The essential role of MEKK3 in TNF-induced NF-κB activation

  title={The essential role of MEKK3 in TNF-induced NF-$\kappa$B activation},
  author={Jianhua Yang and Yong Loo Lin and Zijian Guo and Jinke Cheng and Jianyi H. Huang and Li Deng and Warren S.-L. Liao and Zhijian J. Chen and Zheng-Gang Liu and Bing Su},
  journal={Nature Immunology},
Activation of IκB kinase (IKK) is the key step in stimulation of the transcription factor NF-κB, which regulates many genes in the inflammatory response pathway. The molecular mechanism that underlies IKK activation in response to tumor necrosis factor (TNF) is still unknown. Using mitogen-activated protein kinase kinase kinase 3 (MEKK3)-deficient fibroblast cells, we found that MEKK3 plays a critical role in TNF-induced NF-κB activation. We have shown that MEKK3 is required for IKK activation… 

TAK1 Is Recruited to the Tumor Necrosis Factor-α (TNF-α) Receptor 1 Complex in a Receptor-interacting Protein (RIP)-dependent Manner and Cooperates with MEKK3 Leading to NF-κB Activation*

It is found that TAK1 is recruited to the T NF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-κB in TNF-α signaling.

Restoration of NF-κB Activation by Tumor Necrosis Factor Alpha Receptor Complex-Targeted MEKK3 in Receptor-Interacting Protein-Deficient Cells

The results indicate that the role of RIP is to specifically recruit MEKK3 to the TNF-α receptor complex, whereas the forced recruitment of NEMO to theTNF- α receptor complex is insufficient for T NF-α-induced NF-κB activation.

Regulation of NF-kappaB-dependent T cell activation and development by MEKK3.

Genetic evidence is provided that following TCR signaling, MEKK3 positively regulated the kinase, IkappaB Kinase, leading to NF-kappaB activation, which plays a crucial role in adaptive immunity.

TNFR1‐induced activation of the classical NF‐κB pathway

The known details of TNFR1‐induced IKK activation are summed up, arising contradictions are addressed and possible explanations resolving the apparent discrepancies are discussed.

Emerging complexity of protein ubiquitination in the NF-κB pathway.

The most recent findings relating to the role of TRAFs-mediated protein ubiquitination in regulating IKK activation are focused on, and the newly emerging complexity of protein ubiquItination in receptor-induced NF-κB activation is highlighted.

TNFα- and IKKβ-mediated TANK/I-TRAF phosphorylation: implications for interaction with NEMO/IKKγ and NF-κB activation

The scaffold protein TANK is required for the cellular response to TNFα by connecting upstream signalling molecules to the IKKs and p65, and its subsequent IKKβ-mediated phosphorylation may be a mechanism to terminate the TANK-dependent wave of NF-κB activation.



NAK is an IκB kinase-activating kinase

An IKK-related kinase is described, named NAK (NF-κB-activating kinase), that can activate IKK through direct phosphorylation and induces IκB degradation and NF-κBs activity through IKKβ.

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.

IκB Kinase-β: NF-κB Activation and Complex Formation with IκB Kinase-α and NIK

Overexpression of a catalytically inactive form of IKK-β blocked cytokine-induced NF-κB activation and suggested that an active IκB kinase complex may require three distinct protein kinases.

MEKK1 activates both IκB kinase α and IκB kinase β

It is shown that recombinant IKK-α and Ikk-β can, in fact, directly phosphorylate IκBα at Ser-32 and Ser-36, as well as homologous residues in IKKBβ in vitro, and thus are bona fide IkkB kinases.

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.

An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death

Reintroduction of RelA into RelA−/− fibroblasts resulted in enhanced survival, demonstrating that the presence ofrelA is required for protection from TNF-α.