ArticleProceedings of the National Academy of Sciences of the United States of America2014
CDK5 activator protein p25 preferentially binds and activates GSK3β.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 40 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 75 citations in OpenAlex.
- Pooled it
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Pathological Calcium Signaling in Traumatic Brain Injury and Alzheimer's Disease: From Acute Neuronal Injury to Chronic Neurodegeneration.International journal of molecular sciences · 2025Review
- Dysregulated calcium signaling in the aged primate association cortices: vulnerability to Alzheimer's disease neuropathology.Frontiers in aging neuroscience · 2025Review
- Cyclin-dependent Kinase 5 and Neurodegenerative Diseases.Molecular neurobiology · 2024Review
- GSK3: A potential target and pending issues for treatment of Alzheimer's disease.CNS neuroscience & therapeutics · 2024Review
- Calcium-binding protein 7 expressed in muscle negatively regulates age-related degeneration of neuromuscular junctions in mice.iScience · 2024Article
- Palmitoyl-L-carnitine induces tau phosphorylation and mitochondrial dysfunction in neuronal cells.PloS one · 2024Article
- Tumor-suppressive microRNA-152 inhibits the proliferation of Ewing's sarcoma cells by targeting CDK5R1.Scientific reports · 2023Article
- Involvement of Glycogen Synthase Kinase 3β (GSK3β) in Formation of Phosphorylated Tau and Death of Retinal Ganglion Cells of Rats Caused by Optic Nerve Crush.Current issues in molecular biology · 2023Article
- N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection.Molecular & cellular proteomics : MCP · 2023Article
- Small Extracellular Vesicles' miRNAs: Biomarkers and Therapeutics for Neurodegenerative Diseases.Pharmaceutics · 2023Review
- Three decades of Cdk5.Journal of biomedical science · 2021Review
- Alzheimer's Disease: A Molecular View of β-Amyloid Induced Morbific Events.Biomedicines · 2021Review
- Pseudoginsenoside-F11 attenuates cognitive dysfunction and tau phosphorylation in sporadic Alzheimer's disease rat model.Acta pharmacologica Sinica · 2021Article
- Low-Density Lipoprotein Receptor-Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Article
- Multi-Target Directed Ligands (MTDLs) Binding the σInternational journal of molecular sciences · 2021Review
- When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer's and Huntington's Disease.International journal of molecular sciences · 2021Review
- Interacting Models of Amyloid-β and Tau Proteins: An Approach to Identify Drug Targets in Alzheimer's Disease.Journal of Alzheimer's disease reports · 2021Review
- Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer's Disease.Cell reports · 2020Article
Corrections and comments
- Erratum issued
Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
Glycogen synthase kinase 3β (GSK3β) 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 GSK3β does not bind to p35 but unexpectedly binds to p25, the calpain cleavage product of p35. Indeed, overexpressed GSK3β outcompetes CDK5 for p25, whereas CDK5 is the preferred p35 partner. FRET analysis reveals nanometer apposition of GSK3β:p25 in cell soma as well as in synaptic regions. Interaction with p25 also alters GSK3β substrate specificity. The GSK3β:p25 interaction leads to enhanced phosphorylation of tau, but decreased phosphorylation of β-catenin. A partial explanation for this situation comes from in silico modeling, which predicts that the docking site for p25 on GSK3β is the AXIN-binding domain; because of this, p25 inhibits the formation of the GSK3β/AXIN/APC destruction complex, thus preventing GSK3β from binding to and phosphorylating β-catenin. Coexpression of GSK3β 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 Gsk3β 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 GSK3β activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.