TAK1 is a ubiquitin-dependent kinase of MKK and IKK

  title={TAK1 is a ubiquitin-dependent kinase of MKK and IKK},
  author={chen wang and Li Deng and Mei Hong and Giridhar Rao Akkaraju and Jun-ichiro Inoue and Zhijian J. Chen},
TRAF6 is a signal transducer that activates IκB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS). IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2 (ref. 5). TRIKA1 is a dimeric ubiquitin-conjugating enzyme complex composed of Ubc13 and Uev1A (or the functionally equivalent Mms2). This Ubc complex, together with TRAF6, catalyses the… 

TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6.

Evidence is presented that TIFA (TRAF-interacting protein with a forkhead-associated domain) activates IKK by promoting the oligomerization and Ub ligase activity of TRAF6, which leads to the activation of TAK1 and IKK through a proteasome-independent mechanism.

Ubiquitination in signaling to and activation of IKK

Accumulating evidence strongly supports a central role of K63 polyubiquitination in IKK activation by multiple immune and inflammatory pathways.

Ubiquitin-mediated activation of TAK1 and IKK

The concept of ubiquitin-mediated activation of protein kinases is supported by the discoveries of ubiqu itinination and deubiquitination enzymes as well as ubiquit in-binding proteins that function upstream of TAK1 and IKK.

TAK1‐binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL‐1 signaling pathway

TAK1‐binding protein 2 (TAB2) functions to facilitate TRAF6 ubiquitination and thereby mediates IL‐1‐induced cellular events, and a conserved ubiquitin binding domain in TAB2, the CUE domain, is important for this function.

YOD1/TRAF6 association balances p62-dependent IL-1 signaling to NF-κB

It is shown that YOD1 antagonizes TRAF6/p62-dependent IL-1 signaling to NF-κB, thereby facilitating TRAF 6 auto-ubiquitination as well as NEMO/IKKγ substrate ubiquitination.

Phosphorylation and ubiquitination of the IκB kinase complex by two distinct signaling pathways

This study provides the biochemical and genetic evidence that phosphorylation of IKKα/β and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation.

Polyubiquitination of Transforming Growth Factor β-activated Kinase 1 (TAK1) at Lysine 562 Residue Regulates TLR4-mediated JNK and p38 MAPK Activation

A feedback loop for phosphorylation and ubiquitination of TAK1 is demonstrated, indicating a dynamic regulation between TAK 1 polyubiquitiantion and phosphorylated activation, and the molecular mechanism by which IKK and MAPKs are differentially activated in the TLR4 pathway.

TRAF6 Autoubiquitination-Independent Activation of the NFκB and MAPK Pathways in Response to IL-1 and RANKL

While TRAF6 autoubiquitination may serve as a marker of activation, it is unlikely to underpin RING finger-dependent TRAF 6 function.

The role of hybrid ubiquitin chains in the MyD88 and other innate immune signalling pathways

Innate immune signalling is controlled by the formation and destruction of three different types of ubiquitin linkage, termed K63/M1-Ub hybrids, which is a feature of several innate immune signalling pathways.



The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway

It is shown that the MAPKK kinase TAK1 acts upstream of NIK in the IL-1-activated signalling pathway and that TAK 1 associates with TRAF6 during IL- 1 signalling, which indicates that Taker1 links TRAf6 to the NIK–IKK cascade in theIL-1 signalling pathway.

IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation

Activation of the transcription factor nuclear factor kappa B (NF-κB) is controlled by sequential phosphorylation, ubiquitination, and degradation of its inhibitory subunit IκB. A large multiprotein

Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain.

Oligomerization of the TRAF2 effector domain results in specific binding to MEKK1, a protein kinase capable of JNK, p38, and IKK activation, and induction of TNF-alpha and IL-1 responsive genes.

MAP3K-related kinase involved in NF-KB induction by TNF, CD95 and IL-1

The findings indicate that NIK participates in an NF-KB-inducing signalling cascade common to receptors of the TNF/NGF family and to the interleukin-1 type-I receptor.

The atypical PKC‐interacting protein p62 channels NF‐κB activation by the IL‐1–TRAF6 pathway

It is demonstrated that the inhibition of the aPKCs or the down‐regulation of p62 severely abrogates NF‐κB activation by IL‐1 and TRAF6, suggesting that both proteins are critical intermediaries in this pathway.

Mitogen-activated Protein Kinase/ERK Kinase Kinases 2 and 3 Activate Nuclear Factor-κB through IκB Kinase-α and IκB Kinase-β*

It is concluded that a distinct subset of MAP3Ks can activate NF-κB, and dominant negative versions of either IKK-α or IKK -β abolish NF-π activation induced by MEKK2 or MEKK3, thereby providing evidence that these IKKs mediate the NF-σκB-inducing activities of these MEKKs.

TRAF6 is a signal transducer for interleukin-1

The identification of a new TRAF family member is reported, designated TRAF6, which indicates that TRAF proteins may function as signal transducers for distinct receptor families and that TRAf6 participates in IL-1 signalling.