Affinage

GSK3B

Glycogen synthase kinase-3 beta · UniProt P49841

Length
420 aa
Mass
46.7 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GSK3B is a constitutively active serine/threonine kinase whose output across diverse cellular programs is gated by inhibitory Ser9 phosphorylation downstream of PI3K/AKT signaling (PMID:23514933, PMID:24033914) and by activating Tyr216 phosphorylation that drives its metabolic activity (PMID:37146915). A recurring theme is that active GSK3B phosphorylates target proteins to mark them for ubiquitin-dependent degradation: it phosphorylates MCL1 to trigger FBXW7-mediated degradation that releases BECLIN1 and initiates axonal autophagy (PMID:28053206), phosphorylates BCL2 at Ser70 to promote its ubiquitination and relieve BCL2-mediated autophagy suppression (PMID:23514933), and phosphorylates TRAF6 at Thr266 to drive its K48-linked polyubiquitination (PMID:30806153); it also directly phosphorylates and activates ULK1 at S405/S415 to facilitate ULK1 binding to MAP1LC3B/GABARAPL1 and induce autophagy flux (PMID:33654220). In the nervous system, GSK3B acts downstream of the ZNRF1-AKT axis to phosphorylate CRMP2 and drive the microtubule reorganization of Wallerian degeneration (PMID:22057101), and in vitro it phosphorylates tau at S199/T205/T231/S396/S404 to promote coalescence into neurofibrillary tangle-like structures (PMID:18588978). GSK3B also functions in the nucleus: it phosphorylates 53BP1 at Thr334 to disrupt 53BP1-PTIP/RIF1 NHEJ complexes and instead promote CtIP/RPA32-mediated end resection and homologous recombination, sensitizing tumors to PARP inhibitors (PMID:41243969). Monoallelic de novo loss-of-function variants in GSK3B cause autism spectrum disorder and developmental delay, with knockdown impairing neuronal dendrite arborization and spine maturation that patient missense variants fail to rescue (PMID:39472663). Its activity is further modulated by lithium, which both directly inhibits the kinase and reduces Gsk3b mRNA in hippocampal neurons (PMID:18932008), and by a PREP-PP2A axis controlling its phosphorylation state (PMID:34196102).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2005 Medium

    Established that genetic variation at the GSK3B locus alters splicing and transcription and is linked to tau phosphorylation, connecting GSK3B regulation to neurodegenerative biochemistry.

    Evidence in vitro splicing and transcriptional reporter assays with lymphocyte and brain tissue validation of SNP effects on phospho-Tau

    PMID:16315267

    Open questions at the time
    • does not establish causal disease mechanism in vivo
    • isoform-specific kinase activity not measured directly
  2. 2008 High

    Demonstrated biochemically that GSK3B phosphorylation of tau drives filament coalescence into tangle-like structures, providing a direct molecular route from kinase activity to neurofibrillary pathology.

    Evidence cell-free tau polymerization with site-specific phosphorylation mapping and EM/optical characterization

    PMID:18588978

    Open questions at the time
    • in vitro reconstitution only
    • does not address tangle formation in living neurons
  3. 2011 High

    Placed GSK3B within the ZNRF1-AKT axonal degeneration pathway, showing active GSK3B phosphorylates CRMP2 to drive microtubule reorganization required for Wallerian degeneration.

    Evidence reciprocal genetic epistasis (E3 ligase, AKT, GSK3B, CRMP2) with in vivo degeneration assay

    PMID:22057101

    Open questions at the time
    • direct GSK3B-CRMP2 kinase reaction not isolated from pathway readout
    • site mapping on CRMP2 not detailed
  4. 2013 Medium

    Defined GSK3B as a node coupling PI3K/AKT input to autophagy and cell-death decisions via BCL2 phosphorylation and as a determinant of drug resistance in p53-null cancer cells.

    Evidence Co-IP and ubiquitination assays for GSK3B-BCL2; shRNA screen plus inhibitors and xenografts for necroptosis sensitization

    PMID:23514933 PMID:23729362 PMID:24033914

    Open questions at the time
    • BCL2 Ser70 phosphorylation pathway from single lab
    • necroptosis mechanism downstream of GSK3B not fully resolved
  5. 2017 High

    Showed GSK3B initiates axonal autophagy by phosphorylating MCL1 for FBXW7-mediated degradation, linking the kinase to BECLIN1 release and phagocyte recruitment in vivo.

    Evidence phospho-MCL1 detection, ubiquitination assays, KD/OE and in vivo phagocyte recruitment

    PMID:28053206

    Open questions at the time
    • MCL1 phosphosite not enumerated here
    • generalizability beyond axonal context untested
  6. 2019 Medium

    Extended the GSK3B-to-ubiquitination paradigm to TRAF6, identifying Thr266 phosphorylation as the trigger for K48 degradation that promotes colorectal cancer metastasis.

    Evidence Co-IP, phosphosite mapping, K48-ubiquitination assays, GSK3B inhibition

    PMID:30806153

    Open questions at the time
    • single lab
    • direct kinase assay on TRAF6 not described
  7. 2021 High

    Revealed GSK3B as a positive regulator of autophagy initiation by directly phosphorylating and activating ULK1 at S405/S415, and identified splicing-mediated GSK3B suppression as a route to TFEB-driven lysosomal biogenesis.

    Evidence Co-IP, S405A/S415A mutagenesis, in vitro kinase and autophagy flux assays; eIF4A3 knockdown with GSK3B splicing and TFEB localization analysis

    PMID:33654220 PMID:34158631

    Open questions at the time
    • ULK1 work from single lab
    • reconciliation of pro- vs anti-autophagy roles across contexts not addressed
  8. 2024 Medium

    Established GSK3B haploinsufficiency as a cause of human neurodevelopmental disorder, with loss-of-function impairing dendrite and spine maturation, providing a definitive in vivo functional role.

    Evidence human sequencing cohort, neuronal shRNA knockdown with morphology quantification and failed rescue by patient missense variants

    PMID:39472663

    Open questions at the time
    • substrates mediating neurodevelopmental phenotype not identified
    • single study
  9. 2025 High

    Identified a nuclear DNA-repair function: GSK3B phosphorylation of 53BP1 at T334 switches double-strand break repair from NHEJ toward homologous recombination, with therapeutic PARP-inhibitor implications.

    Evidence in vitro kinase assay, T334A mutagenesis, Co-IPs with PTIP/RIF1 and CtIP/RPA32, HR/NHEJ reporters, PARPi sensitivity

    PMID:41243969

    Open questions at the time
    • how GSK3B is recruited to or activated at DSBs unknown
    • single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GSK3B's many context-specific outputs (axonal degeneration, autophagy, DNA repair, neurodevelopment, metabolism) are selected within a single cell, and what governs its subcellular partitioning, remains unresolved.
  • no unified model of substrate selection
  • regulation of nuclear vs cytoplasmic GSK3B activity not defined
  • in vivo substrate hierarchy untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 4 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 1 R-HSA-73894 DNA Repair 1
Partners
53BP1BCL2CRMP2DNMT1MCL1TFR1TRAF6ULK1

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 ZNRF1, an E3 ubiquitin ligase, promotes Wallerian degeneration by targeting AKT for proteasomal degradation; AKT normally phosphorylates and inactivates GSK3B in axons. When AKT is degraded, active GSK3B phosphorylates CRMP2, which drives microtubule reorganization required for axonal degeneration. Overexpression of active (non-phosphorylated) GSK3B induced CRMP2 phosphorylation and degeneration; inhibition of GSK3B or overexpression of non-phosphorylatable CRMP2 protected axons. E3 ligase overexpression/knockdown, AKT overexpression, active GSK3B overexpression, GSK3B inhibition, in vivo Wallerian degeneration assay, genetic epistasis Nature cell biology High 22057101
2017 GSK3B-mediated phosphorylation of MCL1 triggers its ubiquitination by the FBXW7 ubiquitin ligase and subsequent proteasomal degradation. Degradation of MCL1 releases BECLIN1 to induce axonal autophagy. This axonal autophagy contributes to local ATP production in degenerating axons, promotes phosphatidylserine ('eat-me' signal) exposure on transected axons, and is required for phagocyte recruitment to axonal debris in vivo. GSK3B overexpression/knockdown, phospho-MCL1 detection, ubiquitination assays, BECLIN1 release assay, in vivo phagocyte recruitment assay, phosphatidylserine exposure measurement The Journal of cell biology High 28053206
2021 GSK3B directly interacts with and phosphorylates ULK1 at S405 and S415 within the GABARAP-interacting region following insulin withdrawal, activating ULK1. This phosphorylation facilitates ULK1 interaction with MAP1LC3B and GABARAPL1, thereby inducing autophagy flux. Phosphorylation-defective ULK1 mutants (S405A/S415A) failed to bind these autophagy proteins and failed to induce autophagy. Co-immunoprecipitation (GSK3B-ULK1 interaction), site-directed mutagenesis (S405A/S415A), in vitro phosphorylation assay, autophagy flux assay, interaction with MAP1LC3B/GABARAPL1 Experimental & molecular medicine High 33654220
2013 IL-17A activates PI3K, which phosphorylates GSK3B at Ser9 (inactivating it), thereby attenuating GSK3B-BCL2 interaction. Loss of this interaction prevents GSK3B-mediated phosphorylation of BCL2 at Ser70 that would otherwise trigger BCL2 ubiquitination and degradation. Stabilized BCL2 then promotes BCL2-BECN1 interaction and suppresses autophagy in lung epithelial cells. PI3K inhibition, GSK3B phosphorylation (Ser9) detection, co-immunoprecipitation (GSK3B-BCL2, BCL2-BECN1), BCL2 ubiquitination assay, autophagy measurement Autophagy Medium 23514933
2019 GSK3B phosphorylates TRAF6 at Thr266, which triggers K48-linked polyubiquitination and proteasomal degradation of TRAF6, thereby attenuating TRAF6-driven selective autophagic degradation of CTNNB1/β-catenin and promoting colorectal cancer metastasis. Co-immunoprecipitation, site-specific phosphorylation mapping (Thr266), ubiquitination assays (K48-linked), pharmacological GSK3B inhibition, TRAF6 protein stability assays Autophagy Medium 30806153
2013 Silencing of GSK3B in p53-null colon carcinoma cells enables necroptosis (PARP1-dependent, AIF-mediated, RIP1-independent cell death) in response to 5-fluorouracil, bypassing apoptosis resistance. In vivo, GSK3B inhibition combined with 5-FU significantly reduced drug-resistant xenograft tumor mass. shRNA kinase library screen, siRNA knockdown, GSK3B inhibitors, cell viability and colony assays, AIF/PARP1/caspase mechanistic profiling, in vivo xenograft studies Clinical cancer research Medium 23729362
2008 GSK3beta phosphorylation of pre-assembled tau filaments at S199, T205, T231, S396, and S404 promotes coalescence of tau filaments into large neurofibrillary tangle-like structures in a cell-free in vitro system. Phosphorylation of tau prior to or following polymerization drives polymer-polymer interactions resulting in stable clusters. In vitro cell-free tau polymerization assay (arachidonic acid), GSK3beta phosphorylation, phosphorylation site mapping by mass spectrometry/antibody, optical and electron microscopy of tangle-like structures Neurobiology of disease High 18588978
2005 An intronic GSK3B SNP (rs6438552) regulates alternative splicing, with the T allele associated with altered splice site selection producing transcripts lacking exons 9 and 11 (GSKΔexon9+11). Increased levels of this isoform correlate with enhanced phosphorylation of Tau. A promoter SNP (rs334558) T allele shows greater transcriptional activity in vitro. In vitro splicing assay, in vitro transcriptional reporter assay, lymphocyte splicing analysis, Western blot for phospho-Tau, brain tissue analysis Annals of neurology Medium 16315267
2025 GSK3B phosphorylates 53BP1 at threonine 334 (T334), a site distinct from canonical ATM targets. This phosphorylation disrupts 53BP1 interaction with NHEJ effectors PTIP and RIF1, inhibiting 53BP1-driven non-homologous end joining. Simultaneously, T334 phosphorylation facilitates recruitment of CtIP and RPA32 for DNA end resection and promotes homologous recombination by enabling BRCA1 and RAD51 loading. The phospho-deficient T334A 53BP1 mutant accumulates aberrantly at DSBs with PTIP/RIF1, impairs end resection, and suppresses HR. Disruption of GSK3B-53BP1 axis sensitizes tumors to PARP inhibitors independently of BRCA1 status. In vitro kinase assay (phosphorylation of 53BP1-T334), site-directed mutagenesis (T334A), co-immunoprecipitation (53BP1-PTIP/RIF1, 53BP1-CtIP/RPA32), HR and NHEJ reporter assays, genetic and pharmacologic GSK3B inhibition, PARP inhibitor sensitivity assays The Journal of clinical investigation High 41243969
2015 Combined pharmacological inhibition of DYRK1A and GSK3B with aminopyrazine compounds stimulates robust human β-cell proliferation in adult primary islets. Treated islets retain functionality in vitro and after transplantation into diabetic mice. In vivo oral dosing increases β-cell mass, insulin content, and improves glycemic control. Biochemical and genetic data identify DYRK1A as the key molecular target. Primary human islet culture, pharmacological inhibition, genetic target validation (biochemical/cell biology), in vivo transplantation, diabetic mouse model, oral dosing studies Nature communications Medium 26496802
2018 GSK3B depletion in Mecp2-knockout mice reduces nuclear activity of the NF-κB1 pathway, rescues dendritic networks and spine density, improves excitatory synapse properties, reduces neuroinflammation, and prolongs lifespan. This places GSK3B upstream of NF-κB1 in the Rett syndrome pathomechanism. GSK3B-specific inhibitor SB216763 in vivo, Mecp2-KO mouse model, dendritic morphology and spine density quantification, synapse electrophysiology, NF-κB1 nuclear activity assay, neuroinflammation markers, lifespan analysis Cell reports Medium 29742424
2018 Conditional knockout of GSK3B in mature oligodendrocytes protects them from caspase-dependent (but not caspase-independent) apoptosis during cuprizone-induced demyelination. Active GSK3B is present in oligodendrocyte nuclei at the peak of caspase-dependent apoptosis, and its depletion promotes oligodendrocyte survival and attenuates myelin loss. Inducible conditional KO of GSK3B in mature oligodendrocytes, cuprizone demyelination model, caspase activation assays, nuclear localization of active GSK3B by fractionation/immunostaining, myelin preservation quantification Glia Medium 29761559
2021 eIF4A3 depletion leads to an exon-skipping event in the GSK3B transcript, reducing GSK3B expression and activity, which causes TFEB dephosphorylation and nuclear translocation, driving transcriptional activation of autophagy and lysosome biogenesis genes. eIF4A3 siRNA knockdown, alternative splicing analysis of GSK3B mRNA, GSK3B activity measurement, TFEB phosphorylation and nuclear translocation assay, autophagy/lysosome biogenesis quantification Cell death and differentiation Medium 34158631
2022 GSK3B recruits DNMT1 to the NR4A3 promoter region to promote hypermethylation and transcriptional silencing of NR4A3, thereby inhibiting the NR4A3-mediated JAK2/STAT3 signaling pathway and alleviating posttraumatic osteoarthritis chondrocyte apoptosis and extracellular matrix degradation. Co-immunoprecipitation (GSK3B-DNMT1 interaction), ChIP assay, methylation-specific PCR, GSK3B overexpression/knockdown, NR4A3 rescue experiments, in vivo DMM mouse model with adeno-associated virus delivery Disease markers Medium 35747513
2021 Lithium inhibits GSK3B activity (via Ser9 phosphorylation) and also specifically reduces Gsk3b mRNA levels in hippocampal (but not cortical) neurons in a dose-dependent manner both in vitro and in vivo, indicating a transcriptional regulatory mechanism beyond direct kinase inhibition. Quantitative PCR in primary hippocampal and cortical neuron cultures, in vivo lithium treatment of rats with brain region-specific analysis and peripheral leukocyte measurement European archives of psychiatry and clinical neuroscience Medium 18932008
2013 Insulin and IGF1 activate Akt, which phosphorylates GSK3B at Ser9, thereby inhibiting GSK3B activity. This inhibition enhances IL-17-induced expression of chemokines Cxcl1 and Ccl20 in a GSK3B-dependent manner (the effect was absent in Gsk3b-/- MEF cells). Melatonin counteracts this by inhibiting Akt activation, thus restoring GSK3B activity and suppressing chemokine expression. Gsk3b-/- and wild-type MEF cells, pharmacological Akt activation/inhibition, IL-17 stimulation, Ser9 phosphorylation of GSK3B, Cxcl1/Ccl20 mRNA measurement, in vivo mouse prostate and xenograft tumor validation Journal of pineal research Medium 24033914
2023 GSK3B phosphorylation at Tyr216 (active form) promotes glucose intolerance and impairs insulin sensitivity; inhibition of this phosphorylation (GSK3B-Y216F vs Y216E in HepG2 and NCTC-1469 cells) significantly reduces lipid deposition and increases glycogen synthesis, establishing Tyr216 phosphorylation as a regulatory mechanism for GSK3B activity in glucose and lipid metabolism. Phosphoproteomic mass spectrometry analysis, GSK3B-Y216F and Y216E plasmid transfection, enzyme activity analysis, glucose/insulin level measurement, cell staining for glycogen and lipid Biochimica et biophysica acta. Molecular basis of disease Medium 37146915
2021 Deletion or inhibition of prolyl oligopeptidase (PREP) blocks lithium-induced phosphorylation of GSK3B and Akt. This PREP-related effect is dependent on protein phosphatase 2A (PP2A): pharmacological inhibition of PP2A with okadaic acid abrogated the effect of PREP inhibitor on lithium-induced GSK3B phosphorylation. Thus PREP regulates GSK3B phosphorylation status via PP2A. PREP knockout cells, PREP inhibitor (KYP-2047), lithium treatment, Western blot for phospho-GSK3B and phospho-Akt, PP2A inhibitor (okadaic acid) epistasis experiment in HEK-293 and SH-SY5Y cells Basic & clinical pharmacology & toxicology Medium 34196102
2015 GLP1 protects cardiomyocytes from palmitate-induced apoptosis via the GLP1R/Akt/GSK3b/β-catenin signaling axis. GLP1 restored phosphorylation of Akt and GSK3b reduced by palmitate; inhibition of Akt (MK2206) or GLP1R blockade (exendin-(9-39)) abolished GLP1-mediated GSK3b/β-catenin activation and increased apoptosis. β-catenin silencing blocked anti-apoptotic effects of GLP1. Neonatal rat cardiomyocyte culture, GLP1 treatment, Akt inhibitor MK2206, GLP1R antagonist exendin-(9-39), β-catenin shRNA knockdown, phospho-Akt and phospho-GSK3b Western blot, apoptosis assays Journal of molecular endocrinology Medium 26386043
2024 TFR1 (transferrin receptor) interacts with GSK3B and promotes GSK3B expression. TFR1 knockdown reduced GSK3B expression and ameliorated iron overload and mitochondrial dysfunction in neural cells differentiated from AD iPSCs; GSK3B overexpression reversed the protective effects of TFR1 knockdown, confirming TFR1 acts upstream of GSK3B in this pathway. Co-immunoprecipitation (TFR1-GSK3B interaction), TFR1 knockdown/overexpression, GSK3B overexpression rescue, iron/ROS measurement, mitochondrial function assays in AD-iPSC-derived neurons European journal of medical research Medium 38321571
2020 YBX1 binds to the GSK3B gene promoter (established by dual-luciferase reporter and ChIP assays) and drives GSK3B expression, which in turn regulates cyclin D1 and cyclin E1 levels to promote pancreatic cancer cell-cycle progression and proliferation. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) for YBX1 at GSK3B promoter, YBX1 overexpression/knockdown, Western blot for GSK3B/cyclin D1/E1 Molecular therapy oncolytics Medium 32300640
2019 NGL-3 knockout mice show abnormally enhanced Akt/GSK3β signaling, with GSK3β activity being suppressed. Long-term depression (LTD) is near-completely abolished in Ngl3-/- mice. Pharmacological inhibition of Akt (but not NMDAR activation) normalized the suppressed LTD, demonstrating that Akt hyperactivity and consequent GSK3β suppression is the mechanism underlying deficient LTD in these mice. Ngl3-/- genetic mouse model, Akt/GSK3β phosphorylation Western blot, LTD electrophysiology, pharmacological Akt inhibition epistasis, NMDAR pharmacology PLoS biology Medium 31166939
2024 GSK3B loss-of-function (monoallelic de novo variants) causes autism spectrum disorder and developmental delay. Gsk3b knockdown in mouse excitatory neurons impairs dendrite arborization and spine maturation, and these defects could not be rescued by de novo missense variants identified from affected individuals, confirming pathogenicity. Single-cell transcriptomic data show GSK3B is enriched in dorsal progenitors and intermediate excitatory neurons in the developing brain. Human genomic sequencing cohort analysis, Gsk3b shRNA knockdown in mouse neurons, dendrite/spine morphology quantification, variant rescue experiments, single-cell transcriptomics Molecular psychiatry Medium 39472663
2012 GSK3b inhibition by lithium chloride (LiCl) activates Wnt canonical signaling (measured by luciferase reporter) and enhances osteoblast differentiation markers (osteocalcin, osteoprotegerin) in mesenchymal and osteoblastic cells, specifically on hydrophilic titanium surfaces (modSLA). This effect was demonstrated in C2C12, MC3T3, and primary bone marrow cells. Luciferase-based Wnt canonical signaling reporter assay, real-time PCR for Wnt target and osteoblastic genes, LiCl pharmacological GSK3b inhibition, comparison across titanium surface types Clinical oral implants research Low 22626030
2024 GSK3B activates the 5-LOX/11-HETE pathway: GSK3B inhibition (by Didymin or the specific inhibitor LY2090314) reduces 5-LOX expression and 11-HETE generation, thereby suppressing lipid peroxidation and ferroptosis in chondrocytes. GSK3B is identified as an upstream regulator of 5-LOX-driven arachidonic acid metabolism in osteoarthritis. Metabolomics, network pharmacology, surface plasmon resonance (direct binding validation), co-immunoprecipitation, GSK3B inhibition (LY2090314 and Didymin), 5-LOX expression/activity, 11-HETE measurement, in vivo KOA rat model Phytomedicine Low 41539091
2017 After partial hepatectomy, hepatic AKT and GSK3B phosphorylation (active forms) are downregulated while FOXO3 protein levels increase, activating the GSK3B-FOXO3 pathway. This activation is proposed to upregulate hepatic IGF1R expression and promote liver regeneration. Mouse partial hepatectomy model, Western blot for phospho-AKT, phospho-GSK3B, FOXO3, hepatic IGF1R immunohistochemistry and Western blot, hepatosomatic index Journal of biological regulators and homeostatic agents Low 28952285

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 GSK3B polymorphisms alter transcription and splicing in Parkinson's disease. Annals of neurology 183 16315267
2017 Neurons derived from sporadic Alzheimer's disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimer's research & therapy 174 29191219
2015 Inhibition of DYRK1A and GSK3B induces human β-cell proliferation. Nature communications 170 26496802
2011 ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nature cell biology 132 22057101
2019 TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/β-catenin degradation and is targeted for GSK3B/GSK3β-mediated phosphorylation and degradation. Autophagy 119 30806153
2010 Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer's disease. Journal of psychiatric research 86 20576277
2008 Lithium reduces Gsk3b mRNA levels: implications for Alzheimer Disease. European archives of psychiatry and clinical neuroscience 82 18932008
2013 Interleukin 17A inhibits autophagy through activation of PIK3CA to interrupt the GSK3B-mediated degradation of BCL2 in lung epithelial cells. Autophagy 80 23514933
2013 Inhibition of GSK3B bypass drug resistance of p53-null colon carcinomas by enabling necroptosis in response to chemotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research 79 23729362
2008 Association of GSK3B with Alzheimer disease and frontotemporal dementia. Archives of neurology 78 18852354
2018 An Inhibitor of GSK3B and HDACs Kills Pancreatic Cancer Cells and Slows Pancreatic Tumor Growth and Metastasis in Mice. Gastroenterology 75 30144430
2012 GSK3b-inhibitor lithium chloride enhances activation of Wnt canonical signaling and osteoblast differentiation on hydrophilic titanium surfaces. Clinical oral implants research 70 22626030
2015 GLP1 protects cardiomyocytes from palmitate-induced apoptosis via Akt/GSK3b/b-catenin pathway. Journal of molecular endocrinology 64 26386043
2017 GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration. The Journal of cell biology 60 28053206
2021 GSK3B induces autophagy by phosphorylating ULK1. Experimental & molecular medicine 56 33654220
2018 Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice. Cell reports 49 29742424
2013 Insulin and IGF1 enhance IL-17-induced chemokine expression through a GSK3B-dependent mechanism: a new target for melatonin's anti-inflammatory action. Journal of pineal research 49 24033914
2013 Notch3 inhibition enhances sorafenib cytotoxic efficacy by promoting GSK3b phosphorylation and p21 down-regulation in hepatocellular carcinoma. Oncotarget 48 24113128
2016 MiR-769 promoted cell proliferation in human melanoma by suppressing GSK3B expression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 46 27470346
2013 The role of CDK5 and GSK3B kinases in hyperphosphorylation of microtubule associated protein tau (MAPT) in Alzheimer's disease. Bioinformation 44 24497730
2009 Genetic association of the interaction between the BDNF and GSK3B genes and major depressive disorder in a Chinese population. Journal of neural transmission (Vienna, Austria : 1996) 43 20033742
2018 Increased expression of lncRNA FTH1P3 promotes oral squamous cell carcinoma cells migration and invasion by enhancing PI3K/Akt/GSK3b/ Wnt/β-catenin signaling. European review for medical and pharmacological sciences 37 30556871
2010 The combined effects of the BDNF and GSK3B genes modulate the relationship between negative life events and major depressive disorder. Brain research 37 20682308
2015 The GSK3B gene confers risk for both major depressive disorder and schizophrenia in the Han Chinese population. Journal of affective disorders 35 26186530
2012 Expression profiling of stem cell-related genes in neoadjuvant-treated gastric cancer: a NOTCH2, GSK3B and β-catenin gene signature predicts survival. PloS one 35 22970250
2010 SNCA, MAPT, and GSK3B in Parkinson disease: a gene-gene interaction study. European journal of neurology 35 21159074
2015 Genetic variants of GSK3B are associated with biomarkers for Alzheimer's disease and cognitive function. Journal of Alzheimer's disease : JAD 34 25420549
2011 Platelet GSK3B activity in patients with late-life depression: marker of depressive episode severity and cognitive impairment? The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 34 21314327
2020 PTML Modeling for Alzheimer's Disease: Design and Prediction of Virtual Multi-Target Inhibitors of GSK3B, HDAC1, and HDAC6. Current topics in medicinal chemistry 29 32515311
2014 GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis. PloS one 27 24984063
2014 Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling. Journal of neuro-oncology 27 25344882
2023 Inhibition of GSK3B phosphorylation improves glucose and lipid metabolism disorder. Biochimica et biophysica acta. Molecular basis of disease 26 37146915
2020 Overexpression of YBX1 Promotes Pancreatic Ductal Adenocarcinoma Growth via the GSK3B/Cyclin D1/Cyclin E1 Pathway. Molecular therapy oncolytics 26 32300640
2014 Paclitaxel-induced neuropathy: potential association of MAPT and GSK3B genotypes. BMC cancer 26 25535399
2011 Association analysis of GSK3B and MAPT polymorphisms with Alzheimer's disease in Han Chinese. Brain research 25 21443865
2021 eIF4A3 regulates the TFEB-mediated transcriptional response via GSK3B to control autophagy. Cell death and differentiation 22 34158631
2020 Network Pharmacology and Experimental Evidence Reveal Dioscin Suppresses Proliferation, Invasion, and EMT via AKT/GSK3b/mTOR Signaling in Lung Adenocarcinoma. Drug design, development and therapy 22 32546976
2008 Pre-assembled tau filaments phosphorylated by GSK-3b form large tangle-like structures. Neurobiology of disease 22 18588978
2021 Adenosine and Cordycepin Accelerate Tissue Remodeling Process through Adenosine Receptor Mediated Wnt/β-Catenin Pathway Stimulation by Regulating GSK3b Activity. International journal of molecular sciences 21 34070360
2022 Circ-GSK3B up-regulates GSK3B to suppress the progression of lung adenocarcinoma. Cancer gene therapy 18 35821283
2019 miR-1185-1 and miR-548q Are Biomarkers of Response to Weight Loss and Regulate the Expression of GSK3B. Cells 18 31801236
2018 Conditional depletion of GSK3b protects oligodendrocytes from apoptosis and lessens demyelination in the acute cuprizone model. Glia 18 29761559
2024 TFR1 knockdown alleviates iron overload and mitochondrial dysfunction during neural differentiation of Alzheimer's disease-derived induced pluripotent stem cells by interacting with GSK3B. European journal of medical research 17 38321571
2017 The interaction of GSK3B and FXR1 genotypes may influence the mania and depression dimensions in mood disorders. Journal of affective disorders 17 28242499
2005 No association of GSK3beta gene (GSK3B) with Japanese schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 17 15719395
2022 MicroRNA-214-3p facilitates M2 macrophage polarization by targeting GSK3B. The Kaohsiung journal of medical sciences 16 35005835
2020 Dual targeting of GSK3B and HDACs reduces tumor growth and improves survival in an ovarian cancer mouse model. Gynecologic oncology 16 32698955
2015 Increased iPLA2 activity and levels of phosphorylated GSK3B in platelets are associated with donepezil treatment in Alzheimer's disease patients. European archives of psychiatry and clinical neuroscience 16 25920742
2023 The Impact of BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 Genetic Polymorphisms in Antidepressant Treatment Response Phenotypes. International journal of molecular sciences 15 37047730
2019 NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors. PLoS biology 15 31166939
2017 The interaction of NOS1AP, DISC1, DAOA, and GSK3B confers susceptibility of early-onset schizophrenia in Chinese Han population. Progress in neuro-psychopharmacology & biological psychiatry 15 29100974
2024 Ambient particulate matter exposure induces ferroptosis in hippocampal cells through the GSK3B/Nrf2/GPX4 pathway. Free radical biology & medicine 14 38290604
2018 The functional variant rs334558 of GSK3B is associated with remission in patients with depressive disorders. Pharmacogenomics and personalized medicine 14 30050316
2021 Downregulation of GSK3B by miR-132-3p Enhances Etoposide-Induced Breast Cancer Cell Apoptosis. Annals of clinical and laboratory science 13 34162557
2015 Exploring Genetic Variability at PI, GSK3, HPA, and Glutamatergic Pathways in Lithium Response: Association With IMPA2, INPP1, and GSK3B Genes. Journal of clinical psychopharmacology 13 26267417
2010 Role of tau kinases (CDK5R1 and GSK3B) in Parkinson's disease: a study from India. Neurobiology of aging 13 21130530
2021 Essential meiotic structure-specific endonuclease1 (EME1) promotes malignant features in gastric cancer cells via the Akt/GSK3B/CCND1 pathway. Bioengineered 12 34719326
2010 Association study of the GSK-3B gene with tardive dyskinesia in European Caucasians. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 12 20605420
2020 miR-155-5p regulates mesenchymal stem cell osteogenesis and proliferation by targeting GSK3B in steroid-associated osteonecrosis. Cell biology international 11 32991030
2005 Infrequent mutation of APC, AXIN1, and GSK3B in human pituitary adenomas with abnormal accumulation of CTNNB1. Journal of neuro-oncology 11 15981102
2024 GSK3B inhibition reduced cervical cancer cell proliferation and migration by modulating the PI3K/Akt signaling pathway and epithelial-to-mesenchymal transition. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 10 39166606
2021 Lupin protein isolate improves insulin sensitivity and steatohepatitis in vivo and modulates the expression of the Fasn, Gys2, and Gsk3b genes. Food science & nutrition 10 34026071
2019 Molecular docking based screening analysis of GSK3B. Bioinformation 10 31354196
2018 PM2.5 induced cardiac hypertrophy via CREB/GSK3b/SOS1 pathway and metabolomics alterations. Oncotarget 10 30112104
2013 GSK3B and MAPT polymorphisms are associated with grey matter and intracranial volume in healthy individuals. PloS one 10 23951236
2023 The expression analyses of GSK3B, VEGF, ANG1, and ANG2 in human brain microvascular endothelial cells treated with the synthetic cannabinoid XLR-11. Gene 9 37355149
2019 A comprehensive analysis of GSK3B variation for schizophrenia in Han Chinese individuals. Asian journal of psychiatry 9 31665698
2014 MAPT rs242562 and GSK3B rs334558 are associated with Parkinson's Disease in central China. BMC neuroscience 9 24779391
2024 Mesenchymal stem cell-derived small extracellular vesicles restored nasal barrier function in allergic rhinitis via miR-143-GSK3B in human nasal epithelial cells. The Journal of allergy and clinical immunology 8 39542141
2016 GSK-3b participates in the regulation of hepatic lipid deposition in large yellow croaker (Larmichthys crocea). Fish physiology and biochemistry 8 26483261
2023 Selenium alleviates modafinil-induced neurobehavioral toxicity in rat via PI3K/Akt/mTOR/GSK3B signaling pathway and suppression of oxidative stress and apoptosis: in vivo and in silico study. Environmental science and pollution research international 7 38015391
2017 High-frequency electrical stimulation (HFES) data lean and obese Zucker rat tibialis anterior muscle: Regulation of glycogen synthase kinase 3 beta (GSK3B) associated proteins. Data in brief 7 29234702
2014 Meta-analysis demonstrates lack of association of the GSK3B -50C/T polymorphism with risk of bipolar disorder. Molecular biology reports 7 24929537
2024 β-Sitosterol alleviates the malignant phenotype of hepatocellular carcinoma cells via inhibiting GSK3B expression. Human cell 6 38814517
2023 High Throughput FISH Screening Identifies Small Molecules That Modulate Oncogenic lncRNA MALAT1 via GSK3B and hnRNPs. Non-coding RNA 6 36649031
2025 The Shengmai San Exerts Therapeutic Effects on Type 2 Diabetes by Modulating the PI3K/AKT/GSK3B Signaling Pathway. Diabetes, metabolic syndrome and obesity : targets and therapy 5 40191827
2024 Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay. Molecular psychiatry 5 39472663
2022 GSK3B Overexpression Alleviates Posttraumatic Osteoarthritis in Mice by Promoting DNMT1-Mediated Hypermethylation of NR4A3 Promoter. Disease markers 5 35747513
2015 Amiodarone Induces Overexpression of Similar to Versican b to Repress the EGFR/Gsk3b/Snail Signaling Axis during Cardiac Valve Formation of Zebrafish Embryos. PloS one 5 26650936
2024 TRPC6 Knockout Alleviates Renal Fibrosis through PI3K/AKT/GSK3B Pathway. Current medical science 4 38748370
2024 Synergistic Effect between the APOE ε4 Allele with Genetic Variants of GSK3B and MAPT: Differential Profile between Refractory Epilepsy and Alzheimer Disease. International journal of molecular sciences 4 39337715
2021 Deletion or inhibition of prolyl oligopeptidase blocks lithium-induced phosphorylation of GSK3b and Akt by activation of protein phosphatase 2A. Basic & clinical pharmacology & toxicology 4 34196102
2025 LINC00908 Inactivates Wnt/β-Catenin Signaling Pathway to Inhibit Prostate Cancer Cell Stemness via Upregulating GSK3B and FBXW2. Cancer medicine 3 40344383
2024 miR-709 exerts an angiogenic effect through a FGF2 upregulation induced by a GSK3B downregulation. Scientific reports 3 38762650
2023 EPS8L3 promotes pancreatic cancer proliferation and metastasis by activating GSK3B. Journal of medical biochemistry 3 36819133
2019 No evidence so far of a major role of AKT1 and GSK3B in the pathogenesis of antipsychotic-induced tardive dyskinesia. Human psychopharmacology 3 30623492
2017 Study of GSK3b inhibitors SB415286 and SB216763 to improve osteoblastic differentiation on microstructured titanium. Journal of biological regulators and homeostatic agents 2 28952290
2011 [The relationship between glycogen synthase kinase-3 beta (GSK3B) -50T/C -1727A/T polymorphisms and alcoholism]. Nihon Arukoru Yakubutsu Igakkai zasshi = Japanese journal of alcohol studies & drug dependence 2 22413565
2026 Rational design of k-casein peptides to modulate GSK-3B dynamics for Alzheimer's therapy. Scientific reports 1 41803220
2025 Exosomal miR-224-3p promotes lymphangiogenesis and lymph node metastasis by targeting GSK3B in gastric cancer. Oncology research 1 39866224
2025 Case-control study combined with machine learning techniques to identify key genetic variations in GSK3B that affect susceptibility to diabetic kidney diseases. BMC endocrine disorders 1 40474205
2025 GSK3B directs DNA repair choice and determines tumor response to PARP1 inhibition independent of BRCA1. The Journal of clinical investigation 1 41243969
2017 Hepatic insulin-like growth factor receptor is upregulated by activation of the GSK3B-FOXO3 pathway after partial hepatectomy. Journal of biological regulators and homeostatic agents 1 28952285
2011 [Expression of GSK3B gene in peripheral blood in patient with Parkinson's disease]. Molekuliarnaia biologiia 1 21790007
2026 Didymin halts knee osteoarthritis progression by targeting the GSK3B/5-LOX/11-HETE pathway to suppress chondrocyte ferroptosis. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 41539091
2026 Bovine Preadipocyte-Derived Exosomal miR-26a Promotes Intramuscular Adipogenesis by Directly Targeting GSK3B. Journal of agricultural and food chemistry 0 41736415
2026 Impatiens shenglanii exerts antithrombotic effects by inhibiting the PI3K/Akt/GSK3B signaling pathway and reprogramming arachidonic acid metabolism. Fitoterapia 0 41876033
2025 308-nm excimer laser combined with piperine promotes melanin synthesis through PTEN/PDK1/GSK3b regulation of keratinocyte paracrine. Archives of dermatological research 0 40105984
2025 EPHB1 Protein Promoted the Progression of Prostate Adenocarcinoma Through Phosphorylating GSK3B and Activating EPHB1-GSK3B-SMAD3 Pathway. Human mutation 0 40548257
2025 CircUBE4B attenuates AngII-induced vascular smooth muscle cell proliferation and migration through upregulating GSK3B by sponging miR-199a-5p. International immunopharmacology 0 41330169

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