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

M H Cardone1, G S Salvesen, C Widmann

  • 1The Burnham Institute, La Jolla, California 92037, USA.

Cell
|July 25, 1997
PubMed

Insights

Cells undergo apoptosis, or anoikis, when detached from the extracellular matrix. This process involves the Jun N-terminal kinase (JNK) pathway and requires caspase activity, which activates MEKK-1, creating a feedback loop that promotes cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Anoikis is programmed cell death triggered by loss of cell adhesion to the extracellular matrix.
  • The Jun N-terminal kinase (JNK) pathway is implicated in anoikis, but its upstream regulators remain incompletely understood.
  • Caspase activity is known to be essential for JNK pathway activation during anoikis.

Purpose of the Study:

  • To investigate the specific caspase involved in JNK pathway activation during anoikis.
  • To elucidate the role of MEKK-1 cleavage in anoikis.
  • To characterize the feedback loop between caspases and MEKK-1 in anoikis.

Main Methods:

  • Analysis of caspase activity in detached cells.
  • Site-directed mutagenesis to create cleavage-resistant MEKK-1 mutants.
  • Overexpression studies of wild-type and mutant MEKK-1.
  • Assessment of apoptosis and caspase-7 activation.

Main Results:

  • A DEVD motif-specific caspase cleaves MEKK-1 upon loss of matrix contact, which is essential for MEKK-1 kinase activation.
  • Overexpression of the MEKK-1 cleavage product induces apoptosis, while wild-type MEKK-1 sensitizes cells to anoikis.
  • Cleavage-resistant or kinase-inactive MEKK-1 mutants partially protect cells from anoikis and inhibit full caspase-7 activation.

Conclusions:

  • Caspase-mediated cleavage of MEKK-1 is a critical step in the activation of the JNK pathway during anoikis.
  • This cleavage event initiates a positive feedback loop where activated MEKK-1 further promotes caspase activity, amplifying the apoptotic signal.
  • MEKK-1 acts as a key mediator linking matrix detachment to caspase-dependent apoptosis.

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