Affinage

GSK3A

Glycogen synthase kinase-3 alpha · UniProt P49840

Length
483 aa
Mass
51.0 kDa
Annotated
2026-06-10
94 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GSK3A is a constitutively active serine/threonine protein kinase that phosphorylates a broad substrate repertoire to control cell proliferation, autophagy, metabolism, synaptic plasticity, and host-pathogen interactions, with many of its actions being isoform-specific and non-redundant with GSK3B (PMID:28916722, PMID:35782378, PMID:32581704). Within the WNT pathway, GSK3A acts in a residual destruction complex with APC and AXIN1 to phosphorylate β-catenin and promote its turnover, an activity antagonized by HUWE1 and operating in part independently of β-catenin stability (PMID:40424469); this WNT-suppressive function underlies its requirement for SHH-driven cerebellar granule neuron progenitor proliferation and medulloblastoma growth, which is rescued by β-catenin deletion (PMID:31540917). GSK3A is positioned upstream of mTORC1 to permit autophagy, as its loss activates mTORC1 and suppresses autophagy markers in vivo (PMID:23549082). Its kinase activity is restrained by inhibitory Ser21 phosphorylation imposed by PKA, PKB, and SGK1 (PMID:19911376, PMID:16543730). GSK3A phosphorylates regulatory substrates including splicing factors RBM8A, SRSF9 and PSF (PMID:28916722), RelA/NF-κB p65 at Thr-254 to drive chondrocyte differentiation (PMID:22761446), and MTHFR to control one-carbon metabolism (PMID:30862944); it also modulates cohesin-dependent long-range chromatin looping (PMID:37438531). GSK3A is essential and isoform-specifically required for sperm flagellar function and male fertility, where its inhibitory phosphorylation correlates with progressive motility (PMID:25568307, PMID:30824926), and it uniquely limits long-term potentiation in CA1 hippocampal neurons (PMID:35782378). In disease contexts, GSK3A is co-opted by viruses to phosphorylate the SARS-CoV-2 nucleocapsid protein and the adenovirus L4-22K protein to support replication (PMID:34593624, PMID:40537285), and it promotes tumor immune evasion through effects on T-cell function and LRG1-driven neutrophil NET formation (PMID:34142056, PMID:39174053).

Mechanistic history

Synthesis pass · year-by-year structured walk · 30 steps
  1. 2006 Medium

    Established the upstream kinases that inactivate GSK3A, defining how its constitutive activity is held in check by survival/stress signaling.

    Evidence HEK293 overexpression of wild-type, constitutively active, and kinase-dead SGK1/PKB with pSer21 Western blots, plus in vivo DOCA/salt cardiac model

    PMID:16543730

    Open questions at the time
    • Relative contribution of SGK1 vs PKB in physiological settings not resolved
    • Downstream consequences of Ser21 phosphorylation on specific substrates not mapped
  2. 2010 Medium

    Linked GSK3A Ser21 phosphorylation to a concrete physiological output — sperm motility — via cAMP/PKA and PKC, foreshadowing its reproductive role.

    Evidence Pharmacologic inhibition of PKA/PKC/PI3K with pSer21 Western blots and motility assays in boar spermatozoa

    PMID:19911376

    Open questions at the time
    • Single-species (boar) correlative data
    • Direct sperm substrates of GSK3A not identified here
  3. 2010 Medium

    Identified GSK3A as a transcription-modulating kinase by demonstrating interaction with DEAF1 and control of 5-HT1A receptor promoter activity.

    Evidence Yeast two-hybrid, co-affinity purification, in vitro kinase assay, transcriptional reporter

    PMID:20368287

    Open questions at the time
    • DEAF1 phosphosites not defined
    • In vivo relevance not established
  4. 2012 High

    Defined a developmental substrate (RelA Thr-254) through which GSK-3 drives chondrocyte differentiation, showing GSK3A/GSK3B redundancy in skeletal development.

    Evidence Compound Gsk3a/Gsk3b knockout mice, SOX9/COL2A1 transcriptional assays, phosphosite identification

    PMID:22761446

    Open questions at the time
    • Does not isolate GSK3A-specific contribution from GSK3B
    • Mechanism by which Thr-254 phosphorylation alters RelA activity not detailed
  5. 2012 Medium

    First clear demonstration of isoform-specific signaling, with GSK3A but not GSK3B required for androgen receptor activity in prostate cancer.

    Evidence Isoform-specific siRNA knockdown with AR reporter, colony formation, and pAkt readouts in 22Rv1 cells

    PMID:22539113

    Open questions at the time
    • Direct GSK3A substrate in AR pathway not identified
    • Single cell line
  6. 2013 High

    Placed GSK3A upstream of mTORC1 as a positive regulator of autophagy, answering how its loss produces tissue pathology.

    Evidence Global Gsk3a KO mice, pharmacologic inhibition, mTOR-inhibitor rescue, autophagy marker analysis

    PMID:23549082

    Open questions at the time
    • Molecular intermediates between GSK3A and mTORC1 not defined
    • Whether effect is kinase-dependent substrate phosphorylation not shown
  7. 2014 Medium

    Connected GSK3A to chemoresistance and cell-death decisions by showing it supports DNA repair and a necroptotic switch in p53-null tumor cells.

    Evidence siRNA knockdown of GSK3A/GSK3B, DNA damage and caspase assays, AIF localization, PARP inhibition

    PMID:24984063

    Open questions at the time
    • Redundant with GSK3B; GSK3A-specific role not isolated
    • DNA-repair substrate unknown
  8. 2014 Medium

    Revealed an immunometabolic role wherein GSK3A restrains anti-inflammatory IL-10 during ER stress, modulating atherosclerosis.

    Evidence Gsk3a/LDLR double-KO mice on high-fat diet, macrophage IL-10 assays, CT99021 inhibition

    PMID:25451156

    Open questions at the time
    • Direct GSK3A substrate controlling IL-10 not identified
    • Macrophage-intrinsic vs systemic effects not fully separated
  9. 2015 High

    Established GSK3A as essential and non-redundant for sperm motility and male fertility, the strongest isoform-specific genetic phenotype.

    Evidence Targeted Gsk3a KO mice with flagellar waveform, ATP, PP1γ2 activity, and tyrosine phosphorylation readouts

    PMID:25568307

    Open questions at the time
    • Sperm-specific GSK3A substrates not directly identified
    • Mechanism of PP1γ2 elevation unclear
  10. 2016 Medium

    Identified CREB as a direct transcriptional driver of GSK3A expression, linking GSK3A levels to lung cancer cell growth.

    Evidence CREB knockdown, ChIP on GSK3A promoter, GSK-3α loss-of-function viability/tumor assays

    PMID:27049759

    Open questions at the time
    • Downstream GSK3A substrates in lung cancer not defined
    • Single context
  11. 2017 High

    Unbiased phosphoproteomics defined GSK3A's substrate landscape, including splicing factors and nucleolar proteins, linking it to alternative splicing.

    Evidence SILAC phosphoproteomics in Gsk3a/Gsk3b double-KO ES cells, in vitro kinase assays, RNA-Seq

    PMID:28916722

    Open questions at the time
    • GSK3A vs GSK3B substrate preferences not separated
    • Functional consequences of individual phosphosites not validated
  12. 2017 Medium

    Implicated GSK3A in drug resistance via WNT reactivation, showing its loss in AML confers FLT3-inhibitor resistance.

    Evidence Genome-wide CRISPR screen, GSK3A KO validation in AML lines and primary samples, SPRY3 epistasis

    PMID:28625976

    Open questions at the time
    • Direct GSK3A substrate controlling SPRY3/WNT not defined
    • Single-lab resistance model
  13. 2017 Medium

    Documented a physical GSK3A-MYC interaction in cancer cells, expanding its oncogenic interactome.

    Evidence NanoPCA protein-fragment complementation plus endogenous co-IP

    PMID:28087810

    Open questions at the time
    • Functional consequence of interaction not tested
    • Whether MYC is a GSK3A substrate not shown
  14. 2019 Medium

    Defined GSK3A as an MTHFR kinase, connecting it to one-carbon metabolism through phosphorylation-enhanced allosteric inhibition.

    Evidence In vitro kinase assays and CRISPR phospho-null MTHFR knockins with 5-methyl-THF production assays

    PMID:30862944

    Open questions at the time
    • GSK3A vs GSK3B contribution to MTHFR phosphorylation not separated
    • Physiological metabolic flux consequences in vivo not assessed
  15. 2019 Medium

    Showed GSK3A/B suppress retinoic acid synthesis via WNT/β-catenin repression of ALDH1A2 in fetal kidney development.

    Evidence CHIR99021 inhibition, β-catenin knockdown, ChIP and luciferase reporter assays

    PMID:32258025

    Open questions at the time
    • GSK3A-specific role not isolated from GSK3B
    • Developmental in vivo relevance not directly tested
  16. 2019 High

    Demonstrated GSK3A's WNT-suppressive activity restrains SHH-driven neuronal proliferation, with effects rescued by β-catenin deletion.

    Evidence Conditional Gsk3a/Gsk3b double KO mice, Ctnnb1 rescue, transcriptomics, medulloblastoma model

    PMID:31540917

    Open questions at the time
    • Single-isoform GSK3A contribution within the double KO not separated
    • Direct β-catenin phosphorylation in this context inferred not shown
  17. 2019 Medium

    Established human-relevant isoform specificity, with inhibited GSK3A (not GSK3B) correlating with progressive sperm motility, plus a sperm interactome.

    Evidence Correlation of GSK3 phosphorylation with motility in normo/asthenozoospermic samples, Y2H and co-IP

    PMID:30824926

    Open questions at the time
    • Correlative, not causal in human sperm
    • Specific motility substrates not validated
  18. 2021 High

    Showed GSK3A is dispensable for MPTP-induced dopaminergic neurodegeneration, in contrast to GSK3B, sharpening isoform non-redundancy.

    Evidence Parallel dopaminergic-neuron-specific Gsk3a and Gsk3b conditional KO mice in MPTP model with neuron counts

    PMID:32581704

    Open questions at the time
    • Negative result does not exclude GSK3A roles in other neurodegeneration models
    • Mechanism of GSK3B selectivity not addressed
  19. 2021 High

    Identified GSK3A as a host kinase phosphorylating the SARS-CoV-2 nucleocapsid protein required for viral replication.

    Evidence GSK3A/GSK3B double KO cells, in vitro kinase assay, GSK-3 inhibitor and viral replication assays

    PMID:34593624

    Open questions at the time
    • GSK3A vs GSK3B individual contribution not separated
    • Functional effect of N phosphorylation on viral biology not fully defined
  20. 2021 High

    Assigned a non-redundant role for GSK3A in T cell-mediated tumor rejection, where it cooperates with GSK3B to control PD-1 and effector molecules.

    Evidence T cell-specific conditional Gsk3a/Gsk3b single and double KO mice, tumor growth, flow cytometry for PD-1/IFNγ/granzyme B

    PMID:34142056

    Open questions at the time
    • Direct GSK3A substrate controlling PD-1 not identified
    • GSK3A-alone KO behaved like wild-type, leaving its specific node unclear
  21. 2021 Medium

    Implicated GSK3A in maintaining viral T-antigen transcription and growth of Merkel cell carcinoma.

    Evidence GSK3A CRISPR KO plus inducible GSK3B shRNA, TA expression analysis, xenograft model

    PMID:34715251

    Open questions at the time
    • Mechanism linking GSK3A to TA transcription not defined
    • Reliance on combined GSK3B knockdown for full effect
  22. 2022 High

    Revealed a unique postsynaptic role for GSK3A in limiting CA1 hippocampal LTP, distinct from GSK3B.

    Evidence Conditional CaMK2a-Cre Gsk3a and Gsk3b KO mice, hippocampal slice electrophysiology

    PMID:35782378

    Open questions at the time
    • Synaptic GSK3A substrates mediating LTP restraint not identified
    • Behavioral consequences not tested here
  23. 2022 Medium

    Placed GSK3A protein levels under translational control by MYCT1/RACK1 within the hepatic glycogen shunt.

    Evidence Global Myct1 KO mice, liver glycogen assays, RACK1-dependent translation analysis, Western blot

    PMID:35281731

    Open questions at the time
    • Direct vs indirect translational control of GSK3A not fully resolved
    • GSK3A kinase function in glycogen metabolism not directly assayed
  24. 2022 Medium

    Mapped a SARS-CoV-2 N-protein variant (R203K/G204R) that enhances GSK3A binding and adjacent S206 phosphorylation, linking host kinase recruitment to viral mutation.

    Evidence Comparative biochemical analysis, co-IP with GSK3A, phosphosite mapping of mutant vs WT N protein

    PMID:35105893

    Open questions at the time
    • Functional consequence for viral fitness not demonstrated
    • Single biochemical study
  25. 2023 Medium

    Identified GSK3A as a regulator of nuclear architecture, with its inhibition increasing cohesin-dependent long-range chromatin looping.

    Evidence HiDRO high-throughput Oligopaint imaging screen with GSK3A inhibition and cohesin-dependence validation

    PMID:37438531

    Open questions at the time
    • Chromatin/cohesin substrate of GSK3A not identified
    • Whether effect is direct or via WNT not resolved
  26. 2024 Medium

    Defined a tumor immune-evasion mechanism in HCC whereby GSK3A drives neutrophil recruitment and NET formation via LRG1 to suppress CTLs.

    Evidence In vivo CRISPR screen, flow cytometry, neutrophil RNA-seq, Gsk3a KO HCC model

    PMID:39174053

    Open questions at the time
    • Direct GSK3A substrate upstream of LRG1 not identified
    • Single tumor model
  27. 2024 Medium

    Validated GSK3A as a direct molecular target of quercetin, providing a pharmacological handle and stabilization mechanism.

    Evidence CETSA-MS, Western blot, molecular docking, site-directed mutagenesis, pull-down assays

    PMID:38342014

    Open questions at the time
    • Effect of quercetin on GSK3A kinase activity not established
    • Cellular phenotype of stabilization not defined
  28. 2024 Low

    Identified CCDC28A as a sperm interactor of GSK3A with phenotypically overlapping knockouts, nominating a fertility-relevant complex.

    Evidence Co-immunoprecipitation and Ccdc28a KO mouse sperm morphology/motility analysis

    PMID:38597936

    Open questions at the time
    • Single co-IP without reciprocal/structural validation
    • Phenotypic overlap is indirect evidence for functional connection
    • Whether CCDC28A is a GSK3A substrate unknown
  29. 2025 High

    Dissected GSK3A's role in the β-catenin destruction complex, showing it phosphorylates β-catenin with APC/AXIN1 and is antagonized by HUWE1, including a β-catenin-stability-independent output.

    Evidence CSNK1A1 KO cells, HUWE1 KO, phospho-resistant CTNNB1 knockin, genetic interaction and WNT reporter assays

    PMID:40424469

    Open questions at the time
    • GSK3A vs GSK3B contributions within the complex not separated
    • Nature of the stability-independent WNT mechanism not defined
  30. 2025 High

    Demonstrated GSK3A kinase activity supports adenovirus replication through direct phosphorylation of L4-22K, mapping the kinase-domain interaction.

    Evidence cDNA gain-of-function screen, kinase-dead mutants, phosphoproteomics, co-IP, domain mapping

    PMID:40537285

    Open questions at the time
    • In vivo relevance of L4-22K phosphorylation not tested
    • Whether this generalizes to other adenovirus serotypes unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved which direct GSK3A substrates underlie its isoform-specific phenotypes (sperm motility, LTP limitation, T-cell immunity, chromatin looping), and how GSK3A activity and substrate selection are differentially controlled from GSK3B.
  • No GSK3A-unique substrate has been assigned to its non-redundant neuronal or immune phenotypes
  • Structural/regulatory basis for GSK3A vs GSK3B substrate discrimination not defined
  • Whether chromatin and metabolic roles are direct kinase actions remains open

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 3
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2 R-HSA-8953854 Metabolism of RNA 1 R-HSA-9612973 Autophagy 1
Partners
APCAXIN1CCDC28ACTNNB1DEAF1HUWE1MYCRELA
Complex memberships
β-catenin destruction complex (APC/AXIN1/GSK3)

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 GSK-3α is a critical regulator of mTORC1 and autophagy; global Gsk3a knockout mice show marked activation of mTORC1 and suppression of autophagy markers, and pharmacologic inhibition or gene deletion of Gsk3a suppresses autophagy in fibroblasts. mTOR inhibition rescued both the autophagy defect and established muscle pathologies in KO mice, placing GSK-3α upstream of mTORC1 in this pathway. Global Gsk3a knockout mouse, pharmacologic inhibition, mTOR inhibitor rescue, autophagy marker analysis The Journal of clinical investigation High 23549082
2015 GSK3A is essential for sperm motility and male fertility in mice; targeted Gsk3a knockout causes impaired flagellar waveform, reduced sperm ATP levels, elevated PP1γ2 catalytic activity, and absence of capacitation-associated tyrosine phosphorylation. GSK3B cannot substitute for GSK3A in this context, demonstrating isoform-specific function. Targeted gene knockout mouse, sperm motility parameters, ATP assay, PP1γ2 activity assay, tyrosine phosphorylation analysis Biology of reproduction High 25568307
2012 GSK-3α and GSK-3β function redundantly in early chondrocyte differentiation via phosphorylation of RelA (NF-κB p65) at Thr-254; compound knockout (Gsk3a−/−;Gsk3b+/−) causes dwarfism and impaired chondrocyte differentiation, and computational/transcriptional assays identified Thr-254 as the critical GSK-3 phosphorylation site on RelA for this process. Compound mouse knockout, SOX9 and COL2A1 transcriptional assays, computational prediction, phosphorylation site identification The Journal of biological chemistry High 22761446
2021 GSK3A phosphorylates the SARS-CoV-2 nucleocapsid (N) protein; GSK3A and GSK3B double knockout abolishes N protein phosphorylation, and GSK-3 inhibitors block N phosphorylation and impair SARS-CoV-2 replication in lung epithelial cells. GSK3A/GSK3B knockout cells, in vitro kinase assay, GSK-3 inhibitor treatment, viral replication assay Proceedings of the National Academy of Sciences of the United States of America High 34593624
2017 GSK-3 (including GSK3A) phosphorylates multiple splicing factors including RBM8A, SRSF9, and PSF, as well as nucleolar proteins NPM1 and PHF6; comparison of WT and Gsk3a;Gsk3b double-KO ES cells by SILAC phosphoproteomics revealed prominent GSK-3-dependent phosphorylation of these substrates, and recombinant GSK-3β phosphorylated them in vitro. GSK-3 DKO altered alternative splicing of ~190 genes. SILAC phosphoproteomics, Gsk3a;Gsk3b double-KO mouse ES cells, in vitro kinase assay, RNA-Seq The Journal of biological chemistry High 28916722
2010 PKA, PKC, and PI3K pathways regulate GSK3A Ser21 phosphorylation (inactivation) in boar spermatozoa to control motility; cAMP/8Br-cAMP increases Ser21 phosphorylation coincident with increased motility, effects blocked by PKA inhibitor H89 or PKC inhibitor Ro-32-0432. PI3K inhibition increases basal GSK3A phosphorylation via an intracellular cAMP/PKA-dependent mechanism. Pharmacologic inhibition of PKA (H89), PKC (Ro-32-0432), PI3K (LY294002), Western blot for pSer21-GSK3A, sperm motility assay Journal of cellular biochemistry Medium 19911376
2006 SGK1 and PKB phosphorylate GSK3A at Ser21 in HEK293 cells; overexpression of wild-type and constitutively active SGK1, but not catalytically inactive SGK1, increased GSK3α/β phosphorylation. DOCA/high-salt treatment of mice induced cardiac GSK3α phosphorylation (less robustly than GSK3β). HEK293 overexpression with wild-type, constitutively active, and kinase-inactive SGK1; Western blot for pSer21; in vivo DOCA/salt mouse model Cellular physiology and biochemistry Medium 16543730
2010 GSK3A and GSK3B are identified as in vitro substrates of themselves and as interactors with DEAF1 transcription factor via yeast two-hybrid and co-affinity purification; GSK3 inhibitors increase DEAF1 transcriptional activity on the 5-HT1A serotonin receptor promoter. Yeast two-hybrid screen, co-affinity purification, in vitro kinase assay, transcriptional reporter assay Molecular & cellular proteomics : MCP Medium 20368287
2012 GSK-3α silencing (but not GSK-3β silencing) reduces androgen receptor (AR) transcriptional activity in 22Rv1 prostate cancer cells; silencing of either isoform reduces colony formation. GSK-3β silencing but not GSK-3α silencing reduced Akt phosphorylation, demonstrating distinct isoform-specific signaling roles. siRNA gene silencing, AR transcriptional activity assay, colony formation assay, Western blot for pAkt International journal of cancer Medium 22539113
2017 Loss of GSK3A expression (via CRISPR KO) in AML cells confers resistance to FLT3 inhibitor AC220 by reactivating Wnt signaling, and SPRY3 expression is positioned downstream of GSK3A in this resistance pathway. Genome-wide CRISPR screen, GSK3A KO validation in AML cell lines and primary patient samples, Wnt signaling pathway analysis Cancer research Medium 28625976
2019 GSK-3 (including GSK3A) activity is negatively correlated with human sperm motility in an isoform-specific manner: inhibited (Ser-phosphorylated) GSK3A correlates strongly with progressive motility (r=0.822, p=0.023), whereas inhibited GSK3B does not. GSK3A interactors in sperm were identified by yeast two-hybrid and co-immunoprecipitation. Correlative analysis of GSK3 phosphorylation vs. motility in normospermic and asthenozoospermic samples, yeast two-hybrid, co-immunoprecipitation Molecular human reproduction Medium 30824926
2019 GSK3A/B inhibit ALDH1A2 (retinoic acid synthetic enzyme) expression via Wnt/β-catenin signaling in fetal kidney cells; CHIR99021 represses ALDH1A2, this effect is abolished when β-catenin is inhibited, and ChIP shows β-catenin recruitment to the ALDH1A2 promoter. GSK3A/B inhibitor (CHIR99021), β-catenin knockdown, ChIP, luciferase reporter assay Frontiers in cell and developmental biology Medium 32258025
2019 GSK3A and GSK3B are required for cerebellar granule neuron progenitor (CGNP) proliferation driven by SHH signaling; co-deletion of Gsk3a and Gsk3b blocks proliferation and causes severe cerebellar hypoplasia. Ctnnb1 co-deletion rescues hypoproliferation in Gsk3a/b mutants, demonstrating the GSK-3 effect is mediated through WNT/β-catenin. Co-deletion also blocks SHH-driven medulloblastoma growth. Conditional double Gsk3a/Gsk3b KO mice, Ctnnb1 genetic rescue, transcriptomic analysis, SmoM2 medulloblastoma model Development (Cambridge, England) High 31540917
2021 GSK3A-specific (Gsk3aΔ) neuronal knockout mice do not show resistance to MPTP-induced dopaminergic neurodegeneration, whereas Gsk3bΔ mice do; this establishes non-redundancy between isoforms in Parkinsonian neurodegeneration, with GSK3α dispensable for this process. Dopaminergic neuron-specific conditional Gsk3a KO and Gsk3b KO mice, MPTP model, dopaminergic neuron counting Frontiers in molecular neuroscience High 32581704
2021 GSK-3α contributes to T cell-mediated tumor rejection in a non-redundant manner with GSK-3β; Gsk3b−/− mice suppress tumor growth equivalently to Gsk3a/b double KO, whereas Gsk3a−/− behaves like wild-type. Both isoforms differentially regulate PD-1, IFNγ, and granzyme B expression and synergize to control PD-1 levels and CD4/CD8 T cell tumor infiltration. Conditional T cell-specific Gsk3a and Gsk3b KO mice, tumor growth assays, flow cytometry for PD-1/IFNγ/granzyme B iScience High 34142056
2014 GSK3A silencing abolishes growth of p53-null colon carcinoma cells after DNA-damaging chemotherapy by impairing DNA repair, enabling a necroptotic response (RIP1-independent, PARP-dependent AIF nuclear re-localization without caspase activation); GSK3A is redundant with GSK3B in this drug resistance mechanism. siRNA silencing of GSK3A/GSK3B, DNA damage assays, caspase activity, AIF localization, PARP inhibition PloS one Medium 24984063
2014 GSK3α deficiency in macrophages increases IL-10 production in response to endoplasmic reticulum stress; Gsk3a KO in LDLR-deficient mice attenuates atherosclerosis and hepatic steatosis, associated with elevated plasma IL-10 and enhanced ER stress-induced IL-10 in macrophages treated with GSK3α/β inhibitor CT99021. Gsk3a KO crossed with LDLR KO mice, high-fat diet model, macrophage IL-10 assay, CT99021 pharmacologic inhibition The American journal of pathology Medium 25451156
2016 GSK-3α is a direct transcriptional target of CREB in lung cancer cells; CREB knockdown reduces GSK3A expression, and CREB binds directly to the GSK3A promoter as shown by ChIP. GSK-3α inhibition suppresses cell viability, colony formation, and tumor growth in lung cancer. CREB siRNA knockdown, ChIP of CREB on GSK3A promoter, GSK-3α inhibition with loss-of-function assays PloS one Medium 27049759
2019 GSK3A and GSK3B phosphorylate MTHFR (methylenetetrahydrofolate reductase) at multiple N-terminal sites in vitro and in cells; CRISPR knockin of phospho-null MTHFR mutants showed that phosphorylation enhances SAM-dependent allosteric inhibition and controls one-carbon metabolism. In vitro kinase assay with GSK3A/B, CRISPR knockin phospho-null mutants, 5-methyl-THF production assay Scientific reports Medium 30862944
2023 Genetic or chemical inhibition of GSK3A leads to increased long-range chromatin looping interactions in a genome-wide and cohesin-dependent manner, implicating GSK3A in the regulation of nuclear architecture. HiDRO high-throughput Oligopaint imaging screen, GSK3A genetic inhibition, cohesin-dependence validation Nature Medium 37438531
2022 GSK3A-specific neuronal deletion (Camk2a-Cre driven Gsk3a KO) in adult mice enhances long-term potentiation (LTP) in CA1 hippocampal neurons without affecting basal synaptic function; deletion of Gsk3b does not produce this effect, demonstrating a unique postsynaptic role of GSK3α in limiting LTP. Conditional CaMK2a-Cre Gsk3a KO and Gsk3b KO mice, hippocampal slice electrophysiology, LTP measurement Frontiers in molecular neuroscience High 35782378
2024 Gsk3a promotes immune evasion in hepatocellular carcinoma by inducing neutrophil chemotaxis and neutrophil extracellular trap (NET) formation through the intermediate molecule LRG1, which suppresses cytotoxic T lymphocyte (CTL) function; identified by CRISPR screening in immunocompetent vs. immune-deficient mice. CRISPR in vivo screen, flow cytometry for immune infiltration, RNA sequencing of neutrophils, Gsk3a KO in HCC model Journal for immunotherapy of cancer Medium 39174053
2025 GSK3A promotes human adenovirus B7 (HAdV-B7) replication through its kinase activity; kinase-active S21A mutant enhances, while kinase-inactive Y279A and K148A mutants fail to support, viral replication. GSK3A phosphorylates the viral L4-22K protein at S78 and S81 via direct interaction between GSK3A's kinase domain and residues 92-168 of L4-22K. cDNA gain-of-function screen, GSK3A overexpression/KO/KD, kinase-dead mutants, phosphoproteomics, co-immunoprecipitation, structural modeling and truncation assays Life science alliance High 40537285
2019 SARS-CoV-2 nucleocapsid R203K/G204R mutant protein shows increased interaction with GSK3A kinase simultaneously with hyper-phosphorylation of adjacent serine site S206, as revealed by comparative biochemical analysis of mutant versus wild-type N protein. Comparative biochemical analysis, co-immunoprecipitation with GSK3A, phosphorylation site mapping Nature communications Medium 35105893
2024 GSK3A was validated as a direct binding target of quercetin by CETSA-MS, Western blot, molecular docking, site-directed mutagenesis, and pull-down assays, showing that quercetin stabilizes GSK3A protein in cells. CETSA-MS proteomics, Western blot, molecular docking, site-directed mutagenesis, pull-down assay European journal of medicinal chemistry Medium 38342014
2017 GSK3A was confirmed as a MYC-interacting protein in live cancer cells using NanoLuc-based protein-fragment complementation assay (NanoPCA), with interaction validated by co-immunoprecipitation of endogenous proteins. NanoPCA protein-fragment complementation assay, co-immunoprecipitation of endogenous proteins Molecular pharmacology Medium 28087810
2021 GSK3A KO combined with inducible GSK3B shRNA knockdown in Merkel cell carcinoma (MCC) cells suppresses T-antigen (TA) transcription and MCC cell growth; individual GSK3A KO alone confirmed involvement of GSK3A in TA expression regulation. GSK3A CRISPR KO, inducible GSK3B shRNA, TA expression analysis, MCC xenograft model Cancer letters Medium 34715251
2022 MYCT1 promotes translation of GSK3A (along with PGM1 and UGP2) in hepatic cells via a RACK1-dependent mechanism; global Myct1 inactivation in mice leads to progressive hepatic glycogen accumulation and reduced GSK3A protein, establishing GSK3A as a translationally regulated component of the glycogen shunt. Global Myct1 KO mice, liver glycogen assay, RACK1-dependent translation analysis, Western blot iScience Medium 35281731
2021 GSK3A activity is abnormally elevated during sperm cryopreservation and is identified as the key kinase regulating sperm motility-associated phosphorylation; a GSK3A-centric phosphorylation network was constructed from quantitative phosphoproteomics of fresh vs. cryopreserved sperm. Quantitative phosphoproteomics, kinase enrichment analysis, Western blot for GSK3A activation state Bioscience reports Low 34596222
2024 CCDC28A interacts with GSK3A in sperm (co-immunoprecipitation), and Ccdc28a KO mice show sperm phenotypes overlapping with those of Gsk3a-deficient mice (bent sperm heads, acrosomal defects, reduced motility). Co-immunoprecipitation, Ccdc28a KO mouse, sperm morphology and motility analysis Cellular and molecular life sciences : CMLS Low 38597936
2025 GSK3A (together with GSK3B) functions within the β-catenin destruction complex to phosphorylate β-catenin, promoting its degradation; HUWE1 antagonizes this activity to enhance WNT signaling. In cells lacking CSNK1A1, a residual destruction complex containing APC, AXIN1, and GSK3A/B still phosphorylates β-catenin. HUWE1 loss enhanced GSK3A/B-dependent CTNNB1 phosphorylation. A CTNNB1 variant insensitive to destruction complex phosphorylation still showed reduced WNT signaling upon HUWE1 loss, revealing a GSK3A/B-dependent but β-catenin stability-independent mechanism. CSNK1A1 KO cells, HUWE1 KO, CTNNB1 phospho-resistant knockin, genetic interaction analysis, WNT reporter assay PLoS genetics High 40424469

Source papers

Stage 0 corpus · 94 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer research 835 9515795
2015 Epigenetic regulation in human melanoma: past and future. Epigenetics 239 25587943
2011 Gene networks driving bovine mammary protein synthesis during the lactation cycle. Bioinformatics and biology insights 231 21698073
2013 GSK-3α is a central regulator of age-related pathologies in mice. The Journal of clinical investigation 144 23549082
2018 Phytosomal curcumin inhibits tumor growth in colitis-associated colorectal cancer. Journal of cellular physiology 135 29737515
2021 Targeting the coronavirus nucleocapsid protein through GSK-3 inhibition. Proceedings of the National Academy of Sciences of the United States of America 89 34593624
2008 Lithium reduces Gsk3b mRNA levels: implications for Alzheimer Disease. European archives of psychiatry and clinical neuroscience 82 18932008
2017 A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220. Cancer research 76 28625976
2008 GSK-3beta in mouse fibroblasts controls wound healing and fibrosis through an endothelin-1-dependent mechanism. The Journal of clinical investigation 66 18802478
2020 GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib. Frontiers in molecular neuroscience 64 32581704
2015 Targeted disruption of glycogen synthase kinase 3A (GSK3A) in mice affects sperm motility resulting in male infertility. Biology of reproduction 58 25568307
2020 Targeting bioenergetics prevents CD4 T cell-mediated activation of synovial fibroblasts in rheumatoid arthritis. Rheumatology (Oxford, England) 55 32047926
2019 Phenotypic stability of the human MG-63 osteoblastic cell line at different passages. Cell biology international 55 30444078
2017 Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing. The Journal of biological chemistry 54 28916722
2019 Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome. Cell chemical biology 53 30982749
2007 Insulin signaling in mouse oocytes. Biology of reproduction 52 17625112
2012 Distinct expression and activity of GSK-3α and GSK-3β in prostate cancer. International journal of cancer 49 22539113
2010 Interactome mapping of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway identifies deformed epidermal autoregulatory factor-1 as a new glycogen synthase kinase-3 interactor. Molecular & cellular proteomics : MCP 49 20368287
2022 SARS-CoV-2 genomes from Saudi Arabia implicate nucleocapsid mutations in host response and increased viral load. Nature communications 48 35105893
2015 In vitro activity of the mTOR inhibitor everolimus, in a large panel of breast cancer cell lines and analysis for predictors of response. Breast cancer research and treatment 47 25663547
2019 Estrogen receptor alpha regulates the Wnt/β-catenin signaling pathway in colon cancer by targeting the NOD-like receptors. Cellular signalling 44 31121307
2010 Identification and regulation of glycogen synthase kinase-3 during bovine embryo development. Reproduction (Cambridge, England) 44 20427566
2012 GSK-3α and GSK-3β proteins are involved in early stages of chondrocyte differentiation with functional redundancy through RelA protein phosphorylation. The Journal of biological chemistry 42 22761446
2023 High-throughput Oligopaint screen identifies druggable 3D genome regulators. Nature 40 37438531
2018 Phytosomal-curcumin antagonizes cell growth and migration, induced by thrombin through AMP-Kinase in breast cancer. Journal of cellular biochemistry 39 29600521
2017 miR-34a Regulates Sperm Motility in Zebrafish. International journal of molecular sciences 37 29232857
2006 DOCA-induced phosphorylation of glycogen synthase kinase 3beta. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 34 16543730
2019 Regulation of folate and methionine metabolism by multisite phosphorylation of human methylenetetrahydrofolate reductase. Scientific reports 33 30862944
2023 New insights into the role of GSK-3β in the brain: from neurodegenerative disease to tumorigenesis. PeerJ 32 38107562
2010 Protein kinases A and C and phosphatidylinositol 3 kinase regulate glycogen synthase kinase-3A serine 21 phosphorylation in boar spermatozoa. Journal of cellular biochemistry 29 19911376
2014 GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis. PloS one 27 24984063
2014 Glycogen synthase kinase 3α deficiency attenuates atherosclerosis and hepatic steatosis in high fat diet-fed low density lipoprotein receptor-deficient mice. The American journal of pathology 26 25451156
2013 rbm47, a novel RNA binding protein, regulates zebrafish head development. Developmental dynamics : an official publication of the American Association of Anatomists 26 24038582
2022 Environmental concentrations of benzophenone-3 disturbed lipid metabolism in the liver of clown anemonefish (Amphiprion ocellaris). Environmental pollution (Barking, Essex : 1987) 25 36473638
2017 AKT1, LKB1, and YAP1 Revealed as MYC Interactors with NanoLuc-Based Protein-Fragment Complementation Assay. Molecular pharmacology 25 28087810
2023 Caffeic acid phenethyl ester suppresses EGFR/FAK/Akt signaling, migration, and tumor growth of prostate cancer cells. Phytomedicine : international journal of phytotherapy and phytopharmacology 23 37201366
2019 Isoform-specific GSK3A activity is negatively correlated with human sperm motility. Molecular human reproduction 23 30824926
2019 Non-invasive Potential Circulating mRNA Markers for Colorectal Adenoma Using Targeted Sequencing. Scientific reports 23 31506480
2018 Neonatal-Onset Chronic Diarrhea Caused by Homozygous Nonsense WNT2B Mutations. American journal of human genetics 23 29909964
2016 Analysis of PI3K pathway components in human cancers. Oncology letters 23 27073576
2015 Novel 3-Substituted 7-Phenylpyrrolo[3,2-f]quinolin-9(6H)-ones as Single Entities with Multitarget Antiproliferative Activity. Journal of medicinal chemistry 22 26418966
2023 Downregulation of PI3K/AKT/mTOR Pathway in Juglone-Treated Bovine Oocytes. Antioxidants (Basel, Switzerland) 21 36670976
2016 GSK-3α Is a Novel Target of CREB and CREB-GSK-3α Signaling Participates in Cell Viability in Lung Cancer. PloS one 19 27049759
2019 A six-inhibitor culture medium for improving naïve-type pluripotency of porcine pluripotent stem cells. Cell death discovery 18 31240131
2024 Targeting Gsk3a reverses immune evasion to enhance immunotherapy in hepatocellular carcinoma. Journal for immunotherapy of cancer 17 39174053
2019 Phosphoproteomic Profiling Identifies Aberrant Activation of Integrin Signaling in Aggressive Non-Type Bladder Carcinoma. Journal of clinical medicine 17 31108958
2019 GSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma. Development (Cambridge, England) 17 31540917
2021 Identifying RNA Biomarkers and Molecular Pathways Involved in Multiple Subtypes of Uveitis. American journal of ophthalmology 16 33503442
2016 Identification of breast cancer candidate genes using gene co-expression and protein-protein interaction information. Oncotarget 15 27150055
2015 Comprehensive assessment of expression of insulin signaling pathway components in subcutaneous adipose tissue of women with and without polycystic ovary syndrome. Journal of clinical & translational endocrinology 15 26236647
2022 PU.1 and MYC transcriptional network defines synergistic drug responses to KIT and LSD1 inhibition in acute myeloid leukemia. Leukemia 14 35590033
2021 Cardiomyocyte-produced miR-339-5p mediates pathology in Duchenne muscular dystrophy cardiomyopathy. Human molecular genetics 14 34270708
2023 Machine learning-based predictive models and drug prediction for schizophrenia in multiple programmed cell death patterns. Frontiers in molecular neuroscience 13 36993785
2015 Profiling of differentially expressed genes in sheep T lymphocytes response to an artificial primary Haemonchus contortus infection. Parasites & vectors 13 25903558
2014 PCI-24781 down-regulates EZH2 expression and then promotes glioma apoptosis by suppressing the PIK3K/Akt/mTOR pathway. Genetics and molecular biology 13 25505847
2020 Mtrr hypomorphic mutation alters liver morphology, metabolism and fuel storage in mice. Molecular genetics and metabolism reports 12 32257815
2019 A kinome-wide shRNA screen uncovers vaccinia-related kinase 3 (VRK3) as an essential gene for diffuse intrinsic pontine glioma survival. Oncogene 12 31324890
2024 Quantitative phosphoproteomics explain cryopreservation-induced reductions in ram sperm motility. Journal of proteomics 11 38438079
2021 Non-redundant activity of GSK-3α and GSK-3β in T cell-mediated tumor rejection. iScience 11 34142056
2021 Quantitative phosphoproteomics reveals GSK3A substrate network is involved in the cryodamage of sperm motility. Bioscience reports 11 34596222
2021 Inhibition of T-antigen expression promoting glycogen synthase kinase 3 impairs merkel cell carcinoma cell growth. Cancer letters 11 34715251
2020 Evaluation of the Serum Dkk-1, Tenascin-C, Oxidative Stress Markers Levels and Wnt Signaling Pathway Genes Expression in Patients with Alzheimer's Disease. Journal of molecular neuroscience : MN 11 32935274
2015 Loss of glycogen synthase kinase 3 isoforms during murine oocyte growth induces offspring cardiac dysfunction. Biology of reproduction 10 25833158
2024 CETSA-MS-based target profiling of anti-aging natural compound quercetin. European journal of medicinal chemistry 9 38342014
2023 Ultrarare Missense Variants Implicated in Utah Pedigrees Multiply Affected With Schizophrenia. Biological psychiatry global open science 9 37881554
2022 Downregulation of circular RNA circ-HN1 suppressed the progression of gastric cancer through the miR-485-5p/GSK3A pathway. Bioengineered 9 34607506
2022 MYCT1 alters the glycogen shunt by regulating selective translation of RACK1-mediated enzymes. iScience 9 35281731
2021 Glycogen synthase kinase 3 alpha/beta deletion induces precocious growth plate remodeling in mice. Journal of molecular medicine (Berlin, Germany) 9 33609145
2024 CCDC28A deficiency causes sperm head defects, reduced sperm motility and male infertility in mice. Cellular and molecular life sciences : CMLS 8 38597936
2021 Targeting the Coronavirus Nucleocapsid Protein through GSK-3 Inhibition. medRxiv : the preprint server for health sciences 8 33655282
2017 Influence of TGF-β1 on tumor transition in oral cancer cell and BMSC co-cultures. Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery 8 28318921
2020 Inhibition of GSK3 Represses the Expression of Retinoic Acid Synthetic Enzyme ALDH1A2 via Wnt/β-Catenin Signaling in WiT49 Cells. Frontiers in cell and developmental biology 7 32258025
2025 Proteome-wide Mendelian randomization identifies causal plasma proteins in prostate cancer development. Human genomics 6 39994764
2025 Citrulline Inhibits Clostridioides difficile Infection With Anti-inflammatory Effects. Cellular and molecular gastroenterology and hepatology 5 39923847
2023 The non-invasive diagnosis of colorectal cancer via a SOX9-based gene panel. Clinical and experimental medicine 5 36637582
2022 Specific Role for GSK3α in Limiting Long-Term Potentiation in CA1 Pyramidal Neurons of Adult Mouse Hippocampus. Frontiers in molecular neuroscience 5 35782378
2025 Differential impact of hepatitis delta virus replication and expression of viral antigens on the cellular kinome profile. Cell communication and signaling : CCS 4 40537790
2024 DVL/GSK3/ISL1 pathway signaling: unraveling the mechanism of SIRT3 in neurogenesis and AD therapy. Stem cell research & therapy 4 39267160
2024 Altered hepatic metabolic landscape and insulin sensitivity in response to pulmonary tuberculosis. PLoS pathogens 4 39331683
2023 Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD). Current issues in molecular biology 4 37185710
2022 Effects of heroin self-administration and forced withdrawal on the expression of genes related to the mTOR network in the basolateral complex of the amygdala of male Lewis rats. Psychopharmacology 4 35467104
2024 O-GlcNAcylation regulates osteoblast differentiation through the morphological changes in mitochondria, cytoskeleton, and endoplasmic reticulum. BioFactors (Oxford, England) 3 39405562
2023 Active Ingredient Paeonol of Jijiu Huiyang Decoction Alleviates Isoproterenol-Induced Chronic Heart Failure via the GSK3A/PPARα Pathway. Oxidative medicine and cellular longevity 3 36785789
2026 High-content screening of organoids reveals the mechanisms of human pancreas acinar specification. Cell stem cell 2 41570824
2025 The ubiquitin ligase HUWE1 enhances WNT signaling by antagonizing destruction complex-mediated β-catenin degradation and through a mechanism independent of changes in β-catenin abundance. PLoS genetics 2 40424469
2025 GSK3A promotes human adenovirus replication and phosphorylates viral L4-22K protein. Life science alliance 2 40537285
2025 The Abnormal ERα-miRNA Cross-Talk in AD-Affected Human Hippocampus: A Bioinformatics Perspective. Molecular neurobiology 1 39966328
2025 Nicotinamide dual treatment enhances morula-to-blastocyst transition through binding to Zonula Occludens-1 protein. Theriogenology 1 39987859
2024 QM107, a novel CD148 (RTP Type J) activating peptide therapy for treating neovascular age-related macular degeneration. British journal of pharmacology 1 39428594
2025 Comparative RNA-Seq analysis of differentially expressed genes in the sertoli cells of yak and cattle-yak. BMC veterinary research 0 39987073
2025 Deciphering pathogenic mechanisms of BDCPP exposure in endometrial cancer progression via an integrated approach combining network toxicology, machine learning, and molecular docking. International journal of surgery (London, England) 0 40990645
2025 Identification of Biomarkers for Right Ventricular Dysfunction in Idiopathic Dilated Cardiomyopathy Via Urinary Proteomics and Machine Learning. Journal of the American Heart Association 0 41404738
2024 The ubiquitin ligase HUWE1 enhances WNT signaling by antagonizing destruction complex-mediated β-catenin degradation and through a mechanism independent of β-catenin stability. bioRxiv : the preprint server for biology 0 38410441
2023 Retracted: Active Ingredient Paeonol of Jijiu Huiyang Decoction Alleviates Isoproterenol-Induced Chronic Heart Failure via the GSK3A/PPARα Pathway. Oxidative medicine and cellular longevity 0 37745835

Missed literature

Know a paper Affinage missed for GSK3A? Flag it for the maintainers and the community.

No submissions yet.