Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway

Cell. 1997 Jan 24;88(2):213-22. doi: 10.1016/s0092-8674(00)81842-5.

Abstract

Both NF-kappaB and c-Jun are activated by cytokines such as TNF-alpha and by stresses such as UV irradiation. A key step in the activation of NF-kappaB is the phosphorylation of its inhibitor, IkappaB alpha, by a ubiquitination-inducible multiprotein kinase complex (IkappaB alpha kinase). A central kinase in the c-Jun activation pathway is mitogen-activated protein kinase/ERK kinase kinase-1 (MEKK1). Here, we show that MEKK1 induces the site-specific phosphorylation of IkappaB alpha in vivo and, most strikingly, can directly activate the IkappaB alpha kinase complex in vitro. Thus, MEKK1 is a critical component of both the c-Jun and NF-kappaB stress response pathways. Since the IkappaB alpha kinase complex can be independently activated by ubiquitination or MEKK1-dependent phosphorylation, it may be an integrator of multiple signal transduction pathways leading to the activation of NF-kappaB.

Publication types

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

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Enzyme Induction
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins*
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1*
  • Mitogen-Activated Protein Kinases*
  • Molecular Weight
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human