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Contrasting roles of neuronal Msk1 and Rsk2 in Bad phosphorylation and feedback regulation of Erk signalling

C J Clark1, D M McDade, C T O'Shaughnessy

  • 1Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow, UK.

Journal of Neurochemistry
|August 1, 2007
PubMed

Insights

Mitogen- and stress-activated kinase 1 (Msk1) mediates neuronal Bad phosphorylation after calcium influx, while ribosomal S6 kinase 2 (Rsk2) negatively regulates extracellular signal-regulated kinase (Erk) activity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Signaling

Background:

  • Extracellular signal-regulated kinase (Erk) activates downstream kinases, including Rsk2 and Msk1.
  • Rsk2 is crucial for neuronal plasticity, with its dysfunction linked to cognitive impairment in Coffin-Lowry syndrome.
  • The distinct roles of Rsk2 and Msk1 in Erk-mediated signaling require clarification.

Purpose of the Study:

  • To elucidate the specific roles of Rsk2 and Msk1 in neuronal signaling pathways.
  • To investigate the involvement of these kinases in the phosphorylation of Bcl-2-associated death protein (Bad) following calcium influx.
  • To determine the regulatory relationship between Rsk2, Msk1, and Erk activity.

Main Methods:

  • Utilized PC12 cells and primary cortical neurons.
  • Induced cellular responses using the calcium ionophore A23187.
  • Employed small interfering RNA (siRNA) to specifically knockdown Msk1 and Rsk2.
  • Assessed the phosphorylation status of Erk, Msk1, Rsk2, and Bad proteins.

Main Results:

  • Calcium ionophore A23187 induced phosphorylation of Erk, Msk1, Rsk2, and Bad.
  • Msk1 knockdown diminished A23187-induced Bad phosphorylation.
  • Rsk2 knockdown enhanced Bad phosphorylation and Erk phosphorylation.
  • These findings suggest Msk1 mediates Bad phosphorylation and Rsk2 negatively regulates Erk.

Conclusions:

  • Msk1 is the primary mediator of neuronal Bad phosphorylation downstream of Erk following calcium influx.
  • Rsk2 plays a role in a negative-feedback loop that regulates Erk activity.
  • This study clarifies the differential roles of Msk1 and Rsk2 in neuronal signaling and neuroprotection.

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