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Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription.

Induction of NF-kappaB-dependent transcription requires phosphorylation and subsequent degradation of I-kappaB, an inhibitor of NF-kappaB, followed by nuclear translocation and DNA binding of NF-kappaB. Tumor necrosis factor receptor-associated factor 2 (TRAF2) plays a role in NF-kappaB activation in response to cytokines such as tumor necrosis factor alpha (TNFalpha). 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-kappaBalpha in vitro. The physiological function of T2K was investigated using T2K-deficient mice. Heterozygotes appear normal, but t2k(-/-) animals die at approximately E14.5 of massive liver degeneration and apoptosis. Never theless, hematopoietic progenitors from T2K-deficient fetal liver support normal lymphocyte development. Furthermore, t2k(-/-) embryonic fibroblasts and thymocytes do not display increased sensitivity to TNFalpha-induced apoptosis. In response to either TNFalpha or IL-1 induction, t2k(-/-) embryonic fibroblasts exhibit normal degradation of I-kappaB and kappaB-binding activity. However, NF-kappaB-directed transcription is dramatically reduced. These results demonstrate that, like I-kappaB kinase beta and the RelA subunit of NF-kappaB, T2K is critical in protecting embryonic liver from apoptosis. However, T2K has a unique role in the activation of NF-kappaB-directed transcription, apparently independent of I-kappaB degradation and NF-kappaB DNA binding.

Pubmed ID: 10990461


  • Bonnard M
  • Mirtsos C
  • Suzuki S
  • Graham K
  • Huang J
  • Ng M
  • ItiĆ© A
  • Wakeham A
  • Shahinian A
  • Henzel WJ
  • Elia AJ
  • Shillinglaw W
  • Mak TW
  • Cao Z
  • Yeh WC


The EMBO journal

Publication Data

September 15, 2000

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Blotting, Southern
  • Cycloheximide
  • Dose-Response Relationship, Drug
  • Female
  • Fibroblasts
  • Flow Cytometry
  • Gene Targeting
  • Genes, Reporter
  • Genotype
  • Heterozygote
  • I-kappa B Kinase
  • In Situ Nick-End Labeling
  • Interleukin-1
  • Ligases
  • Liver
  • Lymphocytes
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Genetic
  • Molecular Sequence Data
  • NF-kappa B
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Protein Synthesis Inhibitors
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Recombinant Proteins
  • TNF Receptor-Associated Factor 2
  • Thymus Gland
  • Time Factors
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha