Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase

EMBO J. 1996 Feb 15;15(4):817-26.


The Tpl-2 protein serine/threonine kinase was originally identified, in a C-terminally deleted form, as the product of an oncogene associated with the progression of Moloney murine leukemia virus-induced T cell lymphomas in rats. The kinase domain of Tpl-2 is homologous to the Saccharomyces cerevisiae gene product, STE11, which encodes a MAP kinase kinase kinase. This suggested that Tpl-2 might have a similar activity. Consistent with this hypothesis, immunoprecipitated Tpl-2 and Tpl-2deltaC (a C-terminally truncated mutant) phosphorylated and activated recombinant fusion proteins of the mammalian MAP kinase kinases, MEK-1 and SEK-1, in vitro. Furthermore, transfection of Tpl-2 into COS-1 cells or Jurkat T cells. markedly activated the MAP kinases, ERK-1 and SAP kinase (JNK), which are substrates for MEK-1 and SEK-1, respectively. Tpl-2, therefore, is a MAP kinase kinase kinase which can activate two MAP kinase pathways. After Raf and Mos, Tpl-2 is the third serine/threonine oncoprotein kinase that has been shown to function as a direct activator of MEK-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cells, Cultured
  • Chlorocebus aethiops
  • DNA Primers / chemistry
  • Enzyme Activation
  • Fetal Proteins / metabolism*
  • Humans
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 4*
  • MAP Kinase Kinase Kinases*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases*
  • Mitogen-Activated Protein Kinases*
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-raf
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, EphA4
  • Signal Transduction
  • T-Lymphocytes


  • DNA Primers
  • Fetal Proteins
  • Proto-Oncogene Proteins
  • Protein Kinases
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptor, EphA4
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP3K8 protein, human
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 4
  • MAP2K1 protein, human
  • MAP2K4 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)