gsk-3 (historically sgg-1) encodes the C. elegans ortholog of glycogen synthase kinase-3, a CMGC-group serine/threonine protein kinase that preferentially phosphorylates substrates already phosphorylated by a priming kinase. In the oocyte-to-embryo transition it phosphorylates the CCCH zinc-finger protein OMA-1 at T339 after MBK-2/DYRK priming, promoting CUL-2-dependent OMA-1 degradation after the first mitosis. In the early embryo it is a component of the MOM-2/Wnt signalling network that, unusually, acts positively: it is required for Wnt-dependent endoderm induction in the EMS daughter E and, through a transcription-independent branch, for orientation of the EMS and ABar mitotic spindles; it also represses the mesendoderm GATA factors med-1/2 in the C lineage. A Wnt/Frizzled-GSK-3-APR-1 branch promotes apoptotic cell engulfment and distal tip cell migration via CED-10/Rac. Later in development GSK-3 binds the Axin-like scaffolds PRY-1 and AXL-1 and acts as a negative regulator of BAR-1/beta-catenin-dependent canonical Wnt signalling (Q neuroblast and vulval precursor lineages). In the intestine GSK-3 phosphorylates SKN-1/Nrf and keeps it out of nuclei in the absence of stress, restraining the phase II oxidative stress response. The same beta-catenin-dependent Wnt pathway guides D-type motor neuron axons along the anteroposterior axis, and gsk-3 mutants, like pry-1/Axin mutants, have overextended D-type axons. Maternally rescued gsk-3 null adults are short-lived, and lithium, a GSK-3 inhibitor that extends wild-type lifespan, does not extend theirs.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000132 establishment of mitotic spindle orientation | IMP PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | ACCEPT | Summary: Establishment of mitotic spindle orientation. GSK-3 is required for Wnt-dependent orientation of the ABar (and EMS) mitotic spindle; in ABar this requires MOM-2/Wnt and GSK-3 but not WRM-1 or POP-1, i.e. a non-transcriptional Wnt branch to the cytoskeleton. Full text verified. This is a core, well-replicated worm-specific role of GSK-3. Supporting Evidence: PMID:20126385 ABar spindle positioning required MOM-2/Wnt and GSK-3 function, but not WRM-1/Ξ²-catenin or POP-1/TCF PMID:10444600 gsk-3 represents a branch point in the control of endoderm induction and spindle orientation |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Protein kinase activity from InterPro kinase-domain mapping. Correct (catalytic K65/D161 conserved) but less specific than the protein serine/threonine kinase activity term that is also supported experimentally. Supporting Evidence: PMID:16289132 Phosphorylation at T239 facilitates subsequent phosphorylation of OMA-1 by another kinase, GSK-3, at T339 in vitro |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the PTHR24057 family root (PTN000624299, Eukaryota). Ser/Thr kinase activity is the ancestral family activity and is experimentally supported for worm GSK-3 itself (OMA-1 phosphorylation); worm GSK-3 is among the seeds, which is expected, not circular. Supporting Evidence: PMID:16289132 Phosphorylation at T239 facilitates subsequent phosphorylation of OMA-1 by another kinase, GSK-3, at T339 in vitro |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:16289132 DYRK2 and GSK-3 phosphorylate and promote the timely degrada... | ACCEPT | Summary: IDA: GSK-3 phosphorylates OMA-1 at T339 in vitro after MBK-2 priming phosphorylation at T239, the classic priming-dependent GSK-3 mode. Abstract-only cache but the abstract states the experiment directly. Supporting Evidence: PMID:16289132 Phosphorylation at T239 facilitates subsequent phosphorylation of OMA-1 by another kinase, GSK-3, at T339 in vitro |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:23431196 Wnt and CDK-1 regulate cortical release of WRM-1/Ξ²-catenin t... | ACCEPT | Summary: IDA from Kim et al. 2013 (WRM-1 cortical release). Abstract-only and the abstract does not mention GSK-3, so the assay cannot be verified here; WormBase curators read the full text and the activity is independently established, so accepted. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro IPR039192 (GSK-3 kinase domain) mapping to Ser/Thr kinase activity. Correct and consistent with experimental IDA. Supporting Evidence: PMID:16289132 Phosphorylation at T239 facilitates subsequent phosphorylation of OMA-1 by another kinase, GSK-3, at T339 in vitro |
| GO:0005515 protein binding | IPI PMID:12023307 The Axin-like protein PRY-1 is a negative regulator of a can... | REMOVE | Summary: Protein binding is uninformative. Yeast two-hybrid interaction with the Axin-like scaffold PRY-1 (full text verified). Biologically meaningful (PRY-1 scaffolds a divergent destruction-complex-like assembly with SGG-1/GSK-3, APR-1 and BAR-1), but the information is better captured by the GSK-3 process annotations; no specific Axin-binding MF term exists. REMOVE per project policy for bare protein binding: no more informative MF term is supported; removal does not mean the interaction is false. Supporting Evidence: PMID:12023307 PRY-1 also binds the GSK3Ξ² homolog SGG-1 |
| GO:0005515 protein binding | IPI PMID:17601533 Two functionally distinct Axin-like proteins regulate canoni... | REMOVE | Summary: Protein binding is uninformative. Interaction with PRY-1/Axin reported in the AXL-1 paper (abstract-only). Represents Axin-GSK-3 scaffolding; over-annotation as a bare protein binding term. REMOVE per project policy for bare protein binding: no more informative MF term is supported; removal does not mean the interaction is false. Supporting Evidence: PMID:17601533 Axin is a central component of the canonical Wnt signaling pathway that interacts with the adenomatous polyposis coli protein APC and the kinase GSK3beta |
| GO:0005515 protein binding | IPI PMID:17601533 Two functionally distinct Axin-like proteins regulate canoni... | REMOVE | Summary: Protein binding is uninformative. Interaction with the second Axin AXL-1 (abstract-only; UniProt SUBUNIT confirms). Meaningful for the redundant Axin-dependent negative regulation of BAR-1 signalling, but the bare protein binding term adds nothing. REMOVE per project policy for bare protein binding: no more informative MF term is supported; removal does not mean the interaction is false. Supporting Evidence: PMID:17601533 Axin is a central component of the canonical Wnt signaling pathway that interacts with the adenomatous polyposis coli protein APC and the kinase GSK3beta |
| GO:0005515 protein binding | IPI PMID:17601533 Two functionally distinct Axin-like proteins regulate canoni... | REMOVE | Summary: Protein binding is uninformative. Interaction attributed to PMID:17601533 with WBGene00010497 (AXL-1/K02B12.4, Q3LRZ3). Duplicate of the AXL-1 interaction row from WormBase. REMOVE per project policy for bare protein binding: no more informative MF term is supported; removal does not mean the interaction is false. Supporting Evidence: PMID:17601533 Axin is a central component of the canonical Wnt signaling pathway that interacts with the adenomatous polyposis coli protein APC and the kinase GSK3beta |
| GO:0005515 protein binding | IPI PMID:19123269 Empirically controlled mapping of the Caenorhabditis elegans... | REMOVE | Summary: Protein binding is uninformative. High-throughput Y2H (WI-2007/WI8 interactome) hit with AXL-1. Corroborates the AXL-1 interaction but is uninformative about function. REMOVE per project policy for bare protein binding: no more informative MF term is supported; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:19123269 Empirically controlled mapping of the Caenorhabditis elegans... | REMOVE | Summary: Protein binding is uninformative. High-throughput Y2H hit with MAC-1 (AAA ATPase that binds CED-4). No functional follow-up linking GSK-3 to MAC-1; no biological interpretation possible. REMOVE per project policy for bare protein binding: no more informative MF term is supported; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:26780296 A combined binary interaction and phenotypic map of C.Β elega... | REMOVE | Summary: Protein binding is uninformative. Cell-polarity binary interaction map hit with PRY-1, reproducing the Korswagen 2002 Y2H interaction. Uninformative as protein binding. REMOVE per project policy for bare protein binding: no more informative MF term is supported; removal does not mean the interaction is false. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding from InterPro kinase ATP-binding site signatures; glycine-rich loop 42-50 and catalytic Lys conserved. Correct, as a feature of the kinase activity. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nucleus IBA from the family root. GSK-3 family members are nucleocytoplasmic; SKN-1 nuclear exclusion by GSK-3 and POP-1/Wnt functions are consistent with a nuclear pool, though worm GSK-3 localisation has not been directly imaged in the cited data. Accepted as a reasonable phylogenetic inference. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasm IBA from the family root. Consistent with cytoplasmic substrates (OMA-1 in oocytes/1-cell embryos, cortical Wnt/spindle functions) and with the ISS annotation. |
| GO:0005737 cytoplasm | ISS PMID:10444600 Wnt pathway components orient a mitotic spindle in the early... | ACCEPT | Summary: Cytoplasm by similarity to GSK3B (WormBase ISS citing the gsk-3 cloning paper). Consistent with IBA and with cytoplasmic functions. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosol IBA (node PTN001173193, metazoan). GSK-3 is a soluble cytosolic kinase across animals; acceptable for worm GSK-3. |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Signal transduction IBA from the family root. Correct but very general; worm GSK-3 acts in Wnt signal transduction branches that are captured by more specific terms. Supporting Evidence: PMID:10444600 gsk-3 represents a branch point in the control of endoderm induction and spindle orientation |
| GO:0007281 germ cell development | IGI PMID:19264959 Multiple ERK substrates execute single biological processes ... | KEEP AS NON CORE | Summary: IGI with mpk-1/ERK from the Arur et al. ERK-substrate screen (abstract-only; abstract does not name gsk-3). The curator saw the full text, and GSK-3 roles in the germline/oocyte-to-embryo transition are plausible, so retained, but this is a downstream developmental phenotype rather than a core function. |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cell differentiation IBA from the family root. True in the broad sense (endoderm/mesendoderm fate specification) but very general; the specific fate role is proposed as endodermal cell fate specification. Supporting Evidence: PMID:10444600 Reducing the function of Wnt pathway genes, including a newly identified GSK-3beta homolog called gsk-3, disrupts endoderm induction |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (node PTN001173193). GSK-3 phosphorylation creating phospho-degrons for SCF/CRL ubiquitin ligases is a conserved mechanism; in worm it is experimentally supported by OMA-1 degradation. Accepted. Supporting Evidence: PMID:16343905 Mutations in four conserved protein kinase genes-mbk-2/Dyrk, kin-19/CK1alpha, gsk-3, and cdk-1/CDC2-cause stabilization of OMA-1 protein |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IMP PMID:16343905 The Conserved Kinases CDK-1, GSK-3, KIN-19, and MBK-2 Promot... | ACCEPT | Summary: IMP: gsk-3 loss stabilises OMA-1, whose CUL-2/ZYG-11-dependent proteolysis is needed for the oocyte-to-embryo transition; GSK-3 directly phosphorylates OMA-1 T339 (PMID:16289132). GSK-3 does part of the work (it makes the phospho-degron), so this regulation term is appropriate and core. Supporting Evidence: PMID:16343905 Mutations in four conserved protein kinase genes-mbk-2/Dyrk, kin-19/CK1alpha, gsk-3, and cdk-1/CDC2-cause stabilization of OMA-1 protein PMID:16289132 Phosphorylation at T239 facilitates subsequent phosphorylation of OMA-1 by another kinase, GSK-3, at T339 in vitro |
| GO:0043652 engulfment of apoptotic cell | IMP PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | KEEP AS NON CORE | Summary: IMP: gsk-3 loss causes persistent cell corpses; GSK-3 acts with MOM-5/Fz and APR-1 upstream of the CED-5/CED-10 Rac pathway (full text verified). Genuine but GSK-3 is a regulatory input rather than part of the engulfment machinery; the positive-regulation term (GO:1901076) is the more accurate framing. Kept as non-core. Supporting Evidence: PMID:20126385 Animals lacking MOM-5/Fz, GSK-3, or APR-1 showed both persistent cell corpses and misshapen gonads |
| GO:0050321 tau-protein kinase activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Tau-protein kinase activity from the EC 2.7.11.26 / Rhea mapping. A substrate-named term valid for vertebrate GSK3A/GSK3B. There is no evidence that worm GSK-3 phosphorylates the nematode tau/MAP2-like protein; the PTHR24057 family review scopes this term to vertebrate subfamilies only. Ser/Thr kinase activity already captures the activity. |
| GO:0050321 tau-protein kinase activity | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Tau-protein kinase activity by sequence similarity to human GSK3B. Same issue as the IEA: a substrate-specific vertebrate function transferred without nematode evidence. |
| GO:0060069 Wnt signaling pathway, regulating spindle positioning | IMP PMID:10444600 Wnt pathway components orient a mitotic spindle in the early... | ACCEPT | Summary: IMP: gsk-3 is required for Wnt-dependent EMS spindle orientation, whereas pathway genes downstream of gsk-3 are not, and orientation does not need transcription. This is the defining worm-specific Wnt branch in which GSK-3 acts (positively) toward the cytoskeleton. Core. Supporting Evidence: PMID:10444600 gsk-3 represents a branch point in the control of endoderm induction and spindle orientation PMID:20126385 ABar spindle positioning required MOM-2/Wnt and GSK-3 function, but not WRM-1/Ξ²-catenin or POP-1/TCF |
| GO:0070507 regulation of microtubule cytoskeleton organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA (PTN001173193). Regulation of microtubule organisation by GSK-3 (e.g. MAP phosphorylation) is well established in vertebrates; in worm the related evidence is Wnt/GSK-3-dependent spindle orientation, but direct regulation of microtubule organisation has not been shown. Plausible, non-core. |
| GO:0070986 left/right axis specification | IMP PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | KEEP AS NON CORE | Summary: IMP: gsk-3 loss disrupts ABar spindle orientation, which in turn disrupts the left-right asymmetric cell contacts/fates of the embryo. This is an indirect, downstream consequence of the spindle-orientation role rather than a dedicated L/R patterning function. Kept as non-core. Supporting Evidence: PMID:20126385 ABar spindle positioning required MOM-2/Wnt and GSK-3 function, but not WRM-1/Ξ²-catenin or POP-1/TCF |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PTN001173193 (Metazoa+Choanoflagellida). The PTHR24057 family review marks this node TOO_DEEP because of Monosiga, but C. elegans lies inside Eumetazoa, so the worm leaf would keep the IBA after the node is moved. Worm-specific support exists: GSK-3 binds the Axins PRY-1 and AXL-1, SGG-1 overexpression phenocopies PRY-1 overexpression in the EGL-20/BAR-1 Q-lineage pathway, and an IMP from vulval development. Accepted, with the caveat that in the early embryo GSK-3 acts positively in the Wnt/beta-catenin asymmetry pathway. Supporting Evidence: PMID:12023307 overexpression of SGG-1 (like overexpression of PRY-1) induced anterior migration of the QL daughter cells PMID:12023307 a highly divergent destruction complex consisting of PRY-1, SGG-1, and APR-1 regulates BAR-1/beta-catenin signaling in C. elegans |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IMP PMID:16930586 Multiple redundant Wnt signaling components function in two ... | ACCEPT | Summary: IMP from Gleason et al. 2006 (vulval Wnt redundancy; abstract-only, abstract does not name gsk-3; UniProt also cites this paper for negative regulation of Wnt signalling in vulval precursor cells). Deferred to the curator and consistent with the PRY-1/SGG-1 overexpression data of Korswagen et al. 2002. Supporting Evidence: PMID:12023307 overexpression of SGG-1 (like overexpression of PRY-1) induced anterior migration of the QL daughter cells |
| GO:1901076 positive regulation of engulfment of apoptotic cell | IMP PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | KEEP AS NON CORE | Summary: IMP: gsk-3 mutants have persistent corpses; GSK-3 with APR-1 and MOM-5 promotes engulfment through CED-10/Rac (full text verified). Genuine regulatory role, non-core relative to kinase/Wnt-spindle/OMA-1 functions. Supporting Evidence: PMID:20126385 Animals lacking MOM-5/Fz, GSK-3, or APR-1 showed both persistent cell corpses and misshapen gonads |
| GO:1903356 positive regulation of distal tip cell migration | IMP PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | KEEP AS NON CORE | Summary: IMP: gsk-3 loss yields misshapen gonads from defective distal tip cell migration; GSK-3 acts in the MOM-5/APR-1 -> CED-10 pathway (full text verified). Non-core developmental role. Supporting Evidence: PMID:20126385 Animals lacking MOM-5/Fz, GSK-3, or APR-1 showed both persistent cell corpses and misshapen gonads |
| GO:0001714 endodermal cell fate specification | IMP PMID:10444600 Wnt pathway components orient a mitotic spindle in the early... | NEW | Summary: Proposed new annotation. gsk-3 loss of function blocks endoderm induction in the EMS daughter E, as for mom-2/Wnt; GSK-3 acts as a Wnt-dependent activator of endoderm (and a Wnt-independent repressor of med-1/2 in C). Comparator check: every other signalling component in the same role (mom-2, mom-5, wrm-1, apr-1, lit-1, mom-4, dsh-2, mig-5, src-1) carries GO:0001714 in C. elegans GOA; gsk-3 is the outlier. GSK-3 is a kinase of the specifying signalling cascade, not a substrate of it. Supporting Evidence: PMID:10444600 Reducing the function of Wnt pathway genes, including a newly identified GSK-3beta homolog called gsk-3, disrupts endoderm induction PMID:11463373 SGG-1/GSK-3beta kinase acts both as a Wnt-dependent activator of endoderm in EMS and an apparently Wnt-independent repressor of the meds in the C lineage |
| GO:1900181 negative regulation of protein localization to nucleus | IMP PMID:16251270 Regulation of the Caenorhabditis elegans oxidative stress de... | NEW | Summary: Proposed new annotation. In unstressed animals GSK-3 phosphorylates SKN-1 and prevents its nuclear accumulation in the intestine, restraining the phase II oxidative-stress response. GSK-3 performs the regulatory step itself (phosphorylation of SKN-1). The term is chosen to be agnostic about import vs retention/export. No current GO annotation captures this well-known role. Supporting Evidence: PMID:16251270 in the absence of stress, phosphorylation by glycogen synthase kinase-3 (GSK-3) prevents SKN-1 from accumulating in nuclei and functioning constitutively in the intestine PMID:16251270 GSK-3 inhibits SKN-1 activity in the intestine |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Does worm GSK-3 form a biochemically isolable destruction complex with PRY-1/AXL-1 and APR-1 that phosphorylates the BAR-1 N-terminus in vivo (i.e. is GO:0030877 beta-catenin destruction complex justified for C. elegans, beyond binary Y2H data)?
Q: What is the substrate and mechanism of the positive GSK-3 requirement for endoderm induction in the Wnt/beta-catenin asymmetry pathway (e.g. effects on WRM-1/LIT-1, SYS-1 or POP-1 asymmetry), and is it kinase-dependent?
Q: Which SKN-1 residues does GSK-3 phosphorylate in vivo, is priming required, and does phosphorylation promote nuclear export, block import, or promote WDR-23/CUL4-dependent degradation?
Experiment: Endogenous tagging and co-immunoprecipitation/mass spectrometry of GSK-3 from larvae to test for a PRY-1/AXL-1/APR-1/BAR-1 complex, combined with BAR-1 N-terminal phospho-site mutants and auxin-inducible GSK-3 depletion in the Q lineage to test negative regulation without embryonic lethality.
Experiment: Rescue gsk-3 embryos with kinase-dead (K65R) and priming-pocket (R76A) transgenes to determine which GSK-3 Wnt functions (endoderm induction, spindle orientation, engulfment) require catalytic activity and primed substrate recognition.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)