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p35/cdk5 binds and phosphorylates beta-catenin and regulates beta-catenin/presenilin-1 interaction

S Kesavapany1, K F Lau, D M McLoughlin

  • 1Department of Neuroscience, The Institute of Psychiatry, Denmark Hill, London SE5 8AF, UK.

The European Journal of Neuroscience
|February 13, 2001
PubMed

Insights

The neuronal p35/cdk5 kinase binds and phosphorylates beta-catenin, regulating its interaction with presenilin-1. This discovery provides a new molecular link between p35/cdk5, beta-catenin, and presenilin-1 in Alzheimer's disease pathogenesis.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • The p35/cyclin-dependent kinase 5 (cdk5) complex is crucial in neuronal function.
  • Aberrant p35/cdk5 activity is implicated in Alzheimer's disease (AD).
  • Beta-catenin and presenilin-1 interactions are relevant to AD pathology.

Purpose of the Study:

  • To identify novel substrates of the p35/cdk5 complex.
  • To investigate the role of p35/cdk5 in regulating beta-catenin and presenilin-1 interactions.
  • To establish a molecular framework connecting these proteins in AD.

Main Methods:

  • Yeast two-hybrid screening to identify p35 binding partners.
  • Glutathione S-transferase (GST) pull-down assays and co-immunoprecipitation to confirm protein interactions.
  • Subcellular localization studies.
  • In vitro kinase assays to demonstrate phosphorylation.
  • Pharmacological inhibition of p35/cdk5 activity.

Main Results:

  • Beta-catenin was identified as a novel binding partner of p35.
  • p35/cdk5 directly phosphorylates beta-catenin.
  • p35/cdk5 activity regulates the binding of beta-catenin to presenilin-1.
  • Inhibition of p35/cdk5 reduced presenilin-1 binding to beta-catenin without altering protein levels.

Conclusions:

  • p35/cdk5 binds and phosphorylates beta-catenin.
  • p35/cdk5 modulates the interaction between beta-catenin and presenilin-1.
  • These findings offer a novel molecular mechanism linking p35/cdk5, beta-catenin, and presenilin-1 in the context of Alzheimer's disease.

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