Cadherins and synaptic plasticity: activity-dependent cyclin-dependent kinase 5 regulation of synaptic β-catenin-cadherin interactions

Abstract

Cyclin-dependent kinase 5 (Cdk5)/p35 kinase activity is known to decrease the affinity of β-catenin for cadherin in developing cortical neurons. Our recent work demonstrated that depolarization causes an increased affinity between β-catenin and cadherin. Here, we examine whether Cdk5/p35 regulates β-catenin-cadherin affinity in response to neural activity. In hippocampal neurons depolarization caused a significant decrease in Cdk5 kinase activity, without changing the protein levels of either Cdk5 or p35, suggesting that the proteasome pathway is not involved. Decreasing Cdk5 kinase activity with the inhibitor roscovitine increased the amount of β-catenin that was co-immunoprecipitated with cadherin. Inhibiting Cdk5 activity also resulted in a redistribution of EGFP-β-catenin from the dendritic shaft to the spines, where cadherins are highly concentrated. The redistribution of β-catenin induced by roscovitine is similar to that induced by depolarization. Interestingly, the redistribution induced by the Cdk5 inhibitor was completely blocked by either a tyrosine phosphatase inhibitor, orthovanadate or by point mutations of β-catenin Tyr-654 to Glu or Phe. Immunoprecipitation studies further revealed that roscovitine increases the affinity of the wild-type, but not mutated, EGFP-β-catenin for cadherin. These results suggest that Cdk5 activity regulates the affinity of β-catenin for cadherin by changing the phosphorylation level of β-catenin Tyr-654.