gskA encodes the single glycogen synthase kinase-3 (GSK-3) of the social amoeba Dictyostelium discoideum, a CMGC-family serine/threonine protein kinase. GskA activity is stimulated by extracellular cAMP acting through cell-surface cAMP receptors and the tyrosine kinases ZAK1 and ZAK2, and is also promoted by LKB1. During multicellular development GskA mediates the cAMP signal that induces prespore differentiation and represses prestalk B/stalk differentiation, so null mutants form few spores and an excess of basal-disc/stalk cells. GskA phosphorylates transcription factors such as Dd-STATa and GtaC, promoting their nuclear export. In aggregating cells it is required for efficient chemotaxis to cAMP and folate, phosphorylating chemotaxis regulators including the Ras effector Daydreamer, the RapGEF GflB, PdeD, dynacortin and the Rho GTPase RacE, whose Ser192 phosphorylation promotes mTORC2 activation of PKB. GskA is cytoplasmic and nuclear, associates with the central mitotic spindle and centrosomes, and is needed for spindle elongation and efficient cytokinesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000022 mitotic spindle elongation | IMP PMID:23787121 Aberrant spindle dynamics and cytokinesis in Dictyostelium d... | KEEP AS NON CORE | Summary: gskA-null cells fail to elongate the mitotic spindle; GskA-GFP decorates the central spindle. Reason: Direct loss-of-function phenotype plus localization to the central spindle supports a role in spindle elongation, consistent with conserved GSK-3 spindle roles in animals. The function is likely regulatory (via phosphorylation of spindle-associated proteins, not identified), and is not the best-characterized role of GskA, so it is kept as non-core. Supporting Evidence: PMID:23787121 gskA-null mutants failed to elongate their mitotic spindle PMID:23787121 Immunolabeling of wild-type cells expressing GskA-GFP with anti-Ξ±-tubulin antibodies confirmed the localization of GskA-GFP along the central spindle and centrosomes |
| GO:0000281 mitotic cytokinesis | IMP PMID:23787121 Aberrant spindle dynamics and cytokinesis in Dictyostelium d... | KEEP AS NON CORE | Summary: gskA-null cells become multinucleate in shaking culture due to a cytokinesis defect. Reason: Acts-upstream-of-or-within qualifier appropriately captures that the cytokinesis failure may be secondary to the spindle elongation defect. Valid but non-core. Supporting Evidence: PMID:23787121 When grown in shaking culture, gskA null cells exhibit a defect in cytokinesis |
| GO:0004672 protein kinase activity | IDA PMID:24653039 Nucleocytoplasmic shuttling of a GATA transcription factor f... | ACCEPT | Summary: Purified Flag-GskA phosphorylated GtaC in vitro, restoring its cAMP-induced mobility shift. Reason: Direct in vitro kinase evidence with Dictyostelium GskA. The more specific protein serine/threonine kinase activity term is also annotated; the general parent is correct. Supporting Evidence: PMID:24653039 by adding purified Flag-GskA in vitro, the full extent of shift could be restored |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro Ser/Thr kinase active-site signature mapping to protein kinase activity. Reason: GskA has an intact CMGC kinase domain and demonstrated kinase activity; correct though less specific than GO:0004674. Supporting Evidence: PMID:20534815 no phenotypic rescue was seen after expression of a mutant gene that lacks kinase activity (GskAK85R) |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of Ser/Thr kinase activity for the GSK-3 family node. Reason: Ser/Thr kinase activity is the ancestral activity of the GSK-3 clade, present in all eukaryotic lineages including plants and yeast; Dictyostelium GskA is inside this clade and has its own experimental support (it appears among the donors, which is expected). Supporting Evidence: PMID:11032815 it also induces serine phosphorylation by GskA PMID:29626371 Using phosphoproteomics we identify the GskA substrates PdeD, dynacortin and SogA |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:11032815 Glycogen synthase kinase-3 enhances nuclear export of a Dict... | ACCEPT | Summary: Extracellular cAMP induces GskA-dependent serine phosphorylation of Dd-STATa. Reason: Consistent with the well-established Ser/Thr kinase activity of GskA. In some of these studies in vitro phosphorylation used recombinant human GSK-3beta and in-cell dependence used gskA- cells or GSK-3 inhibitors, but the conclusion that GskA is a Ser/Thr kinase for these substrates is sound; deferring to the curator. Supporting Evidence: PMID:11032815 it also induces serine phosphorylation by GskA |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:22020250 LKB1 regulates development and the stress response in Dictyo... | ACCEPT | Summary: GSK3 kinase activity measured in developing cells (reduced upon LKB1 knockdown). Reason: Consistent with the well-established Ser/Thr kinase activity of GskA. In some of these studies in vitro phosphorylation used recombinant human GSK-3beta and in-cell dependence used gskA- cells or GSK-3 inhibitors, but the conclusion that GskA is a Ser/Thr kinase for these substrates is sound; deferring to the curator. Supporting Evidence: PMID:22020250 lkb1 depleted cells displayed lower GSK3 activity than wild type cells during development |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:23135995 Daydreamer, a Ras effector and GSK-3 substrate, is important... | ACCEPT | Summary: GskA-dependent phosphorylation of the Ras effector Daydreamer (DydA) on GSK-3 consensus sites. Reason: Consistent with the well-established Ser/Thr kinase activity of GskA. In some of these studies in vitro phosphorylation used recombinant human GSK-3beta and in-cell dependence used gskA- cells or GSK-3 inhibitors, but the conclusion that GskA is a Ser/Thr kinase for these substrates is sound; deferring to the curator. Supporting Evidence: PMID:23135995 DydA is phosphorylated by glycogen synthase kinase-3 (GSK-3) |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:31263268 Phosphorylated Rho-GDP directly activates mTORC2 kinase towa... | ACCEPT | Summary: GSK-3-dependent phosphorylation of RacE (Rho) at Ser192 in chemoattractant-stimulated cells. Reason: Consistent with the well-established Ser/Thr kinase activity of GskA. In some of these studies in vitro phosphorylation used recombinant human GSK-3beta and in-cell dependence used gskA- cells or GSK-3 inhibitors, but the conclusion that GskA is a Ser/Thr kinase for these substrates is sound; deferring to the curator. Supporting Evidence: PMID:31263268 chemoattractant stimulation induces GSK-3-mediated S192 phosphorylation of RacE-GDP to activate mTORC2-mediated AKT phosphorylation in directed cell migration |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro GSK-3 family mapping to protein serine/threonine kinase activity. Reason: Correct and consistent with experimental data. |
| GO:0005524 ATP binding | IDA PMID:9784196 An assay for glycogen synthase kinase 3 (GSK-3) for use in c... | KEEP AS NON CORE | Summary: ATP binding inferred from a GSK-3 kinase assay in crude extracts (cached record has title only). Reason: ATP binding is intrinsic to the kinase reaction; correct but uninformative beyond the kinase activity term. Supporting Evidence: PMID:9784196 An assay for glycogen synthase kinase 3 (GSK-3) for use in crude cell extracts |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ATP binding from InterPro protein kinase ATP-binding signature. Reason: Correct (conserved ATP-binding lysine K85; kinase-dead K85R does not rescue) but subsumed by the kinase activity. Supporting Evidence: PMID:20534815 no phenotypic rescue was seen after expression of a mutant gene that lacks kinase activity (GskAK85R) |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: GSK-3 family members are active in the nucleus. Reason: GskA is present in the nucleus during interphase, relocates into the nucleus before mitosis, and phosphorylates nuclear transcription factors (Dd-STATa, GtaC) to promote their export. Node placement is appropriate. Supporting Evidence: PMID:23787121 During interphase, GskA protein is localized throughout the cell, being present in both cytoplasm and nucleus PMID:23787121 GskA-GFP relocates into the nucleus shortly before the onset of mitosis PMID:11032815 Phosphorylation by GskA enhances nuclear export of Dd-STATa |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: GSK-3 family members are active in the cytoplasm. Reason: Consistent with direct localization of GskA-GFP to the cytoplasm and its cytoplasmic substrates (DydA, RacE, GflB). Supporting Evidence: PMID:23787121 During interphase, GskA protein is localized throughout the cell, being present in both cytoplasm and nucleus |
| GO:0005737 cytoplasm | IDA PMID:23787121 Aberrant spindle dynamics and cytokinesis in Dictyostelium d... | ACCEPT | Summary: GskA-GFP is present throughout the cytoplasm in interphase cells. Reason: Direct imaging evidence. Supporting Evidence: PMID:23787121 During interphase, GskA protein is localized throughout the cell, being present in both cytoplasm and nucleus |
| GO:0005813 centrosome | IDA PMID:23787121 Aberrant spindle dynamics and cytokinesis in Dictyostelium d... | ACCEPT | Summary: GskA-GFP co-localizes with centrosomes (spindle poles) during mitosis. Reason: Direct imaging evidence with tubulin co-staining. Supporting Evidence: PMID:23787121 Immunolabeling of wild-type cells expressing GskA-GFP with anti-Ξ±-tubulin antibodies confirmed the localization of GskA-GFP along the central spindle and centrosomes |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: GSK-3 family participates in signal transduction. Reason: GskA is a signalling kinase activated downstream of cAMP receptors via ZAK1/ZAK2, consistent with the ancestral role of GSK-3 in signal transduction. General but correct. Supporting Evidence: PMID:10571182 recombinant ZAK1 phosphorylates and activates GSK3 in vitro |
| GO:0007165 signal transduction | IMP PMID:7813009 Glycogen synthase kinase 3 regulates cell fate in Dictyostel... | ACCEPT | Summary: gskA is required for cAMP effects on cell-type differentiation. Reason: The null mutant is unresponsive to cAMP for prespore induction and pstB inhibition, supporting a signal-transduction role. General term; more specific signalling terms are also annotated. Supporting Evidence: PMID:7813009 We propose that cAMP acts through a common pathway that requires GSK-3 and determines the proportion of prespore and pstB cells |
| GO:0010628 positive regulation of gene expression | IMP PMID:20534815 Glycogen synthase kinase-3 is required for efficient Dictyos... | KEEP AS NON CORE | Summary: Expression of aggregation genes such as pdsA is reduced in gskA null cells. Reason: Acts-upstream qualifier is appropriate; the effect on gene expression is likely indirect (via transcription-factor phosphorylation, e.g. GtaC) and is pleiotropic, so kept as non-core. Supporting Evidence: PMID:20534815 we confirmed that induction of pdsA, which encodes a cAMP phosphodiesterase, is indeed substantially reduced in gskA null cells |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | MODIFY | Summary: GSK-3 family involvement in cell differentiation. Reason: GskA clearly regulates cell differentiation in Dictyostelium, but the role is regulatory (a signalling kinase controlling the prespore versus prestalk B fate choice) rather than execution of differentiation; the specific regulatory sorocarp terms better describe the Dictyostelium function. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH ROLE CONFLATION Sources checked: PANTHER:PTN000624299 Β· PTN000624299 GSK-3 node; inheritance of a role in cell differentiation is plausible, but the general term conflates a regulatory signalling role with execution of differentiation. Proposed replacements: positive regulation of sorocarp spore cell differentiation negative regulation of sorocarp stalk cell differentiation Supporting Evidence: PMID:7813009 We propose that cAMP acts through a common pathway that requires GSK-3 and determines the proportion of prespore and pstB cells |
| GO:0030154 cell differentiation | IMP PMID:7813009 Glycogen synthase kinase 3 regulates cell fate in Dictyostel... | MODIFY | Summary: gskA disruption yields few spores and an excess of pstB/stalk cells; cAMP fails to induce prespore and repress pstB differentiation. Reason: GskA is a signalling kinase that regulates the choice between prespore and prestalk B fates rather than executing differentiation; the specific regulatory terms for sorocarp spore and stalk cell differentiation describe the role better. Proposed replacements: positive regulation of sorocarp spore cell differentiation negative regulation of sorocarp stalk cell differentiation Supporting Evidence: PMID:7813009 We propose that cAMP acts through a common pathway that requires GSK-3 and determines the proportion of prespore and pstB cells PMID:7813009 Disruption of gskA creates a mutant that aggregates but forms few spores and an abnormally high number of stalk cells PMID:15342480 GskA forms part of the repressive signalling pathway that prevents premature commitment to stalk cell differentiation |
| GO:0030155 regulation of cell adhesion | TAS PMID:15366765 Comparison of molecular mechanisms mediating cell contact ph... | UNDECIDED | Summary: Traceable author statement from a broad comparative review of cell-contact mechanisms. Reason: Only the abstract is cached and it does not mention GSK-3; the primary literature on GskA does not establish a direct role in regulating cell adhesion. Cannot verify the curator statement. |
| GO:0030435 sporulation resulting in formation of a cellular spore | IMP PMID:10571182 The novel tyrosine kinase ZAK1 activates GSK3 to direct cell... | KEEP AS NON CORE | Summary: GSK3-regulated developmental pathways (including spore differentiation) are defective when GSK3 activation by ZAK1 is lost. Reason: Spore formation requires GskA, but GskA acts as an upstream regulator of the cell-fate decision rather than in sporulation per se; acts-upstream qualifier fits. Non-core. Supporting Evidence: PMID:10571182 recombinant ZAK1 phosphorylates and activates GSK3 in vitro |
| GO:0030435 sporulation resulting in formation of a cellular spore | IMP PMID:15342480 GSK3 is a multifunctional regulator of Dictyostelium develop... | KEEP AS NON CORE | Summary: Ax2/gskA- mutants show altered patterning and spore formation. Reason: Abstract-only cache; curator read full text. Spore formation is a downstream outcome of GskA-regulated cell-fate choice. Non-core. Supporting Evidence: PMID:15342480 These observations show that GskA functions throughout Dictyostelium development, to regulate several key aspects of cellular patterning |
| GO:0030695 GTPase regulator activity | IDA PMID:23135995 Daydreamer, a Ras effector and GSK-3 substrate, is important... | REMOVE | Summary: Based on altered Ras-GTP kinetics in gskA- cells. Reason: Full text was examined: the evidence is a loss-of-function phenotype (misregulated Ras activation kinetics in gskA- cells), which is indirect. GskA is a Ser/Thr protein kinase; no binding to or direct modulation of a GTPase by GskA is shown. Its effects on small-GTPase signalling are via phosphorylation of effectors/regulators (DydA, GflB, RacE), which is captured by the kinase activity and regulatory process terms. Supporting Evidence: PMID:23135995 indicating a misregulation of Ras levels and kinetics in gskAβ cells PMID:23135995 DydA is phosphorylated by glycogen synthase kinase-3 (GSK-3) |
| GO:0031152 aggregation involved in sorocarp development | IMP PMID:20534815 Glycogen synthase kinase-3 is required for efficient Dictyos... | KEEP AS NON CORE | Summary: gskA null cells aggregate poorly; rescue by wild-type gskA cDNA. Reason: Valid acts-upstream annotation reflecting chemotaxis and cAMP signalling defects. Non-core developmental outcome. Supporting Evidence: PMID:20534815 Restoring GskA activity via expression of the wild-type gskA cDNA in gskA null mutants, rescued aggregation to that seen in the wild type |
| GO:0031154 culmination involved in sorocarp development | IMP PMID:15342480 GSK3 is a multifunctional regulator of Dictyostelium develop... | KEEP AS NON CORE | Summary: Ax2/gskA- mutants show altered timing/morphology through culmination. Reason: Abstract-only cache; curator read the full text. Pleiotropic developmental phenotype, non-core. Supporting Evidence: PMID:15342480 These observations show that GskA functions throughout Dictyostelium development, to regulate several key aspects of cellular patterning |
| GO:0031288 sorocarp morphogenesis | IMP PMID:7813009 Glycogen synthase kinase 3 regulates cell fate in Dictyostel... | KEEP AS NON CORE | Summary: gskA disruption yields abnormal fruiting bodies with excess stalk/basal disc cells. Reason: Downstream morphological consequence of the cell-fate defect. Non-core. Supporting Evidence: PMID:7813009 Disruption of gskA creates a mutant that aggregates but forms few spores and an abnormally high number of stalk cells |
| GO:0031929 TOR signaling | IMP PMID:20534815 Glycogen synthase kinase-3 is required for efficient Dictyos... | MODIFY | Summary: gskA null cells fail to activate TORC2-mediated signalling. Reason: GskA is not a TOR pathway component itself but acts upstream to promote TORC2 activation, mechanistically via phosphorylation of RacE-GDP at Ser192; positive regulation of TORC2 signaling is the more accurate term (already annotated by IDA from PMID:31263268). Proposed replacements: positive regulation of TORC2 signaling Supporting Evidence: PMID:20534815 Mutants fail to activate two important regulatory signaling pathways, mediated by phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) and target of rapamycin complex 2 (TORC2) PMID:31263268 chemoattractant stimulation induces GSK-3-mediated S192 phosphorylation of RacE-GDP to activate mTORC2-mediated AKT phosphorylation in directed cell migration |
| GO:0035556 intracellular signal transduction | IMP PMID:20534815 Glycogen synthase kinase-3 is required for efficient Dictyos... | ACCEPT | Summary: GskA, a cytoplasmic kinase, is required for intracellular PIP3 and TORC2 signalling downstream of cAMP receptors. Reason: Correct general term for a kinase acting in intracellular signalling. Supporting Evidence: PMID:20534815 Mutants fail to activate two important regulatory signaling pathways, mediated by phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) and target of rapamycin complex 2 (TORC2) |
| GO:0043326 chemotaxis to folate | IMP PMID:20534815 Glycogen synthase kinase-3 is required for efficient Dictyos... | ACCEPT | Summary: gskA null cells show defective chemotaxis toward folate. Reason: Direct mutant phenotype with acts-upstream qualifier; appropriate. Supporting Evidence: PMID:20534815 We find that gskA null mutant cells have defective chemotaxis toward cAMP and folate |
| GO:0043327 chemotaxis to cAMP | IMP PMID:20534815 Glycogen synthase kinase-3 is required for efficient Dictyos... | ACCEPT | Summary: gskA null cells show strongly defective chemotaxis toward cAMP, rescued by wild-type but not kinase-dead GskA. Reason: Robust, reproduced phenotype (also PMID:23135995), and GskA phosphorylates multiple chemotaxis effectors; a core biological role. Supporting Evidence: PMID:20534815 We find that gskA null mutant cells have defective chemotaxis toward cAMP and folate PMID:20534815 no phenotypic rescue was seen after expression of a mutant gene that lacks kinase activity (GskAK85R) |
| GO:0043520 regulation of myosin II filament assembly | IMP PMID:23135995 Daydreamer, a Ras effector and GSK-3 substrate, is important... | KEEP AS NON CORE | Summary: cAMP-induced myosin II assembly is greatly reduced in gskA- cells. Reason: Supported by full text; likely mediated via substrates (DydA, PdeD, dynacortin). Non-core. Supporting Evidence: PMID:23135995 the level of MyoII assembly upon chemoattractant stimulation is reduced dramatically in gskAβ cells |
| GO:0046827 positive regulation of protein export from nucleus | IDA PMID:24653039 Nucleocytoplasmic shuttling of a GATA transcription factor f... | ACCEPT | Summary: GskA phosphorylates GtaC, contributing to its receptor-induced nuclear exit. Reason: GskA phosphorylation promotes export of nuclear transcription factors; translocation is reduced but not abolished without GskA. Part of the core GskA function of phosphorylating transcription factors to promote their export. Supporting Evidence: PMID:24653039 by adding purified Flag-GskA in vitro, the full extent of shift could be restored PMID:24653039 receptor occupancy promotes nuclear exit of GtaC |
| GO:0046827 positive regulation of protein export from nucleus | IMP PMID:11032815 Glycogen synthase kinase-3 enhances nuclear export of a Dict... | ACCEPT | Summary: GskA phosphorylation enhances nuclear export of Dd-STATa. Reason: Directly demonstrated mechanism linking GskA kinase activity to STAT nuclear export; a well-supported regulatory function. Supporting Evidence: PMID:11032815 Phosphorylation by GskA enhances nuclear export of Dd-STATa |
| GO:0046827 positive regulation of protein export from nucleus | IMP PMID:22944283 The calcineurin dependent transcription factor TacA is invol... | ACCEPT | Summary: Nuclear export of the calcineurin-regulated transcription factor TacA is partially dependent on GskA. Reason: Abstract states partial dependence; consistent with the general GskA role in TF nuclear export. Supporting Evidence: PMID:22944283 Nuclear export of TacA is partially dependent on GskA |
| GO:0050321 tau-protein kinase activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Automated mapping from EC 2.7.11.26 (tau-protein kinase). Reason: EC 2.7.11.26 is the historical EC name for GSK-3 activity, but Dictyostelium has no tau protein; the term names a substrate absent from this organism. The activity is fully captured by protein serine/threonine kinase activity. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IMP PMID:23135995 Daydreamer, a Ras effector and GSK-3 substrate, is important... | KEEP AS NON CORE | Summary: gskA- cells show reduced PIP3 production but extended PI3K recruitment and PKB/PKBR1 activation kinetics. Reason: Data are partly conflicting: Teo et al. 2010 report reduced PIP3/TORC2 activation, while Kolsch et al. report extended PKB activation; the RacE-mTORC2 mechanism (PMID:31263268) supports a positive role. GskA clearly regulates this pathway; kept as non-core regulatory annotation. Supporting Evidence: PMID:23135995 but a highly extended recruitment of PI3K to the plasma membrane and highly extended kinetics of PKB and PKBR1 activation PMID:31263268 chemoattractant stimulation induces GSK-3-mediated S192 phosphorylation of RacE-GDP to activate mTORC2-mediated AKT phosphorylation in directed cell migration |
| GO:0060176 regulation of aggregation involved in sorocarp development | IMP PMID:21205787 Combinatorial cell-specific regulation of GSK3 directs cell ... | KEEP AS NON CORE | Summary: gsk3-null cells differ in their ability to form multicellular aggregates. Reason: Regulatory developmental phenotype; acts-upstream qualifier appropriate. Non-core. Supporting Evidence: PMID:21205787 we noticed differences in the ability of cells to form multicellular aggregates |
| GO:0061118 regulation of positive chemotaxis to cAMP | IMP PMID:21205787 Combinatorial cell-specific regulation of GSK3 directs cell ... | ACCEPT | Summary: Efficient polarization and directional migration toward cAMP depend on ZAK1-mediated tyrosine phosphorylation of GSK3. Reason: Consistent with GskA as a chemotaxis-regulating kinase. Supporting Evidence: PMID:21205787 efficient polarization of Dictyostelium towards cAMP depends on ZAK1-mediated tyrosine phosphorylation of GSK3 |
| GO:0072686 mitotic spindle | IDA PMID:23787121 Aberrant spindle dynamics and cytokinesis in Dictyostelium d... | ACCEPT | Summary: GskA-GFP associates with the mitotic (central) spindle. Reason: Direct live-cell and immunofluorescence localization. Supporting Evidence: PMID:23787121 Immunolabeling of wild-type cells expressing GskA-GFP with anti-Ξ±-tubulin antibodies confirmed the localization of GskA-GFP along the central spindle and centrosomes |
| GO:0106310 protein serine kinase activity | IDA PMID:29626371 Phosphodiesterase PdeD, dynacortin, and a Kelch repeat-conta... | ACCEPT | Summary: Phosphoproteomics identified PdeD, dynacortin and SogA as direct GskA substrates. Reason: Abstract-only cache; consistent with GSK-3 serine kinase activity; defer to curator. Supporting Evidence: PMID:29626371 Using phosphoproteomics we identify the GskA substrates PdeD, dynacortin and SogA |
| GO:0140582 adenylate cyclase-activating G protein-coupled cAMP receptor signaling pathway | IMP PMID:20534815 Glycogen synthase kinase-3 is required for efficient Dictyos... | ACCEPT | Summary: GskA is required for cAMP receptor-triggered signalling (PIP3, TORC2) and cAMP relay during aggregation. Reason: GskA acts in the cAMP receptor signalling network (activated downstream of cAMP receptors via ZAK kinases; required for downstream effector activation). Supporting Evidence: PMID:20534815 Mutants fail to activate two important regulatory signaling pathways, mediated by phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) and target of rapamycin complex 2 (TORC2) |
| GO:1904515 positive regulation of TORC2 signaling | IDA PMID:31263268 Phosphorylated Rho-GDP directly activates mTORC2 kinase towa... | ACCEPT | Summary: GSK-3 phosphorylation of RacE-GDP at Ser192 promotes Rho-Ras-mTORC2 supercomplex formation and AKT phosphorylation. Reason: Mechanistic, direct demonstration of how GSK-3 activity promotes TORC2 signalling in Dictyostelium. Supporting Evidence: PMID:31263268 chemoattractant stimulation induces GSK-3-mediated S192 phosphorylation of RacE-GDP to activate mTORC2-mediated AKT phosphorylation in directed cell migration |
| GO:1904776 regulation of protein localization to cell cortex | IMP PMID:27237792 A GΞ±-Stimulated RapGEF Is a Receptor-Proximal Regulator of D... | KEEP AS NON CORE | Summary: GSK-3 phosphorylation tunes the kinetics of GflB translocation to the cell cortex/leading edge. Reason: Abstract-only cache; supported by abstract statement; defer to curator. Non-core substrate-level regulatory role. Supporting Evidence: PMID:27237792 The kinetics of GflB translocation are fine-tuned by GSK-3 phosphorylation |
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Download this section (compressed HTML)Q: Which direct GskA substrates mediate its regulation of mitotic spindle elongation and cytokinesis in Dictyostelium, given that no chromosome segregation defect accompanies the spindle defect?
Q: How are the apparently conflicting observations reconciled that gskA- cells show reduced PIP3/TORC2 output (Teo 2010) yet extended PI3K recruitment and PKB/PKBR1 phosphorylation (Kolsch 2013)?
Q: Does GskA require priming phosphorylation of its Dictyostelium substrates (as for metazoan GSK-3), and which kinases provide it?
Experiment: Perform in vitro kinase assays with purified Dictyostelium GskA (wild type vs K85R) on RacE and DydA, and compare phospho-site occupancy in wild-type versus gskA- cells by targeted phosphoproteomics after cAMP stimulation.
Hypothesis: GskA directly phosphorylates RacE Ser192 and Daydreamer in vivo during chemotaxis.
Experiment: Identify mitosis-specific GskA substrates by phosphoproteomics of synchronized wild-type versus gskA- cells and test phospho-site mutants for spindle elongation defects by live imaging of GFP-tubulin.
Hypothesis: GskA phosphorylates spindle-associated proteins required for spindle elongation.
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