Affinage

MAP3K7

Mitogen-activated protein kinase kinase kinase 7 · UniProt O43318

Length
606 aa
Mass
67.2 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K7 (TAK1) is a serine/threonine MAP3K that serves as a central signaling hub integrating innate immune, inflammatory, cell death, and developmental pathways. It functions as the catalytic subunit of TRIKA2 complexes containing TAB1 and TAB2 or TAB3, activated by TRAF6/Ubc13-Uev1A-generated K63-linked polyubiquitin chains or by TAB1-dependent autophosphorylation, and phosphorylates IKK (activating NF-κB) and MKK4/6/7 (activating JNK and p38 MAPK) downstream of IL-1R, TNFR, TLRs, and BCR (PMID:11460167, PMID:16186825, PMID:28507161); TAK1 also directly phosphorylates STING at Ser355 to promote its ER-to-ERGIC trafficking for innate immune activation (PMID:37832545), activates NLK to antagonize Wnt/β-catenin–TCF signaling (PMID:10391247), and controls autophagy via the AMPK/mTORC1 axis and p62 relocalization (PMID:24983318, PMID:31347268). TAK1 activity is negatively regulated by feedback phosphorylation of TAB1/2/3 by p38α (PMID:14592977), by deubiquitinases USP4 and OTUD5 that remove activating K63-ubiquitin chains (PMID:21331078, PMID:38937512), by phosphatases PP2Cβ and POPX2 (PMID:11104763, PMID:28906490), and by E3 ligases TRIM16 and NEDD4 that target TAK1 for K48-ubiquitin-mediated proteasomal degradation (PMID:34146477, PMID:38569496); gain-of-function MAP3K7 mutations cause frontometaphyseal dysplasia while heterozygous loss-of-function mutations cause cardiospondylocarpofacial syndrome (PMID:27426733, PMID:27426734).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Establishing that TAK1 feeds into Wnt signaling revealed an unexpected cross-pathway role: TAK1 activates NLK, which phosphorylates TCF/LEF to inhibit β-catenin–TCF DNA binding, placing TAK1 as a negative regulator of canonical Wnt signaling.

    Evidence Kinase assays, Xenopus embryo injection, C. elegans epistasis, EMSA

    PMID:10391247

    Open questions at the time
    • Direct mechanism of TAK1-to-NLK activation was unclear
    • Physiological Wnt ligand triggering TAK1 not yet demonstrated
  2. 2001 High

    The biochemical basis of TAK1 activation was established: TAK1 was identified as the kinase component of TRIKA2 (TAK1–TAB1–TAB2), activated by TRAF6/Ubc13-Uev1A-synthesized K63-polyubiquitin chains, directly phosphorylating IKK and MKK6 to bifurcate signaling toward NF-κB and JNK/p38.

    Evidence Protein purification, in vitro kinase reconstitution with ubiquitin components, Co-IP

    PMID:11460167

    Open questions at the time
    • Whether TAB2 was strictly required or redundant with other adaptors
    • In vivo genetic validation of TAK1 essentiality pending
  3. 2000 High

    Identification of PP2Cβ as a direct TAK1 phosphatase established that TAK1 activity is kept in check by dephosphorylation, providing the first negative regulatory mechanism.

    Evidence In vitro dephosphorylation assay, Co-IP, dominant-negative PP2C mutant

    PMID:11104763

    Open questions at the time
    • In vivo relevance of PP2Cβ-TAK1 regulation not shown
    • Additional phosphatases not yet explored
  4. 2003 High

    Discovery of p38α-mediated feedback phosphorylation of TAB1 revealed a built-in circuit breaker: p38α, activated by TAK1, phosphorylates TAB1 to limit further TAK1 activity, explaining how inflammatory signaling is self-limiting.

    Evidence In vitro kinase assay, site-directed mutagenesis, p38α KO MEFs, pharmacologic inhibition

    PMID:14592977 PMID:14670075

    Open questions at the time
    • Whether TAB2/TAB3 phosphorylation has identical or distinct regulatory consequences
    • Phosphatases reversing TAB phosphorylation unknown
  5. 2005 High

    Conditional knockout of Map3k7 in B cells provided the first in vivo genetic proof that TAK1 is essential for NF-κB and MAPK activation downstream of multiple receptors (IL-1R, TNFR, TLRs, CD40, BCR), resolving whether TAK1 was required or redundant in immune cells.

    Evidence Conditional Cre-lox knockout, signaling assays in primary B cells

    PMID:16186825

    Open questions at the time
    • Cell-type-specific requirements (macrophages, T cells) not yet addressed
    • Whether TAK1-independent NF-κB activation via BCR is direct
  6. 2010 Medium

    TAB2 was shown to scaffold the TAK1–NLK interaction and mediate NLK-dependent phosphorylation of FOXO1, expanding the TAK1–NLK axis beyond Wnt to include FOXO-regulated gene expression.

    Evidence Co-IP, domain mapping, siRNA, kinase and ubiquitination assays, nuclear/cytoplasmic fractionation

    PMID:20061393 PMID:20194509

    Open questions at the time
    • Whether TAB2 scaffolding of NLK occurs in all cell types
    • In vivo validation of FOXO1 regulation by TAK1-NLK missing
  7. 2011 High

    Identification of USP4 as a K63-deubiquitinase for TAK1 established that removal of activating ubiquitin chains is a distinct layer of negative regulation, complementing dephosphorylation.

    Evidence In vitro deubiquitination assay, catalytic mutant C311A, siRNA, Co-IP

    PMID:21331078

    Open questions at the time
    • Specific K residues on TAK1 targeted by USP4 not mapped
    • Redundancy with other DUBs not addressed
  8. 2013 High

    Crystal structures of TAK1 with covalent inhibitors and demonstration of intrinsic ATPase activity provided the first structural framework for understanding TAK1 catalysis and enabled structure-based drug design.

    Evidence X-ray crystallography, mass spectrometry, in vitro kinase/ATPase assays

    PMID:23272696 PMID:28011204

    Open questions at the time
    • Physiological significance of ATPase activity distinct from kinase activity unknown
    • Full-length TAK1–TAB complex structure not solved
  9. 2014 High

    TAK1 was placed at the decision point between necroptosis and apoptosis: sustained TAK1 hyperactivation drives RIPK3 phosphorylation and necroptosis, while TAK1 loss triggers caspase-dependent apoptosis, revealing TAK1 as a master switch in TNF-induced cell death.

    Evidence Tak1, Ripk3 genetic KO, caspase and necroptosis marker assays

    PMID:24535827

    Open questions at the time
    • Precise TAK1 substrates linking to RIPK3 activation unknown
    • Threshold model for TAK1 activity level determining death mode not quantified
  10. 2014 High

    Hepatocyte-specific TAK1 deletion revealed a non-immune role: TAK1 activates AMPK and suppresses mTORC1 to maintain autophagy and fatty acid oxidation, and pharmacologic mTORC1 inhibition rescues autophagy in TAK1-deficient livers.

    Evidence Hepatocyte-specific conditional KO, rapamycin rescue, AMPK activity assays

    PMID:24983318

    Open questions at the time
    • Direct substrate linking TAK1 to AMPK activation not identified
    • Whether this metabolic role extends to other tissues
  11. 2016 Medium

    Human genetic studies linked MAP3K7 to two Mendelian diseases: gain-of-function mutations (e.g. p.Pro485Leu) cause frontometaphyseal dysplasia via hyperactivated TAK1 signaling, while heterozygous loss-of-function mutations cause cardiospondylocarpofacial syndrome via impaired p38 MAPK signaling.

    Evidence Whole-exome sequencing, autophosphorylation assays, signaling in patient fibroblasts

    PMID:27426733 PMID:27426734

    Open questions at the time
    • Genotype–phenotype relationship for kinase-domain vs. coiled-coil mutations not fully resolved
    • Tissue-specific consequences of these mutations incompletely characterized
  12. 2017 High

    Reconstitution in TAB2/3 double-KO cells showed that early TAK1 activation and NF-κB signaling can proceed via TAB1 alone, while TAB2/3 are specifically required for sustained activation and selective engagement of JNK and p38γ, resolving the distinct roles of the TAB adaptors.

    Evidence TAB2/3 double KO, TAB1/2/3 triple KO reconstitution, kinase assays

    PMID:28507161

    Open questions at the time
    • Structural basis for TAB2/3-specific pathway selectivity unknown
    • Whether TAB1-only activation is sufficient in vivo
  13. 2018 High

    In macrophages, TAK1 was shown to suppress spontaneous NLRP3 inflammasome activation by restraining autocrine TNF–RIPK1 signaling, establishing TAK1 as a tonic suppressor of inflammation and cell death in myeloid cells.

    Evidence Macrophage-specific Tak1 KO, RIPK1 KO epistasis, NLRP3 inhibition

    PMID:29500178

    Open questions at the time
    • Whether TAK1 directly phosphorylates NLRP3 components
    • Contribution of non-TNF cytokines in TAK1-deficient macrophage phenotype
  14. 2019 Medium

    Alternative splicing of TAK1 (exon 12 exclusion by Rbfox2) was found to produce a constitutively active isoform (TAK1ΔE12) that promotes EMT and NF-κB survival, whereas full-length TAK1 supports TGF-β-induced apoptosis, revealing isoform-specific functional divergence.

    Evidence RNA splicing analysis, isoform-specific knockdown/overexpression, Rbfox2 RIP

    PMID:30626936

    Open questions at the time
    • Structural basis for constitutive activity of ΔE12 isoform unknown
    • In vivo tumor relevance not validated genetically
  15. 2023 High

    TAK1 was identified as a direct kinase for STING at Ser355, a phosphorylation event required for STING oligomerization and ER-to-ERGIC translocation, establishing TAK1 as a gatekeeper of cytosolic DNA sensing and innate immune activation.

    Evidence In vitro kinase assay, phosphosite mutagenesis, STING trafficking assays, mouse tumor model

    PMID:37832545

    Open questions at the time
    • Whether TAK1-STING axis is active in all cell types
    • Upstream signals specifically triggering TAK1–STING vs. TAK1–IKK unclear
  16. 2024 High

    OTUD5 was identified as a second K63-deubiquitinase for TAK1 acting specifically at K158, and NEDD4 was identified as a K48-ubiquitin ligase promoting TAK1 degradation, further detailing the ubiquitin code that controls TAK1 activity and stability.

    Evidence Mass spectrometry, in vitro DUB assay with site mutants, podocyte-specific OTUD5 KO; Co-IP, ubiquitination assays for NEDD4

    PMID:38569496 PMID:38937512

    Open questions at the time
    • Full K63-ubiquitin site map on TAK1 incomplete
    • Relative contributions of USP4 vs. OTUD5 in different tissues unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the full-length structure of the TAK1–TAB ternary complex, the direct substrate linking TAK1 to AMPK activation, the molecular basis for isoform-specific signaling outputs, and how TAK1 activity thresholds determine the switch between survival, apoptosis, and necroptosis.
  • No full-length TAK1–TAB1–TAB2/3 structure solved
  • Direct TAK1 substrate activating AMPK not identified
  • Quantitative threshold model for TAK1-dependent cell fate decisions lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 4 GO:0140657 ATP-dependent activity 1
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 12 R-HSA-168256 Immune System 9 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1266738 Developmental Biology 3 R-HSA-9612973 Autophagy 2
Partners
NLKOTUD5STING1TAB1TAB2TAB3TRAF6USP4
Complex memberships
TAK1–TAB1–TAB2 (TRIKA2)TAK1–TAB1–TAB3

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TAK1 (MAP3K7) was identified as the catalytic component of TRIKA2, a complex with TAB1 and TAB2, which phosphorylates and activates IKK in a manner dependent on TRAF6 and Ubc13-Uev1A-generated K63-linked polyubiquitin chains; TAK1 also phosphorylates MKK6 to activate JNK-p38 pathways, and its activity is directly regulated by K63-linked polyubiquitination. Protein purification, in vitro kinase assays, reconstitution with ubiquitin components, Co-IP Nature High 11460167
1999 TAK1 activates NLK (NEMO-like kinase), which phosphorylates TCF/LEF factors and inhibits the interaction of the beta-catenin-TCF complex with DNA, thereby negatively regulating Wnt/beta-catenin signaling; injection of NLK suppresses beta-catenin-induced axis duplication in Xenopus embryos. Kinase activity assays, Xenopus microinjection, epistasis analysis in C. elegans, electrophoretic mobility shift assay for DNA binding Nature High 10391247
2000 Protein phosphatase 2C beta-1 (PP2Cbeta-1) directly dephosphorylates and inactivates TAK1; PP2Cbeta-1 co-immunoprecipitates with the central region of TAK1 and inhibits TAK1-mediated MKK4-JNK and MKK6-p38 signaling pathways. In vitro dephosphorylation assay, Co-IP, dominant-negative PP2C mutant, reporter gene assay The Journal of biological chemistry High 11104763
2003 SAPK2a/p38alpha phosphorylates TAB1 at Ser423, Thr431, and Ser438 in vitro and in cells upon stress or cytokine stimulation; this phosphorylation mediates feedback inhibition of TAK1 activity, limiting downstream JNK and IKK activation. In vitro kinase assay, site-directed mutagenesis, pharmacologic inhibition (SB203580), knockout MEFs The EMBO journal High 14592977
2004 TAB3, a new TAK1-binding protein sharing 48% identity with TAB2, forms a distinct TAK1 complex (TAK1-TAB1-TAB3); both TAK1 complexes are activated by TNF-alpha, IL-1, and LPS and are subject to SAPK2a/p38alpha-mediated feedback control through phosphorylation of TAB2 and TAB3. Protein identification, Co-IP, kinase activity assays, pharmacologic inhibition, phosphatase treatment The Biochemical journal High 14670075
2004 Wnt1 stimulation induces autophosphorylation and activation of TAK1 in a TAB1-dependent fashion, leading to NLK activation and TCF phosphorylation, suggesting Wnt directly activates the TAK1-NLK pathway as a negative feedback mechanism on canonical beta-catenin/TCF signaling. Kinase activity assays, autophosphorylation assay, C. elegans epistasis The Journal of biological chemistry Medium 14960582
2005 TAK1 is essential in B cells for NF-kappaB and MAPK activation downstream of IL-1R, TNFR, TLRs, CD40, and BCR; conditional Map3k7 knockout in B cells abolishes cellular responses to these stimuli, while TAK1-deficient B cells retain NF-kappaB but not JNK activation upon BCR stimulation. Conditional gene knockout (Cre-lox), signaling assays (NF-kappaB, MAPK phosphorylation), immune challenge Nature immunology High 16186825
2011 USP4 is a deubiquitinase for TAK1 that removes K63-linked polyubiquitin chains from TAK1; TNF-alpha induces USP4-TAK1 association, USP4 deubiquitinates TAK1 in vitro and in vivo, and USP4 knockdown enhances TAK1 polyubiquitination and downstream IKK/NF-kappaB activation. In vitro deubiquitination assay, Co-IP, siRNA knockdown, luciferase reporter, catalytic mutant (C311A) Cell death and differentiation High 21331078
2013 TAK1 has intrinsic ATPase activity in addition to kinase activity; (5Z)-7-Oxozeaenol irreversibly inhibits TAK1 by forming a covalent complex with the kinase, blocking both activities; X-ray crystallography and mass spectrometry confirmed covalent adduct formation. X-ray crystallography, mass spectrometry, in vitro kinase and ATPase assays, bi-phase kinetics analysis ACS chemical biology High 23272696
2013 S6K1 negatively regulates TAK1 activity in TLR signaling by interfering with the interaction between TAK1 and TAB1; S6K1 deficiency causes increased TAK1 kinase activity and enhanced NF-kappaB-dependent gene expression upon TLR stimulation. S6K1 KO mice, Co-IP, kinase assays, siRNA knockdown, reporter assays Molecular and cellular biology Medium 24277938
2014 Prolonged or hyperactivation of TAK1 induces RIPK3 phosphorylation and activation, leading to necroptosis without caspase activation; conversely, TAK1 ablation causes caspase-dependent apoptosis. RIPK1 and RIPK3 activation promotes further TAK1 activation (positive feedforward loop). Genetic KO (Tak1, Ripk3), kinase activation assays, cell death assays (caspase activation, necroptosis markers) The Journal of cell biology High 24535827
2014 TAK1 regulates autophagy and fatty acid oxidation (beta-oxidation) in hepatocytes via the AMPK/mTORC1 axis; hepatocyte-specific TAK1 deletion suppresses AMPK activity and autophagy while increasing mTORC1 activity, and mTORC1 inhibition restores autophagy in TAK1-deficient livers. Hepatocyte-specific conditional KO, mTORC1 inhibitor treatment, AMPK activity assays, gene expression analysis The Journal of clinical investigation High 24983318
2014 The TAK1-JNK pathway is activated by lysosome rupture through Ca2+ ions and CaMKII acting upstream of TAK1; this pathway is necessary for ASC oligomerization and complete NLRP3 inflammasome activation in macrophages. Pharmacologic inhibition, siRNA knockdown, Ca2+ manipulation, ASC oligomerization assay The Journal of biological chemistry Medium 25288801
2015 MUC1-C directly binds TAK1 and confers its association with TRAF6, which is necessary for TAK1-mediated NF-kappaB activation; MUC1-C also induces NF-kappaB-mediated TAK1 transcription creating a positive regulatory loop. Co-IP (direct binding), siRNA knockdown, reporter assays, mouse colitis model Oncogene Medium 25659581
2016 Gain-of-function mutations in MAP3K7 (TAK1), particularly the recurrent p.Pro485Leu mutation near the coiled-coil domain, increase TAK1 autophosphorylation and alter activity of multiple TAK1-regulated signaling pathways, causing frontometaphyseal dysplasia; kinase domain mutations cause milder phenotype. Whole-exome sequencing, functional autophosphorylation assays, signaling pathway analysis in patient-derived cells American journal of human genetics Medium 27426733
2016 Heterozygous loss-of-function MAP3K7 mutations cause cardiospondylocarpofacial syndrome by impairing non-canonical TGF-beta/MAPK-p38 signaling; MAPK-p38 signaling is markedly altered in fibroblasts from affected individuals. Whole-exome sequencing, signaling assays in patient fibroblasts American journal of human genetics Medium 27426734
2016 Structure-guided development identified Cys174 (adjacent to the DFG-motif in the activation loop) as the covalent target of TAK1 inhibitors; co-crystal structures of TAK1 with inhibitors enabled structure-based design. X-ray co-crystallography, covalent inhibitor biochemical profiling Bioorganic & medicinal chemistry High 28011204
2017 IL-1beta can activate the TAB1-TAK1 heterodimer in the absence of TAB2/TAB3 via TRAF6 and Ubc13-dependent K63-ubiquitin chains; TAB2/3 are required for sustained TAK1 activation and for directing TAK1-dependent activation of JNK1/2 and p38gamma but not for early NF-kappaB activation. TAB2/TAB3 double KO cells, TAB1/2/3 triple KO reconstitution, siRNA, kinase assays The Biochemical journal High 28507161
2018 Absence of TAK1 in macrophages induces spontaneous NLRP3 inflammasome activation without TLR priming; autocrine TNF signaling in TAK1-deficient macrophages drives RIPK1-dependent NLRP3 activation and cell death, and TAK1 suppresses homeostatic NF-kappaB and ERK activation to limit spontaneous TNF production. Macrophage-specific Tak1 KO, NLRP3 inhibition, RIPK1 KO epistasis, ELISA, cytokine assays The Journal of experimental medicine High 29500178
2019 TGF-beta-induced alternative splicing of TAK1 (exclusion of exon 12, TAK1deltaE12, mediated by Rbfox2 binding to intronic sequences) produces a constitutively active isoform that supports EMT and NF-kappaB survival signaling, whereas full-length TAK1FL promotes TGF-beta-induced apoptosis. RNA splicing analysis, isoform-specific overexpression/knockdown, Rbfox2 RIP, functional cell assays (EMT, apoptosis) Oncogene Medium 30626936
2019 TAK1 prevents YAP/TAZ proteasomal degradation in a kinase-independent manner through a complex with TRAF6, thereby fostering K63-ubiquitination over K48-ubiquitination of YAP/TAZ in pancreatic cancer cells. shRNA knockdown, Co-IP, ubiquitination assays (K63 vs K48), gene expression profiling Molecular cancer therapeutics Medium 31562256
2019 TAK1 governs p62/Sequestosome 1 action by reducing its localization to autophagosomes and relocalizing it into dynamic cytoplasmic signaling bodies, switching p62 from an autophagy receptor to a signaling platform; conversely, p62 facilitates TAK1 complex assembly and activation. Live imaging, fluorescence microscopy, autophagic flux assays, Co-IP EMBO reports Medium 31347268
2021 The E3 ligase TRIM16 preferentially interacts with phospho-TAK1 to promote its K48-linked ubiquitination and proteasomal degradation, suppressing MAPK signaling and NASH progression. Multiomics analysis, Co-IP, in vivo ubiquitination assay, TRIM16 KO and overexpression mouse models Cell metabolism High 34146477
2022 MAP3K7 missplicing caused by SF3B1 mutations deactivates p38 MAPK (MAP3K7 is an upstream positive effector of p38 MAPK), leading to premature GATA1 downregulation, accelerated erythroid differentiation, erythroid hyperplasia, and apoptosis causing anemia in MDS. Isogenic SF3B1 WT/mutant cell lines, patient cells, MAP3K7 rescue experiments, p38 MAPK activity assays Proceedings of the National Academy of Sciences of the United States of America High 34930825
2023 TAK1 is an essential kinase for STING trafficking: STING induces TAK1 activation in a TAB1-dependent manner prior to trafficking; activated TAK1 directly phosphorylates STING at Ser355, facilitating STING interaction with STEEP, promoting STING oligomerization and translocation from ER to ERGIC for activation. In vitro kinase assay, phosphorylation site mutagenesis, Co-IP, STING trafficking assays, mouse allograft tumor model Molecular cell High 37832545
2024 OTUD5 deubiquitinates K63-linked ubiquitin from TAK1 at the K158 site via its active site C224, preventing TAK1 phosphorylation and reducing downstream inflammatory responses in podocytes; OTUD5 KO exacerbates podocyte injury and diabetic kidney disease. Mass spectrometry, Co-IP, in vitro deubiquitination assay, catalytic mutant (C224), podocyte-specific KO mice Nature communications High 38937512
2024 NEDD4 acts as an E3 ligase for TAK1, catalyzing K48-linked ubiquitination of TAK1 and promoting its degradation, which leads to necroptosis in trophoblast cells; THBS1 stabilizes TAK1 by antagonizing NEDD4-mediated ubiquitination. Co-IP, in vitro ubiquitination assay, siRNA knockdown, necroptosis inhibitors, in vivo mouse model Advanced science Medium 38569496
2017 POPX2 serine/threonine phosphatase directly interacts with TAK1 and dephosphorylates it; cells with lower POPX2 exhibit higher TAK1 activity and increased NF-kappaB nuclear translocation after genotoxic stress, leading to upregulation of anti-apoptotic proteins. Co-IP, in vitro dephosphorylation assay, POPX2 overexpression/knockdown, NF-κB reporter Cell death & disease Medium 28906490
2010 TAB2 functions as a scaffold protein to facilitate TAK1-NLK interaction; TAB2 directly binds NLK via its intermediate region (residues 292-417) and mediates TAK1-dependent NLK activation and LEF1 polyubiquitylation, resulting in inhibition of canonical Wnt signaling. Co-IP, siRNA knockdown, domain mapping, ubiquitination assay, NLK kinase assay The Journal of biological chemistry Medium 20194509
2010 TAK1 regulates the TAK1-NLK pathway to negatively regulate FOXO1 by promoting NLK-mediated phosphorylation of FOXO1 at Pro-directed Ser/Thr residues in its transactivation domain, excluding FOXO1 from the nucleus independently of PI3K/Akt. Kinase assay, Co-IP, nuclear/cytoplasmic fractionation, siRNA knockdown, reporter assay The Journal of biological chemistry Medium 20061393
2022 Supraphysiological TAK1 activation in skeletal muscle stimulates protein synthesis and myofiber growth by causing phosphorylation of eIF4E independent of mTOR; TAK1 also favors nuclear translocation of Smad4 and cytoplasmic retention of Smad6 to regulate Smad signaling. Constitutively active TAK1 transgene, eIF4E phosphorylation assays, Smad fractionation, mTOR KO epistasis Nature communications Medium 35459245
2015 In keratinocytes, sorafenib targets MAP3K7 (TAK1) to induce cell death; sorafenib enters keratinocytes via the transporter OAT6 (SLC22A20), and its intracellular activity drives MAP3K7-dependent keratinocyte injury underlying hand-foot skin reaction. RNAi kinome screen, in situ kinome profiling, siRNA validation, in vivo sorafenib model Cancer research Medium 26677977
2001 BMP2-induced neurite outgrowth in PC12 cells requires the TAK1-p38 kinase pathway; kinase-negative TAK1 inhibits BMP2-induced p38 activation and neurite outgrowth; inhibitory Smads (Smad6, Smad7) physically interact with TAB1 and repress TAK1-p38 pathway activation. Dominant-negative TAK1 overexpression, Co-IP (Smad6/7 with TAB1), kinase assays, neurite outgrowth quantification Genes to cells Medium 11737269
2001 IRAK and TAK1 are both required for IL-18-mediated NF-kappaB and JNK activation; dominant-negative TAK1 inhibits IL-18-induced NF-kappaB activation; IL-18 stimulation leads to phosphorylation of TAB1. IRAK-deficient mutant cell line, dominant-negative TAK1, TAB1 phosphorylation assay European journal of immunology Medium 11745395
2024 During influenza A virus infection, TAK1 activates IKK which phosphorylates RIPK1 at Ser25 to inhibit RIPK1 activation; TAK1 also activates p38-MK2 which phosphorylates RIPK1 at Ser321 but does not affect RIPK1 activation. TAK1 thereby suppresses both RIPK3-independent apoptosis and RIPK1-dependent necroptosis. TAK1-specific inhibitor, TAK1 KO, RIPK1 KO, RIPK3 KO, phosphosite-specific antibodies, ZBP1 KO Cell communication and signaling Medium 39044278

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 1718 11460167
2005 Essential function for the kinase TAK1 in innate and adaptive immune responses. Nature immunology 824 16186825
2019 ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis). Frontiers in cellular and infection microbiology 581 31850239
1999 The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature 518 10391247
2007 Ubiquitin-mediated activation of TAK1 and IKK. Oncogene 379 17496917
2012 Targeting of TAK1 in inflammatory disorders and cancer. Trends in pharmacological sciences 327 22795313
2013 Cell type-specific function of TAK1 in innate immune signaling. Trends in immunology 316 23664135
2014 TAK1 control of cell death. Cell death and differentiation 249 25146924
2003 Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. The EMBO journal 245 14592977
2010 The TAK1-TRAF6 signalling pathway. The international journal of biochemistry & cell biology 235 20060931
2018 TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation. The Journal of experimental medicine 212 29500178
2014 The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation. The Journal of biological chemistry 173 25288801
2021 TAK1-TABs Complex: A Central Signalosome in Inflammatory Responses. Frontiers in immunology 163 33469458
2014 TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. The Journal of clinical investigation 147 24983318
2000 TAK1 regulates multiple protein kinase cascades activated by bacterial lipopolysaccharide. Journal of leukocyte biology 144 11129660
2004 TAB3, a new binding partner of the protein kinase TAK1. The Biochemical journal 143 14670075
2011 USP4 targets TAK1 to downregulate TNFα-induced NF-κB activation. Cell death and differentiation 141 21331078
2012 TGF-β signaling via TAK1 pathway: role in kidney fibrosis. Seminars in nephrology 129 22835455
2017 Post-Translational Modifications of the TAK1-TAB Complex. International journal of molecular sciences 127 28106845
2000 Regulation of the TAK1 signaling pathway by protein phosphatase 2C. The Journal of biological chemistry 125 11104763
2013 Mechanism and in vitro pharmacology of TAK1 inhibition by (5Z)-7-Oxozeaenol. ACS chemical biology 124 23272696
2021 TAK1 mediates neuronal pyroptosis in early brain injury after subarachnoid hemorrhage. Journal of neuroinflammation 109 34461942
2004 Wnt activates the Tak1/Nemo-like kinase pathway. The Journal of biological chemistry 98 14960582
2015 MUC1-C activates the TAK1 inflammatory pathway in colon cancer. Oncogene 89 25659581
2021 Tripartite motif 16 ameliorates nonalcoholic steatohepatitis by promoting the degradation of phospho-TAK1. Cell metabolism 86 34146477
2014 TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation. The Journal of cell biology 86 24535827
2014 TAK1 regulates hepatic cell survival and carcinogenesis. Journal of gastroenterology 85 24443058
1994 TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily. Molecular endocrinology (Baltimore, Md.) 84 7708055
2019 TGF-β-induced alternative splicing of TAK1 promotes EMT and drug resistance. Oncogene 79 30626936
2019 Multifaceted roles of TAK1 signaling in cancer. Oncogene 76 31695153
2015 Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer. Cancer research 76 25770290
2010 TAK1 regulates cartilage and joint development via the MAPK and BMP signaling pathways. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 75 20213696
2019 TAK1 mediates convergence of cellular signals for death and survival. Apoptosis : an international journal on programmed cell death 73 30288639
2018 Is TAK1 a Direct Upstream Kinase of AMPK? International journal of molecular sciences 72 30111748
2023 TAK1 deficiency promotes liver injury and tumorigenesis via ferroptosis and macrophage cGAS-STING signalling. JHEP reports : innovation in hepatology 71 36968217
2015 Brain endothelial TAK1 and NEMO safeguard the neurovascular unit. The Journal of experimental medicine 69 26347470
2015 MiR-377 targets E2F3 and alters the NF-kB signaling pathway through MAP3K7 in malignant melanoma. Molecular cancer 68 25889255
2016 Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia. American journal of human genetics 58 27426733
2015 TAK1 modulates satellite stem cell homeostasis and skeletal muscle repair. Nature communications 57 26648529
2016 TAK1 regulates caspase 8 activation and necroptotic signaling via multiple cell death checkpoints. Cell death & disease 56 27685625
2022 SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes. Proceedings of the National Academy of Sciences of the United States of America 53 34930825
2017 TAK-ing aim at chemoresistance: The emerging role of MAP3K7 as a target for cancer therapy. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 52 29145973
2018 TAK1 regulates skeletal muscle mass and mitochondrial function. JCI insight 51 29415881
2012 Suppression of Tak1 promotes prostate tumorigenesis. Cancer research 49 22467172
2017 TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis. Cell discovery 48 28698801
2019 Modulating TAK1 Expression Inhibits YAP and TAZ Oncogenic Functions in Pancreatic Cancer. Molecular cancer therapeutics 47 31562256
2010 Regulation of FOXO1 by TAK1-Nemo-like kinase pathway. The Journal of biological chemistry 45 20061393
2009 Comprehending the complex connection between PKCbeta, TAK1, and IKK in BCR signaling. Immunological reviews 45 19909372
2019 TAK1 regulates endothelial cell necroptosis and tumor metastasis. Cell death and differentiation 44 30683914
2015 Multikinase Inhibitors Induce Cutaneous Toxicity through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death. Cancer research 42 26677977
2005 TAK1 downregulation reduces IL-1beta induced expression of MMP13, MMP1 and TNF-alpha. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 42 16459052
2001 Regulation of MAP kinase by the BMP-4/TAK1 pathway in Xenopus ectoderm. Developmental biology 42 11476570
2001 Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7. Genes to cells : devoted to molecular & cellular mechanisms 42 11737269
2023 Selenium alleviates lead-induced CIK cells pyroptosis and inflammation through IRAK1/TAK1/IKK pathway. Fish & shellfish immunology 40 37758100
2023 TAK1 is an essential kinase for STING trafficking. Molecular cell 40 37832545
2013 S6K1 negatively regulates TAK1 activity in the toll-like receptor signaling pathway. Molecular and cellular biology 39 24277938
2017 Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3. The Biochemical journal 36 28507161
2014 MEKK3 and TAK1 synergize to activate IKK complex in Helicobacter pylori infection. Biochimica et biophysica acta 36 24418622
2024 Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury. Nature communications 35 38937512
2019 TAK1 converts Sequestosome 1/p62 from an autophagy receptor to a signaling platform. EMBO reports 35 31347268
2019 BMP3 suppresses colon tumorigenesis via ActRIIB/SMAD2-dependent and TAK1/JNK signaling pathways. Journal of experimental & clinical cancer research : CR 35 31665064
2018 Molecular cloning and functional characterization of TRAF6 and TAK1 in rainbow trout, Oncorhynchus mykiss. Fish & shellfish immunology 35 30391533
2016 Heterozygous Mutations in MAP3K7, Encoding TGF-β-Activated Kinase 1, Cause Cardiospondylocarpofacial Syndrome. American journal of human genetics 35 27426734
2009 TAK1 kinase determines TRAIL sensitivity by modulating reactive oxygen species and cIAP. Oncogene 35 19421137
2004 Sef interacts with TAK1 and mediates JNK activation and apoptosis. The Journal of biological chemistry 35 15277532
2021 TAK1: A Molecular Link Between Liver Inflammation, Fibrosis, Steatosis, and Carcinogenesis. Frontiers in cell and developmental biology 34 34722513
2019 TAK1 Prevents Endothelial Apoptosis and Maintains Vascular Integrity. Developmental cell 34 30639056
2019 Cutting Edge: TAK1 Safeguards Macrophages against Proinflammatory Cell Death. Journal of immunology (Baltimore, Md. : 1950) 34 31243089
2017 MicroRNA-143 inhibits cell growth by targeting ERK5 and MAP3K7 in breast cancer. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 32 28746466
2009 TAK1 activation for cytokine synthesis and proliferation of endometriotic cells. Molecular and cellular endocrinology 31 19410630
2010 TAB2 scaffolds TAK1 and NLK in repressing canonical Wnt signaling. The Journal of biological chemistry 30 20194509
2003 Expression of TAK1, a mediator of TGF-beta and BMP signaling, during mouse embryonic development. Gene expression patterns : GEP 30 12711537
2022 TAK1 confers antibacterial protection through mediating the activation of MAPK and NF-κB pathways in shrimp. Fish & shellfish immunology 29 35301113
2015 TAK1 selective inhibition: state of the art and future opportunities. Future medicinal chemistry 29 25582331
2016 Structure-guided development of covalent TAK1 inhibitors. Bioorganic & medicinal chemistry 28 28011204
2017 Torilin Inhibits Inflammation by Limiting TAK1-Mediated MAP Kinase and NF-κB Activation. Mediators of inflammation 27 28316375
2016 Tetrandrine regulates hepatic stellate cell activation via TAK1 and NF-κB signaling. International immunopharmacology 27 27179306
2024 Thrombospondin-1 Regulates Trophoblast Necroptosis via NEDD4-Mediated Ubiquitination of TAK1 in Preeclampsia. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 26 38569496
2021 TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma. Haematologica 26 32273474
2017 POPX2 phosphatase regulates apoptosis through the TAK1-IKK-NF-κB pathway. Cell death & disease 26 28906490
2001 IRAK and TAK1 are required for IL-18-mediated signaling. European journal of immunology 26 11745395
2019 The MAP3K7-mTOR Axis Promotes the Proliferation and Malignancy of Hepatocellular Carcinoma Cells. Frontiers in oncology 25 31214512
2014 Activated macrophage survival is coordinated by TAK1 binding proteins. PloS one 25 24736749
2021 TAK1 Is a Novel Target in Hepatocellular Carcinoma and Contributes to Sorafenib Resistance. Cellular and molecular gastroenterology and hepatology 24 33962073
2009 Combined inhibition of PAK7, MAP3K7 and CK2alpha kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts. Cancer gene therapy 24 19363471
2023 Macrophage DCLK1 promotes obesity-induced cardiomyopathy via activating RIP2/TAK1 signaling pathway. Cell death & disease 23 37443105
2020 PCAT-1 promotes cell growth by sponging miR-129 via MAP3K7/NF-κB pathway in multiple myeloma. Journal of cellular and molecular medicine 22 32048803
2020 Paclitaxel induces apoptosis through the TAK1-JNK activation pathway. FEBS open bio 22 32594651
2020 Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis. Journal of cellular physiology 22 32700766
2016 Increased apoptosis and browning of TAK1-deficient adipocytes protects against obesity. JCI insight 22 27699262
2022 Selective autophagy controls innate immune response through a TAK1/TAB2/SH3PX1 axis. Cell reports 21 35081354
2021 iRhom2 Promotes Hepatic Steatosis by Activating MAP3K7-Dependent Pathway. Hepatology (Baltimore, Md.) 21 32592194
2023 USP7 Inhibits Osteoclastogenesis via Dual Effects of Attenuating TRAF6/TAK1 Axis and Stimulating STING Signaling. Aging and disease 20 37199589
2022 Topical application of TAK1 inhibitor encapsulated by gelatin particle alleviates corneal neovascularization. Theranostics 20 34976206
2022 Supraphysiological activation of TAK1 promotes skeletal muscle growth and mitigates neurogenic atrophy. Nature communications 20 35459245
2024 Desulfovibrio vulgaris flagellin exacerbates colorectal cancer through activating LRRC19/TRAF6/TAK1 pathway. Gut microbes 19 39718561
2019 Loss of MAP3K7 Sensitizes Prostate Cancer Cells to CDK1/2 Inhibition and DNA Damage by Disrupting Homologous Recombination. Molecular cancer research : MCR 19 31300540
2024 Influenza virus infection activates TAK1 to suppress RIPK3-independent apoptosis and RIPK1-dependent necroptosis. Cell communication and signaling : CCS 18 39044278
2021 MAP3K7 Loss Drives Enhanced Androgen Signaling and Independently Confers Risk of Recurrence in Prostate Cancer with Joint Loss of CHD1. Molecular cancer research : MCR 18 33846123
2016 Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. Bioorganic & medicinal chemistry 18 28038940