Activation of MEK kinase 1 by the c-Abl protein tyrosine kinase in response to DNA damage

Mol Cell Biol. 2000 Jul;20(14):4979-89. doi: 10.1128/MCB.20.14.4979-4989.2000.

Abstract

The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents and regulates induction of the stress-activated c-Jun N-terminal protein kinase (SAPK). Here we show that nuclear c-Abl associates with MEK kinase 1 (MEKK-1), an upstream effector of the SEK1-->SAPK pathway, in the response of cells to genotoxic stress. The results demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo. Transient-transfection studies with wild-type and kinase-inactive c-Abl demonstrate c-Abl kinase-dependent activation of MEKK-1. Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage. The results also demonstrate that c-Abl induces MEKK-1-mediated phosphorylation and activation of SEK1-SAPK in coupled kinase assays. These findings indicate that c-Abl functions upstream of MEKK-1-dependent activation of SAPK in the response to genotoxic stress.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cisplatin / pharmacology
  • DNA Damage / physiology*
  • DNA Damage / radiation effects
  • Enzyme Activation / radiation effects
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4*
  • MAP Kinase Kinase Kinase 1*
  • Mice
  • Mice, Mutant Strains
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-abl / drug effects
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Radiation, Ionizing
  • U937 Cells

Substances

  • Proto-Oncogene Proteins c-abl
  • Protein Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Map3k1 protein, mouse
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human
  • Map2k4 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases
  • Cisplatin