Glycogen synthase kinase-3 beta (GSK-3beta, also tau protein kinase I) is a constitutively active, proline-directed serine/threonine protein kinase that prefers substrates pre-phosphorylated (primed) at a site four residues C-terminal to the target. Its activity is switched off by phosphorylation of Ser-9 by AKT/PKB, PKA, CaMKII and other kinases downstream of insulin, growth factors, depolarisation and mechanical strain, and supported by Tyr-216 phosphorylation. GSK3B inhibits glycogen synthase and so restrains glycogen synthesis; in the Axin/APC beta-catenin destruction complex it phosphorylates beta-catenin, targeting it for SCF(beta-TrCP) ubiquitination and proteasomal degradation, which keeps canonical Wnt signalling off. It also phosphorylates microtubule-associated proteins (tau, CRMP2, APC, MACF1), shaping microtubule organisation, axon-dendrite polarity and dendrite growth, and at glutamatergic synapses it phosphorylates PSD-95 Thr-19 to enable AMPA receptor removal during NMDA receptor-dependent long-term depression. Further substrates include transcription factors (JUN, NFATC1, SNAI1, GLI2/3), circadian clock proteins and apoptosis regulators, giving context-dependent pro- or anti-apoptotic effects. GSK3B is mainly cytosolic, with nuclear, centrosomal, membrane-associated and mitochondrial pools, and is abundant in brain.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000320 re-entry into mitotic cell cycle | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Mouse knockout phenotype (re-entry into mitotic cycle); GSK3B does not execute cell-cycle re-entry. Reason: acts_upstream_of_or_within ISO from mouse Gsk3b reflects a mutant phenotype downstream of many GSK3B substrates; it does not identify a step GSK3B performs. Over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0001558 regulation of cell growth | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Broad regulation of cell growth from a mouse phenotype. Reason: acts_upstream_of_or_within ISO from mouse Gsk3b; a pleiotropic growth phenotype of a kinase with dozens of substrates. Too indirect to be informative. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0001837 epithelial to mesenchymal transition | ISO GO_REF:0000121 | MODIFY | Summary: GSK3B restrains EMT (via SNAI1 degradation); the sign-neutral EMT term should be the negative-regulation term. Reason: GSK3B does not execute EMT; it phosphorylates SNAI1, leading to its ubiquitination and degradation, which inhibits EMT. The gene already carries GO:0010719 negative regulation of epithelial to mesenchymal transition from the same donor. Lateral correction from the process to its negative regulation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: negative regulation of epithelial to mesenchymal transition Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation |
| GO:0001837 epithelial to mesenchymal transition | ISS GO_REF:0000024 | MODIFY | Summary: GSK3B restrains EMT (via SNAI1 degradation); the sign-neutral EMT term should be the negative-regulation term. Reason: GSK3B does not execute EMT; it phosphorylates SNAI1, leading to its ubiquitination and degradation, which inhibits EMT. The gene already carries GO:0010719 negative regulation of epithelial to mesenchymal transition from the same donor. Lateral correction from the process to its negative regulation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: negative regulation of epithelial to mesenchymal transition Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation |
| GO:0001954 positive regulation of cell-matrix adhesion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of cell-matrix adhesion: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0002020 protease binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Protease binding (MMP2 interaction) transferred from human GSK3B. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Interacts with ARRB2, AXIN1, CABYR, DISC1, MMP2, MUC1, NIN, PRUNE1 and ZBED3 |
| GO:0002039 p53 binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: p53 binding transferred from human GSK3B. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: Protein kinase activity is correct but less specific than the established Ser/Thr kinase activity. Reason: GSK3B is a Ser/Thr protein kinase (rat IDA rows for GO:0004674 exist, e.g. PMID:2164470). Protein kinase activity is a correct but general parent; refine to protein serine/threonine kinase activity, which the gene already carries. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells |
| GO:0004672 protein kinase activity | ISO GO_REF:0000121 | MODIFY | Summary: Protein kinase activity is correct but less specific than the established Ser/Thr kinase activity. Reason: GSK3B is a Ser/Thr protein kinase (rat IDA rows for GO:0004674 exist, e.g. PMID:2164470). Protein kinase activity is a correct but general parent; refine to protein serine/threonine kinase activity, which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells |
| GO:0004672 protein kinase activity | ISO GO_REF:0000121 | MODIFY | Summary: Protein kinase activity is correct but less specific than the established Ser/Thr kinase activity. Reason: GSK3B is a Ser/Thr protein kinase (rat IDA rows for GO:0004674 exist, e.g. PMID:2164470). Protein kinase activity is a correct but general parent; refine to protein serine/threonine kinase activity, which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells |
| GO:0004672 protein kinase activity | ISS GO_REF:0000024 | MODIFY | Summary: Protein kinase activity is correct but less specific than the established Ser/Thr kinase activity. Reason: GSK3B is a Ser/Thr protein kinase (rat IDA rows for GO:0004674 exist, e.g. PMID:2164470). Protein kinase activity is a correct but general parent; refine to protein serine/threonine kinase activity, which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:11035810 Phosphorylation and inactivation of glycogen synthase kinase... | ACCEPT | Summary: Core catalytic activity: constitutively active, priming-dependent protein Ser/Thr kinase. Reason: Rat GSK-3beta clones are active kinases (PMID:2164470), recombinant protein has autonomous protein kinase activity (PMID:1346104), and its Ser/Thr kinase activity is measured and regulated in rat brain and hippocampal slices (PMID:16879317, PMID:17329210) and on Axin/beta-catenin (PMID:9482734). Kinase domain and ATP-binding signatures are present. Supporting Evidence: PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells PMID:1346104 The protein has autonomous protein kinase activity PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt Requires primed phosphorylation of the majority of its substrates file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:16879317 Melatonin arrests peroxynitrite-induced tau hyperphosphoryla... | ACCEPT | Summary: Core catalytic activity: constitutively active, priming-dependent protein Ser/Thr kinase. Reason: Rat GSK-3beta clones are active kinases (PMID:2164470), recombinant protein has autonomous protein kinase activity (PMID:1346104), and its Ser/Thr kinase activity is measured and regulated in rat brain and hippocampal slices (PMID:16879317, PMID:17329210) and on Axin/beta-catenin (PMID:9482734). Kinase domain and ATP-binding signatures are present. Supporting Evidence: PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells PMID:1346104 The protein has autonomous protein kinase activity PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt Requires primed phosphorylation of the majority of its substrates file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:17329210 LTP inhibits LTD in the hippocampus via regulation of GSK3be... | ACCEPT | Summary: Core catalytic activity: constitutively active, priming-dependent protein Ser/Thr kinase. Reason: Rat GSK-3beta clones are active kinases (PMID:2164470), recombinant protein has autonomous protein kinase activity (PMID:1346104), and its Ser/Thr kinase activity is measured and regulated in rat brain and hippocampal slices (PMID:16879317, PMID:17329210) and on Axin/beta-catenin (PMID:9482734). Kinase domain and ATP-binding signatures are present. Supporting Evidence: PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells PMID:1346104 The protein has autonomous protein kinase activity PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt Requires primed phosphorylation of the majority of its substrates file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:2164470 Molecular cloning and expression of glycogen synthase kinase... | ACCEPT | Summary: Core catalytic activity: constitutively active, priming-dependent protein Ser/Thr kinase. Reason: Rat GSK-3beta clones are active kinases (PMID:2164470), recombinant protein has autonomous protein kinase activity (PMID:1346104), and its Ser/Thr kinase activity is measured and regulated in rat brain and hippocampal slices (PMID:16879317, PMID:17329210) and on Axin/beta-catenin (PMID:9482734). Kinase domain and ATP-binding signatures are present. Supporting Evidence: PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells PMID:1346104 The protein has autonomous protein kinase activity PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt Requires primed phosphorylation of the majority of its substrates file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:9482734 Axin, a negative regulator of the Wnt signaling pathway, for... | ACCEPT | Summary: Core catalytic activity: constitutively active, priming-dependent protein Ser/Thr kinase. Reason: Rat GSK-3beta clones are active kinases (PMID:2164470), recombinant protein has autonomous protein kinase activity (PMID:1346104), and its Ser/Thr kinase activity is measured and regulated in rat brain and hippocampal slices (PMID:16879317, PMID:17329210) and on Axin/beta-catenin (PMID:9482734). Kinase domain and ATP-binding signatures are present. Supporting Evidence: PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells PMID:1346104 The protein has autonomous protein kinase activity PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt Requires primed phosphorylation of the majority of its substrates file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core catalytic activity: constitutively active, priming-dependent protein Ser/Thr kinase. Reason: Rat GSK-3beta clones are active kinases (PMID:2164470), recombinant protein has autonomous protein kinase activity (PMID:1346104), and its Ser/Thr kinase activity is measured and regulated in rat brain and hippocampal slices (PMID:16879317, PMID:17329210) and on Axin/beta-catenin (PMID:9482734). Kinase domain and ATP-binding signatures are present. Supporting Evidence: PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells PMID:1346104 The protein has autonomous protein kinase activity PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt Requires primed phosphorylation of the majority of its substrates file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] |
| GO:0004674 protein serine/threonine kinase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Core catalytic activity: constitutively active, priming-dependent protein Ser/Thr kinase. Reason: Rat GSK-3beta clones are active kinases (PMID:2164470), recombinant protein has autonomous protein kinase activity (PMID:1346104), and its Ser/Thr kinase activity is measured and regulated in rat brain and hippocampal slices (PMID:16879317, PMID:17329210) and on Axin/beta-catenin (PMID:9482734). Kinase domain and ATP-binding signatures are present. Supporting Evidence: PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells PMID:1346104 The protein has autonomous protein kinase activity PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt Requires primed phosphorylation of the majority of its substrates file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] |
| GO:0004674 protein serine/threonine kinase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Core catalytic activity: constitutively active, priming-dependent protein Ser/Thr kinase. Reason: Rat GSK-3beta clones are active kinases (PMID:2164470), recombinant protein has autonomous protein kinase activity (PMID:1346104), and its Ser/Thr kinase activity is measured and regulated in rat brain and hippocampal slices (PMID:16879317, PMID:17329210) and on Axin/beta-catenin (PMID:9482734). Kinase domain and ATP-binding signatures are present. Supporting Evidence: PMID:2164470 Both alpha and beta clones exhibit kinase activity when expressed in COS-1 cells PMID:1346104 The protein has autonomous protein kinase activity PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase file:rat/Gsk3b/Gsk3b-uniprot.txt Requires primed phosphorylation of the majority of its substrates file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] |
| GO:0005178 integrin binding | IPI PMID:18677563 Dp71f modulates GSK3-beta recruitment to the beta1-integrin ... | MARK AS OVER ANNOTATED | Summary: Integrin binding over-states recruitment of GSK3B to the beta1-integrin adhesion complex. Reason: The cached abstract (full text unavailable) shows co-IP of GSK3-beta with Dp71f and reduced recruitment of GSK3-beta to the beta1-integrin complex when Dp71f is reduced. This supports association with an integrin-containing complex, likely via Dp71f/ILK, rather than direct binding of integrin by GSK3B. Not removed because the full text was not read. Supporting Evidence: PMID:18677563 GSK3-beta is recruited to the beta1-integrin complex PMID:18677563 an interaction between Dp71f and GSK3-beta occurs |
| GO:0005515 protein binding | IPI PMID:10228155 An F-box protein, FWD1, mediates ubiquitin-dependent proteol... | REMOVE | Summary: Bare protein binding is uninformative; the Axin interaction is captured by destruction-complex and beta-catenin-binding terms. Reason: Per the protein-binding policy, GO:0005515 is removed as uninformative; this does not dispute the interaction. GSK3B-Axin interaction (PMID:9482734, PMID:10228155) is represented by GO:0030877 beta-catenin destruction complex and GO:0097110 scaffold protein binding. Supporting Evidence: PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC |
| GO:0005515 protein binding | IPI PMID:9482734 Axin, a negative regulator of the Wnt signaling pathway, for... | REMOVE | Summary: Bare protein binding is uninformative; the Axin interaction is captured by destruction-complex and beta-catenin-binding terms. Reason: Per the protein-binding policy, GO:0005515 is removed as uninformative; this does not dispute the interaction. GSK3B-Axin interaction (PMID:9482734, PMID:10228155) is represented by GO:0030877 beta-catenin destruction complex and GO:0097110 scaffold protein binding. Supporting Evidence: PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC |
| GO:0005524 ATP binding | IDA PMID:16879317 Melatonin arrests peroxynitrite-induced tau hyperphosphoryla... | KEEP AS NON CORE | Summary: ATP binding is correct for a protein kinase but is part of the catalytic mechanism rather than an informative function. Reason: The kinase domain carries the PROSITE ATP-binding signature and binding sites for ATP; ATP binding follows from kinase activity. As precise as warranted for this aspect, but peripheral to the informative kinase activity term. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt PS00107; PROTEIN_KINASE_ATP file:rat/Gsk3b/Gsk3b-uniprot.txt PF00069; Pkinase |
| GO:0005524 ATP binding | IDA PMID:17329210 LTP inhibits LTD in the hippocampus via regulation of GSK3be... | KEEP AS NON CORE | Summary: ATP binding is correct for a protein kinase but is part of the catalytic mechanism rather than an informative function. Reason: The kinase domain carries the PROSITE ATP-binding signature and binding sites for ATP; ATP binding follows from kinase activity. As precise as warranted for this aspect, but peripheral to the informative kinase activity term. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt PS00107; PROTEIN_KINASE_ATP file:rat/Gsk3b/Gsk3b-uniprot.txt PF00069; Pkinase |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ATP binding is correct for a protein kinase but is part of the catalytic mechanism rather than an informative function. Reason: The kinase domain carries the PROSITE ATP-binding signature and binding sites for ATP; ATP binding follows from kinase activity. As precise as warranted for this aspect, but peripheral to the informative kinase activity term. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt PS00107; PROTEIN_KINASE_ATP file:rat/Gsk3b/Gsk3b-uniprot.txt PF00069; Pkinase |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: A nuclear pool of GSK3B phosphorylates transcription factors. Reason: GSK3B phosphorylates nuclear transcription factors such as JUN and NFATC1 (promoting NFAT nuclear export), which requires a nuclear pool; UniProt records nuclear localisation by similarity to human. Nucleus is not covered by the root-organelle policy; retained as a core location. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Nucleus {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: A nuclear pool of GSK3B phosphorylates transcription factors. Reason: GSK3B phosphorylates nuclear transcription factors such as JUN and NFATC1 (promoting NFAT nuclear export), which requires a nuclear pool; UniProt records nuclear localisation by similarity to human. Nucleus is not covered by the root-organelle policy; retained as a core location. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Nucleus {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain |
| GO:0005634 nucleus | ISO GO_REF:0000121 | ACCEPT | Summary: A nuclear pool of GSK3B phosphorylates transcription factors. Reason: GSK3B phosphorylates nuclear transcription factors such as JUN and NFATC1 (promoting NFAT nuclear export), which requires a nuclear pool; UniProt records nuclear localisation by similarity to human. Nucleus is not covered by the root-organelle policy; retained as a core location. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Nucleus {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain |
| GO:0005634 nucleus | ISO GO_REF:0000121 | ACCEPT | Summary: A nuclear pool of GSK3B phosphorylates transcription factors. Reason: GSK3B phosphorylates nuclear transcription factors such as JUN and NFATC1 (promoting NFAT nuclear export), which requires a nuclear pool; UniProt records nuclear localisation by similarity to human. Nucleus is not covered by the root-organelle policy; retained as a core location. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Nucleus {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: A nuclear pool of GSK3B phosphorylates transcription factors. Reason: GSK3B phosphorylates nuclear transcription factors such as JUN and NFATC1 (promoting NFAT nuclear export), which requires a nuclear pool; UniProt records nuclear localisation by similarity to human. Nucleus is not covered by the root-organelle policy; retained as a core location. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Nucleus {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain |
| GO:0005654 nucleoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Nucleoplasmic localisation transferred from human GSK3B. Reason: Consistent with the nuclear pool that acts on transcription factors; sound ortholog transfer. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Nucleus {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: Cytoplasm is correct but less specific than cytosol, where the soluble GSK3B pool and the destruction complex reside. Reason: GSK3B is a soluble cytoplasmic kinase; its cytoplasmic activity (destruction complex, glycogen synthase, tau) is cytosolic, and the gene already carries GO:0005829 cytosol (IBA, ISO, Reactome TAS). Refine cytoplasm to cytosol. Organelle pools (mitochondria) are captured separately. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: AGI_LocusCode:AT3G05840 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. AGI_LocusCode:AT4G18710 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. FB:FBgn0003371 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. MGI:MGI:1861437 Β· mouse Gsk3b SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. UniProtKB:Q388M1 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. UniProtKB:Q60EZ2 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. dictyBase:DDB_G0272110 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: cytosol Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: Cytoplasm is correct but less specific than cytosol, where the soluble GSK3B pool and the destruction complex reside. Reason: GSK3B is a soluble cytoplasmic kinase; its cytoplasmic activity (destruction complex, glycogen synthase, tau) is cytosolic, and the gene already carries GO:0005829 cytosol (IBA, ISO, Reactome TAS). Refine cytoplasm to cytosol. Organelle pools (mitochondria) are captured separately. Proposed replacements: cytosol Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | MODIFY | Summary: Cytoplasm is correct but less specific than cytosol, where the soluble GSK3B pool and the destruction complex reside. Reason: GSK3B is a soluble cytoplasmic kinase; its cytoplasmic activity (destruction complex, glycogen synthase, tau) is cytosolic, and the gene already carries GO:0005829 cytosol (IBA, ISO, Reactome TAS). Refine cytoplasm to cytosol. Organelle pools (mitochondria) are captured separately. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: cytosol Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | MODIFY | Summary: Cytoplasm is correct but less specific than cytosol, where the soluble GSK3B pool and the destruction complex reside. Reason: GSK3B is a soluble cytoplasmic kinase; its cytoplasmic activity (destruction complex, glycogen synthase, tau) is cytosolic, and the gene already carries GO:0005829 cytosol (IBA, ISO, Reactome TAS). Refine cytoplasm to cytosol. Organelle pools (mitochondria) are captured separately. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: cytosol Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0005813 centrosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Centrosomal pool of GSK3B, consistent with its role in centrosome polarisation. Reason: In rat astrocytes Par6-PKCzeta regulates GSK-3beta to polarise the centrosome (PMID:12610628). Ortholog transfer is sound; location is peripheral. Supporting Evidence: PMID:12610628 Par6-PKCzeta interacts directly with and regulates glycogen synthase kinase-3beta (GSK-3beta) to promote polarization of the centrosome |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosol is the main site of GSK3B activity (destruction complex, glycogen synthase, tau). Reason: GSK3B is a soluble kinase acting on cytosolic substrates; the beta-catenin destruction complex is cytosolic. IBA, ISO and Reactome rows agree. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Cytosol is the main site of GSK3B activity (destruction complex, glycogen synthase, tau). Reason: GSK3B is a soluble kinase acting on cytosolic substrates; the beta-catenin destruction complex is cytosolic. IBA, ISO and Reactome rows agree. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0005829 cytosol | TAS Reactome:R-RNO-198601 | ACCEPT | Summary: Cytosol is the main site of GSK3B activity (destruction complex, glycogen synthase, tau). Reason: GSK3B is a soluble kinase acting on cytosolic substrates; the beta-catenin destruction complex is cytosolic. IBA, ISO and Reactome rows agree. Reactome TAS (R-RNO-198601) is a curated pathway inference from human. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0005874 microtubule | IDA PMID:8576078 Different localization of tau protein kinase I/glycogen synt... | UNDECIDED | Summary: The cited paper reports mitochondrial, not microtubule, localisation of TPKI/GSK-3beta. Reason: PMID:8576078 (abstract only) is titled "Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria" and reports immunoEM and fractionation placing GSK-3beta in mitochondria. Nothing in the abstract supports a microtubule location. The full text was not read, so the row is not removed; a mitochondrion row is proposed instead and the term is flagged upstream. Supporting Evidence: PMID:8576078 was present in mitochondria, but GSK-3 alpha was not |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A phosphorylated pool of GSK3B is found at the plasma membrane. Reason: UniProt records cell-membrane localisation of phosphorylated GSK3B (by similarity) and membrane localisation from MACF1-dependent translocation of the Axin complex to LRP6 (PMID:16815997). Peripheral to core function. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt Membrane {ECO:0000269|PubMed:16815997} PMID:16815997 MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: A phosphorylated pool of GSK3B is found at the plasma membrane. Reason: UniProt records cell-membrane localisation of phosphorylated GSK3B (by similarity) and membrane localisation from MACF1-dependent translocation of the Axin complex to LRP6 (PMID:16815997). Peripheral to core function. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt Membrane {ECO:0000269|PubMed:16815997} PMID:16815997 MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A phosphorylated pool of GSK3B is found at the plasma membrane. Reason: UniProt records cell-membrane localisation of phosphorylated GSK3B (by similarity) and membrane localisation from MACF1-dependent translocation of the Axin complex to LRP6 (PMID:16815997). Peripheral to core function. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P49841} file:rat/Gsk3b/Gsk3b-uniprot.txt Membrane {ECO:0000269|PubMed:16815997} PMID:16815997 MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC |
| GO:0005977 glycogen metabolic process | ISO GO_REF:0000121 | MODIFY | Summary: GSK3B regulates glycogen metabolism by inhibiting glycogen synthase; it does not perform a step of glycogen metabolism. Reason: GSK3B phosphorylates and inhibits glycogen synthase, negatively regulating glycogen synthesis. It is a regulator, so the specific regulatory term GO:0045719 (already carried) is the correct statement. Lateral correction from process to its regulation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: negative regulation of glycogen biosynthetic process Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis PMID:8524413 GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors |
| GO:0006611 protein export from nucleus | ISO GO_REF:0000121 | MODIFY | Summary: GSK3B promotes nuclear export of substrates (NFATC1) by phosphorylation rather than mediating export itself. Reason: GSK3B phosphorylates NFATC1 promoting its nuclear export; it regulates export rather than carrying it out. Use positive regulation of protein export from nucleus (GO:0046827), already carried. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: positive regulation of protein export from nucleus Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0006983 ER overload response | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ER overload response: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates mTORC2 complex component RICTOR |
| GO:0006983 ER overload response | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ER overload response: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates mTORC2 complex component RICTOR |
| GO:0007005 mitochondrion organization | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mitochondrion organization: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0007127 meiosis I | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Meiosis I: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0007163 establishment or maintenance of cell polarity | IDA PMID:12610628 Cdc42 regulates GSK-3beta and adenomatous polyposis coli to ... | MODIFY | Summary: Establishment or maintenance of cell polarity is correct but general; rat evidence supports both establishment and maintenance specifically. Reason: In rat astrocytes GSK-3beta regulation by Par6-PKCzeta polarises the centrosome (PMID:12610628), and in rat hippocampal neurons GSK-3beta is needed for establishing and maintaining axon-dendrite polarity (PMID:15652487). Both descendants are carried by the gene. Proposed replacements: establishment of cell polarity maintenance of cell polarity Supporting Evidence: PMID:12610628 Par6-PKCzeta interacts directly with and regulates glycogen synthase kinase-3beta (GSK-3beta) to promote polarization of the centrosome PMID:15652487 conversion of preexisting dendrites into axons upon GSK-3 inhibition |
| GO:0007409 axonogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Axonogenesis: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Is necessary for the establishment of neuronal polarity and axon outgrowth |
| GO:0007520 myoblast fusion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Myoblast fusion: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0007623 circadian rhythm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Circadian rhythm: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Regulates the circadian clock via phosphorylation of the major clock components |
| GO:0007623 circadian rhythm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Circadian rhythm: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Regulates the circadian clock via phosphorylation of the major clock components |
| GO:0008013 beta-catenin binding | IBA GO_REF:0000033 | ACCEPT | Summary: Beta-catenin binding underlies GSK3B function in the destruction complex. Reason: Rat Axin forms a ternary complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin (PMID:9482734); FWD1 forms a complex with beta-catenin, Axin, GSK-3beta and APC (PMID:10228155). GSK3B binding and phosphorylation of beta-catenin is the core Wnt-off mechanism. Supporting Evidence: PMID:9482734 these three proteins formed a ternary complex PMID:9482734 rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0008013 beta-catenin binding | ISO GO_REF:0000121 | ACCEPT | Summary: Beta-catenin binding underlies GSK3B function in the destruction complex. Reason: Rat Axin forms a ternary complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin (PMID:9482734); FWD1 forms a complex with beta-catenin, Axin, GSK-3beta and APC (PMID:10228155). GSK3B binding and phosphorylation of beta-catenin is the core Wnt-off mechanism. Supporting Evidence: PMID:9482734 these three proteins formed a ternary complex PMID:9482734 rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0008013 beta-catenin binding | ISO GO_REF:0000121 | ACCEPT | Summary: Beta-catenin binding underlies GSK3B function in the destruction complex. Reason: Rat Axin forms a ternary complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin (PMID:9482734); FWD1 forms a complex with beta-catenin, Axin, GSK-3beta and APC (PMID:10228155). GSK3B binding and phosphorylation of beta-catenin is the core Wnt-off mechanism. Supporting Evidence: PMID:9482734 these three proteins formed a ternary complex PMID:9482734 rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0008286 insulin receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: GSK3B is a downstream effector node of insulin receptor signalling, inactivated by Akt. Reason: Insulin inhibits GSK3 by serine phosphorylation through PKB (PMID:8524413); in rat soleus insulin acts via PKB on GSK-3 (PMID:16934435). GSK3B is the effector that couples insulin signalling to glycogen synthesis. Supporting Evidence: PMID:8524413 GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors PMID:8524413 it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC) file:rat/Gsk3b/Gsk3b-uniprot.txt In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 |
| GO:0008286 insulin receptor signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B is a downstream effector node of insulin receptor signalling, inactivated by Akt. Reason: Insulin inhibits GSK3 by serine phosphorylation through PKB (PMID:8524413); in rat soleus insulin acts via PKB on GSK-3 (PMID:16934435). GSK3B is the effector that couples insulin signalling to glycogen synthesis. Supporting Evidence: PMID:8524413 GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors PMID:8524413 it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC) file:rat/Gsk3b/Gsk3b-uniprot.txt In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 |
| GO:0009410 response to xenobiotic stimulus | IEP PMID:19359144 Chronic psychotropic drug treatment causes differential expr... | MARK AS OVER ANNOTATED | Summary: Gsk3b mRNA/protein changes after chronic psychotropic drugs; expression readout only. Reason: IEP evidence: the paper reports a change in GSK3B abundance, mRNA or phosphorylation after the treatment. That GSK3B is regulated by a stimulus does not show that it performs a step of the response; this is an expression readout rather than a function, and over-annotates the gene. (PMID:19359144: qRT-PCR/western after clozapine, fluoxetine, lithium etc.) Supporting Evidence: PMID:19359144 mRNAs for Reelin, Vldlr, Dab-1, Gsk3 beta, and Gad65 were each significantly altered by at least one of the drugs tested |
| GO:0009887 animal organ morphogenesis | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Animal organ morphogenesis from a mouse knockout phenotype. Reason: The mouse Gsk3b knockout has broad developmental defects (via Wnt and other pathways). A generic morphogenesis term from a phenotype does not identify a GSK3B function. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0010043 response to zinc ion | IDA PMID:27295130 Zinc stimulates glucose consumption by modulating the insuli... | KEEP AS NON CORE | Summary: Zinc increases GSK3beta phosphorylation as part of insulin-mimetic signalling in L6 myotubes. Reason: PMID:27295130 (abstract only): zinc enhanced glucose consumption via Akt phosphorylation, GLUT4 translocation and GSK3beta phosphorylation. Regulated node; non-core. Supporting Evidence: PMID:27295130 GSK3Ξ² phosphorylation |
| GO:0010508 positive regulation of autophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Positive regulation of autophagy: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates KAT5/TIP60 under starvation, promoting acetylation of autophagy regulators (UniProt by similarity). Sound IBA/ISO transfer; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Acts as a regulator of autophagy |
| GO:0010508 positive regulation of autophagy | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of autophagy: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates KAT5/TIP60 under starvation, promoting acetylation of autophagy regulators (UniProt by similarity). Sound IBA/ISO transfer; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Acts as a regulator of autophagy |
| GO:0010508 positive regulation of autophagy | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of autophagy: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates KAT5/TIP60 under starvation, promoting acetylation of autophagy regulators (UniProt by similarity). Sound IBA/ISO transfer; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Acts as a regulator of autophagy |
| GO:0010614 negative regulation of cardiac muscle hypertrophy | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of cardiac muscle hypertrophy: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0010628 positive regulation of gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of gene expression: indirect downstream readout. Reason: GSK3B affects gene expression indirectly through many substrates (beta-catenin, JUN, NFAT, CREB). The term captures readouts, not a function GSK3B executes; true-but-broad over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P49841 Β· human GSK3B SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0010628 positive regulation of gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of gene expression: indirect downstream readout. Reason: GSK3B affects gene expression indirectly through many substrates (beta-catenin, JUN, NFAT, CREB). The term captures readouts, not a function GSK3B executes; true-but-broad over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0010629 negative regulation of gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Negative regulation of gene expression: indirect downstream readout. Reason: As for positive regulation of gene expression; an indirect readout of a pleiotropic kinase. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P49841 Β· human GSK3B SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0010719 negative regulation of epithelial to mesenchymal transition | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of epithelial to mesenchymal transition: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates SNAI1 leading to its proteasomal degradation, which restrains EMT (UniProt). Sound transfer; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation |
| GO:0010719 negative regulation of epithelial to mesenchymal transition | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of epithelial to mesenchymal transition: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates SNAI1 leading to its proteasomal degradation, which restrains EMT (UniProt). Sound transfer; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation |
| GO:0010918 positive regulation of mitochondrial membrane potential | IMP PMID:19318234 Anti-hypertrophic effect of NHE-1 inhibition involves GSK-3b... | KEEP AS NON CORE | Summary: Active GSK3B prevents mPTP opening and mitochondrial depolarisation in cardiomyocytes. Reason: PMID:19318234 (abstract only): GSK-3beta interacts with mPTP components VDAC and ANT; GSK-3beta inhibition mimicked ET-1-induced mPTP opening and depolarisation. Non-core. Supporting Evidence: PMID:19318234 GSK-3beta interacts with components of the mPTP, voltage-dependent anion channel (VDAC) and adenine nucleotide translocase PMID:19318234 activation of GSK-3beta which in turn induces inhibition of mPTP opening |
| GO:0010954 positive regulation of protein processing | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of protein processing: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylation of GLI2 and GLI3 in absence of smoothened |
| GO:0010975 regulation of neuron projection development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Regulation of neuron projection development: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Is necessary for the establishment of neuronal polarity and axon outgrowth |
| GO:0010975 regulation of neuron projection development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of neuron projection development: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Is necessary for the establishment of neuronal polarity and axon outgrowth |
| GO:0010977 negative regulation of neuron projection development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of neuron projection development: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Is necessary for the establishment of neuronal polarity and axon outgrowth |
| GO:0014043 negative regulation of neuron maturation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of neuron maturation: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Is necessary for the establishment of neuronal polarity and axon outgrowth |
| GO:0014069 postsynaptic density | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Postsynaptic density localisation, consistent with GSK3B phosphorylating PSD-95. Reason: GSK-3beta phosphorylates PSD-95 Thr-19 in rat hippocampal neurons (PMID:23864697). Synaptic location is real but peripheral to the core kinase function. Supporting Evidence: PMID:23864697 is phosphorylated on threonine-19 (T19) by GSK-3Ξ² |
| GO:0014069 postsynaptic density | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Postsynaptic density localisation, consistent with GSK3B phosphorylating PSD-95. Reason: GSK-3beta phosphorylates PSD-95 Thr-19 in rat hippocampal neurons (PMID:23864697). Synaptic location is real but peripheral to the core kinase function. Supporting Evidence: PMID:23864697 is phosphorylated on threonine-19 (T19) by GSK-3Ξ² |
| GO:0014823 response to activity | IEP PMID:22252247 Treadmill training regulates Ξ²-catenin signaling through pho... | MARK AS OVER ANNOTATED | Summary: Treadmill training changes GSK-3beta phosphorylation in rat vertebrae; correlative readout. Reason: IEP evidence: the paper reports a change in GSK3B abundance, mRNA or phosphorylation after the treatment. That GSK3B is regulated by a stimulus does not show that it performs a step of the response; this is an expression readout rather than a function, and over-annotates the gene. (PMID:22252247.) Supporting Evidence: PMID:22252247 treadmill training could activate the GSK-3Ξ²/Ξ²-catenin signaling |
| GO:0014902 myotube differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Myotube differentiation: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0016020 membrane | IDA PMID:16815997 The role of microtubule actin cross-linking factor 1 (MACF1)... | MODIFY | Summary: Membrane is correct but general; the evidence points to the plasma membrane (LRP6/Axin complex). Reason: PMID:16815997 describes MACF1-dependent translocation of the Axin/GSK3beta complex to LRP6 at the cell membrane, and UniProt records cell-membrane localisation. Refine to plasma membrane, which the gene already carries. Proposed replacements: plasma membrane Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Membrane {ECO:0000269|PubMed:16815997} PMID:16815997 MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC file:rat/Gsk3b/Gsk3b-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P49841} |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: Membrane is correct but general; the evidence points to the plasma membrane (LRP6/Axin complex). Reason: PMID:16815997 describes MACF1-dependent translocation of the Axin/GSK3beta complex to LRP6 at the cell membrane, and UniProt records cell-membrane localisation. Refine to plasma membrane, which the gene already carries. Proposed replacements: plasma membrane Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Membrane {ECO:0000269|PubMed:16815997} PMID:16815997 MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC file:rat/Gsk3b/Gsk3b-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P49841} |
| GO:0016055 Wnt signaling pathway | ISO GO_REF:0000121 | MODIFY | Summary: Wnt signaling pathway is correct but general; GSK3B acts in canonical Wnt/beta-catenin signalling. Reason: GSK3B function in Wnt signalling is the beta-catenin destruction complex, i.e. canonical Wnt signalling (GO:0060070, a descendant the gene already carries). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: canonical Wnt signaling pathway Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes PMID:9482734 rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin |
| GO:0016055 Wnt signaling pathway | ISO GO_REF:0000121 | MODIFY | Summary: Wnt signaling pathway is correct but general; GSK3B acts in canonical Wnt/beta-catenin signalling. Reason: GSK3B function in Wnt signalling is the beta-catenin destruction complex, i.e. canonical Wnt signalling (GO:0060070, a descendant the gene already carries). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: canonical Wnt signaling pathway Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes PMID:9482734 rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin |
| GO:0016301 kinase activity | IDA PMID:1346104 Baculovirus-mediated expression and characterisation of rat ... | MODIFY | Summary: Kinase activity is correct but generic; GSK3B is a protein Ser/Thr kinase. Reason: Rat GSK-3beta expressed in insect cells has autonomous protein kinase activity (PMID:1346104), and its substrates are serine/threonine residues of proteins. Kinase activity is a correct but uninformative ancestor; refine to GO:0004674, which the gene already carries. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:1346104 The protein has autonomous protein kinase activity file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0016301 kinase activity | ISO GO_REF:0000121 | MODIFY | Summary: Kinase activity is correct but generic; GSK3B is a protein Ser/Thr kinase. Reason: Rat GSK-3beta expressed in insect cells has autonomous protein kinase activity (PMID:1346104), and its substrates are serine/threonine residues of proteins. Kinase activity is a correct but uninformative ancestor; refine to GO:0004674, which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:1346104 The protein has autonomous protein kinase activity file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0016301 kinase activity | ISS GO_REF:0000024 | MODIFY | Summary: Kinase activity is correct but generic; GSK3B is a protein Ser/Thr kinase. Reason: Rat GSK-3beta expressed in insect cells has autonomous protein kinase activity (PMID:1346104), and its substrates are serine/threonine residues of proteins. Kinase activity is a correct but uninformative ancestor; refine to GO:0004674, which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:1346104 The protein has autonomous protein kinase activity file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0016477 cell migration | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cell migration: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0018105 peptidyl-serine phosphorylation | ISS GO_REF:0000024 | ACCEPT | Summary: Peptidyl-serine phosphorylation is the reaction GSK3B performs on its substrates. Reason: Direct consequence of its Ser/Thr kinase activity; sound ortholog transfer. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0019901 protein kinase binding | IPI PMID:16478782 Regulation of dishevelled and beta-catenin in rat skeletal m... | KEEP AS NON CORE | Summary: Dvl1, the recorded partner, is not a protein kinase; the row looks like an inverted or mis-termed interaction. Reason: PMID:16478782 (abstract only) shows exercise increases the association between Dvl and GSK-3beta in rat skeletal muscle. The With/From is RGD:620632 (Dvl1), which is not a kinase, so "protein kinase binding" by GSK3B is not what the experiment shows (the binding of a kinase would be a Dvl1 annotation). GSK3B binds kinases in other contexts (CaMKII, PKA, Akt), so the claim is kept as non-core like the term's other rows, and this row's partner/term combination is flagged for checking. Supporting Evidence: PMID:16478782 increases the association between Dvl and GSK-3beta in skeletal muscle |
| GO:0019901 protein kinase binding | IPI PMID:20841359 Inhibitory phosphorylation of GSK-3 by CaMKII couples depola... | KEEP AS NON CORE | Summary: GSK3B binds several protein kinases that regulate it (CaMKII, Akt, PKA). Reason: CaMKII associates with and phosphorylates GSK-3 (PMID:20841359); PKA physically associates with it (PMID:11035810). Binding of regulatory kinases is real but peripheral to GSK3B core catalytic function. Supporting Evidence: PMID:20841359 CaMKII associated with and phosphorylated GSK-3Ξ±/Ξ² PMID:11035810 Protein kinase A physically associates with, phosphorylates, and inactivates both isoforms of GSK-3 |
| GO:0019901 protein kinase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: GSK3B binds several protein kinases that regulate it (CaMKII, Akt, PKA). Reason: CaMKII associates with and phosphorylates GSK-3 (PMID:20841359); PKA physically associates with it (PMID:11035810). Binding of regulatory kinases is real but peripheral to GSK3B core catalytic function. Supporting Evidence: PMID:20841359 CaMKII associated with and phosphorylated GSK-3Ξ±/Ξ² PMID:11035810 Protein kinase A physically associates with, phosphorylates, and inactivates both isoforms of GSK-3 |
| GO:0019901 protein kinase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: GSK3B binds several protein kinases that regulate it (CaMKII, Akt, PKA). Reason: CaMKII associates with and phosphorylates GSK-3 (PMID:20841359); PKA physically associates with it (PMID:11035810). Binding of regulatory kinases is real but peripheral to GSK3B core catalytic function. Supporting Evidence: PMID:20841359 CaMKII associated with and phosphorylated GSK-3Ξ±/Ξ² PMID:11035810 Protein kinase A physically associates with, phosphorylates, and inactivates both isoforms of GSK-3 |
| GO:0021766 hippocampus development | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Hippocampus development transferred from human GSK3B; association-level donor evidence. Reason: The human donor annotation cites PMID:19581563 (IMP); no developmental step executed by GSK3B in hippocampus formation is described for rat or in UniProt. Anatomical development terms over-annotate a pleiotropic kinase. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P49841 Β· human GSK3B SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0030010 establishment of cell polarity | IDA PMID:12610628 Cdc42 regulates GSK-3beta and adenomatous polyposis coli to ... | KEEP AS NON CORE | Summary: Spatial regulation of GSK3B is required to establish cell and neuronal polarity. Reason: Rat astrocytes: Cdc42/Par6-PKCzeta regulate GSK-3beta to polarise the centrosome (PMID:12610628). Rat hippocampal neurons: active GSK-3beta inhibits axon formation, and reduced activity yields multiple axons (PMID:15652487). A real, conserved role; non-core relative to the kinase activity. Supporting Evidence: PMID:12610628 Par6-PKCzeta interacts directly with and regulates glycogen synthase kinase-3beta (GSK-3beta) to promote polarization of the centrosome PMID:15652487 A constitutively active GSK-3beta mutant inhibited axon formation |
| GO:0030010 establishment of cell polarity | IMP PMID:15652487 Both the establishment and the maintenance of neuronal polar... | KEEP AS NON CORE | Summary: Spatial regulation of GSK3B is required to establish cell and neuronal polarity. Reason: Rat astrocytes: Cdc42/Par6-PKCzeta regulate GSK-3beta to polarise the centrosome (PMID:12610628). Rat hippocampal neurons: active GSK-3beta inhibits axon formation, and reduced activity yields multiple axons (PMID:15652487). A real, conserved role; non-core relative to the kinase activity. Supporting Evidence: PMID:12610628 Par6-PKCzeta interacts directly with and regulates glycogen synthase kinase-3beta (GSK-3beta) to promote polarization of the centrosome PMID:15652487 A constitutively active GSK-3beta mutant inhibited axon formation |
| GO:0030011 maintenance of cell polarity | IMP PMID:15652487 Both the establishment and the maintenance of neuronal polar... | KEEP AS NON CORE | Summary: GSK3B activity is required to maintain neuronal polarity. Reason: GSK-3 inhibition converts preexisting dendrites into axons (PMID:15652487, abstract only). Non-core. Supporting Evidence: PMID:15652487 conversion of preexisting dendrites into axons upon GSK-3 inhibition |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | TOO GENERAL | Summary: Cell differentiation is true but uninformative; specific descendants are carried. Reason: GSK3B influences differentiation of many cell types; descendants carried by the gene (fat cell differentiation, myotube differentiation) entail this generic term. The IBA is phylogenetically sound but uninformative. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: AGI_LocusCode:AT4G18710 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. FB:FBgn0003371 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. MGI:MGI:1861437 Β· mouse Gsk3b SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. MGI:MGI:2152453 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. RGD:70982 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. SGD:S000004747 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. SGD:S000005251 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. WB:WBGene00001746 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. ZFIN:ZDB-GENE-990714-3 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. dictyBase:DDB_G0272110 SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0030336 negative regulation of cell migration | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of cell migration: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0030424 axon | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Axonal GSK3B, with differential activity in axon versus dendrites. Reason: PMID:15652487 reports differential distribution of GSK-3beta activity in the axon versus the dendrites of rat hippocampal neurons. Real neuronal sub-location; non-core. Supporting Evidence: PMID:15652487 a differential distribution of GSK-3beta activity in the axon versus the dendrites |
| GO:0030424 axon | IDA PMID:15652487 Both the establishment and the maintenance of neuronal polar... | KEEP AS NON CORE | Summary: Axonal GSK3B, with differential activity in axon versus dendrites. Reason: PMID:15652487 reports differential distribution of GSK-3beta activity in the axon versus the dendrites of rat hippocampal neurons. Real neuronal sub-location; non-core. Supporting Evidence: PMID:15652487 a differential distribution of GSK-3beta activity in the axon versus the dendrites |
| GO:0030425 dendrite | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Dendritic GSK3B, with differential activity in axon versus dendrites. Reason: PMID:15652487 reports GSK-3beta activity in axons and dendrites. Non-core neuronal sub-location. Supporting Evidence: PMID:15652487 a differential distribution of GSK-3beta activity in the axon versus the dendrites |
| GO:0030425 dendrite | IDA PMID:15652487 Both the establishment and the maintenance of neuronal polar... | KEEP AS NON CORE | Summary: Dendritic GSK3B, with differential activity in axon versus dendrites. Reason: PMID:15652487 reports GSK-3beta activity in axons and dendrites. Non-core neuronal sub-location. Supporting Evidence: PMID:15652487 a differential distribution of GSK-3beta activity in the axon versus the dendrites |
| GO:0030426 growth cone | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Growth cone localisation transferred from the mouse/human ortholog. Reason: Sound ortholog transfer of a sub-cellular location of a ubiquitous soluble kinase; peripheral to core function. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} |
| GO:0030516 regulation of axon extension | IMP PMID:15652487 Both the establishment and the maintenance of neuronal polar... | KEEP AS NON CORE | Summary: GSK3B activity shapes axon/dendrite formation in rat hippocampal neurons. Reason: PMID:15652487 (abstract only): constitutively active GSK-3beta inhibits axon formation, inhibition yields multiple axons and converts dendrites into axons. Real neuronal-development role, non-core. Supporting Evidence: PMID:15652487 A constitutively active GSK-3beta mutant inhibited axon formation PMID:15652487 conversion of preexisting dendrites into axons upon GSK-3 inhibition |
| GO:0030877 beta-catenin destruction complex | IBA GO_REF:0000033 | ACCEPT | Summary: GSK3B is the catalytic subunit of the beta-catenin destruction complex. Reason: Rat Axin forms a ternary complex with GSK-3beta and beta-catenin (PMID:9482734); FWD1 forms a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC (PMID:10228155). Core complex membership. Supporting Evidence: PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC PMID:9482734 these three proteins formed a ternary complex file:rat/Gsk3b/Gsk3b-uniprot.txt Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B |
| GO:0030877 beta-catenin destruction complex | IDA PMID:10228155 An F-box protein, FWD1, mediates ubiquitin-dependent proteol... | ACCEPT | Summary: GSK3B is the catalytic subunit of the beta-catenin destruction complex. Reason: Rat Axin forms a ternary complex with GSK-3beta and beta-catenin (PMID:9482734); FWD1 forms a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC (PMID:10228155). Core complex membership. Supporting Evidence: PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC PMID:9482734 these three proteins formed a ternary complex file:rat/Gsk3b/Gsk3b-uniprot.txt Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B |
| GO:0030877 beta-catenin destruction complex | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B is the catalytic subunit of the beta-catenin destruction complex. Reason: Rat Axin forms a ternary complex with GSK-3beta and beta-catenin (PMID:9482734); FWD1 forms a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC (PMID:10228155). Core complex membership. Supporting Evidence: PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC PMID:9482734 these three proteins formed a ternary complex file:rat/Gsk3b/Gsk3b-uniprot.txt Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B |
| GO:0030877 beta-catenin destruction complex | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B is the catalytic subunit of the beta-catenin destruction complex. Reason: Rat Axin forms a ternary complex with GSK-3beta and beta-catenin (PMID:9482734); FWD1 forms a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC (PMID:10228155). Core complex membership. Supporting Evidence: PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC PMID:9482734 these three proteins formed a ternary complex file:rat/Gsk3b/Gsk3b-uniprot.txt Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B |
| GO:0031175 neuron projection development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Neuron projection development: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Is necessary for the establishment of neuronal polarity and axon outgrowth |
| GO:0031175 neuron projection development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuron projection development: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Is necessary for the establishment of neuronal polarity and axon outgrowth |
| GO:0031333 negative regulation of protein-containing complex assembly | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of protein-containing complex assembly: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0031334 positive regulation of protein-containing complex assembly | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of protein-containing complex assembly: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0031398 positive regulation of protein ubiquitination | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of protein ubiquitination: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation |
| GO:0031625 ubiquitin protein ligase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ubiquitin ligase binding transferred from human GSK3B; consistent with GSK3B priming substrates for SCF ligases. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Lipopolysaccharide-mediated signaling pathway: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Probably regulates NF-kappa-B (NFKB1) at the transcriptional level |
| GO:0032007 negative regulation of TOR signaling | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Negative regulation of TOR signaling: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates mTORC2 complex component RICTOR |
| GO:0032007 negative regulation of TOR signaling | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of TOR signaling: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates mTORC2 complex component RICTOR |
| GO:0032092 positive regulation of protein binding | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Positive regulation of protein binding: vague downstream effect. Reason: GSK3B phosphorylation can alter many protein-protein interactions (e.g. reduces MACF1 microtubule binding, MUC1-beta-catenin interaction). The generic "positive regulation of protein binding" term is uninformative and not established as a GSK3B function. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q9WV60 Β· mouse GSK3B SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0032355 response to estradiol | IEP PMID:22252247 Treadmill training regulates Ξ²-catenin signaling through pho... | MARK AS OVER ANNOTATED | Summary: Estradiol replacement in OVX rats measured alongside P-GSK-3beta; correlative readout. Reason: IEP evidence: the paper reports a change in GSK3B abundance, mRNA or phosphorylation after the treatment. That GSK3B is regulated by a stimulus does not show that it performs a step of the response; this is an expression readout rather than a function, and over-annotates the gene. (PMID:22252247; the estrogen effect is a group comparison, not a GSK3B function.) Supporting Evidence: PMID:22252247 treadmill training could activate the GSK-3Ξ²/Ξ²-catenin signaling |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: GSK3B priming phosphorylation targets substrates (beta-catenin, SNAI1 and others) for SCF-mediated proteasomal degradation. Reason: Phosphorylation of beta-catenin by GSK-3beta/Axin precedes its ubiquitination by FWD1 (PMID:10228155); UniProt lists further phospho-degron substrates (SNAI1, CLOCK, BMAL1, FXR1). Supporting Evidence: PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B priming phosphorylation targets substrates (beta-catenin, SNAI1 and others) for SCF-mediated proteasomal degradation. Reason: Phosphorylation of beta-catenin by GSK-3beta/Axin precedes its ubiquitination by FWD1 (PMID:10228155); UniProt lists further phospho-degron substrates (SNAI1, CLOCK, BMAL1, FXR1). Supporting Evidence: PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B priming phosphorylation targets substrates (beta-catenin, SNAI1 and others) for SCF-mediated proteasomal degradation. Reason: Phosphorylation of beta-catenin by GSK-3beta/Axin precedes its ubiquitination by FWD1 (PMID:10228155); UniProt lists further phospho-degron substrates (SNAI1, CLOCK, BMAL1, FXR1). Supporting Evidence: PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation |
| GO:0032481 positive regulation of type I interferon production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of type I interferon production: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0032481 positive regulation of type I interferon production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of type I interferon production: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0032868 response to insulin | IEP PMID:16934435 GSK-3beta regulation in skeletal muscles by adrenaline and i... | KEEP AS NON CORE | Summary: Insulin inactivates GSK-3 in skeletal muscle via PKB. Reason: PMID:16934435 (abstract only): insulin (via PKB) and adrenaline (via PKA) regulate GSK-3beta Ser9 phosphorylation in rat soleus. GSK3B inhibition is a component of the insulin response; non-core (the insulin receptor signalling term is accepted). Supporting Evidence: PMID:16934435 adrenaline alone increased phosphorylation of GSK-3beta Ser9 |
| GO:0032880 regulation of protein localization | ISO GO_REF:0000121 | TOO GENERAL | Summary: Regulation of protein localization is true but uninformative; specific descendants are asserted. Reason: GSK3B regulates the localisation of specific substrates (NFATC1 nuclear export, GATA6 nuclear accumulation, centrosome and cilium targeting). More specific descendants (GO:1900181, GO:0046827, GO:1903566) are carried by the gene and entail this term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export PMID:23624080 GSK3Ξ² antagonists, LiCl and TDZD8, restored the nuclear accumulation of GATA6 |
| GO:0032880 regulation of protein localization | ISS GO_REF:0000024 | TOO GENERAL | Summary: Regulation of protein localization is true but uninformative; specific descendants are asserted. Reason: GSK3B regulates the localisation of specific substrates (NFATC1 nuclear export, GATA6 nuclear accumulation, centrosome and cilium targeting). More specific descendants (GO:1900181, GO:0046827, GO:1903566) are carried by the gene and entail this term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export PMID:23624080 GSK3Ξ² antagonists, LiCl and TDZD8, restored the nuclear accumulation of GATA6 |
| GO:0032886 regulation of microtubule-based process | ISO GO_REF:0000121 | MODIFY | Summary: Regulation of microtubule-based process is correct but general; refine to regulation of microtubule cytoskeleton organization. Reason: GSK3B affects microtubules by phosphorylating MAPs (tau, CRMP2, APC); the specific descendant GO:0070507 is already carried (IBA, IMP PMID:18268107). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: regulation of microtubule cytoskeleton organization Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU PMID:18268107 precedes the formation of multiple axons in morphologically still unpolarized stage 2 neurons treated with GSK-3Ξ² inhibitor |
| GO:0032886 regulation of microtubule-based process | ISO GO_REF:0000121 | MODIFY | Summary: Regulation of microtubule-based process is correct but general; refine to regulation of microtubule cytoskeleton organization. Reason: GSK3B affects microtubules by phosphorylating MAPs (tau, CRMP2, APC); the specific descendant GO:0070507 is already carried (IBA, IMP PMID:18268107). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: regulation of microtubule cytoskeleton organization Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU PMID:18268107 precedes the formation of multiple axons in morphologically still unpolarized stage 2 neurons treated with GSK-3Ξ² inhibitor |
| GO:0032886 regulation of microtubule-based process | ISS GO_REF:0000024 | MODIFY | Summary: Regulation of microtubule-based process is correct but general; refine to regulation of microtubule cytoskeleton organization. Reason: GSK3B affects microtubules by phosphorylating MAPs (tau, CRMP2, APC); the specific descendant GO:0070507 is already carried (IBA, IMP PMID:18268107). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: regulation of microtubule cytoskeleton organization Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU PMID:18268107 precedes the formation of multiple axons in morphologically still unpolarized stage 2 neurons treated with GSK-3Ξ² inhibitor |
| GO:0032991 protein-containing complex | IDA PMID:17329210 LTP inhibits LTD in the hippocampus via regulation of GSK3be... | TOO GENERAL | Summary: Protein-containing complex is true but uninformative; the specific complex (beta-catenin destruction complex) is asserted elsewhere. Reason: PMID:17329210 (abstract only) presumably shows GSK3beta in a co-immunoprecipitated complex with synaptic proteins. The bare complex term adds no information beyond the more specific GO:0030877 beta-catenin destruction complex rows. True of the gene; uninformative. Supporting Evidence: PMID:17329210 the activity of GSK3beta is enhanced during LTD via activation of PP1 |
| GO:0033690 positive regulation of osteoblast proliferation | IMP PMID:26722385 Roles of TNF-Ξ±, GSK-3Ξ² and RANKL in the occurrence and devel... | MARK AS OVER ANNOTATED | Summary: Lithium/GSK-3beta inhibitor reduced osteoblast proliferation in a single MTT-based study. Reason: PMID:26722385 (full text) uses lithium chloride and a GSK-3beta inhibitor and MTT assays in primary diabetic-rat osteoblasts; lithium is non-specific and the result conflicts with the well-supported Wnt-mediated pro-osteogenic effect of GSK3 inhibition (PMID:28731198). Weak evidence; over-annotation. Supporting Evidence: PMID:26722385 Osteoblast proliferation in GSK-3Ξ² inhibitor and lithium chloride groups were weaker than the untreated group |
| GO:0034236 protein kinase A catalytic subunit binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: PKA catalytic subunit binding; PKA associates with and phosphorylates GSK3B. Reason: PKA physically associates with and inactivates GSK-3 (PMID:11035810) and UniProt records a PRKAR2/GSKIP/GSK3B complex. Regulatory interaction, non-core. Supporting Evidence: PMID:11035810 Protein kinase A physically associates with, phosphorylates, and inactivates both isoforms of GSK-3 file:rat/Gsk3b/Gsk3b-uniprot.txt Forms a complex composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP |
| GO:0034392 negative regulation of smooth muscle cell apoptotic process | IMP PMID:21557011 Glycogen synthase kinase 3 beta positively regulates Notch s... | KEEP AS NON CORE | Summary: In vascular SMC, GSK-3beta supports Notch signalling and inhibits apoptosis. Reason: PMID:21557011 (full text): GSK-3beta overexpression, siRNA and SB-216763 show that it positively regulates Notch signalling while promoting vSMC proliferation and inhibiting apoptosis. Context-dependent, non-core. Supporting Evidence: PMID:21557011 GSK-3Ξ² positively regulates Notch intracellular domain expression PMID:21557011 while concomitantly promoting vSMC proliferation and inhibiting apoptosis |
| GO:0034452 dynactin binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Dynactin binding transferred from human GSK3B. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0034976 response to endoplasmic reticulum stress | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Response to endoplasmic reticulum stress: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates mTORC2 complex component RICTOR |
| GO:0035255 ionotropic glutamate receptor binding | IPI PMID:17329210 LTP inhibits LTD in the hippocampus via regulation of GSK3be... | KEEP AS NON CORE | Summary: Association of GSK3B with ionotropic glutamate (AMPA) receptor subunits in hippocampal synapses. Reason: PMID:17329210 (abstract only) shows GSK3beta regulation during LTP/LTD in rat hippocampus; RGD recorded IPI with Gria1 and Gria2. Consistent with the PSD-95/AMPA receptor work (PMID:23864697). Kept as non-core binding. Supporting Evidence: PMID:17329210 the activity of GSK3beta is enhanced during LTD via activation of PP1 PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0035255 ionotropic glutamate receptor binding | IPI PMID:17329210 LTP inhibits LTD in the hippocampus via regulation of GSK3be... | KEEP AS NON CORE | Summary: Association of GSK3B with ionotropic glutamate (AMPA) receptor subunits in hippocampal synapses. Reason: PMID:17329210 (abstract only) shows GSK3beta regulation during LTP/LTD in rat hippocampus; RGD recorded IPI with Gria1 and Gria2. Consistent with the PSD-95/AMPA receptor work (PMID:23864697). Kept as non-core binding. Supporting Evidence: PMID:17329210 the activity of GSK3beta is enhanced during LTD via activation of PP1 PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0035372 protein localization to microtubule | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Protein localization to microtubule: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex |
| GO:0035556 intracellular signal transduction | ISO GO_REF:0000121 | TOO GENERAL | Summary: Intracellular signal transduction is true but uninformative; PI3K/PKB signalling is asserted. Reason: GSK3B is an intracellular signalling kinase; the more specific GO:0043491 PI3K/PKB signal transduction (a descendant, carried) entails this. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 |
| GO:0035729 cellular response to hepatocyte growth factor stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to hepatocyte growth factor stimulus: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0035733 hepatic stellate cell activation | IMP PMID:28061416 Purinergic P2X7 receptor mediates acetaldehyde-induced hepat... | KEEP AS NON CORE | Summary: GSK3B signalling downstream of P2X7R/PKC supports acetaldehyde-induced hepatic stellate cell activation. Reason: PMID:28061416 (abstract only): GSK3beta inhibition decreased alpha-SMA and collagen I in activated HSCs. Pharmacological, tissue-context; non-core. Supporting Evidence: PMID:28061416 GSK3Ξ² inhibition harvested a dramatic decrease of the mRNA and protein levels of Ξ±-SMA and collagen I |
| GO:0036016 cellular response to interleukin-3 | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to interleukin-3: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0036016 cellular response to interleukin-3 | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cellular response to interleukin-3: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0036018 cellular response to erythropoietin | IEP PMID:17952604 Protective effect of erythropoietin against ketamine-induced... | KEEP AS NON CORE | Summary: EPO signalling inactivates GSK-3beta via PI3K/Akt in neuroprotection. Reason: PMID:17952604 (abstract only): EPO induced Akt activation and GSK-3beta phosphorylation/inactivation in cortical neurons. GSK3B is a regulated node in the EPO response; non-core. Supporting Evidence: PMID:17952604 EPO induced the phosphorylation/activation of Akt and phosphorylation/inactivation of glycogen synthase kinase-3beta (GSK-3beta) |
| GO:0042752 regulation of circadian rhythm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of circadian rhythm: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Regulates the circadian clock via phosphorylation of the major clock components |
| GO:0042752 regulation of circadian rhythm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of circadian rhythm: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Regulates the circadian clock via phosphorylation of the major clock components |
| GO:0042981 regulation of apoptotic process | ISO GO_REF:0000121 | MODIFY | Summary: Regulation of apoptotic process is correct but general; GSK3B has both pro- and anti-apoptotic roles. Reason: GSK3B is pro-apoptotic in neurons and astrocytes (PMID:12393899, PMID:12808104) and anti-apoptotic at death receptors (UniProt). Both specific descendants are carried by the gene, so list both. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Proposed replacements: positive regulation of apoptotic process negative regulation of apoptotic process Supporting Evidence: PMID:12808104 overexpression of a constitutively active GSK-3beta mutant (S9A) is sufficient to cause astrocyte apoptosis file:rat/Gsk3b/Gsk3b-uniprot.txt Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors |
| GO:0043025 neuronal cell body | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Neuronal cell body localisation transferred from the mouse/human ortholog. Reason: Sound ortholog transfer of a sub-cellular location of a ubiquitous soluble kinase; peripheral to core function. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:12393899 ERK1/2 antagonizes glycogen synthase kinase-3beta-induced ap... | KEEP AS NON CORE | Summary: Active GSK3B promotes apoptosis of neural cells. Reason: Expression of recombinant GSK3beta induces cortical neuron apoptosis (PMID:12393899) and constitutively active S9A, but not kinase-dead K85M, GSK-3beta induces astrocyte apoptosis (PMID:12808104, full text). Context-dependent, non-core. Supporting Evidence: PMID:12393899 cortical neuron apoptosis induced by expression of recombinant GSK3beta PMID:12808104 overexpression of a constitutively active GSK-3beta mutant (S9A) is sufficient to cause astrocyte apoptosis |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:12808104 Glycogen synthase kinase 3beta-mediated apoptosis of primary... | KEEP AS NON CORE | Summary: Active GSK3B promotes apoptosis of neural cells. Reason: Expression of recombinant GSK3beta induces cortical neuron apoptosis (PMID:12393899) and constitutively active S9A, but not kinase-dead K85M, GSK-3beta induces astrocyte apoptosis (PMID:12808104, full text). Context-dependent, non-core. Supporting Evidence: PMID:12393899 cortical neuron apoptosis induced by expression of recombinant GSK3beta PMID:12808104 overexpression of a constitutively active GSK-3beta mutant (S9A) is sufficient to cause astrocyte apoptosis |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of apoptotic process: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of apoptotic process: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors |
| GO:0043197 dendritic spine | IDA PMID:17329210 LTP inhibits LTD in the hippocampus via regulation of GSK3be... | KEEP AS NON CORE | Summary: Dendritic spine localisation of GSK3B in rat hippocampal neurons. Reason: PMID:17329210 (abstract only) studies GSK3beta at hippocampal synapses during LTP/LTD; the spine location is consistent with PMID:23864697 (PSD-95 phosphorylation in spines). Non-core. Supporting Evidence: PMID:17329210 the activity of GSK3beta is enhanced during LTD via activation of PP1 PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0043198 dendritic shaft | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Dendritic shaft localisation transferred from the mouse/human ortholog. Reason: Sound ortholog transfer of a sub-cellular location of a ubiquitous soluble kinase; peripheral to core function. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} |
| GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Phosphatidylinositol 3-kinase/protein kinase B signal transduction: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 |
| GO:0043525 positive regulation of neuron apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: GSK3B promotes neuronal apoptosis after trophic withdrawal or ER stress. Reason: Nonphosphorylatable GSK-3 mutants promoted apoptosis of rat cerebellar granule neurons (PMID:20841359); ER stress and trophic withdrawal activate GSK-3beta and intrinsic apoptosis (PMID:16765055). Context-dependent, non-core. Supporting Evidence: PMID:20841359 Nonphosphorylatable GSK-3Ξ±/Ξ² mutants (S21A/S9A) promoted apoptosis PMID:16765055 ER stress and TFW elicit distinct signals that activate GSK-3beta and intrinsic apoptosis in neurons |
| GO:0043525 positive regulation of neuron apoptotic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: GSK3B promotes neuronal apoptosis after trophic withdrawal or ER stress. Reason: Nonphosphorylatable GSK-3 mutants promoted apoptosis of rat cerebellar granule neurons (PMID:20841359); ER stress and trophic withdrawal activate GSK-3beta and intrinsic apoptosis (PMID:16765055). Context-dependent, non-core. Supporting Evidence: PMID:20841359 Nonphosphorylatable GSK-3Ξ±/Ξ² mutants (S21A/S9A) promoted apoptosis PMID:16765055 ER stress and TFW elicit distinct signals that activate GSK-3beta and intrinsic apoptosis in neurons |
| GO:0043525 positive regulation of neuron apoptotic process | IMP PMID:16765055 Endoplasmic reticulum stress and trophic factor withdrawal a... | KEEP AS NON CORE | Summary: GSK3B promotes neuronal apoptosis after trophic withdrawal or ER stress. Reason: Nonphosphorylatable GSK-3 mutants promoted apoptosis of rat cerebellar granule neurons (PMID:20841359); ER stress and trophic withdrawal activate GSK-3beta and intrinsic apoptosis (PMID:16765055). Context-dependent, non-core. Supporting Evidence: PMID:20841359 Nonphosphorylatable GSK-3Ξ±/Ξ² mutants (S21A/S9A) promoted apoptosis PMID:16765055 ER stress and TFW elicit distinct signals that activate GSK-3beta and intrinsic apoptosis in neurons |
| GO:0043525 positive regulation of neuron apoptotic process | IMP PMID:20841359 Inhibitory phosphorylation of GSK-3 by CaMKII couples depola... | KEEP AS NON CORE | Summary: GSK3B promotes neuronal apoptosis after trophic withdrawal or ER stress. Reason: Nonphosphorylatable GSK-3 mutants promoted apoptosis of rat cerebellar granule neurons (PMID:20841359); ER stress and trophic withdrawal activate GSK-3beta and intrinsic apoptosis (PMID:16765055). Context-dependent, non-core. Supporting Evidence: PMID:20841359 Nonphosphorylatable GSK-3Ξ±/Ξ² mutants (S21A/S9A) promoted apoptosis PMID:16765055 ER stress and TFW elicit distinct signals that activate GSK-3beta and intrinsic apoptosis in neurons |
| GO:0044297 cell body | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cell body localisation transferred from the mouse/human ortholog. Reason: Sound ortholog transfer of a sub-cellular location of a ubiquitous soluble kinase; peripheral to core function. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} |
| GO:0045444 fat cell differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Fat cell differentiation: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0045597 positive regulation of cell differentiation | ISO GO_REF:0000121 | TOO GENERAL | Summary: Positive regulation of cell differentiation is uninformative; specific descendants are carried. Reason: Descendants carried (positive regulation of cardiac muscle cell differentiation, of stem cell differentiation, of osteoclast differentiation) entail this term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P49841 Β· human GSK3B SUPPORTS TRANSFER Donor annotation is sound; the term is less precise than the gene-level evidence supports. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0045667 regulation of osteoblast differentiation | IMP PMID:28731198 GSK-3Ξ² inhibition suppresses instability-induced osteolysis ... | MODIFY | Summary: GSK-3beta inhibition increases osteoblast differentiation markers, so the direction is negative regulation. Reason: PMID:28731198 (full text): GSK-3beta inhibition with AR28 increased Runx2, Osterix, Col1a1 and ALP mRNA and osteoblast numbers. GSK3B therefore negatively regulates osteoblast differentiation (via beta-catenin); refine to GO:0045668, already carried. Proposed replacements: negative regulation of osteoblast differentiation Supporting Evidence: PMID:28731198 mRNA levels of Ξ²-catenin, Runx2, Osterix, Col1Ξ±1, and ALP were increased leading to higher osteoblast numbers |
| GO:0045668 negative regulation of osteoblast differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of osteoblast differentiation: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0045672 positive regulation of osteoclast differentiation | IMP PMID:28731198 GSK-3Ξ² inhibition suppresses instability-induced osteolysis ... | KEEP AS NON CORE | Summary: GSK-3beta inhibition reduces osteoclast numbers in a rat peri-implant osteolysis model. Reason: PMID:28731198 (full text): osteoclast numbers fell after GSK-3beta inhibition, correlating with increased OPG expression, i.e. probably indirect via osteoblast OPG/RANKL. Kept as non-core. Supporting Evidence: PMID:28731198 Osteoclast numbers were decreased significantly after 3 days of GSK-3Ξ² inhibition, which correlated with enhanced OPG mRNA expression |
| GO:0045719 negative regulation of glycogen biosynthetic process | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B inhibits glycogen synthesis by phosphorylating glycogen synthase; relieved by insulin/Akt. Reason: Classical GSK3 function; insulin inhibits GSK3 via PKB (PMID:8524413), relieving inhibition of glycogen synthase. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis PMID:8524413 GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors file:rat/Gsk3b/Gsk3b-uniprot.txt In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 |
| GO:0045724 positive regulation of cilium assembly | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of cilium assembly: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0045724 positive regulation of cilium assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of cilium assembly: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0045732 positive regulation of protein catabolic process | IMP PMID:17686886 GSK-3beta activity is increased in skeletal muscle after bur... | KEEP AS NON CORE | Summary: GSK3B knockdown reduces glucocorticoid-induced muscle protein degradation. Reason: PMID:17686886 (abstract only): siRNA against GSK-3beta inhibited dexamethasone-induced protein degradation in cultured muscle cells by about 50%. Real but tissue-context finding; non-core. Supporting Evidence: PMID:17686886 Reducing the expression of GSK-3beta in cultured muscle cells with siRNA inhibited dexamethasone-induced protein degradation by approximately 50% |
| GO:0045773 positive regulation of axon extension | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of axon extension: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Is necessary for the establishment of neuronal polarity and axon outgrowth |
| GO:0045879 negative regulation of smoothened signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of smoothened signaling pathway: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates GLI2/GLI3 in the absence of smoothened signalling, promoting their processing (UniProt by similarity). Sound transfer; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Acts as a negative regulator of smoothened signaling |
| GO:0045879 negative regulation of smoothened signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of smoothened signaling pathway: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates GLI2/GLI3 in the absence of smoothened signalling, promoting their processing (UniProt by similarity). Sound transfer; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Acts as a negative regulator of smoothened signaling |
| GO:0045886 negative regulation of synaptic assembly at neuromuscular junction | IMP PMID:25764078 GSK3Ξ² inhibition promotes synaptogenesis in Drosophila and m... | MODIFY | Summary: The rat experiments in this paper were in cultured hippocampal neurons, not at the neuromuscular junction. Reason: PMID:25764078 (full text read) compares the Drosophila larval neuromuscular junction with cultured rat hippocampal neurons; all NMJ data are from Drosophila shaggy mutants. In rat hippocampal cultures, GSK3 inhibition increased synapse density at 3 weeks but decreased it at 12 days. The rat finding is regulation of (CNS) synapse assembly; the NMJ-specific term is wrong for rat. Generalise to GO:0051963 regulation of synapse assembly (an ancestor of the NMJ terms). Proposed replacements: regulation of synapse assembly Supporting Evidence: PMID:25764078 a comparative study between the neuromuscular junction of Drosophila larvae and cultured hippocampal rat neurons PMID:25764078 the pharmacological inhibition of GSK3Ξ² increases synapse density and Synapsin expression |
| GO:0045887 positive regulation of synaptic assembly at neuromuscular junction | IMP PMID:25764078 GSK3Ξ² inhibition promotes synaptogenesis in Drosophila and m... | MODIFY | Summary: The rat experiments in this paper were in cultured hippocampal neurons, not at the neuromuscular junction. Reason: PMID:25764078 (full text read) compares the Drosophila larval neuromuscular junction with cultured rat hippocampal neurons; all NMJ data are from Drosophila shaggy mutants. In rat hippocampal cultures, GSK3 inhibition increased synapse density at 3 weeks but decreased it at 12 days. The rat finding is regulation of (CNS) synapse assembly; the NMJ-specific term is wrong for rat. Generalise to GO:0051963 regulation of synapse assembly (an ancestor of the NMJ terms). Proposed replacements: regulation of synapse assembly Supporting Evidence: PMID:25764078 a comparative study between the neuromuscular junction of Drosophila larvae and cultured hippocampal rat neurons PMID:25764078 the pharmacological inhibition of GSK3Ξ² increases synapse density and Synapsin expression |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of transcription by RNA polymerase II from mouse; indirect. Reason: GSK3B is not a transcriptional regulator itself; most of its transcriptional effects are indirect (e.g. via beta-catenin) and many are inhibitory (JUN, NFAT). The mouse-derived row over-annotates. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of transcription by RNA polymerase II from mouse; indirect. Reason: GSK3B is not a transcriptional regulator itself; most of its transcriptional effects are indirect (e.g. via beta-catenin) and many are inhibitory (JUN, NFAT). The mouse-derived row over-annotates. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0046627 negative regulation of insulin receptor signaling pathway | IDA PMID:8524413 Inhibition of glycogen synthase kinase-3 by insulin mediated... | UNDECIDED | Summary: The cited paper shows insulin inhibiting GSK3 via PKB, not GSK3B negatively regulating insulin signalling. Reason: PMID:8524413 (abstract only) demonstrates that GSK3 is a target inhibited downstream of insulin. A negative feedback role of GSK3B on insulin receptor signalling (e.g. via IRS1) is plausible ("May also mediate the development of insulin resistance", by similarity) but is not shown in the cached text for rat. Cannot verify the curated direction from the abstract. Supporting Evidence: PMID:8524413 GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors file:rat/Gsk3b/Gsk3b-uniprot.txt May also mediate the development of insulin resistance |
| GO:0046627 negative regulation of insulin receptor signaling pathway | IEA GO_REF:0000117 | UNDECIDED | Summary: The cited paper shows insulin inhibiting GSK3 via PKB, not GSK3B negatively regulating insulin signalling. Reason: ARBA rule-based electronic annotation. A feedback role of GSK3B on insulin signalling is plausible ("May also mediate the development of insulin resistance", by similarity), but the rat experimental row from PMID:8524413 shows GSK3B as an insulin-inhibited target rather than a negative regulator, and the electronic rule adds no independent evidence. Supporting Evidence: PMID:8524413 GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors file:rat/Gsk3b/Gsk3b-uniprot.txt May also mediate the development of insulin resistance |
| GO:0046825 regulation of protein export from nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of protein export from nucleus: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0046827 positive regulation of protein export from nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of protein export from nucleus: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0046849 bone remodeling | IDA PMID:29224185 Tension force-induced bone formation in orthodontic tooth mo... | MARK AS OVER ANNOTATED | Summary: Bone remodeling during orthodontic tooth movement modulated by GSK-3beta inhibition; downstream tissue outcome. Reason: PMID:29224185 (full text) shows GSK-3beta inhibition further increased bone parameters at tension sites via beta-catenin. GSK3B negatively regulates osteogenesis through beta-catenin (captured by GO:0045668); "involved in bone remodeling" over-states its role in a tissue-level process. Supporting Evidence: PMID:29224185 Downregulation of GSK-3Ξ² activity further increased bone parameters |
| GO:0048156 tau protein binding | IDA PMID:16735023 Recruitment of active glycogen synthase kinase-3 into neuron... | KEEP AS NON CORE | Summary: Tau binding is the substrate-binding side of tau-protein kinase activity. Reason: PMID:16735023 shows GSK-3beta recruitment to lipid rafts and phosphorylation of raft-associated tau. Binding of substrate is implied by tau-protein kinase activity (accepted as core), so this is retained as a non-core, enzyme-substrate binding term. Supporting Evidence: PMID:16735023 Inhibition of GSK-3beta by small molecule inhibitors blocks specific phosphorylation of lipid raft associated protein Tau file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU |
| GO:0048168 regulation of neuronal synaptic plasticity | IMP PMID:17329210 LTP inhibits LTD in the hippocampus via regulation of GSK3be... | ACCEPT | Summary: GSK3beta is required for NMDAR-dependent LTD and its inhibition after LTP blocks LTD. Reason: PMID:17329210 (abstract only): GSK3beta inhibitors block LTD induction in rat hippocampal slices, and LTP inhibits GSK3beta. Core synaptic role, mechanistically explained by PSD-95 Thr-19 phosphorylation (PMID:23864697). Supporting Evidence: PMID:17329210 GSK3beta inhibitors block the induction of LTD PMID:17329210 the activity of GSK3beta is enhanced during LTD via activation of PP1 |
| GO:0048471 perinuclear region of cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Perinuclear region of cytoplasm localisation transferred from the mouse/human ortholog. Reason: Sound ortholog transfer of a sub-cellular location of a ubiquitous soluble kinase; peripheral to core function. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} |
| GO:0048661 positive regulation of smooth muscle cell proliferation | IMP PMID:21557011 Glycogen synthase kinase 3 beta positively regulates Notch s... | KEEP AS NON CORE | Summary: GSK-3beta promotes vSMC proliferation via Notch signalling. Reason: PMID:21557011 (full text), as above. Non-core. Supporting Evidence: PMID:21557011 while concomitantly promoting vSMC proliferation and inhibiting apoptosis |
| GO:0048814 regulation of dendrite morphogenesis | IMP PMID:15652487 Both the establishment and the maintenance of neuronal polar... | KEEP AS NON CORE | Summary: GSK3B activity shapes axon/dendrite formation in rat hippocampal neurons. Reason: PMID:15652487 (abstract only): constitutively active GSK-3beta inhibits axon formation, inhibition yields multiple axons and converts dendrites into axons. Real neuronal-development role, non-core. Supporting Evidence: PMID:15652487 A constitutively active GSK-3beta mutant inhibited axon formation PMID:15652487 conversion of preexisting dendrites into axons upon GSK-3 inhibition |
| GO:0050321 tau-protein kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Tau-protein kinase activity; GSK3B was first purified as tau protein kinase I. Reason: GSK3B phosphorylates MAPT/tau (curated UniProt function, EC 2.7.11.26). In rat neurons GSK-3beta inhibitors block phosphorylation of raft-associated tau (PMID:16735023), and GSK-3beta activation accompanies tau hyperphosphorylation in rat hippocampus (PMID:16879317). The IBA, IEA, ISO and ISS rows reinforce the same claim. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] PMID:16735023 Inhibition of GSK-3beta by small molecule inhibitors blocks specific phosphorylation of lipid raft associated protein Tau PMID:16879317 The injection of SIN-1 induced hyperphosphorylation of tau at pS396 epitope with a concomitant activation of GSK-3beta |
| GO:0050321 tau-protein kinase activity | IDA PMID:16735023 Recruitment of active glycogen synthase kinase-3 into neuron... | ACCEPT | Summary: Tau-protein kinase activity; GSK3B was first purified as tau protein kinase I. Reason: GSK3B phosphorylates MAPT/tau (curated UniProt function, EC 2.7.11.26). In rat neurons GSK-3beta inhibitors block phosphorylation of raft-associated tau (PMID:16735023), and GSK-3beta activation accompanies tau hyperphosphorylation in rat hippocampus (PMID:16879317). The IBA, IEA, ISO and ISS rows reinforce the same claim. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] PMID:16735023 Inhibition of GSK-3beta by small molecule inhibitors blocks specific phosphorylation of lipid raft associated protein Tau PMID:16879317 The injection of SIN-1 induced hyperphosphorylation of tau at pS396 epitope with a concomitant activation of GSK-3beta |
| GO:0050321 tau-protein kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Tau-protein kinase activity; GSK3B was first purified as tau protein kinase I. Reason: GSK3B phosphorylates MAPT/tau (curated UniProt function, EC 2.7.11.26). In rat neurons GSK-3beta inhibitors block phosphorylation of raft-associated tau (PMID:16735023), and GSK-3beta activation accompanies tau hyperphosphorylation in rat hippocampus (PMID:16879317). The IBA, IEA, ISO and ISS rows reinforce the same claim. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] PMID:16735023 Inhibition of GSK-3beta by small molecule inhibitors blocks specific phosphorylation of lipid raft associated protein Tau PMID:16879317 The injection of SIN-1 induced hyperphosphorylation of tau at pS396 epitope with a concomitant activation of GSK-3beta |
| GO:0050321 tau-protein kinase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Tau-protein kinase activity; GSK3B was first purified as tau protein kinase I. Reason: GSK3B phosphorylates MAPT/tau (curated UniProt function, EC 2.7.11.26). In rat neurons GSK-3beta inhibitors block phosphorylation of raft-associated tau (PMID:16735023), and GSK-3beta activation accompanies tau hyperphosphorylation in rat hippocampus (PMID:16879317). The IBA, IEA, ISO and ISS rows reinforce the same claim. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] PMID:16735023 Inhibition of GSK-3beta by small molecule inhibitors blocks specific phosphorylation of lipid raft associated protein Tau PMID:16879317 The injection of SIN-1 induced hyperphosphorylation of tau at pS396 epitope with a concomitant activation of GSK-3beta |
| GO:0050321 tau-protein kinase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Tau-protein kinase activity; GSK3B was first purified as tau protein kinase I. Reason: GSK3B phosphorylates MAPT/tau (curated UniProt function, EC 2.7.11.26). In rat neurons GSK-3beta inhibitors block phosphorylation of raft-associated tau (PMID:16735023), and GSK-3beta activation accompanies tau hyperphosphorylation in rat hippocampus (PMID:16879317). The IBA, IEA, ISO and ISS rows reinforce the same claim. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] PMID:16735023 Inhibition of GSK-3beta by small molecule inhibitors blocks specific phosphorylation of lipid raft associated protein Tau PMID:16879317 The injection of SIN-1 induced hyperphosphorylation of tau at pS396 epitope with a concomitant activation of GSK-3beta |
| GO:0050321 tau-protein kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Tau-protein kinase activity; GSK3B was first purified as tau protein kinase I. Reason: GSK3B phosphorylates MAPT/tau (curated UniProt function, EC 2.7.11.26). In rat neurons GSK-3beta inhibitors block phosphorylation of raft-associated tau (PMID:16735023), and GSK-3beta activation accompanies tau hyperphosphorylation in rat hippocampus (PMID:16879317). The IBA, IEA, ISO and ISS rows reinforce the same claim. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] PMID:16735023 Inhibition of GSK-3beta by small molecule inhibitors blocks specific phosphorylation of lipid raft associated protein Tau PMID:16879317 The injection of SIN-1 induced hyperphosphorylation of tau at pS396 epitope with a concomitant activation of GSK-3beta |
| GO:0050770 regulation of axonogenesis | IMP PMID:15652487 Both the establishment and the maintenance of neuronal polar... | KEEP AS NON CORE | Summary: GSK3B activity shapes axon/dendrite formation in rat hippocampal neurons. Reason: PMID:15652487 (abstract only): constitutively active GSK-3beta inhibits axon formation, inhibition yields multiple axons and converts dendrites into axons. Real neuronal-development role, non-core. Supporting Evidence: PMID:15652487 A constitutively active GSK-3beta mutant inhibited axon formation PMID:15652487 conversion of preexisting dendrites into axons upon GSK-3 inhibition |
| GO:0050774 negative regulation of dendrite morphogenesis | IMP PMID:17182785 An essential role for the integrin-linked kinase-glycogen sy... | KEEP AS NON CORE | Summary: GSK3B downstream of ILK restrains dendrite initiation and growth. Reason: In rat sympathetic and cortical neurons, inhibition of GSK-3beta (pharmacological, dominant-negative or knockdown) caused robust dendrite initiation (PMID:17182785). Non-core developmental role. Supporting Evidence: PMID:17182785 caused robust dendrite initiation |
| GO:0051059 NF-kappaB binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: NF-kappaB binding transferred from human GSK3B. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Probably regulates NF-kappa-B (NFKB1) at the transcriptional level |
| GO:0060070 canonical Wnt signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B is a central component of canonical Wnt/beta-catenin signalling. Reason: GSK3B in the destruction complex phosphorylates beta-catenin, targeting it for degradation; Wnt and other inputs inhibit this (PMID:9482734, PMID:20042609). Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes PMID:9482734 rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin PMID:20042609 AKT in turn generates inhibitory phosphorylation of GSK-3Ξ² resulting in activation of Ξ²-catenin and stimulation of Lef/TCF-mediated transcription |
| GO:0060070 canonical Wnt signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B is a central component of canonical Wnt/beta-catenin signalling. Reason: GSK3B in the destruction complex phosphorylates beta-catenin, targeting it for degradation; Wnt and other inputs inhibit this (PMID:9482734, PMID:20042609). Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes PMID:9482734 rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin PMID:20042609 AKT in turn generates inhibitory phosphorylation of GSK-3Ξ² resulting in activation of Ξ²-catenin and stimulation of Lef/TCF-mediated transcription |
| GO:0061049 cell growth involved in cardiac muscle cell development | IDA PMID:27854077 Prohibitin confers cytoprotection against ISO-induced hypert... | MARK AS OVER ANNOTATED | Summary: Cardiomyocyte hypertrophy in H9c2 cells associated with Akt/Gsk-3beta phosphorylation changes. Reason: PMID:27854077 (abstract only) studies prohibitin; Gsk-3beta phosphorylation is a readout of Akt signalling and GSK3B was not manipulated. The precomposed "cell growth involved in cardiac muscle cell development" term is not supported as a GSK3B process. Supporting Evidence: PMID:27854077 significant constitutive activation of Gsk-3Ξ² via inactivation of Akt was observed |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Binding of DNA-binding transcription factors that GSK3B phosphorylates (e.g. JUN, NFAT). Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates JUN at sites proximal to its DNA-binding domain file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates mTORC2 complex component RICTOR |
| GO:0070301 cellular response to hydrogen peroxide | IEP PMID:18005341 Neuroprotective effects of atypical D1 receptor agonist SKF8... | KEEP AS NON CORE | Summary: H2O2 activates GSK-3beta in cortical cells, contributing to oxidative injury. Reason: PMID:18005341 (abstract only): H2O2-activated GSK-3beta was inhibited by SKF83959 and a GSK-3beta inhibitor attenuated H2O2 effects on iNOS/NO. Non-core. Supporting Evidence: PMID:18005341 SKF83959 treatment significantly inhibited H2O2-activated glycogen synthase kinase-3beta (GSK-3beta) |
| GO:0070507 regulation of microtubule cytoskeleton organization | IBA GO_REF:0000033 | ACCEPT | Summary: GSK3B regulates microtubule cytoskeleton organisation through phosphorylation of MAPs (tau, CRMP2, APC, MACF1). Reason: In rat hippocampal neurons GSK-3beta inhibition increases microtubule stabilisation (acetylation) before formation of multiple axons (PMID:18268107); UniProt describes phosphorylation of tau decreasing its microtubule binding. Supporting Evidence: PMID:18268107 precedes the formation of multiple axons in morphologically still unpolarized stage 2 neurons treated with GSK-3Ξ² inhibitor file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU file:rat/Gsk3b/Gsk3b-uniprot.txt Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex |
| GO:0070507 regulation of microtubule cytoskeleton organization | IMP PMID:18268107 Microtubule stabilization specifies initial neuronal polariz... | ACCEPT | Summary: GSK3B regulates microtubule cytoskeleton organisation through phosphorylation of MAPs (tau, CRMP2, APC, MACF1). Reason: In rat hippocampal neurons GSK-3beta inhibition increases microtubule stabilisation (acetylation) before formation of multiple axons (PMID:18268107); UniProt describes phosphorylation of tau decreasing its microtubule binding. Supporting Evidence: PMID:18268107 precedes the formation of multiple axons in morphologically still unpolarized stage 2 neurons treated with GSK-3Ξ² inhibitor file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates MAPT/TAU file:rat/Gsk3b/Gsk3b-uniprot.txt Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex |
| GO:0070840 dynein complex binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Dynein complex binding transferred from mouse Gsk3b. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0070885 negative regulation of calcineurin-NFAT signaling cascade | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of calcineurin-NFAT signaling cascade: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates NFATC1 promoting its nuclear export, opposing calcineurin (curated UniProt function). Sound ortholog transfer; a well-defined substrate-level output, but not core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0070885 negative regulation of calcineurin-NFAT signaling cascade | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of calcineurin-NFAT signaling cascade: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates NFATC1 promoting its nuclear export, opposing calcineurin (curated UniProt function). Sound ortholog transfer; a well-defined substrate-level output, but not core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt promoting NFATC1/NFATC nuclear export |
| GO:0071109 superior temporal gyrus development | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Superior temporal gyrus development transferred from human GSK3B; association-level donor evidence. Reason: The superior temporal gyrus has no rodent counterpart, and the human donor annotation (PMID:19581563) is association-level. Over-annotation for rat Gsk3b. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P49841 Β· human GSK3B SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0071260 cellular response to mechanical stimulus | IDA PMID:20042609 Mechano-transduction in osteoblastic cells involves strain-r... | KEEP AS NON CORE | Summary: GSK-3beta inhibition by AKT relays mechanical strain to beta-catenin signalling in osteoblastic cells. Reason: PMID:20042609 (full text read): in UMR-106 cells and primary osteoblasts, strain activates IGF-IR/PI3K/AKT, which phosphorylates and inhibits GSK-3beta, activating beta-catenin independently of Wnt/LRP5. GSK3B is a relay node whose inactivation transmits the signal. Real but context-specific; non-core. Supporting Evidence: PMID:20042609 AKT in turn generates inhibitory phosphorylation of GSK-3Ξ² resulting in activation of Ξ²-catenin and stimulation of Lef/TCF-mediated transcription |
| GO:0071282 cellular response to iron(II) ion | IEP PMID:19608791 Iron-induced oxidative injury differentially regulates PI3K/... | KEEP AS NON CORE | Summary: Iron-induced oxidative stress alters PI3K/Akt-dependent GSK3beta phosphorylation in synaptosomes. Reason: PMID:19608791 (abstract only): GSK3beta phosphorylation tracks Akt activation after FeSO4 exposure. GSK3B is a regulated pathway node; non-core. Supporting Evidence: PMID:19608791 GSK3beta phosphorylation showed the same activation pattern as that observed for Akt |
| GO:0071285 cellular response to lithium ion | IEP PMID:18932008 Lithium reduces Gsk3b mRNA levels: implications for Alzheime... | MARK AS OVER ANNOTATED | Summary: Lithium lowers Gsk3b mRNA in hippocampal neurons; expression readout only. Reason: IEP evidence: the paper reports a change in GSK3B abundance, mRNA or phosphorylation after the treatment. That GSK3B is regulated by a stimulus does not show that it performs a step of the response; this is an expression readout rather than a function, and over-annotates the gene. (PMID:18932008 measured Gsk3b transcript levels; lithium is also a direct GSK3 inhibitor, but that is not what the row records.) Supporting Evidence: PMID:18932008 We found a significant and dose-dependent reduction in the expression of Gsk3b, which was specific to hippocampal cells |
| GO:0071300 cellular response to retinoic acid | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to retinoic acid: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0071385 cellular response to glucocorticoid stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to glucocorticoid stimulus: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0071871 response to epinephrine | IEP PMID:16934435 GSK-3beta regulation in skeletal muscles by adrenaline and i... | KEEP AS NON CORE | Summary: Adrenaline increases inhibitory Ser9 phosphorylation of GSK-3beta in skeletal muscle via PKA. Reason: PMID:16934435 (abstract only): adrenaline alone increased phosphorylation of GSK-3beta Ser9; PKA-specific cAMP analogue mimicked it. Regulated node; non-core. Supporting Evidence: PMID:16934435 adrenaline alone increased phosphorylation of GSK-3beta Ser9 |
| GO:0072687 meiotic spindle | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Meiotic spindle localisation transferred from the mouse/human ortholog. Reason: Sound ortholog transfer of a sub-cellular location of a ubiquitous soluble kinase; peripheral to core function. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: GSK3B negatively regulates canonical Wnt signalling by phosphorylating beta-catenin for degradation. Reason: Rat Axin promotes GSK-3beta-dependent phosphorylation of beta-catenin (PMID:9482734), leading to FWD1-mediated ubiquitination (PMID:10228155). Core function. Supporting Evidence: PMID:9482734 rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B negatively regulates canonical Wnt signalling by phosphorylating beta-catenin for degradation. Reason: Rat Axin promotes GSK-3beta-dependent phosphorylation of beta-catenin (PMID:9482734), leading to FWD1-mediated ubiquitination (PMID:10228155). Core function. Supporting Evidence: PMID:9482734 rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B negatively regulates canonical Wnt signalling by phosphorylating beta-catenin for degradation. Reason: Rat Axin promotes GSK-3beta-dependent phosphorylation of beta-catenin (PMID:9482734), leading to FWD1-mediated ubiquitination (PMID:10228155). Core function. Supporting Evidence: PMID:9482734 rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin PMID:10228155 specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:0090290 positive regulation of osteoclast proliferation | IMP PMID:26722385 Roles of TNF-Ξ±, GSK-3Ξ² and RANKL in the occurrence and devel... | MARK AS OVER ANNOTATED | Summary: Lithium/GSK-3beta inhibitor reduced osteoclast proliferation in a single MTT-based study. Reason: PMID:26722385 (full text): MTT readout after lithium chloride or a GSK-3beta inhibitor; non-specific pharmacology and indirect. Over-annotation. Supporting Evidence: PMID:26722385 osteoclast proliferation in GSK-3Ξ² inhibitor and lithium chloride groups were weaker than the untreated group |
| GO:0097110 scaffold protein binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Scaffold protein binding, notably the Axin scaffold of the destruction complex. Reason: Rat Axin directly binds GSK-3beta (PMID:9482734); Axin is the scaffold of the destruction complex. Real, but the informative claim is captured by the complex and kinase terms. Supporting Evidence: PMID:9482734 rAxin interacted directly with, and was phosphorylated by, GSK-3beta file:rat/Gsk3b/Gsk3b-uniprot.txt Interacts with AXIN1; the interaction mediates hyperphosphorylation of CTNNB1 |
| GO:0097191 extrinsic apoptotic signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Extrinsic apoptotic signaling pathway: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors |
| GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Extrinsic apoptotic signaling pathway in absence of ligand: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt may control cell apoptosis in response to growth factors deprivation |
| GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Extrinsic apoptotic signaling pathway in absence of ligand: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt may control cell apoptosis in response to growth factors deprivation |
| GO:0097284 hepatocyte apoptotic process | IDA PMID:28638224 Inhibitory effect of oxymatrine on hepatocyte apoptosis via ... | MARK AS OVER ANNOTATED | Summary: Hepatocyte apoptosis in LPS/D-GalN liver failure correlated with P-GSK3beta levels. Reason: PMID:28638224 (full text) shows oxymatrine pretreatment up-regulates P-Akt and P-GSK3beta(Ser9) while reducing hepatocyte apoptosis; GSK3B itself was not manipulated. Correlative pathway readout; over-annotation. Supporting Evidence: PMID:28638224 up-regulated expression of P-AktSer473 (Akt phosphorylated at serine 473) and P-GSK3Ξ²Ser9 |
| GO:0098685 Schaffer collateral - CA1 synapse | IDA PMID:23864697 Phosphorylation of threonine-19 of PSD-95 by GSK-3Ξ² is requi... | KEEP AS NON CORE | Summary: GSK3B acts at Schaffer collateral-CA1 synapses during LTD. Reason: PMID:23864697 studies PSD-95 Thr-19 phosphorylation and LTD in rat hippocampal neurons and slices. Real site of action; non-core. Supporting Evidence: PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0098685 Schaffer collateral - CA1 synapse | IMP PMID:23864697 Phosphorylation of threonine-19 of PSD-95 by GSK-3Ξ² is requi... | KEEP AS NON CORE | Summary: GSK3B acts at Schaffer collateral-CA1 synapses during LTD. Reason: PMID:23864697 studies PSD-95 Thr-19 phosphorylation and LTD in rat hippocampal neurons and slices. Real site of action; non-core. This row uses IMP, which cannot by itself establish a location; the action follows the IDA row for the same term and the evidence code is flagged upstream. Supporting Evidence: PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0098696 regulation of neurotransmitter receptor localization to postsynaptic specialization membrane | IDA PMID:23864697 Phosphorylation of threonine-19 of PSD-95 by GSK-3Ξ² is requi... | ACCEPT | Summary: GSK3B phosphorylation of PSD-95 is required for AMPA receptor mobilisation during LTD. Reason: PMID:23864697 (full text) shows Thr-19 phosphorylation of PSD-95 by GSK-3beta destabilises PSD-95 and is critical for AMPA receptor internalisation. Direct kinase role in this process; core synaptic function of rat GSK3B. Supporting Evidence: PMID:23864697 is phosphorylated on threonine-19 (T19) by GSK-3Ξ² PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0098696 regulation of neurotransmitter receptor localization to postsynaptic specialization membrane | IMP PMID:23864697 Phosphorylation of threonine-19 of PSD-95 by GSK-3Ξ² is requi... | ACCEPT | Summary: GSK3B phosphorylation of PSD-95 is required for AMPA receptor mobilisation during LTD. Reason: PMID:23864697 (full text) shows Thr-19 phosphorylation of PSD-95 by GSK-3beta destabilises PSD-95 and is critical for AMPA receptor internalisation. Direct kinase role in this process; core synaptic function of rat GSK3B. Supporting Evidence: PMID:23864697 is phosphorylated on threonine-19 (T19) by GSK-3Ξ² PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0098793 presynapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Presynaptic location inferred from presynaptic modulation of transmission. Reason: Electronic CC inference from a BP annotation; plausible but peripheral. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0098978 glutamatergic synapse | IBA GO_REF:0000033 | ACCEPT | Summary: GSK3B acts at glutamatergic synapses, phosphorylating PSD-95 during LTD. Reason: GSK-3beta phosphorylates PSD-95 at Thr-19 in rat hippocampal neurons, destabilising PSD-95 and enabling AMPA receptor mobilisation and LTD (PMID:23864697, full text). Core site of the synaptic PSD-95 kinase function in rat. Supporting Evidence: PMID:23864697 is phosphorylated on threonine-19 (T19) by GSK-3Ξ² PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0098978 glutamatergic synapse | IDA PMID:23864697 Phosphorylation of threonine-19 of PSD-95 by GSK-3Ξ² is requi... | ACCEPT | Summary: GSK3B acts at glutamatergic synapses, phosphorylating PSD-95 during LTD. Reason: GSK-3beta phosphorylates PSD-95 at Thr-19 in rat hippocampal neurons, destabilising PSD-95 and enabling AMPA receptor mobilisation and LTD (PMID:23864697, full text). Core site of the synaptic PSD-95 kinase function in rat. Supporting Evidence: PMID:23864697 is phosphorylated on threonine-19 (T19) by GSK-3Ξ² PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0098978 glutamatergic synapse | IMP PMID:23864697 Phosphorylation of threonine-19 of PSD-95 by GSK-3Ξ² is requi... | ACCEPT | Summary: GSK3B acts at glutamatergic synapses, phosphorylating PSD-95 during LTD. Reason: GSK-3beta phosphorylates PSD-95 at Thr-19 in rat hippocampal neurons, destabilising PSD-95 and enabling AMPA receptor mobilisation and LTD (PMID:23864697, full text). Core site of the synaptic PSD-95 kinase function in rat. This row uses IMP, which cannot by itself establish a location; the action follows the IDA row for the same term and the evidence code is flagged upstream. Supporting Evidence: PMID:23864697 is phosphorylated on threonine-19 (T19) by GSK-3Ξ² PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0098978 glutamatergic synapse | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B acts at glutamatergic synapses, phosphorylating PSD-95 during LTD. Reason: GSK-3beta phosphorylates PSD-95 at Thr-19 in rat hippocampal neurons, destabilising PSD-95 and enabling AMPA receptor mobilisation and LTD (PMID:23864697, full text). Core site of the synaptic PSD-95 kinase function in rat. Supporting Evidence: PMID:23864697 is phosphorylated on threonine-19 (T19) by GSK-3Ξ² PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0098978 glutamatergic synapse | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B acts at glutamatergic synapses, phosphorylating PSD-95 during LTD. Reason: GSK-3beta phosphorylates PSD-95 at Thr-19 in rat hippocampal neurons, destabilising PSD-95 and enabling AMPA receptor mobilisation and LTD (PMID:23864697, full text). Core site of the synaptic PSD-95 kinase function in rat. Supporting Evidence: PMID:23864697 is phosphorylated on threonine-19 (T19) by GSK-3Ξ² PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0099159 regulation of modification of postsynaptic structure | IDA PMID:23864697 Phosphorylation of threonine-19 of PSD-95 by GSK-3Ξ² is requi... | KEEP AS NON CORE | Summary: GSK3B phosphorylation of PSD-95 destabilises the postsynaptic density during LTD. Reason: PMID:23864697 shows PSD-95-T19A has enhanced stability in spines while T19D is dispersed, linking GSK-3beta phosphorylation to PSD remodelling. Supporting Evidence: PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0099159 regulation of modification of postsynaptic structure | IMP PMID:23864697 Phosphorylation of threonine-19 of PSD-95 by GSK-3Ξ² is requi... | KEEP AS NON CORE | Summary: GSK3B phosphorylation of PSD-95 destabilises the postsynaptic density during LTD. Reason: PMID:23864697 shows PSD-95-T19A has enhanced stability in spines while T19D is dispersed, linking GSK-3beta phosphorylation to PSD remodelling. Supporting Evidence: PMID:23864697 phosphorylation on T19 by GSK-3Ξ² destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD |
| GO:0099171 presynaptic modulation of chemical synaptic transmission | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Presynaptic modulation of transmission transferred from human GSK3B. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0106027 neuron projection organization | IMP PMID:15652487 Both the establishment and the maintenance of neuronal polar... | KEEP AS NON CORE | Summary: GSK3B activity shapes axon/dendrite formation in rat hippocampal neurons. Reason: PMID:15652487 (abstract only): constitutively active GSK-3beta inhibits axon formation, inhibition yields multiple axons and converts dendrites into axons. Real neuronal-development role, non-core. Supporting Evidence: PMID:15652487 A constitutively active GSK-3beta mutant inhibited axon formation PMID:15652487 conversion of preexisting dendrites into axons upon GSK-3 inhibition |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Protein serine kinase activity, a correct description of GSK3B catalysis on serine residues of substrates. Reason: GSK3B phosphorylates serine residues of primed substrates (e.g. beta-catenin, glycogen synthase, tau, PSD-95 is a threonine example). The Rhea mapping for L-seryl-[protein] phosphorylation is correct for this enzyme. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0106310 protein serine kinase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Protein serine kinase activity, a correct description of GSK3B catalysis on serine residues of substrates. Reason: GSK3B phosphorylates serine residues of primed substrates (e.g. beta-catenin, glycogen synthase, tau, PSD-95 is a threonine example). The Rhea mapping for L-seryl-[protein] phosphorylation is correct for this enzyme. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0106310 protein serine kinase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Protein serine kinase activity, a correct description of GSK3B catalysis on serine residues of substrates. Reason: GSK3B phosphorylates serine residues of primed substrates (e.g. beta-catenin, glycogen synthase, tau, PSD-95 is a threonine example). The Rhea mapping for L-seryl-[protein] phosphorylation is correct for this enzyme. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0106310 protein serine kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Protein serine kinase activity, a correct description of GSK3B catalysis on serine residues of substrates. Reason: GSK3B phosphorylates serine residues of primed substrates (e.g. beta-catenin, glycogen synthase, tau, PSD-95 is a threonine example). The Rhea mapping for L-seryl-[protein] phosphorylation is correct for this enzyme. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0120283 protein serine/threonine kinase binding | IPI PMID:8524413 Inhibition of glycogen synthase kinase-3 by insulin mediated... | KEEP AS NON CORE | Summary: Akt/PKB is a Ser/Thr kinase that phosphorylates and inhibits GSK3B. Reason: PMID:8524413 (abstract only) identifies PKB/Akt as the insulin-stimulated kinase that inactivates GSK3. The enzyme-substrate interaction with a Ser/Thr kinase is real but describes how GSK3B is regulated rather than what it does. Supporting Evidence: PMID:8524413 it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC) file:rat/Gsk3b/Gsk3b-uniprot.txt In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 |
| GO:0141068 autosome genomic imprinting | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Autosome genomic imprinting (acts upstream, positive effect) from mouse; indirect. Reason: GSK3B is not an imprinting factor; the mouse-derived acts_upstream_of_positive_effect annotation reflects an indirect phenotype. Over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1861437 Β· mouse Gsk3b SOURCE WEAK OR INFERRED Donor annotation reflects an indirect or phenotype-level effect rather than a step GSK3B performs. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:0150101 regulation of microtubule anchoring at centrosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of microtubule anchoring at centrosome: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:1900026 positive regulation of substrate adhesion-dependent cell spreading | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of substrate adhesion-dependent cell spreading: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:1900181 negative regulation of protein localization to nucleus | IMP PMID:23624080 miR-145 inhibits isoproterenol-induced cardiomyocyte hypertr... | KEEP AS NON CORE | Summary: GSK3B activity limits nuclear accumulation of GATA6 in cardiomyocytes. Reason: PMID:23624080 (full text): GSK3beta antagonists restored nuclear accumulation of GATA6. Indirect, pharmacological; kept as non-core. Supporting Evidence: PMID:23624080 GSK3Ξ² antagonists, LiCl and TDZD8, restored the nuclear accumulation of GATA6 |
| GO:1900271 regulation of long-term synaptic potentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of LTP transferred from mouse. Reason: Consistent with rat data on GSK3beta at LTP/LTD (PMID:17329210) and UniProt; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Regulates the circadian rhythmicity of hippocampal long-term potentiation PMID:17329210 the activity of GSK3beta is enhanced during LTD via activation of PP1 |
| GO:1900271 regulation of long-term synaptic potentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of LTP transferred from mouse. Reason: Consistent with rat data on GSK3beta at LTP/LTD (PMID:17329210) and UniProt; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Regulates the circadian rhythmicity of hippocampal long-term potentiation PMID:17329210 the activity of GSK3beta is enhanced during LTD via activation of PP1 |
| GO:1901030 positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt may control cell apoptosis in response to growth factors deprivation |
| GO:1901030 positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt may control cell apoptosis in response to growth factors deprivation |
| GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of extrinsic apoptotic signaling pathway: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors |
| GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of extrinsic apoptotic signaling pathway: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors |
| GO:1902065 response to L-glutamate | IEP PMID:18445133 Concomitant degradation of beta-catenin and GSK-3 beta poten... | MARK AS OVER ANNOTATED | Summary: Glutamate causes GSK-3beta degradation in hippocampal slices; GSK3B is a passive target. Reason: IEP evidence: the paper reports a change in GSK3B abundance, mRNA or phosphorylation after the treatment. That GSK3B is regulated by a stimulus does not show that it performs a step of the response; this is an expression readout rather than a function, and over-annotates the gene. PMID:18445133 shows GSK-3beta is degraded by glutamate exposure, independently of the beta-catenin loss. Supporting Evidence: PMID:18445133 glutamate promotes the down-regulations of beta-catenin and GSK-3beta |
| GO:1903351 cellular response to dopamine | IEP PMID:20007479 Activation of glycogen synthase kinase-3 beta is required fo... | KEEP AS NON CORE | Summary: High dopamine activates GSK-3beta via D2 receptors in prefrontal cortex. Reason: PMID:20007479 (abstract only): hyperdopaminergic suppression of NMDA receptors involved increased GSK-3beta activity. GSK3B is a mediator of the response; non-core. Supporting Evidence: PMID:20007479 was involved in the increase of glycogen synthase kinase-3beta (GSK-3beta) activity |
| GO:1903566 positive regulation of protein localization to cilium | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of protein localization to cilium: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:1903566 positive regulation of protein localization to cilium | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of protein localization to cilium: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:1903940 negative regulation of TORC2 signaling | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of TORC2 signaling: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates RICTOR in response to ER stress, inhibiting mTORC2 (UniProt by similarity). Sound transfer; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates mTORC2 complex component RICTOR |
| GO:1903940 negative regulation of TORC2 signaling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of TORC2 signaling: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: GSK3B phosphorylates RICTOR in response to ER stress, inhibiting mTORC2 (UniProt by similarity). Sound transfer; non-core. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Phosphorylates mTORC2 complex component RICTOR |
| GO:1904313 response to methamphetamine hydrochloride | IDA PMID:32670551 Cannabidiol attenuates methamphetamine-induced conditioned p... | MARK AS OVER ANNOTATED | Summary: Methamphetamine CPP raises p-GSK3beta in rat brain regions; correlative readout. Reason: PMID:32670551 (full text available) reports western blots of p-GSK3beta in the METH-CPP model and its reversal by cannabidiol. A change in phosphorylation level in a drug model does not show GSK3B performs a step of the response to methamphetamine. Supporting Evidence: PMID:32670551 The expression levels of Sigma1R, p-AKT, p-GSK3Ξ², and p-CREB increased significantly in the METH-induced CPP model |
| GO:1904339 negative regulation of dopaminergic neuron differentiation | IMP PMID:15522889 GSK-3beta inhibition/beta-catenin stabilization in ventral m... | KEEP AS NON CORE | Summary: GSK-3beta inhibition increases dopaminergic differentiation of ventral midbrain precursors. Reason: PMID:15522889 (abstract only): kenpaullone increases tyrosine hydroxylase positive DA neurons via beta-catenin stabilisation. Non-core developmental output of Wnt regulation. Supporting Evidence: PMID:15522889 the GSK-3beta-specific inhibitor kenpaullone increased the size of the DA neuron population |
| GO:1904646 cellular response to amyloid-beta | IDA PMID:26224839 Na, K-ATPase Ξ±3 is a death target of Alzheimer patient amylo... | UNDECIDED | Summary: Cellular response to amyloid-beta: the cached abstract does not mention GSK3B. Reason: PMID:26224839 (abstract only) describes amylospheroid binding to Na,K-ATPase alpha3 leading to tau abnormalities; GSK3B is not mentioned in the cached text. GSK3B involvement in Abeta-induced tau phosphorylation is plausible, but the curated observation cannot be verified here. |
| GO:1904780 negative regulation of protein localization to centrosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of protein localization to centrosome: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:1904781 positive regulation of protein localization to centrosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of protein localization to centrosome: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:1990418 response to insulin-like growth factor stimulus | IEP PMID:17686886 GSK-3beta activity is increased in skeletal muscle after bur... | UNDECIDED | Summary: Response to IGF stimulus: the cached abstract of the cited burn-injury paper does not mention IGF. Reason: PMID:17686886 (abstract only) reports burn-induced GSK-3beta activation and dexamethasone experiments; no IGF treatment is described in the cached text. GSK3B is inhibited downstream of IGF-I receptor/AKT in other rat cells (PMID:20042609), so the claim is plausible, but the curated observation cannot be verified from this source. Supporting Evidence: PMID:20042609 AKT in turn generates inhibitory phosphorylation of GSK-3Ξ² resulting in activation of Ξ²-catenin and stimulation of Lef/TCF-mediated transcription |
| GO:1990478 response to ultrasound | IEP PMID:20708505 LIPUS enhance elongation of neurites in rat cortical neurons... | MARK AS OVER ANNOTATED | Summary: Ultrasound lowers GSK-3beta expression/phosphorylation in cortical neurons; expression readout only. Reason: IEP evidence: the paper reports a change in GSK3B abundance, mRNA or phosphorylation after the treatment. That GSK3B is regulated by a stimulus does not show that it performs a step of the response; this is an expression readout rather than a function, and over-annotates the gene. (PMID:20708505.) Supporting Evidence: PMID:20708505 LIPUS can enhance elongation of neurites and it is possible through the decreased expression of GSK-3beta |
| GO:1990708 conditioned place preference | IDA PMID:32670551 Cannabidiol attenuates methamphetamine-induced conditioned p... | MARK AS OVER ANNOTATED | Summary: Conditioned place preference is an organism-level behaviour; p-GSK3beta levels were only measured. Reason: PMID:32670551 measured p-GSK3beta in brain regions of rats showing METH-induced CPP; no GSK3B manipulation was used to establish a role in the behaviour. Behavioural process terms from correlative westerns over-annotate a kinase. Supporting Evidence: PMID:32670551 The expression levels of Sigma1R, p-AKT, p-GSK3Ξ², and p-CREB increased significantly in the METH-induced CPP model |
| GO:1990776 response to angiotensin | IEP PMID:22982863 Central angiotensin II-induced Alzheimer-like tau phosphoryl... | KEEP AS NON CORE | Summary: GSK3B mediates angiotensin II-induced tau phosphorylation in rat brain. Reason: PMID:22982863 (abstract only): central angiotensin II elevates p-tau via GSK3beta, attenuated by a GSK3beta inhibitor. GSK3B acts as the tau kinase in this response; non-core. Supporting Evidence: PMID:22982863 p-tau levels were significantly elevated by central angiotensin II via glycogen synthase kinase 3Ξ² (GSK 3Ξ²) and other tau kinases |
| GO:1990904 ribonucleoprotein complex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ribonucleoprotein complex localisation transferred from the mouse/human ortholog. Reason: Sound ortholog transfer of a sub-cellular location of a ubiquitous soluble kinase; peripheral to core function. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:P49841} |
| GO:1990909 Wnt signalosome | ISO GO_REF:0000121 | ACCEPT | Summary: GSK3B is recruited to the Wnt signalosome at LRP6. Reason: MACF1 helps translocate the Axin/GSK3beta complex to LRP6 at the membrane (PMID:16815997), where GSK3B participates in LRP6 signalosome function. Part of the canonical Wnt core mechanism. Supporting Evidence: PMID:16815997 MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC file:rat/Gsk3b/Gsk3b-uniprot.txt Membrane {ECO:0000269|PubMed:16815997} |
| GO:2000171 negative regulation of dendrite development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: GSK3B phosphorylation of CRMP-2 restrains activity-dependent dendritic growth. Reason: In cerebellar granule neurons constitutively active GSK-3 inhibits dendritic growth through CRMP-2 Thr514 phosphorylation (PMID:23470087). Non-core. Supporting Evidence: PMID:23470087 expression of Thr514 nonphosphorylated form of CRMP-2 counteracted the inhibitory effect of constitutively active GSK-3 |
| GO:2000171 negative regulation of dendrite development | IMP PMID:23470087 GSK-3Ξ±/Ξ²-mediated phosphorylation of CRMP-2 regulates activi... | KEEP AS NON CORE | Summary: GSK3B phosphorylation of CRMP-2 restrains activity-dependent dendritic growth. Reason: In cerebellar granule neurons constitutively active GSK-3 inhibits dendritic growth through CRMP-2 Thr514 phosphorylation (PMID:23470087). Non-core. Supporting Evidence: PMID:23470087 expression of Thr514 nonphosphorylated form of CRMP-2 counteracted the inhibitory effect of constitutively active GSK-3 |
| GO:2000463 positive regulation of excitatory postsynaptic potential | IMP PMID:20007479 Activation of glycogen synthase kinase-3 beta is required fo... | UNDECIDED | Summary: The cited abstract implicates GSK-3beta activation in suppressing NMDA receptor currents, the opposite direction. Reason: PMID:20007479 (abstract only): excessive dopamine attenuates synaptic NMDA receptor currents through D2 receptors, and this suppression involved increased GSK-3beta activity, which disrupts beta-catenin-NR2B. That reads as GSK3B negatively regulating excitatory postsynaptic potentials. The curator may have recorded a rescue experiment, but the full text was not available; flagged for checking. Supporting Evidence: PMID:20007479 the synaptic NMDA receptor-mediated currents were significantly attenuated by excessive dopamine stimulation PMID:20007479 was involved in the increase of glycogen synthase kinase-3beta (GSK-3beta) activity |
| GO:2000573 positive regulation of DNA biosynthetic process | IMP PMID:12721208 Evidence for a role of glycogen synthase kinase-3 beta in ro... | KEEP AS NON CORE | Summary: GSK-3 activity is needed for meiotic S-phase DNA synthesis in rat seminiferous tubules. Reason: PMID:12721208 (abstract only): GSK-3 inhibitors suppressed meiotic S-phase DNA synthesis in cultured rat tubule segments. Inhibitors do not distinguish GSK-3 alpha and beta; non-core. Supporting Evidence: PMID:12721208 These compounds markedly and dose-dependently suppressed meiotic synthesis (S)-phase DNA |
| GO:2000727 positive regulation of cardiac muscle cell differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of cardiac muscle cell differentiation: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:2000738 positive regulation of stem cell differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of stem cell differentiation: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt Constitutively active protein kinase |
| GO:2000740 negative regulation of mesenchymal stem cell differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of mesenchymal stem cell differentiation: a context-dependent output of GSK3B kinase activity transferred from the mouse/human ortholog. Reason: Transferred from the mouse/human ortholog. GSK3B function is highly conserved (rat and human GSK3B are near-identical in sequence), so the transfer is sound, but the term describes one of many context-dependent downstream outputs of a pleiotropic kinase rather than its core activity. Supporting Evidence: file:rat/Gsk3b/Gsk3b-uniprot.txt phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes |
| GO:2001223 negative regulation of neuron migration | IMP PMID:11403684 Activation of glycogen synthase kinase 3 beta (GSK-3beta) by... | KEEP AS NON CORE | Summary: GSK-3beta activation by PAF inhibits cerebellar granule neuron migration. Reason: PMID:11403684 (abstract only): PAF-mediated inhibition of CGN migration is reversed by the GSK-3 inhibitors lithium or valproate. Pharmacological, non-isoform-specific evidence; kept as non-core. Supporting Evidence: PMID:11403684 the GSK-3beta inhibitors lithium or valproic acid |
| GO:0005739 mitochondrion | IDA PMID:8576078 Different localization of tau protein kinase I/glycogen synt... | NEW | Summary: A pool of TPKI/GSK-3beta localises to mitochondria in rat cerebellum. Reason: PMID:8576078 (abstract only) reports immunoelectron microscopy and subcellular fractionation placing TPKI/GSK-3beta, but not GSK-3alpha, in rat cerebellar mitochondria. Independently, GSK-3beta co-immunoprecipitates with the mPTP components VDAC and ANT in rat cardiomyocytes (PMID:19318234). The GOA row for this paper is to microtubule (flagged); the mitochondrion location is what the paper reports. Sub-compartment not assigned: the two lines do not agree on a single sub-mitochondrial site. Supporting Evidence: PMID:8576078 was present in mitochondria, but GSK-3 alpha was not PMID:19318234 GSK-3beta interacts with components of the mPTP, voltage-dependent anion channel (VDAC) and adenine nucleotide translocase |
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Download this section (compressed HTML)Q: Which of the many tissue-level rat GSK3B annotations (bone, liver, heart, testis) rest on GSK3B-selective manipulation rather than lithium or pan-GSK3 inhibitors that also hit GSK3A?
Q: Does PMID:8576078 show any microtubule association of TPKI/GSK-3beta, or should the RGD row be repointed to mitochondrion?
Q: In PMID:20007479, does GSK-3beta activity raise or lower NMDA receptor-mediated EPSCs, i.e. is the positive-regulation row sign-inverted?
Experiment: Protease-protection and submitochondrial fractionation of rat cerebellar mitochondria with ER-marker controls, combined with phospho-VDAC measurement after GSK3B-selective knockdown or analog-sensitive GSK3B.
Hypothesis: The mitochondrial pool of GSK3B in rat neurons resides on the outer membrane and regulates the permeability transition via VDAC phosphorylation.
Type: subcellular fractionation and phosphorylation assay
Experiment: Isoform-specific knockdown or knock-in of kinase-dead GSK3B vs GSK3A in rat hippocampal slices, measuring PSD-95 pT19, AMPA receptor internalisation and LTD.
Hypothesis: GSK3B, not GSK3A, is the kinase for PSD-95 Thr-19 during hippocampal LTD.
Type: isoform-specific loss-of-function electrophysiology
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