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The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling

Rana Anjum1, Philippe P Roux, Bryan A Ballif

  • 1Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Current Biology : CB
|October 11, 2005
PubMed

Insights

Death-associated protein kinase (DAPK) is regulated by Ras-extracellular signal-regulated kinase (ERK) pathway signaling. RSK-mediated phosphorylation of DAPK at Ser-289 suppresses its pro-apoptotic function, impacting cell viability and tumor suppression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cell viability relies on balancing survival and cell-death signals.
  • Dysregulation of this balance leads to pathological conditions like cancer.
  • Death-associated protein kinase (DAPK) regulates apoptosis and tumor suppression, but its signaling is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms regulating Death-associated protein kinase (DAPK) activity.
  • To identify upstream signaling pathways and specific phosphorylation sites controlling DAPK's function.
  • To investigate the role of DAPK phosphorylation in cell proliferation and apoptosis.

Main Methods:

  • Investigated DAPK phosphorylation in response to Ras-extracellular signal-regulated kinase (ERK) pathway activation.
  • Identified DAPK as a substrate for p90 ribosomal S6 kinases (RSK) 1 and 2 using biochemical assays.
  • Utilized mass spectrometry to pinpoint Ser-289 as a key RSK phosphorylation site on DAPK.
  • Employed site-directed mutagenesis (Ser-289Ala and Ser-289Glu) to assess the functional impact of phosphorylation on DAPK's apoptotic activity.

Main Results:

  • DAPK phosphorylation was observed upon activation of the Ras-ERK pathway.
  • DAPK was identified as a direct target of RSK1 and RSK2.
  • Phosphorylation at Ser-289 by RSK was confirmed as a regulatory mechanism for DAPK.
  • Mutation of Ser-289 to alanine enhanced DAPK's apoptotic activity, while the phosphomimetic mutation attenuated it.

Conclusions:

  • RSK-mediated phosphorylation of DAPK at Ser-289 is a novel mechanism to suppress its pro-apoptotic function.
  • This regulatory pathway plays a role in controlling cell death in both normal and Ras/Raf-transformed cells.
  • Understanding this signaling axis offers insights into cancer development and potential therapeutic strategies.

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