{"gene":"GSK3B","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2011,"finding":"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.","method":"E3 ligase overexpression/knockdown, AKT overexpression, active GSK3B overexpression, GSK3B inhibition, in vivo Wallerian degeneration assay, genetic epistasis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis across multiple manipulations (E3 ligase, AKT, GSK3B, CRMP2) with defined cellular phenotype, published in high-quality journal","pmids":["22057101"],"is_preprint":false},{"year":2017,"finding":"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.","method":"GSK3B overexpression/knockdown, phospho-MCL1 detection, ubiquitination assays, BECLIN1 release assay, in vivo phagocyte recruitment assay, phosphatidylserine exposure measurement","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (phosphorylation, ubiquitination, genetic KD/OE, in vivo phenotype) establishing a mechanistic cascade","pmids":["28053206"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation (GSK3B-ULK1 interaction), site-directed mutagenesis (S405A/S415A), in vitro phosphorylation assay, autophagy flux assay, interaction with MAP1LC3B/GABARAPL1","journal":"Experimental & molecular medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct kinase-substrate interaction with mutagenesis validation and functional readout (autophagy flux), single lab but multiple orthogonal methods","pmids":["33654220"],"is_preprint":false},{"year":2013,"finding":"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.","method":"PI3K inhibition, GSK3B phosphorylation (Ser9) detection, co-immunoprecipitation (GSK3B-BCL2, BCL2-BECN1), BCL2 ubiquitination assay, autophagy measurement","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs and phosphorylation assays establishing pathway order, single lab","pmids":["23514933"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, site-specific phosphorylation mapping (Thr266), ubiquitination assays (K48-linked), pharmacological GSK3B inhibition, TRAF6 protein stability assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site identified with functional ubiquitination and degradation readout, single lab","pmids":["30806153"],"is_preprint":false},{"year":2013,"finding":"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.","method":"shRNA kinase library screen, siRNA knockdown, GSK3B inhibitors, cell viability and colony assays, AIF/PARP1/caspase mechanistic profiling, in vivo xenograft studies","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identified by functional shRNA screen and validated with pharmacological inhibitors and in vivo model, single lab","pmids":["23729362"],"is_preprint":false},{"year":2008,"finding":"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.","method":"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","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with site-specific phosphorylation mapping and structural characterization of tangle formation, single lab but rigorous biochemical methods","pmids":["18588978"],"is_preprint":false},{"year":2005,"finding":"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.","method":"In vitro splicing assay, in vitro transcriptional reporter assay, lymphocyte splicing analysis, Western blot for phospho-Tau, brain tissue analysis","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional SNP assays plus ex vivo validation in lymphocytes and brain tissue, single lab","pmids":["16315267"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay plus mutagenesis plus multiple Co-IPs plus functional DNA repair assays and drug sensitivity readout, single rigorous study","pmids":["41243969"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Primary human islet culture, pharmacological inhibition, genetic target validation (biochemical/cell biology), in vivo transplantation, diabetic mouse model, oral dosing studies","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combined pharmacological and genetic evidence with in vivo functional validation, but GSK3B contribution defined as secondary to DYRK1A","pmids":["26496802"],"is_preprint":false},{"year":2018,"finding":"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.","method":"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","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with multiple cellular and behavioral readouts in a genetic mouse model, single lab","pmids":["29742424"],"is_preprint":false},{"year":2018,"finding":"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.","method":"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","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with mechanistic dissection of caspase-dependent vs. independent pathways and subcellular localization, single lab","pmids":["29761559"],"is_preprint":false},{"year":2021,"finding":"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.","method":"eIF4A3 siRNA knockdown, alternative splicing analysis of GSK3B mRNA, GSK3B activity measurement, TFEB phosphorylation and nuclear translocation assay, autophagy/lysosome biogenesis quantification","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with splicing analysis, kinase activity, and transcription factor localization, single lab","pmids":["34158631"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Disease markers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus methylation-specific PCR plus in vivo validation, single lab","pmids":["35747513"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Quantitative PCR in primary hippocampal and cortical neuron cultures, in vivo lithium treatment of rats with brain region-specific analysis and peripheral leukocyte measurement","journal":"European archives of psychiatry and clinical neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro dose-response plus in vivo confirmation across multiple tissues, single lab, limited to transcriptional regulation","pmids":["18932008"],"is_preprint":false},{"year":2013,"finding":"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.","method":"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":"Journal of pineal research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO cells plus pharmacological manipulation with in vivo confirmation, single lab","pmids":["24033914"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Phosphoproteomic mass spectrometry analysis, GSK3B-Y216F and Y216E plasmid transfection, enzyme activity analysis, glucose/insulin level measurement, cell staining for glycogen and lipid","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — phospho-site mutagenesis with functional metabolic readouts, single lab","pmids":["37146915"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"Basic & clinical pharmacology & toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological inhibition plus epistasis experiment, single lab","pmids":["34196102"],"is_preprint":false},{"year":2015,"finding":"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.","method":"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":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic pathway dissection with multiple interventions, single lab","pmids":["26386043"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation (TFR1-GSK3B interaction), TFR1 knockdown/overexpression, GSK3B overexpression rescue, iron/ROS measurement, mitochondrial function assays in AD-iPSC-derived neurons","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP identifying interaction plus genetic rescue experiments, single lab","pmids":["38321571"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) for YBX1 at GSK3B promoter, YBX1 overexpression/knockdown, Western blot for GSK3B/cyclin D1/E1","journal":"Molecular therapy oncolytics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assays identifying transcriptional regulation, single lab","pmids":["32300640"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Ngl3-/- genetic mouse model, Akt/GSK3β phosphorylation Western blot, LTD electrophysiology, pharmacological Akt inhibition epistasis, NMDAR pharmacology","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with electrophysiology and pharmacological epistasis, single lab","pmids":["31166939"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Human genomic sequencing cohort analysis, Gsk3b shRNA knockdown in mouse neurons, dendrite/spine morphology quantification, variant rescue experiments, single-cell transcriptomics","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in neurons with morphological phenotype and failed rescue by patient variants confirming LOF mechanism, single study","pmids":["39472663"],"is_preprint":false},{"year":2012,"finding":"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.","method":"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","journal":"Clinical oral implants research","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibition with functional readout, no direct GSK3B biochemistry, single lab","pmids":["22626030"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Phytomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibitor used rather than direct GSK3B-5-LOX mechanistic proof, SPR validates Didymin binding but pathway is inferred, single lab","pmids":["41539091"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Mouse partial hepatectomy model, Western blot for phospho-AKT, phospho-GSK3B, FOXO3, hepatic IGF1R immunohistochemistry and Western blot, hepatosomatic index","journal":"Journal of biological regulators and homeostatic agents","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative Western blots without direct manipulation of GSK3B, single lab","pmids":["28952285"],"is_preprint":false}],"current_model":"GSK3B is a constitutively active serine/threonine kinase (inactivated by Ser9 phosphorylation by AKT, activated at Tyr216) that phosphorylates a broad range of substrates including Tau (at S199, T205, T231, S396, S404, promoting neurofibrillary tangle formation), 53BP1 (at T334, directing DNA double-strand break repair from NHEJ toward homologous recombination), MCL1 (triggering FBXW7-mediated ubiquitination and degradation to induce axonal autophagy), CRMP2 (driving microtubule reorganization in Wallerian degeneration downstream of the ZNRF1-AKT-GSK3B axis), BCL2 (at Ser70, promoting its ubiquitination and autophagy), TRAF6 (at Thr266, causing its K48-ubiquitination and degradation), and ULK1 (at S405/S415, activating autophagy initiation); GSK3B activity is regulated by Wnt/β-catenin signaling, PI3K/AKT, PP2A, PREP, and lithium (which both directly inhibits kinase activity and reduces GSK3B mRNA in hippocampal neurons), and its nuclear localization is linked to pro-apoptotic function in oligodendrocytes, while its loss-of-function causes neurodevelopmental disorders including autism spectrum disorder with dendritic and spine maturation defects."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2005,"claim":"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","pmids":["16315267"],"confidence":"Medium","gaps":["does not establish causal disease mechanism in vivo","isoform-specific kinase activity not measured directly"]},{"year":2008,"claim":"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","pmids":["18588978"],"confidence":"High","gaps":["in vitro reconstitution only","does not address tangle formation in living neurons"]},{"year":2011,"claim":"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","pmids":["22057101"],"confidence":"High","gaps":["direct GSK3B-CRMP2 kinase reaction not isolated from pathway readout","site mapping on CRMP2 not detailed"]},{"year":2013,"claim":"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","pmids":["23514933","23729362","24033914"],"confidence":"Medium","gaps":["BCL2 Ser70 phosphorylation pathway from single lab","necroptosis mechanism downstream of GSK3B not fully resolved"]},{"year":2017,"claim":"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","pmids":["28053206"],"confidence":"High","gaps":["MCL1 phosphosite not enumerated here","generalizability beyond axonal context untested"]},{"year":2019,"claim":"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","pmids":["30806153"],"confidence":"Medium","gaps":["single lab","direct kinase assay on TRAF6 not described"]},{"year":2021,"claim":"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","pmids":["33654220","34158631"],"confidence":"High","gaps":["ULK1 work from single lab","reconciliation of pro- vs anti-autophagy roles across contexts not addressed"]},{"year":2024,"claim":"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","pmids":["39472663"],"confidence":"Medium","gaps":["substrates mediating neurodevelopmental phenotype not identified","single study"]},{"year":2025,"claim":"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","pmids":["41243969"],"confidence":"High","gaps":["how GSK3B is recruited to or activated at DSBs unknown","single study"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unified model of substrate selection","regulation of nuclear vs cytoplasmic GSK3B activity not defined","in vivo substrate hierarchy untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,6,8]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,6,8,16]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2,3,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,11,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,15,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[22]}],"complexes":[],"partners":["MCL1","ULK1","BCL2","TRAF6","53BP1","CRMP2","DNMT1","TFR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49841","full_name":"Glycogen synthase kinase-3 beta","aliases":["Serine/threonine-protein kinase GSK3B"],"length_aa":420,"mass_kda":46.7,"function":"Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1 (PubMed:11430833, PubMed:12554650, PubMed:14690523, PubMed:16484495, PubMed:1846781, PubMed:20937854, PubMed:9072970). Requires primed phosphorylation of the majority of its substrates (PubMed:11430833, PubMed:16484495). In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:8397507). May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:8397507). Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase (PubMed:8397507). In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes (PubMed:12554650). Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA (PubMed:1846781). Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin (PubMed:9072970). Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules (PubMed:14690523). MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease (PubMed:14690523). Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854). Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair (By similarity). Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF (TNF/TNFA) (By similarity). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes (By similarity). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin (PubMed:9819408). Is necessary for the establishment of neuronal polarity and axon outgrowth (PubMed:20067585). Phosphorylates MARK2, leading to inhibition of its activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to sustainment of its activity (PubMed:18348280). Phosphorylates ZC3HAV1 which enhances its antiviral activity (PubMed:22514281). Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation (PubMed:15448698, PubMed:15647282, PubMed:25827072, PubMed:29059170). Phosphorylates SFPQ at 'Thr-687' upon T-cell activation (PubMed:20932480). Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391). Phosphorylates FBXL2 at 'Thr-404' and primes it for ubiquitination by the SCF(FBXO3) complex and proteasomal degradation (By similarity). Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (PubMed:19946213). Phosphorylates BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). Regulates the circadian rhythmicity of hippocampal long-term potentiation and BMAL1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, activating KAT5/TIP60 acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (PubMed:18846110). Phosphorylates E2F1, promoting the interaction between E2F1 and USP11, stabilizing E2F1 and promoting its activity (PubMed:17050006, PubMed:28992046). Phosphorylates mTORC2 complex component RICTOR at 'Ser-1235' in response to endoplasmic stress, inhibiting mTORC2 (PubMed:21343617). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075). Phosphorylates FXR1, promoting FXR1 ubiquitination by the SCF(FBXO4) complex and FXR1 degradation by the proteasome (By similarity). Phosphorylates interleukin-22 receptor subunit IL22RA1, preventing its proteasomal degradation (By similarity). Phosphorylates and inhibits the CTP synthase and protein-asparagine deamidase activities of CTPS1 (PubMed:17681942). Phosphorylates DSP at multiple sequential serine residues in the C-terminus tail, promoting its recruitment to developing desmosome cell-cell junctions (PubMed:25733715)","subcellular_location":"Cytoplasm; Nucleus; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P49841/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GSK3B","classification":"Not 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AUNIP","url":"https://www.omim.org/entry/620397"},{"mim_id":"620054","title":"PHD FINGER PROTEIN 13; PHF13","url":"https://www.omim.org/entry/620054"},{"mim_id":"619415","title":"TAU TUBULIN KINASE 1; TTBK1","url":"https://www.omim.org/entry/619415"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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inhibiting GSK3B expression.","date":"2024","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/38814517","citation_count":6,"is_preprint":false},{"pmid":"36649031","id":"PMC_36649031","title":"High Throughput FISH Screening Identifies Small Molecules That Modulate Oncogenic lncRNA MALAT1 via GSK3B and hnRNPs.","date":"2023","source":"Non-coding RNA","url":"https://pubmed.ncbi.nlm.nih.gov/36649031","citation_count":6,"is_preprint":false},{"pmid":"39472663","id":"PMC_39472663","title":"Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay.","date":"2024","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/39472663","citation_count":5,"is_preprint":false},{"pmid":"35747513","id":"PMC_35747513","title":"GSK3B Overexpression Alleviates Posttraumatic Osteoarthritis in Mice by Promoting DNMT1-Mediated Hypermethylation of NR4A3 Promoter.","date":"2022","source":"Disease 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FBXW2.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40344383","citation_count":3,"is_preprint":false},{"pmid":"36819133","id":"PMC_36819133","title":"EPS8L3 promotes pancreatic cancer proliferation and metastasis by activating GSK3B.","date":"2023","source":"Journal of medical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36819133","citation_count":3,"is_preprint":false},{"pmid":"30623492","id":"PMC_30623492","title":"No evidence so far of a major role of AKT1 and GSK3B in the pathogenesis of antipsychotic-induced tardive dyskinesia.","date":"2019","source":"Human psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30623492","citation_count":3,"is_preprint":false},{"pmid":"38762650","id":"PMC_38762650","title":"miR-709 exerts an angiogenic effect through a FGF2 upregulation induced by a GSK3B downregulation.","date":"2024","source":"Scientific 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research","url":"https://pubmed.ncbi.nlm.nih.gov/40105984","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55112,"output_tokens":7546,"usd":0.139263,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16943,"output_tokens":3530,"usd":0.086483,"stage2_stop_reason":"end_turn"},"total_usd":0.225746,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"E3 ligase overexpression/knockdown, AKT overexpression, active GSK3B overexpression, GSK3B inhibition, in vivo Wallerian degeneration assay, genetic epistasis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis across multiple manipulations (E3 ligase, AKT, GSK3B, CRMP2) with defined cellular phenotype, published in high-quality journal\",\n      \"pmids\": [\"22057101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"GSK3B overexpression/knockdown, phospho-MCL1 detection, ubiquitination assays, BECLIN1 release assay, in vivo phagocyte recruitment assay, phosphatidylserine exposure measurement\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (phosphorylation, ubiquitination, genetic KD/OE, in vivo phenotype) establishing a mechanistic cascade\",\n      \"pmids\": [\"28053206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (GSK3B-ULK1 interaction), site-directed mutagenesis (S405A/S415A), in vitro phosphorylation assay, autophagy flux assay, interaction with MAP1LC3B/GABARAPL1\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct kinase-substrate interaction with mutagenesis validation and functional readout (autophagy flux), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33654220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"PI3K inhibition, GSK3B phosphorylation (Ser9) detection, co-immunoprecipitation (GSK3B-BCL2, BCL2-BECN1), BCL2 ubiquitination assay, autophagy measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs and phosphorylation assays establishing pathway order, single lab\",\n      \"pmids\": [\"23514933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, site-specific phosphorylation mapping (Thr266), ubiquitination assays (K48-linked), pharmacological GSK3B inhibition, TRAF6 protein stability assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site identified with functional ubiquitination and degradation readout, single lab\",\n      \"pmids\": [\"30806153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA kinase library screen, siRNA knockdown, GSK3B inhibitors, cell viability and colony assays, AIF/PARP1/caspase mechanistic profiling, in vivo xenograft studies\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identified by functional shRNA screen and validated with pharmacological inhibitors and in vivo model, single lab\",\n      \"pmids\": [\"23729362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with site-specific phosphorylation mapping and structural characterization of tangle formation, single lab but rigorous biochemical methods\",\n      \"pmids\": [\"18588978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro splicing assay, in vitro transcriptional reporter assay, lymphocyte splicing analysis, Western blot for phospho-Tau, brain tissue analysis\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional SNP assays plus ex vivo validation in lymphocytes and brain tissue, single lab\",\n      \"pmids\": [\"16315267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay plus mutagenesis plus multiple Co-IPs plus functional DNA repair assays and drug sensitivity readout, single rigorous study\",\n      \"pmids\": [\"41243969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Primary human islet culture, pharmacological inhibition, genetic target validation (biochemical/cell biology), in vivo transplantation, diabetic mouse model, oral dosing studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combined pharmacological and genetic evidence with in vivo functional validation, but GSK3B contribution defined as secondary to DYRK1A\",\n      \"pmids\": [\"26496802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with multiple cellular and behavioral readouts in a genetic mouse model, single lab\",\n      \"pmids\": [\"29742424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with mechanistic dissection of caspase-dependent vs. independent pathways and subcellular localization, single lab\",\n      \"pmids\": [\"29761559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"eIF4A3 siRNA knockdown, alternative splicing analysis of GSK3B mRNA, GSK3B activity measurement, TFEB phosphorylation and nuclear translocation assay, autophagy/lysosome biogenesis quantification\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with splicing analysis, kinase activity, and transcription factor localization, single lab\",\n      \"pmids\": [\"34158631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Disease markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus methylation-specific PCR plus in vivo validation, single lab\",\n      \"pmids\": [\"35747513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Quantitative PCR in primary hippocampal and cortical neuron cultures, in vivo lithium treatment of rats with brain region-specific analysis and peripheral leukocyte measurement\",\n      \"journal\": \"European archives of psychiatry and clinical neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro dose-response plus in vivo confirmation across multiple tissues, single lab, limited to transcriptional regulation\",\n      \"pmids\": [\"18932008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of pineal research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO cells plus pharmacological manipulation with in vivo confirmation, single lab\",\n      \"pmids\": [\"24033914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphoproteomic mass spectrometry analysis, GSK3B-Y216F and Y216E plasmid transfection, enzyme activity analysis, glucose/insulin level measurement, cell staining for glycogen and lipid\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — phospho-site mutagenesis with functional metabolic readouts, single lab\",\n      \"pmids\": [\"37146915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Basic & clinical pharmacology & toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological inhibition plus epistasis experiment, single lab\",\n      \"pmids\": [\"34196102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic pathway dissection with multiple interventions, single lab\",\n      \"pmids\": [\"26386043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (TFR1-GSK3B interaction), TFR1 knockdown/overexpression, GSK3B overexpression rescue, iron/ROS measurement, mitochondrial function assays in AD-iPSC-derived neurons\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP identifying interaction plus genetic rescue experiments, single lab\",\n      \"pmids\": [\"38321571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) for YBX1 at GSK3B promoter, YBX1 overexpression/knockdown, Western blot for GSK3B/cyclin D1/E1\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assays identifying transcriptional regulation, single lab\",\n      \"pmids\": [\"32300640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Ngl3-/- genetic mouse model, Akt/GSK3β phosphorylation Western blot, LTD electrophysiology, pharmacological Akt inhibition epistasis, NMDAR pharmacology\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with electrophysiology and pharmacological epistasis, single lab\",\n      \"pmids\": [\"31166939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Human genomic sequencing cohort analysis, Gsk3b shRNA knockdown in mouse neurons, dendrite/spine morphology quantification, variant rescue experiments, single-cell transcriptomics\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in neurons with morphological phenotype and failed rescue by patient variants confirming LOF mechanism, single study\",\n      \"pmids\": [\"39472663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Clinical oral implants research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibition with functional readout, no direct GSK3B biochemistry, single lab\",\n      \"pmids\": [\"22626030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibitor used rather than direct GSK3B-5-LOX mechanistic proof, SPR validates Didymin binding but pathway is inferred, single lab\",\n      \"pmids\": [\"41539091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse partial hepatectomy model, Western blot for phospho-AKT, phospho-GSK3B, FOXO3, hepatic IGF1R immunohistochemistry and Western blot, hepatosomatic index\",\n      \"journal\": \"Journal of biological regulators and homeostatic agents\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative Western blots without direct manipulation of GSK3B, single lab\",\n      \"pmids\": [\"28952285\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GSK3B is a constitutively active serine/threonine kinase (inactivated by Ser9 phosphorylation by AKT, activated at Tyr216) that phosphorylates a broad range of substrates including Tau (at S199, T205, T231, S396, S404, promoting neurofibrillary tangle formation), 53BP1 (at T334, directing DNA double-strand break repair from NHEJ toward homologous recombination), MCL1 (triggering FBXW7-mediated ubiquitination and degradation to induce axonal autophagy), CRMP2 (driving microtubule reorganization in Wallerian degeneration downstream of the ZNRF1-AKT-GSK3B axis), BCL2 (at Ser70, promoting its ubiquitination and autophagy), TRAF6 (at Thr266, causing its K48-ubiquitination and degradation), and ULK1 (at S405/S415, activating autophagy initiation); GSK3B activity is regulated by Wnt/β-catenin signaling, PI3K/AKT, PP2A, PREP, and lithium (which both directly inhibits kinase activity and reduces GSK3B mRNA in hippocampal neurons), and its nuclear localization is linked to pro-apoptotic function in oligodendrocytes, while its loss-of-function causes neurodevelopmental disorders including autism spectrum disorder with dendritic and spine maturation defects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#3, #15] and by activating Tyr216 phosphorylation that drives its metabolic activity [#16]. 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 [#1], phosphorylates BCL2 at Ser70 to promote its ubiquitination and relieve BCL2-mediated autophagy suppression [#3], and phosphorylates TRAF6 at Thr266 to drive its K48-linked polyubiquitination [#4]; it also directly phosphorylates and activates ULK1 at S405/S415 to facilitate ULK1 binding to MAP1LC3B/GABARAPL1 and induce autophagy flux [#2]. In the nervous system, GSK3B acts downstream of the ZNRF1-AKT axis to phosphorylate CRMP2 and drive the microtubule reorganization of Wallerian degeneration [#0], and in vitro it phosphorylates tau at S199/T205/T231/S396/S404 to promote coalescence into neurofibrillary tangle-like structures [#6]. 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 [#8]. 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 [#22]. Its activity is further modulated by lithium, which both directly inhibits the kinase and reduces Gsk3b mRNA in hippocampal neurons [#14], and by a PREP-PP2A axis controlling its phosphorylation state [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that genetic variation at the GSK3B locus alters splicing and transcription and is linked to tau phosphorylation, connecting GSK3B regulation to neurodegenerative biochemistry.\",\n      \"evidence\": \"in vitro splicing and transcriptional reporter assays with lymphocyte and brain tissue validation of SNP effects on phospho-Tau\",\n      \"pmids\": [\"16315267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"does not establish causal disease mechanism in vivo\", \"isoform-specific kinase activity not measured directly\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"cell-free tau polymerization with site-specific phosphorylation mapping and EM/optical characterization\",\n      \"pmids\": [\"18588978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"in vitro reconstitution only\", \"does not address tangle formation in living neurons\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed GSK3B within the ZNRF1-AKT axonal degeneration pathway, showing active GSK3B phosphorylates CRMP2 to drive microtubule reorganization required for Wallerian degeneration.\",\n      \"evidence\": \"reciprocal genetic epistasis (E3 ligase, AKT, GSK3B, CRMP2) with in vivo degeneration assay\",\n      \"pmids\": [\"22057101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct GSK3B-CRMP2 kinase reaction not isolated from pathway readout\", \"site mapping on CRMP2 not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP and ubiquitination assays for GSK3B-BCL2; shRNA screen plus inhibitors and xenografts for necroptosis sensitization\",\n      \"pmids\": [\"23514933\", \"23729362\", \"24033914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BCL2 Ser70 phosphorylation pathway from single lab\", \"necroptosis mechanism downstream of GSK3B not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed GSK3B initiates axonal autophagy by phosphorylating MCL1 for FBXW7-mediated degradation, linking the kinase to BECLIN1 release and phagocyte recruitment in vivo.\",\n      \"evidence\": \"phospho-MCL1 detection, ubiquitination assays, KD/OE and in vivo phagocyte recruitment\",\n      \"pmids\": [\"28053206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MCL1 phosphosite not enumerated here\", \"generalizability beyond axonal context untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the GSK3B-to-ubiquitination paradigm to TRAF6, identifying Thr266 phosphorylation as the trigger for K48 degradation that promotes colorectal cancer metastasis.\",\n      \"evidence\": \"Co-IP, phosphosite mapping, K48-ubiquitination assays, GSK3B inhibition\",\n      \"pmids\": [\"30806153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single lab\", \"direct kinase assay on TRAF6 not described\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, S405A/S415A mutagenesis, in vitro kinase and autophagy flux assays; eIF4A3 knockdown with GSK3B splicing and TFEB localization analysis\",\n      \"pmids\": [\"33654220\", \"34158631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ULK1 work from single lab\", \"reconciliation of pro- vs anti-autophagy roles across contexts not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"human sequencing cohort, neuronal shRNA knockdown with morphology quantification and failed rescue by patient missense variants\",\n      \"pmids\": [\"39472663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"substrates mediating neurodevelopmental phenotype not identified\", \"single study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"in vitro kinase assay, T334A mutagenesis, Co-IPs with PTIP/RIF1 and CtIP/RPA32, HR/NHEJ reporters, PARPi sensitivity\",\n      \"pmids\": [\"41243969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how GSK3B is recruited to or activated at DSBs unknown\", \"single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unified model of substrate selection\", \"regulation of nuclear vs cytoplasmic GSK3B activity not defined\", \"in vivo substrate hierarchy untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6, 8]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 6, 8, 16]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2, 3, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 11, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 15, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MCL1\", \"ULK1\", \"BCL2\", \"TRAF6\", \"53BP1\", \"CRMP2\", \"DNMT1\", \"TFR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}