MAP3K7

The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase mediates the signaling transduction induced by TGF beta and morphogenetic protein (BMP), and controls a variety of cell functions including transcription regulation and apoptosis. In response to IL-1, this protein forms a kinase complex including TRAF6, MAP3K7P1/TAB1 and MAP3K7P2/TAB2; this complex is required for the activation of nuclear factor kappa B. This kinase can also activate MAPK8/JNK, MAP2K4/MKK4, and thus plays a role in the cell response to environmental stresses. Four alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

Mitogen-Activated Protein Kinase Kinase Kinase 7

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (By similarity).

Activation of NF-kappaB-inducing kinase activityManual Assertion Based On ExperimentIMP:UniProtKB
AnoikisISS:BHF-UCL
Cytoplasmic pattern recognition receptor signaling pathwayTAS:Reactome
Fc-epsilon receptor signaling pathwayTAS:Reactome
Histone H3 acetylationManual Assertion Based On ExperimentIDA:BHF-UCL
I-kappaB kinase/NF-kappaB signalingTAS:Reactome
I-kappaB phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Interleukin-1-mediated signaling pathwayTAS:Reactome
JNK cascadeManual Assertion Based On ExperimentIDA:UniProtKB
MAPK cascadeManual Assertion Based On ExperimentIDA:UniProtKB
MyD88-dependent toll-like receptor signaling pathwayTAS:Reactome
Nucleotide-binding oligomerization domain containing signaling pathwayTAS:Reactome
p38MAPK cascadeTAS:Reactome
Positive regulation of I-kappaB kinase/NF-kappaB signalingManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of interleukin-2 productionManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of JUN kinase activityManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of macroautophagyISS:BHF-UCL
Positive regulation of NF-kappaB transcription factor activityTAS:Reactome
Positive regulation of T cell cytokine productionManual Assertion Based On ExperimentIMP:UniProtKB
Stimulatory C-type lectin receptor signaling pathwayTAS:Reactome
Stress-activated MAPK cascadeManual Assertion Based On ExperimentIDA:UniProtKB
T cell receptor signaling pathwayTAS:Reactome
Transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentTAS:ProtInc

Cytoplasm
Cell membrane
Although the majority of MAP3K7/TAK1 is found in the cytosol, when complexed with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2, it is also localized at the cell membrane.

Frontometaphyseal dysplasia 2 (FMD2):
A form of frontometaphyseal dysplasia, a progressive sclerosing skeletal dysplasia affecting the long bones and skull. Characteristic features include supraorbital hyperostosis, cranial hyperostosis, undermodeling of the small bones, flared metaphyses, and digital anomalies. Extra-skeletal manifestations include hearing loss, cardiac malformations, and stenosis, particularly of the upper airway and urinary tract. FMD2 inheritance is autosomal dominant.
Cardiospondylocarpofacial syndrome (CSCF):
A syndrome characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion and extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations. CSCF transmission pattern is consistent with autosomal dominant inheritance.

Association with TAB1/MAP3K7IP1 promotes autophosphorylation at Ser-192 and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and PPP6C leads to inactivation.
'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation. Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (By similarity).
Requires 'Lys-63'-linked polyubiquitination for autophosphorylation and subsequent activation. 'Lys-63'-linked ubiquitination does not lead to proteasomal degradation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains. Deubiquitinated by Y.enterocolitica YopP.
(Microbial infection) Cleaved and inactivated by the proteases 3C of coxsackievirus A16 and human enterovirus D68, allowing the virus to disrupt TRAF6-triggered NF-kappa-B induction.
(Microbial infection) Acetylation of Thr-184 and Thr-187 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.