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Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx

H Y Chang1, H Nishitoh, X Yang

  • 1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02138, USA.

Science (New York, N.Y.)
|September 22, 1998
PubMed

Insights

The Fas death receptor pathway activates Jun NH2-terminal kinase (JNK) signaling via the Daxx protein, which interacts with and activates ASK1 kinase, promoting apoptosis.

Area of Science:

  • Cellular signaling pathways
  • Apoptosis and cell death
  • Molecular biology

Background:

  • The Fas death receptor initiates cellular apoptosis.
  • Daxx is a protein associated with the Fas receptor.
  • Jun NH2-terminal kinase (JNK) pathway activation is crucial in apoptosis.

Purpose of the Study:

  • To elucidate the role of Daxx in Fas-mediated JNK activation.
  • To identify the interaction between Daxx and ASK1 in the Fas signaling pathway.
  • To understand how Daxx regulates ASK1 kinase activity.

Main Methods:

  • Overexpression of wild-type and kinase-deficient ASK1 mutants.
  • Analysis of Fas- and Daxx-induced apoptosis.
  • Assessment of JNK activation.
  • Co-immunoprecipitation to study protein interactions.

Main Results:

  • Daxx activates the JNK kinase kinase ASK1.
  • Overexpression of a kinase-deficient ASK1 mutant inhibits Fas- and Daxx-induced apoptosis and JNK activation.
  • Fas activation promotes Daxx interaction with ASK1.
  • Daxx binding relieves intramolecular inhibition of ASK1, activating its kinase activity.

Conclusions:

  • The Daxx-ASK1 interaction is essential for Fas-induced JNK activation and apoptosis.
  • This study defines a signaling cascade from Fas receptor to JNK pathway activation.
  • The findings reveal a mechanism for regulating ASK1 kinase activity through receptor-associated proteins.

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