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Mitotic activation of the DISC1-inducible cyclic AMP phosphodiesterase-4D9 (PDE4D9), through multi-site

Catherine L Sheppard1, Louisa C Y Lee1, Elaine V Hill1

  • 1Institute of Neuroscience and Psychology, Wolfson Link and Davidson Buildings, University of Glasgow, University Avenue, Glasgow G12 8QQ, Scotland, UK.

Cellular Signalling
|May 13, 2014
PubMed

Insights

During mitosis, phosphodiesterase-4D9 (PDE4D9) activity increases, degrading cyclic AMP (cAMP) and reducing protein kinase A (PKA) activity. PDE4D9 activation regulates cell cycle progression in Rat-1 cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitosis is characterized by decreased intracellular cyclic adenosine monophosphate (cAMP) and cAMP-activated protein kinase A (PKA) activity.
  • This decrease is paralleled by increased activity of cAMP-hydrolyzing phosphodiesterase-4 (PDE4).

Purpose of the Study:

  • To investigate the role of PDE4 in regulating cAMP and PKA levels during mitosis.
  • To identify the specific PDE4 isoform responsible for mitotic PDE4 activity and its regulatory mechanisms.

Main Methods:

  • Using Rat-1 cells and selective PDE inhibitors (rolipram for PDE4, cilostamide for PDE3).
  • Employing selective immunopurification to identify PDE4 sub-families.
  • Analyzing PDE4D9 phosphorylation sites and localization using techniques like SDS-PAGE and microscopy.

Main Results:

  • PDE4 activation, not PDE3, underlies the reduction in PKA activity during mitosis.
  • PDE4 inhibition accelerates cell cycle transit through G2/M and prolongs G1 phase.
  • PDE4D9 is the sole PDE4 isoform activated during mitosis, undergoing multi-site phosphorylation by ERK, a switch kinase, MK2, and AMPK.
  • PDE4D9 is localized to the perinuclear region and cell margins.

Conclusions:

  • Mitotic decrease in cAMP and PKA activity is mediated by enhanced cAMP degradation by PDE4D9.
  • Multi-site phosphorylation regulates PDE4D9 activation during mitosis.
  • PDE4D9 localization and regulation are critical for controlling cell cycle dynamics.
Keywords:
AMPKDISC1MK2MitosisPDE4PDE4D9

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