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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons

Sung-Wuk Jang1, Xia Liu, Haian Fu

  • 1Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

The Journal of Biological Chemistry
|July 14, 2009
PubMed

Insights

Mature neurons normally do not divide. This study reveals how SRPK2 activation promotes neuronal cell cycle reentry and apoptosis, mediated by Akt signaling and cyclin D1 regulation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Terminally differentiated neurons are terminally arrested and cannot reenter the cell cycle.
  • Aberrant cell cycle activation in neurons leads to cell death, while inhibition promotes survival.
  • The molecular mechanisms governing cell cycle regulation and cell death in mature neurons are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which mature neurons regulate cell cycle progression and apoptosis.
  • To identify key signaling pathways and proteins involved in neuronal cell cycle control and survival.

Main Methods:

  • Investigated the role of SRPK2 (serine/arginine (SR) protein kinase 2) in neuronal cell cycle regulation.
  • Utilized phosphorylation assays, Western blotting, and immunohistochemistry to analyze protein modifications and expression levels.
  • Examined the impact of Akt signaling on SRPK2 activity and its downstream targets, including cyclin D1 and p53.
  • Assessed SRPK2 phosphorylation in ischemia-affected brain tissue.

Main Results:

  • SRPK2 triggers neuronal cell cycle progression and apoptosis by regulating nuclear cyclin D1.
  • Akt-mediated phosphorylation of SRPK2 at Thr-492 promotes its nuclear translocation, up-regulating cyclin D1 and inducing apoptosis.
  • SRPK2 phosphorylates SC35, leading to p53 inactivation and subsequent cyclin D1 up-regulation.
  • 14-3-3 binding to SRPK2, modulated by Akt, inhibits these pro-apoptotic and cell cycle-promoting events.
  • Increased SRPK2 phosphorylation was observed in ischemia-attacked brain, correlating with elevated cyclin D1 levels.

Conclusions:

  • Phosphatidylinositol 3-kinase/Akt signaling pathway mediates neuronal cell cycle and cell death through SRPK2 phosphorylation.
  • SRPK2 acts as a critical regulator linking Akt signaling to cell cycle reentry and apoptosis in mature neurons.
  • Targeting the SRPK2-mediated pathway may offer therapeutic strategies for neurological conditions involving neuronal loss.

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