-beta (TGFB; 190180) in mammalian cells. Only Tak1 protein missing the N-terminal 22 amino acids could suppress a yeast defect in the mating pheromone response pathway. This activated form also signaled in the absence of TGFB in mammalian cells.
Using supershift analysis, Sakurai et al. (1998) determined that all 3 isoforms of TAK1 could induce translocation of NFKB, composed of the p50/p65 heterodimer (see 164011 and 164014), to the nucleus, accompanied by the degradation of IKBA (NFKBIA; 164008) and IKBB (NFKBIB; 604495) in a NIK (604655)-independent manner.
Dempsey et al. (2000) noted that TGFB activation of TAK1 results in the activation of SAPK1 (JNK1; 601158) and SAPK2 (MAPK14; 600289) through the phosphorylation of MKK3 (602315), MKK4 (601335), and MKK6 (601254).
TRAF6 (602355)-regulated I-kappa-B kinase (IKK; see IKKB, 603258) activator-2 (TRIKA2) activity is defined as the stimulation of IKK in the presence of TRAF6 and the UBC13 (603679)-UBE2V1 (602995) complex (TRIKA1). By sequential chromatographic purification and immunoblot analysis, Wang et al. (2001) identified TAK1, together with its binding partners TAB1 and TAB2, as the protein that copurifies with TRIKA2 activity. Mutation analysis showed that the TAK1 ATP-binding domain, which mediates kinase activity and contains a lysine at position 63, is essential for TRIKA2 function. Upon activation by UBC13-UBE2V1-mediated ubiquitination, TAK1 phosphorylates IKKB at ser177 and ser181. Ubiquitin-activated TAK1 also phosphorylates MKK6 (601254) at ser207 and thr211, thereby allowing MKK6 to stimulate the kinase activity of JNK. Inhibition of polyubiquitination abolishes the activation of JNK and IKK by TRAF6. Mutation analysis showed that lys63 of ubiquitin (191339) is necessary and sufficient for the activation of TAK1. Wang et al. (2001) proposed that TAK1, when activated by ubiquitinated TRAF6 that has bound to TAB2 after the translocation of TAB2 from the membrane to the cytoplasm, is an IKK kinase. Furthermore, they suggested that lys63-linked polyubiquitin chains may provide a kinase-independent mechanism for the activation of the initial kinase in stress kinase pathways.
Li et al. (2003) found that ectopic expression of mouse Pp2ce (PPM1L; 611931) in HEK293 human embryonic kidney cells inhibited IL1 (see 147760)- and TAK1-induced activation of the MKK4/JNK or MKK3/p38 (MAPK14) signaling pathways. Pp2ce dephosphorylated TAK1 in vitro. Coimmunoprecipitation experiments revealed that Pp2ce associated stably with TAK1 and attenuated binding of TAK1 to MKK4 or MKK6. A phosphatase-negative Pp2ce mutant acted as a dominant-negative form and enhanced both association of TAK1 with MKK4 or MKK6 and TAK1-induced activation of an AP1 (165160) reporter gene. The association between Pp2ce and TAK1 was transiently suppressed by IL1 treatment. Li et al. (2003) concluded that, in the absence of IL1 signaling, PP2CE inactivates the TAK1 signaling pathway by associating with and dephosphorylating TAK1.
By reconstituting TAK1 activation in vitro using purified proteins, Xia et al. (2009) demonstrated that free Lys63 polyubiquitin chains, which are not conjugated to any target protein, directly activate TAK1 by binding to the ubiquitin receptor TAB2 (also known as MAP3K7IP2; 605101). This binding leads to autophosphorylation and activation of TAK1. Furthermore, Xia et al. (2009) found that unanchored polyubiquitin chains synthesized by TRAF6 (602355) and UBCH5C (also known as UBE2D3, 602963) activate the IKK (see 600664) complex. Disassembly of the polyubiquitin chains by deubiquitination enzymes prevented TAK1 and IKK activation. Xia et al. (2009) concluded that unanchored polyubiquitin chains directly activate TAK1 and IKK, suggesting a new mechanism of protein kinase regulation.
HuangFu et al. (2006) stated that TAK1 is activated by physical and chemical stress as well as by proinflammatory cytokines, and that osmotic stress is a potent TAK1 activator in HEK293 cells and mouse embryonic fibroblasts. In these cells, HuangFu et al. (2006) found that osmotic stress led to TAK1-induced activation of JNK, but not activation of NFKB. Yeast 2-hybrid analysis revealed TAK1 interacted with TAO1 (TAOK1; 610266) and TAO2 (TAOK2; 613199), and had higher affinity for TAO2. TAO2 enhanced TAK1-mediated activation of JNK, but blocked the interaction of TAK1 with the IKK complex, thereby inhibiting TAK1 activation of NFKB. Small interfering RNA directed against TAO2 reduced osmotic stress-induced JNK activation, but had no effect on osmotic stress-induced TAK1 activation. HuangFu et al. (2006) concluded that TAO2 and TAK1 act in parallel pathways leading to osmotic stress-induced JNK activation.
Using mass spectrometry, Wang et al. (2008) identified MAP3K7 as a component of the ADA2A (TADA2A; 602276)-containing (ATAC) histone acetyltransferase complex in HeLa cells.
Pertel et al. (2011) demonstrated that TRIM5 (608487) promotes innate immune signaling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric ubiquitin-conjugating enzyme UBC13-UEV1A, TRIM5 catalyzes the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 kinase complex and stimulate AP1 and NF-kappa-B (see 164011) signaling. Interaction with the HIV-1 capsid lattice greatly enhanced the UBC13-UEV1A-dependent E3 activity of TRIM5, and challenge with retroviruses induced the transcription of AP1- and NF-kappa-B-dependent factors with a magnitude that tracked with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13-UEV1A contribute to capsid-specific restriction by TRIM5. Pertel et al. (2011) concluded that the retroviral restriction factor TRIM5 has 2 additional activities that are linked to restriction: it constitutively promotes innate immune signaling, and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice.
Yu et al. (2012) adapted a microfluidic device for efficient capture of circulating tumor cells from an endogenous mouse pancreatic cancer model and subjected these cells to single-molecule RNA sequencing, identifying Wnt2 (147870) as a candidate gene enriched in circulating tumor cells. Expression of WNT2 in pancreatic cancer cells suppressed anoikis, enhanced anchorage-independent sphere formation, and increased metastatic propensity in vivo. This effect was correlated with fibronectin (135600) upregulation and suppressed by inhibition of MAP3K7. In humans, formation of nonadherent tumor spheres by pancreatic cancer cells was associated with upregulation of multiple WNT genes, and pancreatic circulating tumor cells revealed enrichment for WNT signaling in 5 of 11 cases.
Shinohara et al. (2014) showed that the CARMA1 (607210)-TAK1-IKBKB (603258) module is a switch mechanism for NFKB activation in B-cell receptor signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKBKB to TAK1, generating a steep dose response to B-cell receptor stimulation. Mutation of the scaffolding protein CARMA1 at ser578, an IKBKB target, not only abrogated late TAK1 activity but also abrogated the switchlike activation of NFKB in single cells, suggesting that phosphorylation of this residue accounts for the feedback.
Frontometaphyseal Dysplasia 2
In 15 of 18 unrelated patients from diverse ethnic backgrounds with frontometaphyseal dysplasia-2 (FMD2; 617137), Wade et al. (2016) identified heterozygosity for a recurrent missense mutation in the MAP3K7 gene (P485L; 602614.0001), affecting a residue immediately N-terminal to the coiled-coil domain. The remaining 3 patients, who exhibited a 'notably milder' phenotype, were heterozygous for MAP3K7 missense mutations involving the TAK1 kinase domain: E70Q (602614.0002), V100E (602614.0003), and G168R (602614.0004).
Cardiospondylocarpofacial Syndrome
In 3 unrelated patients and a father and 2 children with cardiospondylocarpofacial syndrome (CSCF; 157800), Le Goff et al. (2016) identified heterozygosity for mutations in the MAP3K7 gene: 2 in-frame deletions (602614.0005 and 602614.0007) and 2 missense mutations, G110C (602614.0006) and W241R (602614.0008), all located in the TAK1 kinase domain.
In a 7-year-old girl with features of cardiospondylocarpofacial syndrome and a connective tissue disorder, Morlino et al. (2018) identified a de novo heterozygous splice site mutation (c.737-7A-G, NM_145331.2) in intron 7 of the MAP3K7 gene (602614.0009), resulting in a new splice acceptor site with retention of the last 6 bases of intron 7 and an in-frame insertion of 2 valine residues within the TAK1 kinase domain. The variant was not present in the ExAC database or in 500 ethnicity matched samples. The authors noted that their report expands the CSCFS phenotype and reinforces the role of the TAK1-dependent signaling pathway in human morphogenesis.
Sato et al. (2005) found that Tak1 deficiency resulted in early embryonic death in mice. They generated Tak1 -/- fibroblasts and showed that Tak1 was required for Il1b (147720)- and Tnf (191160)-induced Nfkb and Jnk activation, as well as cytokine production. B cell-specific deletion of Tak1 led to impaired activation in response to TLR (e.g., TLR9; 605474) ligands and B-cell receptor stimulation, probably due to lack of interaction with Bcl10 (603517). Sato et al. (2005) concluded that TAK1 has nonredundant functions in signaling pathways in inflammatory and immune responses.
Liu et al. (2006) targeted Tak1 deletion to T cells in mice and found that Tak1 was essential for thymocyte development and activation. Deletion of Tak1 prevented maturation of single-positive thymocytes displaying Cd4 (186940) or Cd8 (see 186910), leading to reduction of T cells in the peripheral tissues. Thymocytes lacking Tak1 failed to activate Nfkb and Jnk and were prone to apoptosis upon stimulation. Liu et al. (2006) concluded that TAK1 is required for activation of NFKB in thymocytes and that TAK1 plays a central role in both innate and adaptive immunity.
In 15 unrelated patients from diverse ethnic backgrounds with frontometaphyseal dysplasia-2 (FMD2; 617137), including 5 patients previously reported by Basart et al. (2015), Wade et al. (2016) identified heterozygosity for a c.1454C-T transition (c.1454C-T, NM_003188.3) in the MAP3K7 gene, resulting in a pro485-to-leu (P485L) substitution at a phylogenetically conserved residue immediately N-terminal to the coiled-coil domain, within a region of TAK1 that mediates interactions with TAB2 (605101). In addition to the typical features of FMD, 8 of the 15 patients exhibited keloid scarring. Wade et al. (2016) noted that this recurrent mutation occurs at a hypermutable CpG dinucleotide, where the observation of a C-T transition is expected to be more common than other mutations. Functional analysis in HEK293FT cells demonstrated significantly more autophosphorylation at T187 with the P485L mutant than with wildtype TAK1. In addition, luciferase reporter assay measuring activation of several MAPK targets, including ERK (see 176872), p38 (MAPK14; 600289), and JNK (see MAPK8, 601158), showed significantly enhanced activation with the P485L mutant compared to wildtype TAK1; Western blot analysis confirmed a substantial increase in phosphorylation of p38 with the mutant compared to wildtype. In contrast, luciferase reporter assay of the NFKB (see 164011) pathway showed significantly reduced reporter activity with P485L TAK1 compared to wildtype.
In a French Canadian mother and daughter with a mild form of frontometaphyseal dysplasia-2 (FMD2; 617137), Wade et al. (2016) identified heterozygosity for a c.208G-C transversion in the MAP3K7 gene, resulting in a glu70-to-gln (E70Q) substitution at a highly conserved residue within the TAK1 kinase domain. The phenotype in this family did not include cervical vertebral fusion, flared metaphyses, or digital and wrist contractures, which are features commonly seen in patients with FMD. (In the article by Wade et al. (2016), the nucleotide change is stated as c.208G-A in the text, but as c.208G-C in the abstract and the tables and figures.)
In a Hungarian mother and daughter with a mild form of frontometaphyseal dysplasia-2 (FMD2; 617137), originally reported by Morava et al. (2003), Wade et al. (2016) identified heterozygosity for a c.299T-A transversion (c.299T-A, NM_003188.3) in the MAP3K7 gene, resulting in a val100-to-glu (V100E) substitution at a highly conserved residue within the TAK1 kinase domain. The affected mother and daughter experienced no significant health problems in childhood, and exhibited less striking facial dysmorphism and milder contractures of the fingers, compared to typical FMD patients.
In a Brazilian male patient with a mild form of frontometaphyseal dysplasia-2 (FMD2; 617137), Wade et al. (2016) identified heterozygosity for a de novo c.502G-C transversion (c.502G-C, NM_003188.3) in the MAP3K7 gene, resulting in a gly168-to-arg (G168R) substitution at a highly conserved residue within the kinase domain of TAK1. The proband did not exhibit some of the features commonly seen in patients with FMD, including small chin, hearing loss, downslanting palpebral fissures, and flared metaphyses. Functional analysis in HEK293FT cells demonstrated significantly more autophosphorylation at T187 with the G168R mutant than with wildtype TAK1. However, luciferase reporter assay measuring activation of MAPK targets, as well as immunoblot for phosphorylation of p38 (MAPK14; 600289), showed no increase in signaling with the G168R mutant compared to wildtype TAK1. In addition, luciferase reporter assay of the NFKB (see 164011) pathway showed significantly reduced reporter activity with G168R TAK1 compared to wildtype.
In a 13-year-old Moroccan-Algerian girl with cardiospondylocarpofacial syndrome (CSCF; 157800), originally reported by Sousa et al. (2010), Le Goff et al. (2016) identified heterozygosity for a de novo 6-bp in-frame deletion (c.130_135delAGAGGA, NM_145331.2) in the MAP3K7 gene, resulting in deletion of 2 highly conserved residues (Arg44_Gly45del) within the kinase domain of TAK1. The mutation was not found in her unaffected parents, in 200 ethnically matched controls, in 11,040 in-house exome samples, or in the ExAC database. Analysis of patient fibroblasts showed significantly decreased phosphorylation of p38 (MAPK14; 600289) compared to control fibroblasts. Real-time qPCR analyses showed decreased mRNA expression of the downstream TGFB (190180) target genes CTGF (121009) and SERPINE1 (173360), whereas an inhibitor of MAPK14, SMAD6 (602931) showed increased expression, in patient fibroblasts compared to controls.
In a 16-year-old French girl with cardiospondylocarpofacial syndrome (CSCF; 157800), originally reported by Sousa et al. (2010), Le Goff et al. (2016) identified heterozygosity for a de novo c.328G-T transversion (c.328G-T, NM_145331.2) in the MAP3K7 gene, resulting in a gly110-to-cys (G110C) substitution at a highly conserved residue within the kinase domain of TAK1. The mutation was not found in her unaffected parents, in 200 ethnically matched controls, in 11,040 in-house exome samples, or in the ExAC database. Analysis of patient fibroblasts showed significantly decreased phosphorylation of p38 (MAPK14; 600289) compared to control fibroblasts. Real-time qPCR analyses showed decreased mRNA expression of the downstream TGFB (190180) target genes CTGF (121009) and SERPINE1 (173360), whereas an inhibitor of MAPK14, SMAD6 (602931) showed increased expression, in patient fibroblasts compared to controls.
In a French father and son with cardiospondylocarpofacial syndrome (CSCF; 157800), Le Goff et al. (2016) identified heterozygosity for a 3-bp in-frame deletion (c.148_150delGTT, NM_145331.2), resulting in deletion of a highly conserved residue (Val50del) within the kinase domain of TAK1. The mutation was also detected in DNA from an affected daughter who died at 9 days of life, but was not found in the paternal grandparents, indicating de novo occurrence in the father. The mutation was not found in 200 ethnically matched controls, in 11,040 in-house exome samples, or in the ExAC database. Analysis of the father's fibroblasts showed significantly decreased phosphorylation of p38 (MAPK14; 600289) compared to control fibroblasts. Real-time qPCR analyses showed decreased mRNA expression of the downstream TGFB (190180) target genes CTGF (121009) and SERPINE1 (173360), whereas an inhibitor of MAPK14, SMAD6 (602931) showed increased expression, in patient fibroblasts compared to controls.
In a 22-year-old woman of Chinese ancestry with cardiospondylocarpofacial syndrome (CSCF; 157800), Le Goff et al. (2016) identified heterozygosity for a de novo c.721T-A transversion (c.721T-A, NM_145331.2) in the MAP3K7 gene, resulting in a trp241-to-arg (W241R) substitution at a highly conserved residue within the kinase domain of TAK1. The mutation was not found in her unaffected parents, in 200 ethnically matched controls, in 11,040 in-house exome samples, or in the ExAC database.
In a 7-year-old girl with features of cardiospondylocarpofacial syndrome (CSCF; 157800) and a connective tissue disorder, Morlino et al. (2018) identified a de novo heterozygous c.737-7A-G mutation (c.737-7A-G, NM_145331.2) in intron 7 of the MAP3K7 gene (602614.0009), predicted to produce a new splice acceptor site with retention of the last 6 bases of intron 7 and an in-frame insertion of 2 valine residues within the TAK1 kinase domain. RNA studies confirmed this prediction. The variant was not found in the ExAC database or in 500 ethnicity matched samples.
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