| GSK-3β (Glycogen Synthase Kinase-3 Beta) | |
|---|---|
| Gene | [GSK3B](/genes/gsk3b) |
| UniProt ID | [P49841](https://www.uniprot.org/uniprot/P49841) |
| PDB | 1PYX, 2OW3, 4J7B, 5HLN |
| Molecular Weight | 46.7 kDa |
| Localization | Cytoplasm, nucleus, mitochondria |
| Family | CMGC kinase family, GSK-3 subfamily |
| Disease | AD, PD, BD, Diabetes |
Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase originally identified for its role in glycogen metabolism. It has since emerged as a central signaling hub that phosphorylates over 100 substrates, making it one of the most promiscuous kinases in the human proteome. GSK-3β is a key tau kinase in Alzheimer's disease and is implicated in Parkinson's disease, bipolar disorder, and cancer.
GSK-3β has a typical kinase domain architecture:
Key regulatory features:
GSK-3β regulates multiple cellular pathways[1]:
GSK-3β is constitutively active and inhibited by upstream signals (insulin, growth factors).
GSK-3β is a major tau kinase, phosphorylating ~40 tau sites[2]:
Key tau sites phosphorylated by GSK-3β:
Mechanisms of tau hyperphosphorylation:
Consequences of tau hyperphosphorylation:
GSK-3β contributes to PD through:
GSK-3β is a therapeutic target for mood disorders:
GSK-3β inhibition is a major therapeutic strategy:
| Agent | Mechanism | Status |
|---|---|---|
| Lithium | Competitive (Mg²⁺), indirect (AKT) | FDA approved (BD) |
| Tideglusib | Irreversible inhibitor | Phase II (AD, PSP - failed) |
| LY2090314 | ATP-competitive | Phase II (cancer) |
| 9-ING-41 | ATP-competitive | Phase I/II (cancer) |
| Kenpaullone | ATP-competitive | Preclinical |
Challenges with GSK-3β inhibitors:
Jope and Yuskaitis. GSK-3: A central hub of signaling pathways. Neuropsychopharmacology. 2007. ↩︎
Hanger et al. Tau phosphorylation: the therapeutic challenge for AD. Trends Mol Med. 2009. ↩︎
Dill et al. GSK-3β in Parkinson's disease. Neurochem Res. 2019. ↩︎
Lovestone et al. GSK-3 inhibitors for AD. J Nutr Health Aging. 2010. ↩︎