Identifiers
HUGO:MAP3K7
mitogen-activated protein kinase kinase kinase 7
HUGO:MAP3K7 hgnc_id:HGNC:6859 HGNC:6859 ENTREZ:6885 UNIPROT:O43318
TAK1
HUGO:MAP3K7 HGNC:6859 ENTREZ:6885 UNIPROT:O43318
Maps_Modules
HMC:AVOIDING_IMMUNE_DESTRUCTION
Adaptive Immune Response / TCR_SIGNALING
HMC:TUMOR_PROMOTING_INFLAMMATION
HMC:ACTIVATING_INVASION_AND_METASTASIS
Cancer Associated Fibroblasts / CORE
EMT Senescence / EMT_REGULATORS
EMT Senescence / CYTOSKELETON_POLARITY
Innate Immunity / IMMUNOSTIMULATORY_CORE_PATHWAYS
References
PMID:15125833
The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes.
PMID:24403530
the activation of MKK4 and IKK is inhibited by DUSP14; thus, DUSP14 may function upstream of both MKK4 and IKK upon T cell activation
The phosphorylation levels of the TAB1???TAK1 complex and its downstream molecules, including JNK and I??B kinase, were enhanced in DUSP14-deficient T cells upon stimulation.
The enhanced JNK and IKK, but not ERK, activation of DUSP14-deficient T cells was attenuated by TAB1 shRNA knockdown
PMID:17363905
PKC-?? regulates TGF-?????activated kinase 1 (TAK1), a member of the MAPKK kinase family, leading to activation of IKK and NF-??B in a CARMA1-independent manner in the TCR pathway
TAK1 activation was significantly inhibited with the pretreatment of the PKC inhibitor in both Jurkat and JPM50.6 cells (Figure 6A, lower panels). Together, these results suggest that PKC functions upstream of TAK1 and TAK1 regulates IKK??/?? phosphorylation in the TCR signaling pathway.
PKC??, TAK1, and IKK assemble into a complex in a signal???dependent but CARMA1???independent manner, whereas BCL10 and MALT1 require CARMA1 to associate with the PKC?????TAK1???IKK complex. Together, our results suggest a model in which TAK1 functions downstream of PKC and phosphorylates IKK??/?? in a CARMA1???independent manner, and, together with CARMA1???dependent ubiquitination of NEMO, leads to activation of the IKK complex and NF?????B in antigen receptor signaling pathways
PMID:22941947
TAK1 can also activate MKK4/7 and MKK3/6, resulting in the activation of JNK and p38, respectively.
PMID:16799562
Thymic generation of Treg cells requires TAK1
Foxp3 and Cd25 mRNA was also much lower in TAK1-deficient CD4 SP thymocytes, indicating that the reduced Foxp3 and CD25 were a result of decreased expression of their mRNA
IL-7-mediated T cell survival depends on TAK1
TAK1 is required for TCR-mediated cellular responses and NF-B and Jnk activation in mature thymocytes.
TCR-induced Jnk but not NF-B in effector T cells requires TAK1
TAK1 is essential for IL-2-, IL-7- and IL-15-mediated p38 activation in effector T cells.
TAK1 is essential for JNK and NF-??B activation during TCR signaling in primary T cells
PMID:20164171
a novel site in ADAP that is critical for association with the TAK1 kinase. ADAP is critical for recruitment of TAK1 and the CBM complex, but not IKK, to protein kinase C-theta. ADAP is not required for TAK1 activation. Although both the TAK1 and the CARMA1 binding sites in ADAP are essential for IkappaB alpha phosphorylation and degradation and NF-kappaB nuclear translocation, only the TAK1 binding site in ADAP is necessary for IKK phosphorylation. In contrast, only the CARMA1 binding site in ADAP is required for ubiquitination of IKKgamma. Thus, distinct sites within ADAP control two key activation responses that are required for NF-kappaB activation in T cells.
PMID:19161412, PMID:12620219
IRAK-1 interacts with the downstream adaptor TRAF6,
resulting in formation of a complex that also includes TAK1 and TAB2.
IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol,
where they form a multiprotein complex with other cytosolic proteins,
which are needed for stimulation of TAK1 kinase activity.
K63-pUb-Traf6 can then recruit transforming growth factor ??-activated protein kinase (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (41). This somehow activates TAK1, which then couples to the inhibitor of NF-??B (I??B) kinase (IKK) complex, which contains the scaffold protein NF-??B essential modulator (NEMO) and IKK2, the kinase responsible for phosphorylation of I??B.
PMID:21041997
TGFB has been shown to induce p38 and JNK MAP kinase signaling through activation of TAK1 (MAP3K7) by the ubiquitin ligase TRAF6 that interacts with the TGFB receptor complex
PMID:15082531
The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1???NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells.
The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation.
Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein.
Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest.
PMID:10391247
TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF.
PMID:14660645, PMID:18264787, PMID:12620219
PMID:21232017, PMID:21133840 PMID:17301840, PMID:18641653, PMID:24958845, PMID:16603398, PMID:14633987
cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modieed RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it for K48-ubiquitination and proteasomal degradation
+ TAB2@INNATE_IMMUNE_CELL_Cytosol + TAB3@INNATE_IMMUNE_CELL_Cytosol → (MAP3K7:TAB2:TAB3)|active@INNATE_IMMUNE_CELL_Cytosol
→ IKK_alpha_*|pho|hm2|active@INNATE_IMMUNE_CELL_Cytosol
→ IKBKG|ubi:IKK_beta_*|pho:MHC_class_I*@INNATE_IMMUNE_CELL_Cytosol
→ MAP2K4|pho@INNATE_IMMUNE_CELL_Cytosol
→ MAP2K3|pho@INNATE_IMMUNE_CELL_Cytosol