Journal
CELLULAR SIGNALLING
Volume 20, Issue 4, Pages 705-713Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2007.12.007
Keywords
TAK1; TAB1; MEKK3; NF-kappa B regulation; TNF alpha signaling; tandem affinity purification
Categories
Funding
- NINDS NIH HHS [R01 NS042900, R01NS042900, R01 NS042900-04] Funding Source: Medline
- CSR NIH HHS [RG3871A4] Funding Source: Medline
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Several members of the mitogen-activated protein kinase kinase kinase (MAP3K) family including MEKK3 and TGF beta-activating kinase (TAK1) play nonredundant roles in activation of the NF-kappa B transcription factor. However, the mechanism by which MEKK3 mediates NF-kappa B signaling is not fully understood. In this report we investigate the association of murine MEKK3 with other proteins and their roles in NF-kappa B activation. Using tandem affinity purification TAK1 was identified as an endogenous protein that interacts with MEKK3. MEKK3-TAK1 interactions were confirmed by fluorescence resonance energy transfer and coimmunoprecipitation. MEKK3-TAK1 complexes contain non-phosphorylated forms of both molecules. Expression of non-phosphorylated TAK1 interferes with MEKK3 phosphorylation and NF-kappa B reporter activity induced by transient MEKK3 expression or TNF alpha stimulation. Addition of TAB1 facilitates TAK1 autophosphorylation and reverses the inhibitory effects of TAK1 on MEKK3 phosphorylation and NF-kappa B signal transduction in human 293 cells and TAK1 deficient mouse embryonic fibroblasts. The data provide insights into the homeostatic interactions that maintain basal NF-kappa B levels by holding the enzymes MEKK3 and TAK1 in their inactive state. (C) 2008 Elsevier Inc. All rights reserved.
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