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

The neuronal cyclin-dependent kinase p35/cdk5 comprises a catalytic subunit (cdk5) and an activator subunit (p35). To identify novel p35/cdk5 substrat es, we utilized the yeast two-hybrid system to screen for human p35 binding partners. From one such screen, we identified beta -catenin as an interact ing protein. Confirmation that p35 binds to beta -catenin was obtained by u sing glutathione S-transferase (GST)-beta -catenin fusion proteins that int eracted with both endogenous and transfected p35, and by showing that beta -catenin was present in p35 immunoprecipitates. p35 and beta -catenin also displayed overlapping subcellular distribution patterns in cells including neurons. Finally, we demonstrated that p35/cdk5 phosphorylates beta -cateni n. beta -catenin also binds to presenilin-1 and altered beta -catenin/prese nilin-1 interactions may be mechanistic in Alzheimer's disease (AD). Abnorm al p35/cdk5 activity has also been suggested to contribute to AD. We theref ore investigated how modulation of p35/cdk5 activity influenced beta -caten in/presenilin-1 interactions. Inhibition of p35/cdk5 with roscovitine did n ot alter the steady state levels of either beta -catenin or presenilin-1 bu t reduced the amount of presenilin-1 bound to beta -catenin. Thus, p35/cdk5 binds and phosphorylates beta -catenin and regulates its binding to presen ilin-1. The findings reported here therefore provide a novel molecular fram ework to connect p35/cdk5 with beta -catenin and presenilin-1 in AD.