CDK5 activator protein p25 preferentially binds and activates GSK3?.

Glycogen synthase kinase 3? (GSK3?) and cyclin-dependent kinase 5 (CDK5) are tau kinases and have been proposed to contribute to the pathogenesis of Alzheimer's disease. The 3D structures of these kinases are remarkably similar, which led us to hypothesize that both might be capable of binding cyclin proteins--the activating cofactors ...
of all CDKs. CDK5 is normally activated by the cyclin-like proteins p35 and p39. By contrast, we show that GSK3? does not bind to p35 but unexpectedly binds to p25, the calpain cleavage product of p35. Indeed, overexpressed GSK3? outcompetes CDK5 for p25, whereas CDK5 is the preferred p35 partner. FRET analysis reveals nanometer apposition of GSK3?:p25 in cell soma as well as in synaptic regions. Interaction with p25 also alters GSK3? substrate specificity. The GSK3?:p25 interaction leads to enhanced phosphorylation of tau, but decreased phosphorylation of ?-catenin. A partial explanation for this situation comes from in silico modeling, which predicts that the docking site for p25 on GSK3? is the AXIN-binding domain; because of this, p25 inhibits the formation of the GSK3?/AXIN/APC destruction complex, thus preventing GSK3? from binding to and phosphorylating ?-catenin. Coexpression of GSK3? and p25 in cultured neurons results in a neurodegeneration phenotype that exceeds that observed with CDK5 and p25. When p25 is transfected alone, the resulting neuronal damage is blocked more effectively with a specific siRNA against Gsk3? than with one against Cdk5. We propose that the effects of p25, although normally attributed to activate CDK5, may be mediated in part by elevated GSK3? activity.
Mesh Terms:
Adenomatous Polyposis Coli Protein, Animals, Axin Protein, Cyclin-Dependent Kinase 5, Enzyme Activation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Mice, Mice, Knockout, Multiprotein Complexes, Neurodegenerative Diseases, Neurons, Phosphorylation, Phosphotransferases, Protein Binding, beta Catenin
Proc. Natl. Acad. Sci. U.S.A.
Date: Nov. 11, 2014
Download Curated Data For This Publication
Switch View:
  • Interactions 8