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Functional role of death-associated protein 3 (DAP3) in anoikis

Tadaaki Miyazaki1, Min Shen, Daisuke Fujikura

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

The Journal of Biological Chemistry
|August 11, 2004
PubMed

Insights

Death-associated protein 3 (DAP3) is crucial for anoikis, a form of apoptosis triggered by cell detachment. Kinase Akt phosphorylation of DAP3 inhibits this cell death pathway, revealing a new mechanism in anoikis signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Anoikis is apoptosis induced by epithelial cell detachment from the extracellular matrix.
  • Integrin signaling plays a protective role against anoikis, but the underlying mechanisms remain unclear.
  • Death-associated protein 3 (DAP3) is a pro-apoptotic GTP-binding protein.

Purpose of the Study:

  • To investigate the role of DAP3 in anoikis induction.
  • To elucidate the signaling pathways involving DAP3 in response to cell detachment.
  • To determine the regulatory mechanism of DAP3 by kinase Akt (PKB).

Main Methods:

  • Antisense oligonucleotides to down-regulate DAP3 expression.
  • Overexpression of DAP3 to study its effects on cell death.
  • Analysis of DAP3 association with FADD and caspase-8 activation.
  • Site-directed mutagenesis to investigate Akt phosphorylation site on DAP3.
  • Assessment of Akt activation and DAP3 phosphorylation upon integrin ligation.

Main Results:

  • Down-regulation of DAP3 inhibited anoikis, while its overexpression augmented cell death and caspase activation.
  • Cell detachment induced DAP3 association with FADD and caspase-8 activation.
  • Kinase Akt phosphorylates DAP3, and active Akt suppresses DAP3-mediated apoptosis induction.
  • A mutated DAP3, resistant to Akt phosphorylation, failed to be suppressed by active Akt.
  • Integrin ligation activated Akt, leading to DAP3 phosphorylation and suppression of DAP3-induced anoikis.

Conclusions:

  • DAP3 is a critical mediator in the induction of anoikis.
  • Akt-mediated phosphorylation of DAP3 represents a novel mechanism for regulating anoikis.
  • This study reveals a new role for DAP3 in apoptosis signaling pathways triggered by cell detachment.

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