Apoptosis stimulated by the 91-kDa caspase cleavage MEKK1 fragment requires translocation to soluble cellular compartments

J Biol Chem. 2002 Mar 22;277(12):10283-91. doi: 10.1074/jbc.M106885200. Epub 2002 Jan 8.

Abstract

MEKK1, a 196-kDa mitogen-activated protein kinase (MAPK) kinase kinase, generates anti-apoptotic signaling as a full-length protein but induces apoptosis when cleaved by caspases. Here, we show that caspase-dependent cleavage of MEKK1 relocalizes the protease-generated 91-kDa kinase fragment from a particulate fraction to a soluble cytoplasmic fraction. Relocalization of MEKK1 catalytic activity is necessary for the pro-apoptotic function of MEKK1. The addition of a membrane-targeting signal to the 91-kDa fragment inhibits caspase activation and the induction of apoptosis but does not change the activation of JNK, ERK, NFkappaB, or p300. These results identify the caspase cleavage of MEKK1 as a dynamic regulatory mechanism that alters the subcellular distribution of MEKK1, changing its function to pro-apoptotic signaling, which does not depend on the currently described MEKK1 effectors.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis*
  • Blotting, Western
  • Catalysis
  • Cell Line
  • Cell Membrane / enzymology
  • Cell Nucleus / enzymology
  • Cytoplasm / enzymology
  • Cytoplasm / metabolism
  • DNA, Complementary / metabolism
  • Dose-Response Relationship, Drug
  • E1A-Associated p300 Protein
  • Humans
  • MAP Kinase Kinase Kinase 1*
  • Mice
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Nuclear Proteins / metabolism
  • Plasmids / metabolism
  • Protein Binding
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Structure, Tertiary
  • Protein Transport
  • Subcellular Fractions / metabolism
  • Time Factors
  • Trans-Activators / metabolism
  • Transfection
  • Ultraviolet Rays

Substances

  • DNA, Complementary
  • NF-kappa B
  • Nuclear Proteins
  • Trans-Activators
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Map3k1 protein, mouse