Functional interactions of transforming growth factor β-activated kinase I with IκB kinases to stimulate NF-κB activation

Hiroaki Sakurai, Hidetaka Miyoshi, Wataru Toriumi, Takahisa Sugita*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

Abstract

Several mitogen-activated protein kinase kinase kinases play critical roles in nuclear factor-κB (NF-κB) activation. We recently reported that the overexpression of transforming growth factor-β-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, together with its activator TAK1-binding protein 1 (TAB1) stimulates NF-κB activation. Here we investigated the molecular mechanism of TAK1- induced NF-κB activation. Dominant negative mutants of IκB kinase (IKK) α and IKKβ inhibited TAK1-induced NF-κB activation. TAK1 activated IKKα and IKKβ in the presence of TAB1. IKKα and IKKβ were coimmunoprecipitated with TAK1 in the absence of TAB1. TAB1-induced TAK1 activation promoted the dissociation of active forms of IKKα and IKKβ from active TAK1, whereas the IKK mutants remained to interact with active TAK1. Furthermore, tumor necrosis factor-α activated endogenous TAK1, and the kinase-negative TAK1 acted as a dominant negative inhibitor against tumor necrosis factor-α- induced NF-κB activation. These results demonstrated a novel signaling pathway to NF-κB activation through TAK1 in which TAK1 may act as a regulatory kinase of IKKs.

Original languageEnglish
Pages (from-to)10641-10648
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number15
DOIs
StatePublished - 1999/04/09

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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