Cdk5-Mediated Phosphorylation of  -Catenin Regulates Its Localization and GluR2-Mediated Synaptic Activity

Abstract

Cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation plays an important role in proper synaptic function and transmission. Loss of Cdk5 activity results in abnormal development of the nervous system accompanied by massive disruptions in cortical migration and lamination, therefore impacting synaptic activity. The Cdk5 activator p35 associates with ␦-catenin, the synaptic adherens junction protein that serves as part of the anchorage complex of AMPA receptor at the postsynaptic membrane. However, the implications of Cdk5-mediated phosphorylation of ␦-catenin have not been fully elucidated. Here we show that Cdk5-mediated phosphorylation of ␦-catenin regulates its subcellular localization accompanied by changes in dendritic morphogenesis and synaptic activity. We identified two Cdk5 phosphorylation sites in mouse ␦-catenin, serines 300 and 357, and report that loss of Cdk5 phosphorylation of ␦-catenin increased its localization to the membrane. Furthermore, mutations of the serines 300 and 357 to alanines to mimic nonphosphorylated ␦-catenin resulted in increased dendritic protrusions accompanied by increased AMPA receptor subunit GluR2 localization at the membrane. Consistent with these observations, loss of Cdk5 phosphorylation of ␦-catenin increased the AMPA/NMDA ratio. This study reveals how Cdk5 phosphorylation of the synaptic mediator protein ␦-catenin can alter its localization at the synapse to impact neuronal synaptic activity.

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

“…In vitro kinase assays to investigate the changes in Cdk5 activity were performed as published previously (Poore et al, 2010).…”

Functional roles of p120ctn family of proteins in central neurons

“…The ability of δ-catenin to regulate synaptic density is influenced by its ability to be phosphorylated by cyclin dependent kinase 5 (CDK5). δ-catenin can be directly phosphorylated by CDK5 at residues S300 and S357 [75]. This phosphorylation promotes its membrane association [75].…”

“…δ-catenin can be directly phosphorylated by CDK5 at residues S300 and S357 [75]. This phosphorylation promotes its membrane association [75]. A mutant form of δ-catenin expressing S to A mutations at residues 300 and 357, representing constitutively activated forms, enhances the density of dendritic protrusions [75].…”

“…This phosphorylation promotes its membrane association [75]. A mutant form of δ-catenin expressing S to A mutations at residues 300 and 357, representing constitutively activated forms, enhances the density of dendritic protrusions [75]. Loss of CDK5-mediated phosphorylation of δ-catenin enhances the association between δ-catenin and N-cadherin, GRIP and PSD95, resulting in an increase in the surface AMPAR and ratio of AMPA/NMDA compared to the wild type δ-catenin [75].…”

“…Multiple residues spanning the entire protein are phosphorylated in the central nervous system as indicated in Fig. 2 which includes data pooled from multiple sources [28,30–32,48,55,75,81,83–86]. p0071 has the highest number of phosphorylation sites, followed by δ-catenin, p120ctn, finally ARVCF.…”