Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1

Nature. 1994 Dec 22-29;372(6508):798-800. doi: 10.1038/372798a0.


A kinase distinct from the MEK activator Raf, termed MEK kinase-1 (MEKK), was originally identified by virtue of its homology to kinases involved in yeast mating signal cascades. Like Raf, MEKK is capable of activating MEK in vitro. High-level expression of MEKK in COS-7 cells or using vaccinia virus vectors also activates MEK and MAPK, indicating that MEKK and Raf provide alternative means of activating the MAPK signalling pathway. We have derived NIH3T3 cell sublines that can be induced to express active MEKK. Here we show that induction of MEKK does not result in the activation of MAPK, but instead stimulates the stress-activated protein kinases (SAPKs) which are identical to a Jun amino-terminal kinase. We find that MEKK regulates a new signalling cascade by phosphorylating an SAPK activator, SEK1 which in turn phosphorylates and activates SAPK.

MeSH terms

  • 3T3 Cells
  • Animals
  • Enzyme Activation
  • Enzyme Induction
  • Heat-Shock Proteins / metabolism
  • MAP Kinase Kinase 4*
  • MAP Kinase Kinase Kinase 1*
  • Mice
  • Mitogen-Activated Protein Kinase Kinases*
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / biosynthesis
  • Protein-Tyrosine Kinases / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Transfection


  • Heat-Shock Proteins
  • Recombinant Fusion Proteins
  • Protein Kinases
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase Kinase 1
  • Map3k1 protein, mouse
  • MAP Kinase Kinase 4
  • Map2k4 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases