The regulation of anoikis: MEKK-1 activation requires cleavage by caspases

Cell. 1997 Jul 25;90(2):315-23. doi: 10.1016/s0092-8674(00)80339-6.

Abstract

Certain cell types undergo apoptosis when they lose integrin-mediated contacts with the extracellular matrix ("anoikis"). The Jun N-terminal kinase (JNK) pathway is activated in and promotes anoikis. This activation requires caspase activity. We presently report that a DEVD motif-specific caspase that cleaves MEKK-1 specifically is activated when cells lose matrix contact. This cleavage is required for the activation of the kinase activity. When overexpressed, the MEKK-1 cleavage product stimulates apoptosis; the wild-type, full-length MEKK-1 sensitizes cells to anoikis; and a cleavage-resistant mutant of MEKK-1 partially protects cells against anoikis. The cleavage-resistant or kinase-inactive mutants also prevent caspase-7 from being activated completely. Thus, caspases can induce apoptosis by activating MEKK-1, which in turn activates more caspase activity, comprising a positive feedback loop.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 7
  • Caspases*
  • Cells, Cultured
  • Cysteine Endopeptidases / isolation & purification
  • Cysteine Endopeptidases / metabolism*
  • Dogs
  • Enzyme Activation
  • Kidney Tubules, Distal / cytology
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Serpins / pharmacology
  • Transfection
  • Viral Proteins*

Substances

  • Serpins
  • Viral Proteins
  • interleukin-1beta-converting enzyme inhibitor
  • Protein-Serine-Threonine Kinases
  • Caspase 7
  • Caspases
  • Cysteine Endopeptidases