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Apoptosis induced by cytoskeletal disruption requires distinct domains of MEKK1

Erin Tricker1, Afsane Arvand, Raymond Kwan

  • 1Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.

Plos One
|March 3, 2011
PubMed

Insights

Mitogen-activated protein kinase kinase kinase 1 (MEKK1) is crucial for apoptosis induced by cytoskeletal disruption. Its kinase activity and Plant Homeodomain (PHD) are essential for activating JNK signaling and cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitogen-activated protein kinase kinase kinase 1 (MEKK1) is a MAP3K that activates JNK.
  • MEKK1 is known to be essential for apoptosis induced by microtubule inhibitors in B cells.

Purpose of the Study:

  • To investigate the functional requirements for MEKK1 activation in apoptosis.
  • To determine the role of MEKK1 domains in cytoskeletal disruption-induced apoptosis.

Main Methods:

  • Created MEKK1 mutations in UIM, PHD, caspase cleavage site, and kinase domains.
  • Complemented MEKK1-deficient cells with mutated MEKK1 and tested drug sensitivity.
  • Assessed JNK activation and apoptosis induction.

Main Results:

  • MEKK1 kinase activity and PHD domain are required for JNK activation and apoptosis.
  • Drugs causing cytoskeletal disruption induce apoptosis via MEKK1.
  • MEKK1 modification and localization depend on PHD integrity.

Conclusions:

  • MEKK1 is a key regulator of apoptosis induced by cytoskeletal disruption.
  • Both MEKK1 kinase activity and its PHD domain are critical for this process.

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