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Cdk5 regulates Rap1 activity

Elias Utreras1, Daniel Henriquez, Erick Contreras-Vallejos

  • 1Laboratory of Cellular and Neuronal Dynamics, Department of Biology, Faculty of Sciences, Universidad de Chile, Chile.

Neurochemistry International
|February 19, 2013
PubMed

Insights

Cyclin-dependent kinase 5 (Cdk5) phosphorylates C3G, influencing Rap1 protein stability and activity. This Cdk5-mediated phosphorylation of C3G impacts neuronal functions like migration and differentiation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Signaling

Background:

  • Rap1 signaling pathways are crucial for fundamental neuronal processes including migration, differentiation, and polarity.
  • Cyclin-dependent kinase 5 (Cdk5) plays a significant role in neuronal development and migration.
  • Cdk5 activity is regulated by its activator p35, and its inhibition affects Rap1 levels.

Purpose of the Study:

  • To investigate the potential link between Cdk5-dependent phosphorylation of C3G and its regulation of Rap1 expression and activity.
  • To elucidate the molecular mechanism by which Cdk5 influences Rap1 signaling.

Main Methods:

  • Co-transfection of C3G and a tet-OFF system for p35 (Cdk5 activator) in COS-7 cells.
  • Immunoprecipitation and Western blot analysis to assess C3G phosphorylation and Rap1 protein levels.
  • Utilized roscovitine (Cdk5 inhibitor) and MG-132 (proteasome inhibitor) to modulate signaling pathways.
  • Analysis of Cdk5(-/-) and Cdk5(+/+) mouse brains to confirm in vivo findings.

Main Results:

  • Overexpression of p35 increased serine phosphorylation of C3G, while its inhibition or Cdk5 inhibition decreased it.
  • Proteasome inhibition rescued Rap1 protein levels when Cdk5 activity was inhibited.
  • C3G phosphorylation and Rap1 protein levels were reduced in Cdk5 knockout brains.
  • p35 overexpression enhanced Rap1 activity, whereas inhibition of p35 or Cdk5 reduced Rap1 activity.

Conclusions:

  • Cdk5-mediated serine phosphorylation of C3G is a key regulator of Rap1 protein stability and activity.
  • This regulatory mechanism involving Cdk5, C3G, and Rap1 signaling has significant implications for neuronal functions such as migration, differentiation, and polarity.

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