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The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase

Céline Guenebeaud1, David Goldschneider, Marie Castets

  • 1Apoptosis, Cancer and Development Laboratory-Equipe Labellisée "La Ligue," CNRS UMR5238, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.

Molecular Cell
|December 22, 2010
PubMed

Insights

UNC5H2 receptors induce cell death by activating DAPk through protein phosphatase 2A (PP2A) dephosphorylation. Netrin-1 binding inhibits this process, impacting angiogenesis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Developmental Biology

Background:

  • UNC5H dependence receptors trigger apoptosis without netrin-1, crucial for development and cancer suppression.
  • UNC5H2/B signaling involves the serine-threonine kinase DAPk for cell death induction.

Purpose of the Study:

  • To identify genes involved in UNC5H-induced apoptosis.
  • To elucidate the mechanism of UNC5H2/B-mediated cell death and its regulation by netrin-1.

Main Methods:

  • siRNA screening to identify key apoptotic genes.
  • Co-immunoprecipitation to analyze protein complex formation.
  • Enzyme activity assays to measure PP2A and DAPk activity.

Main Results:

  • PR65β, a subunit of protein phosphatase 2A (PP2A), was identified as crucial for UNC5H2/B-induced apoptosis.
  • UNC5H2/B recruits a complex containing PR65β and DAPk, maintaining PP2A activity.
  • PP2A activation of DAPk via dephosphorylation is essential for UNC5H2/B-induced apoptosis.
  • Netrin-1 binding prevents PP2A recruitment by engaging the inhibitor CIP2A.

Conclusions:

  • Netrin-1 absence allows UNC5H2/B to recruit PP2A, activating DAPk through dephosphorylation, thus inducing apoptosis.
  • This PP2A-DAPk pathway regulated by netrin-1 is critical for angiogenesis control.

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