Cadherins and synaptic plasticity: activity-dependent cyclin-dependent kinase 5 regulation of synaptic beta-catenin-cadherin interactions.
Cyclin-dependent kinase 5 (Cdk5)/p35 kinase activity is known to decrease the affinity of beta-catenin for cadherin in developing cortical neurons. Our recent work demonstrated that depolarization causes an increased affinity between beta-catenin and cadherin. Here, we examine whether Cdk5/p35 regulates beta-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 beta-catenin that was co-immunoprecipitated with cadherin. Inhibiting Cdk5 activity also resulted in a redistribution of EGFP-beta-catenin from the dendritic shaft to the spines, where cadherins are highly concentrated. The redistribution of beta-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 beta-catenin Tyr-654 to Glu or Phe. Immunoprecipitation studies further revealed that roscovitine increases the affinity of the wild-type, but not mutated, EGFP-beta-catenin for cadherin. These results suggest that Cdk5 activity regulates the affinity of beta-catenin for cadherin by changing the phosphorylation level of beta-catenin Tyr-654.
Caltech/Howard Hughes Medical Institute, Division of Biology, 114-96, Pasadena, CA 91125, USA. schumane@cco.caltech.edu
Erin M
EM
Schuman
Sachiko
S
Murase
D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D015820:Cadherins / Q000502:physiology*; D002478:Cells, Cultured; D002645:Chickens; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D017354:Point Mutation / Q000502:physiology; D051381:Rats; D013569:Synapses / Q000502:physiology*; D014018:Tissue Distribution; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin
D015820:Cadherins; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D014443:Tyrosine; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases