Journal
EMBO JOURNAL
Volume 19, Issue 18, Pages 4976-4985Publisher
OXFORD UNIV PRESS
DOI: 10.1093/emboj/19.18.4976
Keywords
apoptosis; I-kappa B kinase; NF-kappa B; T2K; TNF signaling
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induction of NF-kappa B-dependent transcription requires phosphorylation and subsequent degradation of I-kappa B, an inhibitor of NF-kappa B, followed by nuclear translocation and DNA binding of NF-kappa B. Tumor necrosis factor receptor-associated factor 2 (TRAF2) plays a role in NF-kappa B activation in response to cytokines such as tumor necrosis factor alpha (TNF alpha). In this study, we purified and characterized a novel kinase (T2K, also known as TBK1 or NAK), which associates with TRAF2 and exhibits kinase activity towards I-kappa B alpha in vitro. The physiological function of T2K was investigated using T2K-deficient mice. Heterozygotes appear normal, but t2k(-/-) animals die at similar to E14.5 of massive liver degeneration and apoptosis, Nevertheless, hematopoietic progenitors from T2K-deficient fetal liver support normal lymphocyte development. Furthermore, t2k(-/-) embryonic fibroblasts and thymocytes do not display increased sensitivity to TNF alpha-induced apoptosis. In response to either TNF alpha or IL-1, induction, t2k(-/-) embryonic fibroblasts exhibit normal degradation of I-kappa B and kappa B-binding activity. However, NF-kappa B-directed transcription is dramatically reduced. These results demonstrate that, like I-kappa B kinase beta and the ReIA subunit of NF-kappa B, T2K is critical in protecting embryonic liver from apoptosis, However, T2K has a unique role in the activation of NF-kappa B-directed transcription, apparently independent of I-kappa B degradation and NF-kappa B DNA binding.
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