A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK

Cell. 1998 Nov 13;95(4):521-30. doi: 10.1016/s0092-8674(00)81619-0.


The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis. A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in response to environmental stresses. Using a yeast two-hybrid method, three related proteins, GADD45alpha (= GADD45), GADD45, (= MyD118), and GADD45gamma, were identified that bound to an N-terminal domain of MTK1. These proteins activated MTK1 kinase activity, both in vivo and in vitro. The GADD45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation. Expression of the GADD45-like genes induces p38/JNK activation and apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein. We propose that the GADD45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • COS Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology
  • Cells, Cultured
  • DNA Damage / physiology*
  • Enzyme Activation
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • MAP Kinase Kinase Kinase 4
  • MAP Kinase Kinase Kinases*
  • Mitogen-Activated Protein Kinases*
  • Molecular Sequence Data
  • Multigene Family
  • Peptide Mapping
  • Protein Binding
  • Protein Biosynthesis
  • Protein Kinases / metabolism
  • Protein Kinases / physiology*
  • Proteins / genetics
  • Proteins / physiology*
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Stress, Physiological / metabolism*
  • Transfection
  • p38 Mitogen-Activated Protein Kinases


  • GADD45 protein
  • GADD45G protein, human
  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 4
  • MAP Kinase Kinase Kinases
  • MAP3K4 protein, human

Associated data

  • GENBANK/AF078077
  • GENBANK/AF078078