Coordinate regulation of IkappaB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-kappaB-inducing kinase

Mol Cell Biol. 1998 Dec;18(12):7336-43. doi: 10.1128/MCB.18.12.7336.


IkappaB kinases (IKKalpha and IKKbeta) are key components of the IKK complex that mediates activation of the transcription factor NF-kappaB in response to extracellular stimuli such as inflammatory cytokines, viral and bacterial infection, and UV irradiation. Although NF-kappaB-inducing kinase (NIK) interacts with and activates the IKKs, the upstream kinases for the IKKs still remain obscure. We identified mitogen-activated protein kinase kinase kinase 1 (MEKK1) as an immediate upstream kinase of the IKK complex. MEKK1 is activated by tumor necrosis factor alpha (TNF-alpha) and interleukin-1 and can potentiate the stimulatory effect of TNF-alpha on IKK and NF-kappaB activation. The dominant negative mutant of MEKK1, on the other hand, partially blocks activation of IKK by TNF-alpha. MEKK1 interacts with and stimulates the activities of both IKKalpha and IKKbeta in transfected HeLa and COS-1 cells and directly phosphorylates the IKKs in vitro. Furthermore, MEKK1 appears to act in parallel to NIK, leading to synergistic activation of the IKK complex. The formation of the MEKK1-IKK complex versus the NIK-IKK complex may provide a molecular basis for regulation of the IKK complex by various extracellular signals.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • COS Cells
  • Enzyme Activation / physiology
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Interleukin-1 / pharmacology
  • MAP Kinase Kinase Kinase 1*
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Transfection / genetics
  • Tumor Necrosis Factor-alpha / pharmacology


  • Interleukin-1
  • NF-kappa B
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • NF-kappa B kinase