Homeostatic interactions between MEKK3 and TAK1 involved in NF-kappaB signaling.

Abstract:

:Several members of the mitogen-activated protein kinase kinase kinase (MAP3K) family including MEKK3 and TGFbeta-activating kinase (TAK1) play nonredundant roles in activation of the NF-kappaB transcription factor. However, the mechanism by which MEKK3 mediates NF-kappaB signaling is not fully understood. In this report we investigate the association of murine MEKK3 with other proteins and their roles in NF-kappaB 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-kappaB reporter activity induced by transient MEKK3 expression or TNFalpha stimulation. Addition of TAB1 facilitates TAK1 autophosphorylation and reverses the inhibitory effects of TAK1 on MEKK3 phosphorylation and NF-kappaB signal transduction in human 293 cells and TAK1 deficient mouse embryonic fibroblasts. The data provide insights into the homeostatic interactions that maintain basal NF-kappaB levels by holding the enzymes MEKK3 and TAK1 in their inactive state.

journal_name

Cell Signal

journal_title

Cellular signalling

authors

Di Y,Li S,Wang L,Zhang Y,Dorf ME

doi

10.1016/j.cellsig.2007.12.007

subject

Has Abstract

pub_date

2008-04-01 00:00:00

pages

705-13

issue

4

eissn

0898-6568

issn

1873-3913

pii

S0898-6568(07)00378-6

journal_volume

20

pub_type

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