id: MODULE:dicty_jak_independent_stat_signaling title: JAK-independent STAT signaling in Dictyostelium discoideum description: >- The social amoeba Dictyostelium discoideum has four STAT-family transcription factors (STATa to STATd) but no Janus kinase and no kinases of the tyrosine-kinase group. Its STATs are instead tyrosine phosphorylated by tyrosine kinase-like (TKL) kinases, and they dimerize, accumulate in the nucleus and regulate transcription during multicellular development and stress. The two best-studied paralogs are wired to different inputs. STATc is activated by the prestalk morphogen DIF-1 and by hyperosmotic and other stresses. Its activating Tyr922 is phosphorylated by the TKL kinases Pyk2 and Pyk3, which bind the STATc SH2 domain through autophosphorylated tyrosines. The kinase activity is largely constitutive, so the signal is set mainly by the tyrosine phosphatase PTP3: DIF-1 and stress induce serine phosphorylation of PTP3 (in part by the TKL kinase Phg2), which inhibits it and shifts STATc toward the phosphorylated state. Nuclear STATc activates stress-response genes and restricts graded expression of the prestalk gene ecmA. STATa is tyrosine phosphorylated on Tyr702 within seconds of extracellular cAMP binding the serpentine receptor cAR1, apparently without the G-beta subunit. The receptor-like TKL kinase DrkA phosphorylates STATa in vitro and is a candidate STATa kinase. STATa stays nuclear in the prestalk cells of the slug tip, where it represses the stalk gene ecmB and directly activates cudA, a transcription factor needed for culmination. status: DRAFT scope: CONCRETE evidence: - source_id: PMID:16596165 title: The dictyostelium kinome--analysis of the protein kinases from a simple model organism. statement: >- The Dictyostelium kinome has no JAK and no tyrosine-kinase-group kinases; tyrosine phosphorylation is attributed to the expanded TKL group. supporting_text: >- Dictyostelium lacks tyrosine kinase group kinases, and most tyrosine phosphorylation appears to be mediated by TKL kinases. - source_id: PMID:16596165 title: The dictyostelium kinome--analysis of the protein kinases from a simple model organism. statement: Of the human dual-domain kinase families, only GCN2 is present; there is no JAK. supporting_text: >- The human kinases are in the Jak, RSK, Trio, and GCN2 families, of which only GCN2 (IfkA) is found in Dictyostelium. - source_id: PMID:16596165 title: The dictyostelium kinome--analysis of the protein kinases from a simple model organism. statement: The genome encodes four STATs among its SH2-domain proteins. supporting_text: >- Dictyostelium also has 12 phosphotyrosine-binding SH2-domain proteins: the Shk1–5 protein kinases in the TKL group, four STATs - source_id: PMID:22699506 title: >- Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling. statement: >- No orthologs of animal tyrosine kinases exist in Dictyostelium; a TKL kinase directly activates a STAT. supporting_text: >- There are no orthologs of the animal tyrosine kinases, but there are very many tyrosine kinase-like kinases (TKLs) - source_id: PMID:24058748 title: Comparative evolutionary genomics of the STAT family of transcription factors. statement: The four Dictyostelium STATs form a distinct clade, separate from animal STATs. supporting_text: >- the Dictyostelium genome encodes four STATs, dstA, dstB, dstC and dstD - source_id: PMID:24058787 title: Evolution of the JAK-STAT pathway. statement: >- JAK-like proteins first appear in sponges, after the divergence of amoebozoa, while STAT domains are older. supporting_text: >- The first bona fide JAK-like protein is represented in the basal metazoan porifera lineage - source_id: PMID:21534947 title: STAT signaling in Dictyostelium development. statement: >- Review of the four Dictyostelium STATs and their signaling molecules during development (abstract only in cache). supporting_text: >- The cellular slime mould, Dictyostelium discoideum, is the simplest multicellular organism using molecules homologous to STATs, Dd-STATa-d. - source_id: GO:0097696 title: cell surface receptor signaling pathway via STAT statement: >- The GO pathway term for STAT signaling without JAK. Its definition names D. discoideum and TKL-mediated STAT activation explicitly. - source_id: file:modules/jak_stat_signaling.yaml title: Canonical JAK-STAT cytokine signaling pathway module statement: >- The canonical, taxon-neutral receptor-JAK-STAT module that this module is explicitly contrasted with. - source_id: file:modules/c_elegans_jak_independent_stat_signaling.yaml title: JAK-independent STAT signaling in Caenorhabditis elegans statement: >- Sister module for the other JAK-less lineage in the repository; same structure (paralog variants, each with input and STAT parts). - source_id: file:modules/dicty_jak_independent_stat_signaling-deep-research-openscientist.md title: OpenScientist module deep research statement: >- Used only for retrieval. Its structure (two paralog branches, phosphatase gating of STATc, DrkA as a candidate STATa kinase, STATb/STATd uncharacterized) agrees with the module. Every claim used here was checked against cached primary papers. It led to adding PMID:11245573 (cAR1 inhibitor blocks STATa nuclear translocation). Its STATa-MybC-ecmF and AmtC/DhkC leads (PMID:27125566, PMID:16188250) were not modeled. - source_id: file:genes/DICDI/statA/statA-ai-review.yaml title: statA gene review statement: >- Completed review. Core functions are GO:0000981 with repression of stalk genes, and GO:0097696; the IBA GO:0007259 is modified to GO:0097696. - source_id: file:genes/DICDI/statC/statC-ai-review.yaml title: statC gene review statement: >- Completed review. Core functions are GO:0000981 and GO:1990782 protein tyrosine kinase binding (Pyk2/Pyk3); the IBA GO:0007259 is modified. - source_id: file:genes/DICDI/splB/splB-ai-review.yaml title: splB (Pyk2) gene review statement: >- Completed review. Core function is GO:0004713 protein tyrosine kinase activity in GO:0097696, GO:1903013 and GO:0006972, located in the cytosol. Matches the pyk2_kinase annoton. - source_id: file:genes/DICDI/pyk3/pyk3-ai-review.yaml title: pyk3 gene review statement: >- Completed review. Core function is GO:0004713 in the hyperosmotic response, in cytosol and cell cortex. The serine-kinase IEA is removed and the dual-specificity IEA marked over-annotated. The Ax3/Ax2 discrepancy in Pyk3 sign is kept as an open question. - source_id: file:genes/DICDI/ptpC/ptpC-ai-review.yaml title: ptpC (PTP3) gene review statement: >- Completed review. Core function is GO:0004725 protein tyrosine phosphatase activity in GO:0035335 and GO:1904893, located in the cytosol. - source_id: file:genes/DICDI/phg2/phg2-ai-review.yaml title: phg2 gene review statement: >- Completed review. Core functions are Ser/Thr kinase activity (GO:0004674) as a Rap1 effector in adhesion, phagocytosis and chemotaxis. The STATc role (GO:1904894) is kept as non-core. - source_id: file:genes/DICDI/drkA/drkA-ai-review.yaml title: drkA gene review statement: >- Completed review. Core function is GO:0004713 protein tyrosine kinase activity in GO:0097696, located at the membrane. GO:0004674 IEA is kept as non-core. - source_id: file:genes/DICDI/gskA/gskA-ai-review.yaml title: gskA gene review statement: >- Completed review. Core functions are GO:0004674 in cAMP chemotaxis and TORC2 signalling, and in prespore versus prestalk-B fate, including GO:0046827 positive regulation of protein export from nucleus for STATa and GtaC. Only the STATa export role belongs in this module. - source_id: file:interpro/panther/PTHR11801/PTHR11801-review.yaml title: STAT family (PTHR11801) review statement: >- Places STATa/STATb in SF65, STATc in SF50 and STATd in the default SF43. Rates the JAK-STAT IBD on PTN000927860 as too deep for Dictyostelium. - source_id: file:projects/TAXON_PATHWAY_VARIANCE.md title: Taxon Pathway Variance, case study 2 statement: >- Documents STAT signaling without JAK in Dictyostelium and the taxon constraint TPV-003 (only in Metazoa on GO:0007259), accepted by GO in go-ontology#32689 without its GO:0007260 re-parenting prerequisite. notes: >- Boundary. This is a concrete D. discoideum module. Its theme is STAT transcription factors activated without JAK kinases. It has two paralog-specific pathway variants that coexist in the same organism (selection ONE_OR_MORE) but differ in input, cell type and kinase. Each variant has an upstream-input part and a STAT transcriptional-control part. The STATc variant is the best evidenced. Its kinases (Pyk2, Pyk3) are established by null mutants, a double mutant, in vitro phosphorylation of Tyr922 and co-immunoprecipitation, and its phosphatase arm (PTP3, Phg2) by substrate trapping, overexpression and phosphosite mapping. The STATa variant has a well-established receptor input (cAR1) and transcriptional output (ecmB repression, cudA activation). Its kinase is less certain: DrkA rests on overexpression and in vitro phosphorylation, with no loss-of-function test. STATb and STATd are not modeled as variants. STATb is constitutively nuclear, has an SH2 domain lacking the phosphotyrosine-binding arginine, keeps its behaviour when the predicted phosphotyrosine is mutated, and has no known input (PMID:14701681), so it has no input part to model. STATd (dstD, UniProtKB:Q86I20, unreviewed) has no functional characterization in the cached literature. Relation to MODULE:jak_stat_signaling. That module is a taxon-neutral receptor-JAK-STAT trunk: cytokine-receptor engagement, JAK trans-activation, receptor phosphotyrosine docking sites, STAT recruitment and tyrosine phosphorylation by JAK, dimerization and nuclear import, then GAS/ISRE transcription, with SOCS, phosphatase and PIAS feedback. Here the STAT end of that trunk is conserved: tyrosine phosphorylation of a C-terminal tyrosine, SH2-phosphotyrosine dimerization (shown in the STATa crystal structure), nuclear accumulation and binding to promoter elements (STATa binds a mammalian ISRE). The upstream end is not. There is no JAK and no receptor-docked kinase. For STATc the receptor for DIF-1 is unknown and stress is sensed through F-actin remodelling. The kinase is a TKL that the STAT SH2 domain binds directly through the kinase's own autophosphorylated tyrosines, not through a phosphorylated receptor tail. The kinase is largely constitutive, and the signal is gated by inhibiting a tyrosine phosphatase (PTP3) by serine phosphorylation. In the canonical module phosphatases only terminate signaling. Pyk3 does carry a pseudokinase domain N-terminal to its kinase domain that inhibits the kinase domain, as JAK JH2 does, which is convergent architecture, not JAK homology. For STATa the receptor is a G-protein-coupled cAMP receptor, and its signal to STATa does not need the G-beta subunit. This module therefore does not conform to the jak_stat_signaling template. It is a lineage-specific wiring around a conserved STAT core, as in the C. elegans module (MODULE:c_elegans_jak_independent_stat_signaling), but the two lineages differ: Dictyostelium STATs keep phosphotyrosine-SH2 activation and are activated by TKL kinases, whereas STA-2 in the worm has lost the phosphotyrosine motif. GO terms. The pathway term is GO:0097696 cell surface receptor signaling pathway via STAT, whose definition names D. discoideum and TKL kinases. GO:0007259 (via JAK-STAT) is deliberately absent; the statA and statC reviews modify the inherited IBA to GO:0097696. GO:0007260 tyrosine phosphorylation of STAT protein describes the Pyk2/Pyk3 and DrkA step exactly, but it is currently part_of GO:0007259. Asserting it here would imply JAK-STAT signaling by inference. The kinase annotons therefore carry GO:0097696 and give GO:0007260 only in text. GO has since added an only_in_taxon Metazoa constraint on GO:0007259 (TPV-003 in projects/TAXON_PATHWAY_VARIANCE.md; go-ontology#32689) without first re-parenting GO:0007260 under GO:0097696, so GO:0007260 now inherits the constraint by part_of and asserting it for D. discoideum would be a constraint violation, not just an implication. Pyk2 phosphorylating STATc on Tyr922 without a JAK (PMID:22699506) is the counterexample. GO:0007260 is listed for obsoletion in go-ontology#27064. The case is written up for GO and PAINT curators in the public cross-gene briefing JAK-STAT Without JAK (https://claude.ai/artifact/4MLfbbbWWnLchDvspwdPuM). Relation to other Dictyostelium modules. MODULE:dicty_dif1_response_prestalk_patterning models the DIF-1 response through the bZIP factors DimA and DimB and their outputs ecmA and ecmB. STATc is a second, parallel DIF-1 effector. It is not included there and is modeled here only. The two modules share an output: STATc restricts graded ecmA expression among prestalk cells, while DimA/DimB induce it. DIF-1 production is in MODULE:dicty_dif1_biosynthesis. MODULE:dicty_extracellular_camp_relay models the cAR1-Galpha2-CRAC-ACA aggregation oscillator. cAR1 (UniProtKB:P13773) is reused here as the input to STATa, but in a different context: at the mound and slug stage, and independently of G-beta, whereas the relay depends on heterotrimeric G proteins. ACA is not modeled here. Its tip-restricted expression directs the tip-specific nuclear accumulation of STATa (PMID:11356026), so the relay supplies the cAMP that the STATa variant reads. The dif1_response module explicitly leaves the STATa-CudA culmination circuit out; that circuit is the STATa variant here. Other modulators kept as context. CblA, a Cbl homologue, promotes DIF-1-induced STATc tyrosine phosphorylation by downregulating PTP3 (PMID:18840649). Cytoskeletal perturbation (latrunculin A, cytochalasin A) induces PTP3 S747 phosphorylation and STATc activation (PMID:22365144). cGMP (via GbpC) and Ca2+ are proposed parallel second messengers acting on the kinase and phosphatase arms, respectively (PMID:20159963). The PIAS homologue Dd-PIAS has a genetic and expression-pattern link to STATa (PMID:21933174); it is raised as a knowledge gap, not modeled. GskA in other Dictyostelium modules. GskA has larger roles outside this module: cAMP-receptor-driven prespore versus prestalk-B fate choice and chemotaxis via TORC2/RacE (see its gene review). No existing Dictyostelium module models those processes, so GskA appears here only for STATa nuclear export. Family context. All four STATs are PANTHER PTHR11801 members. STATa, STATb and STATc (dictyBase DDB_G0281381, DDB_G0268638, DDB_G0293532) are seeds of the family-root PAINT node PTN000210448 (nucleus, cytoplasm) in interpro/panther/PTHR11801/PTHR11801-paint.tsv. Concrete GENE_PRODUCT selectors are used instead of family descriptors because the module is species-scoped. PTP3 is in PTHR19134:SF549 and GskA in PTHR24057:SF0. The four TKL kinases are in the large Ser/Thr kinase family PTHR23257: Pyk2/splB in SF975, Pyk3 in SF969, DrkA in SF921 and Phg2 in SF776. Their UniProt cross-references (InterPro 110.0 HMM best hits on the same PANTHER 19.0 release) instead give PTHR44329:SF298 for Pyk2, Pyk3 and DrkA and PTHR46716:SF1 (TAK1) for Phg2. The disagreement was resolved in favour of PANTHER's own placement. PANTHER 19.0's classification files and tree put each kinase in a Dictyostelium clade of PTHR23257, and all four take their IBAs from the PTHR23257 node PTN001148170, not from any PTHR44329 or PTHR46716 node. The placement is pinned in interpro/panther/panther-members-overrides.tsv, and the PTHR44329 and PTHR46716 family reviews no longer list these kinases as representatives. Pyk2, Pyk3 and DrkA tyrosine-kinase activity therefore remains a gene-level (and lineage-specific) property and is not a subfamily-level PTHR44329 inference. module: id: dicty_jak_independent_stat_signaling label: JAK-independent STAT signaling in D. discoideum module_type: SIGNALING_PATHWAY description: >- Two STAT paralog-specific signaling pathways that operate without JAK kinases: a STATc pathway responding to DIF-1 and hyperosmotic stress, gated by TKL kinases and the PTP3 phosphatase, and a STATa pathway responding to extracellular cAMP through cAR1 in prestalk tip cells. concepts: - preferred_term: cell surface receptor signaling pathway via STAT term: id: GO:0097696 label: cell surface receptor signaling pathway via STAT description: >- Shared process of both variants: STAT activation by kinases other than JAK, dimerization, nuclear accumulation and regulation of target genes. context: taxa: - preferred_term: Dictyostelium discoideum term: id: NCBITaxon:44689 label: Dictyostelium discoideum cellular_components: - preferred_term: cytoplasm term: id: GO:0005737 label: cytoplasm description: Latent STATs and their activating kinases. - preferred_term: nucleus term: id: GO:0005634 label: nucleus description: Activated STATs. variant_sets: - id: stat_paralog_pathways label: STAT paralog-specific JAK-independent pathways axis: STAT paralog, upstream input and activating kinase selection: ONE_OR_MORE notes: >- The two variants coexist in the same organism and are not alternatives for one step. They are grouped because each uses a STAT without a JAK. They differ in input (DIF-1 and stress vs extracellular cAMP via cAR1), kinase (Pyk2/Pyk3 vs candidate DrkA), regulatory logic (phosphatase gating vs receptor-triggered phosphorylation) and principal cell type (pstO and stressed cells vs the pstA tip). variants: - id: statc_dif_stress label: STATc DIF-1 and hyperosmotic stress pathway module_type: SIGNALING_PATHWAY description: >- STATc is tyrosine phosphorylated on Tyr922 by the TKL kinases Pyk2 and Pyk3 and dephosphorylated by PTP3. The kinases are largely constitutive. DIF-1 and hyperosmotic stress inhibit PTP3 by serine phosphorylation (S448 and S747), so phosphorylated STATc builds up, dimerizes and accumulates in the nucleus by reduced CRM1-dependent export. Nuclear STATc activates stress genes such as rtoA and gapA, about 20% of the hyperosmotic transcriptional response, and represses ecmA in parts of the prestalk zone. concepts: - preferred_term: response to differentiation-inducing factor 1 term: id: GO:1903013 label: response to differentiation-inducing factor 1 - preferred_term: hyperosmotic response term: id: GO:0006972 label: hyperosmotic response context: conditions: - preferred_term: DIF-1 exposure - preferred_term: hyperosmotic stress (sorbitol) description: Heat shock and oxidative stress also activate STATc (PMID:12771188). evidence: - source_id: PMID:18305004 title: >- Evidence that DIF-1 and hyper-osmotic stress activate a Dictyostelium STAT by inhibiting a specific protein tyrosine phosphatase. statement: >- STATc activation is set by inhibiting its tyrosine phosphatase PTP3, not by activating a kinase. supporting_text: >- These observations suggest a novel mode of STAT activation, whereby serine-threonine phosphorylation of a cognate protein tyrosine phosphatase results in the inhibition of its activity, shifting the phosphorylation-dephosphorylation equilibrium in favour of phosphorylation. - source_id: PMID:22365144 title: Perturbations of the actin cytoskeleton activate a Dictyostelium STAT signalling pathway. statement: DIF-1 and stress converge on PTP3 S747 phosphorylation. supporting_text: >- the more highly regulated of the two PTP3 serine residues, S747, is also phosphorylated in response to DIF-1, suggesting a common activation mechanism parts: - order: 1 role: TKL tyrosine kinase input that phosphorylates STATc node: id: statc_tkl_kinases label: Pyk2 and Pyk3 phosphorylate STATc Tyr922 module_type: REGULATORY_STEP description: >- Two tyrosine-specific TKL kinases act redundantly. Each single null mutant is only partly impaired in stress-induced STATc activation, and the double mutant cannot activate STATc. Both autophosphorylate on tyrosine; the STATc SH2 domain binds these sites, and the kinase then phosphorylates STATc Tyr922. This is the step that GO:0007260 tyrosine phosphorylation of STAT protein describes; that term is not asserted because it is currently part_of GO:0007259 (see notes). annotons: - id: pyk2_kinase label: Pyk2 STATc tyrosine kinase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: Pyk2 term: id: UniProtKB:P18161 label: Dual specificity protein kinase splB function: preferred_term: protein tyrosine kinase activity term: id: GO:0004713 label: protein tyrosine kinase activity targets: - preferred_term: STATc Tyr922 processes: - preferred_term: cell surface receptor signaling pathway via STAT term: id: GO:0097696 label: cell surface receptor signaling pathway via STAT - preferred_term: response to differentiation-inducing factor 1 term: id: GO:1903013 label: response to differentiation-inducing factor 1 - preferred_term: hyperosmotic response term: id: GO:0006972 label: hyperosmotic response locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol description: Concentrates in cytoplasmic granules with PTP3 after osmotic stress. role_description: >- Constitutively active STATc kinase; required for DIF-1-induced STATc activation and, with Pyk3, for stress-induced activation. evidence: - source_id: PMID:22699506 title: >- Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling. statement: >- Pyk2 is required for DIF-1-induced STATc activation and phosphorylates STATc Tyr922 in vitro. supporting_text: >- We show that in a null mutant for Pyk2, a tyrosine-specific TKL, exposure to DIF-1 does not activate STATc. - source_id: PMID:22699506 title: >- Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling. statement: Direct phosphorylation and complex formation. supporting_text: >- Pyk2 phosphorylates STATc on Tyr922 in vitro and complexes with STATc both in vitro and in vivo. - source_id: PMID:22699506 title: >- Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling. statement: The STATc SH2 domain docks on Pyk2 autophosphorylation sites. supporting_text: >- the STATc-Pyk2 complex is formed constitutively by an interaction between the STATc SH2 domain and phosphotyrosine residues on Pyk2 that are generated by autophosphorylation - source_id: PMID:25143406 title: >- Two Dictyostelium tyrosine kinase-like kinases function in parallel, stress-induced STAT activation pathways. statement: Pyk2 relocalizes to cytoplasmic granules with PTP3 under stress. supporting_text: >- Before sorbitol treatment, Pyk2 is localized predominantly in the cytosol, but after treatment, it becomes concentrated in cytoplasmic granules. - id: pyk3_kinase label: Pyk3 STATc tyrosine kinase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: Pyk3 term: id: UniProtKB:Q54I36 label: Dual specificity protein kinase pyk3 function: preferred_term: protein tyrosine kinase activity term: id: GO:0004713 label: protein tyrosine kinase activity targets: - preferred_term: STATc Tyr922 processes: - preferred_term: cell surface receptor signaling pathway via STAT term: id: GO:0097696 label: cell surface receptor signaling pathway via STAT - preferred_term: hyperosmotic response term: id: GO:0006972 label: hyperosmotic response locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol description: Location in resting cells. - preferred_term: cell cortex term: id: GO:0005938 label: cell cortex description: Moves from the cytosol to the cortex after osmotic stress. role_description: >- Second, partly redundant STATc kinase in the stress response. Its N-terminal pseudokinase domain inhibits its kinase domain, as JAK JH2 does. evidence: - source_id: PMID:25143406 title: >- Two Dictyostelium tyrosine kinase-like kinases function in parallel, stress-induced STAT activation pathways. statement: Pyk2 and Pyk3 are redundant STATc kinases under stress. supporting_text: >- for stress-induced STATc activation, single null mutants are only marginally impaired, but the double mutant is nonactivatable - source_id: PMID:25143406 title: >- Two Dictyostelium tyrosine kinase-like kinases function in parallel, stress-induced STAT activation pathways. statement: The isolated Pyk3 kinase domain phosphorylates STATc Tyr922. supporting_text: >- In the construct GST-Pyk3-KI, where KI was expressed in isolation from KII, the TKL directed tyrosine phosphorylation of His-STATc on Y922. - source_id: PMID:25143406 title: >- Two Dictyostelium tyrosine kinase-like kinases function in parallel, stress-induced STAT activation pathways. statement: Autophosphorylated sites recruit the STATc SH2 domain. supporting_text: >- The site(s) that are generated bind the SH2 domain of STATc, and then STATc becomes the target of further kinase action. - source_id: PMID:25143406 title: >- Two Dictyostelium tyrosine kinase-like kinases function in parallel, stress-induced STAT activation pathways. statement: The Pyk3 pseudokinase domain is a JH2-like negative regulator. supporting_text: >- Pyk3 contains both a TKL domain and a pseudokinase domain. The latter functions, like the JH2 domain of metazoan JAKs, as a negative regulator of the kinase domain. - source_id: PMID:24587195 title: >- Identification of the protein kinases Pyk3 and Phg2 as regulators of the STATc-mediated response to hyperosmolarity. statement: Pyk3 loss reduces phospho-STATc and STATc target induction. supporting_text: >- phospho-STATc levels were significantly reduced in pyk3(-) and phg2(-) cells - order: 2 role: tyrosine phosphatase gate that sets STATc activation node: id: statc_ptp3_gate label: PTP3 dephosphorylates STATc and is inhibited by serine phosphorylation module_type: REGULATORY_STEP description: >- PTP3 binds and dephosphorylates STATc. DIF-1 and stress induce phosphorylation of PTP3 on S448 and S747, which reduces its activity. Phg2 is needed for S747 phosphorylation and binds PTP3; the S448 kinase is unknown. Inhibiting PTP3 is the main regulated step in STATc activation. annotons: - id: ptp3_phosphatase label: PTP3 STATc phosphotyrosine phosphatase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTP3 term: id: UniProtKB:P54637 label: Tyrosine-protein phosphatase 3 function: preferred_term: protein tyrosine phosphatase activity term: id: GO:0004725 label: protein tyrosine phosphatase activity targets: - preferred_term: STATc phospho-Tyr922 processes: - preferred_term: negative regulation of receptor signaling pathway via STAT term: id: GO:1904893 label: negative regulation of receptor signaling pathway via STAT - preferred_term: peptidyl-tyrosine dephosphorylation term: id: GO:0035335 label: peptidyl-tyrosine dephosphorylation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Keeps STATc dephosphorylated in unstimulated cells. Inhibition of PTP3 by serine phosphorylation activates STATc. evidence: - source_id: PMID:18305004 title: >- Evidence that DIF-1 and hyper-osmotic stress activate a Dictyostelium STAT by inhibiting a specific protein tyrosine phosphatase. statement: >- PTP3 binds STATc directly; overexpressing PTP3 blocks STATc activation, and inhibiting it activates STATc. supporting_text: >- We show that the protein tyrosine phosphatase PTP3 interacts directly with STATc and that STATc is refractory to activation in PTP3 overexpressing cells. - source_id: PMID:18305004 title: >- Evidence that DIF-1 and hyper-osmotic stress activate a Dictyostelium STAT by inhibiting a specific protein tyrosine phosphatase. statement: A dominant PTP3 inhibitor causes constitutive STATc activation. supporting_text: >- overexpression of a dominant inhibitor of PTP3 leads to constitutive tyrosine phosphorylation and ectopic nuclear localisation of STATc - source_id: PMID:20159963 title: Dual regulation of a Dictyostelium STAT by cGMP and Ca2+ signalling. statement: PTP3 S448 and S747 are phosphorylated rapidly after osmotic stress. supporting_text: >- We show that two serine residues in PTP3, S448 and S747, are rapidly phosphorylated after osmotic stress. - source_id: PMID:24587195 title: >- Identification of the protein kinases Pyk3 and Phg2 as regulators of the STATc-mediated response to hyperosmolarity. statement: Unphosphorylated PTP3 is constitutively active on STATc Tyr922. supporting_text: >- PTP3 is constitutively active in its non-phosphorylated form and removes the phosphate from Tyr922 of STATc. - id: phg2_ptp3_kinase label: Phg2 inhibitory kinase for PTP3 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: Phg2 term: id: UniProtKB:Q54QQ1 label: Serine/threonine-protein kinase phg2 function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity targets: - preferred_term: PTP3 Ser747 processes: - preferred_term: positive regulation of receptor signaling pathway via STAT term: id: GO:1904894 label: positive regulation of receptor signaling pathway via STAT role_description: >- Serine/threonine TKL kinase needed for PTP3 S747 phosphorylation under hyperosmotic stress. It binds PTP3 in pull-downs and is proposed to phosphorylate it directly. This is a secondary role: the phg2 review keeps GO:1904894 as non-core, and Phg2's core role is as a Rap1 effector in adhesion, phagocytosis and chemotaxis. evidence: - source_id: PMID:24587195 title: >- Identification of the protein kinases Pyk3 and Phg2 as regulators of the STATc-mediated response to hyperosmolarity. statement: Phg2 is needed for PTP3 S747 phosphorylation and binds PTP3. supporting_text: >- In pull-down assays Phg2 and PTP3 interact directly, suggesting that Phg2 phosphorylates PTP3 on S747 in vivo. - source_id: PMID:24587195 title: >- Identification of the protein kinases Pyk3 and Phg2 as regulators of the STATc-mediated response to hyperosmolarity. statement: Phg2 acts on S747 but not on S448. supporting_text: >- Phosphorylation of S448 was unchanged in phg2(-) cells. connections: - source: phg2_ptp3_kinase target: ptp3_phosphatase connection_type: NEGATIVELY_REGULATES description: Phg2-dependent S747 phosphorylation inhibits PTP3. - order: 3 role: STATc dimerization, nuclear accumulation and transcriptional control node: id: statc_transcription label: STATc-dependent transcription of stress and prestalk genes module_type: MOLECULAR_FUNCTION description: >- Tyrosine-phosphorylated STATc dimerizes and accumulates in the nucleus, where it activates hyperosmotic stress genes and restricts ecmA expression to particular prestalk populations. Nuclear accumulation is controlled at the level of CRM1-dependent export. DIF-1-induced nuclear translocation does not need the SH2-phosphotyrosine interaction and is directed by the N-terminal half of STATc, so tyrosine phosphorylation and nuclear entry are separable for this STAT. annotons: - id: statc_transcription_factor label: STATc DNA-binding transcription factor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STATc term: id: UniProtKB:Q54BD4 label: Signal transducer and activator of transcription C function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific description: >- Acts as an activator of stress genes and as a repressor of ecmA, following the statC review core function. targets: - preferred_term: rtoA, gapA, sigG (stress-induced genes) - preferred_term: ecmA (repressed in parts of the prestalk zone) processes: - preferred_term: hyperosmotic response term: id: GO:0006972 label: hyperosmotic response - preferred_term: response to differentiation-inducing factor 1 term: id: GO:1903013 label: response to differentiation-inducing factor 1 - preferred_term: negative regulation of DNA-templated transcription term: id: GO:0045892 label: negative regulation of DNA-templated transcription locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus - preferred_term: cytoplasm term: id: GO:0005737 label: cytoplasm description: Latent pool before activation. role_description: >- Signal-dependent STAT that integrates DIF-1 and stress inputs. It also binds its activating kinases through its SH2 domain (GO:1990782 protein tyrosine kinase binding in the statC review). evidence: - source_id: PMID:12771188 title: A STAT-regulated, stress-induced signalling pathway in Dictyostelium. statement: STATc is the activator of the osmotic stress genes gapA and rtoA. supporting_text: >- Osmotic stress induction of gapA and rtoA is entirely dependent on Dd-STATc. - source_id: PMID:17517120 title: STATc is a key regulator of the transcriptional response to hyperosmotic shock. statement: About 20% of hyperosmotic-response genes depend on STATc. supporting_text: >- Approximately 20% of the differentially regulated genes were dependent on the presence of STATc. - source_id: PMID:11336701 title: >- Tyrosine phosphorylation-independent nuclear translocation of a dictyostelium STAT in response to DIF signaling. statement: >- STATc represses graded ecmA expression and enters the nucleus on DIF-1 without needing SH2-phosphotyrosine interaction. supporting_text: >- Dd-STATc also functions as a repressor, which directs graded expression of the ecmA gene in different prestalk cell populations. - source_id: PMID:11336701 title: >- Tyrosine phosphorylation-independent nuclear translocation of a dictyostelium STAT in response to DIF signaling. statement: DIF-induced nuclear translocation is SH2-phosphotyrosine-independent. supporting_text: >- Surprisingly, however, SH2 domain-phosphotyrosine interaction is not necessary for the DIF-induced nuclear translocation of Dd-STATc. - source_id: PMID:12506009 title: >- The Dictyostelium prestalk cell inducer DIF regulates nuclear accumulation of a STAT protein by controlling its rate of export from the nucleus. statement: DIF-1 inhibits STATc nuclear export. supporting_text: >- we show that DIF inhibits the nuclear export of Dd-STATc connections: - source: statc_tkl_kinases target: statc_transcription connection_type: POSITIVELY_REGULATES description: >- Pyk2 and Pyk3 phosphorylate STATc Tyr922, which activates it. - source: statc_ptp3_gate target: statc_transcription connection_type: NEGATIVELY_REGULATES description: >- PTP3 dephosphorylates STATc Tyr922. DIF-1 and stress relieve this repression by inhibiting PTP3. - id: stata_camp_tip label: STATa extracellular cAMP and cAR1 pathway in the prestalk tip module_type: SIGNALING_PATHWAY description: >- From the mound stage onward, extracellular cAMP acting through the serpentine receptor cAR1 induces STATa tyrosine phosphorylation on Tyr702 within seconds, and STATa enters the nucleus. The response does not need the only G-beta subunit. Nuclear STATa is later kept only in the prestalk cells of the slug tip (the organizer), where the tip-restricted adenylyl cyclase ACA supplies cAMP. GskA serine-phosphorylates STATa and promotes its nuclear export. In the nucleus STATa represses the stalk gene ecmB and directly activates the cudA gene, whose product is needed for culmination. concepts: - preferred_term: culmination involved in sorocarp development term: id: GO:0031154 label: culmination involved in sorocarp development - preferred_term: sorocarp stalk cell differentiation term: id: GO:0031149 label: sorocarp stalk cell differentiation description: STATa regulates commitment to stalk differentiation as a repressor of ecmB. context: conditions: - preferred_term: mound and slug stage of multicellular development description: >- STATa is not tyrosine phosphorylated before late aggregation; nuclear STATa is later restricted to prestalk tip cells. evidence: - source_id: PMID:9670017 title: >- Developmentally and spatially regulated activation of a Dictyostelium STAT protein by a serpentine receptor. statement: >- cAMP through cAR1 induces rapid STATa tyrosine phosphorylation and nuclear entry, independently of G-beta. supporting_text: >- The tyrosine phosphorylation and nuclear localization of Dd-STAT are induced very rapidly by extracellular cAMP through the serpentine cAMP receptor cAR1 - source_id: PMID:9670017 title: >- Developmentally and spatially regulated activation of a Dictyostelium STAT protein by a serpentine receptor. statement: Nuclear STATa is maintained in prestalk tip cells. supporting_text: >- Nuclear enrichment of Dd-STAT is selectively maintained within the sub-population of prestalk cells that form the tip, the organizing center of the slug - source_id: PMID:11356026 title: >- Adenylyl cyclase A expression is tip-specific in Dictyostelium slugs and directs StatA nuclear translocation and CudA gene expression. statement: Tip-specific ACA expression directs tip-specific nuclear STATa. supporting_text: >- This suggests that the tip-specific expression of ACA directs tip-specific nuclear translocation of StatA and tip-specific expression of CudA. parts: - order: 1 role: serpentine cAMP receptor input node: id: stata_car1_input label: cAR1 senses extracellular cAMP upstream of STATa module_type: REGULATORY_STEP description: >- cAR1, the same receptor that drives the aggregation relay (MODULE:dicty_extracellular_camp_relay), triggers STATa tyrosine phosphorylation at the mound stage. The receptor C-terminal tail is not needed, and a constitutively phosphorylated tail gives constitutive STATa phosphorylation. How cAR1 reaches the STATa kinase is unknown. annotons: - id: car1_receptor label: cAR1 cAMP receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: cAR1 term: id: UniProtKB:P13773 label: Cyclic AMP receptor 1 function: preferred_term: cAMP receptor activity term: id: GO:0001646 label: cAMP receptor activity processes: - preferred_term: cell surface receptor signaling pathway via STAT term: id: GO:0097696 label: cell surface receptor signaling pathway via STAT locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Serpentine receptor whose activation by cAMP triggers STATa tyrosine phosphorylation, apparently without heterotrimeric G-protein signaling. evidence: - source_id: PMID:9670017 title: >- Developmentally and spatially regulated activation of a Dictyostelium STAT protein by a serpentine receptor. statement: The cAR1-to-STATa signal may be G-protein-independent. supporting_text: >- This activation is independent of the only known Gbeta subunit, suggesting that it may be G-protein independent. - source_id: PMID:11245573 title: >- Inducible nuclear translocation of a STAT protein in Dictyostelium prespore cells: implications for morphogenesis and cell-type regulation. statement: >- A cAR1 inhibitor blocks cAMP-induced STATa nuclear translocation in slugs, so cAR1 carries most or all of the signal. supporting_text: >- Co-injection of a specific inhibitor of the cAR1 serpentine cAMP receptor almost completely prevents the cAMP-induced nuclear translocation, showing that most or all of the cAMP signal is transduced by cAR1. - source_id: PMID:11319871 title: >- The phosphorylated C-terminus of cAR1 plays a role in cell-type-specific gene expression and STATa tyrosine phosphorylation. statement: >- A constitutively phosphorylated cAR1 tail gives constitutive STATa tyrosine phosphorylation. supporting_text: >- A mutant receptor, in which the C-terminal tail is constitutively phosphorylated, exhibits constitutive activation of STATa tyrosine phosphorylation in pulsed cells in suspension - order: 2 role: candidate TKL tyrosine kinase for STATa node: id: stata_kinase label: DrkA phosphorylates STATa Tyr702 module_type: REGULATORY_STEP description: >- DrkA is a receptor-like TKL kinase expressed almost only in pstA cells, where STATa is active. Overexpression raises STATa phosphorylation, and recombinant DrkA phosphorylates STATa Tyr702 in vitro in an SH2-dependent manner, mirroring the Pyk2-STATc mechanism. No loss-of-function test has been reported, so DrkA is a candidate, not an established, STATa kinase. As for Pyk2/Pyk3, GO:0007260 is given only in text. annotons: - id: drka_kinase label: DrkA candidate STATa kinase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DrkA term: id: UniProtKB:Q54H46 label: Probable serine/threonine-protein kinase drkA function: preferred_term: protein tyrosine kinase activity term: id: GO:0004713 label: protein tyrosine kinase activity targets: - preferred_term: STATa Tyr702 processes: - preferred_term: cell surface receptor signaling pathway via STAT term: id: GO:0097696 label: cell surface receptor signaling pathway via STAT locations: - preferred_term: membrane term: id: GO:0016020 label: membrane description: >- Single-pass receptor-like kinase (signal peptide, extracellular domain, one transmembrane helix); the kinase domain is cytoplasmic. role_description: >- Prestalk-A-enriched TKL kinase that phosphorylates STATa Tyr702 in vitro and increases STATa phosphorylation when overexpressed. evidence: - source_id: PMID:31002205 title: Analysis of DrkA kinase's role in STATa activation. statement: >- DrkA phosphorylates STATa Tyr702 in vitro in an SH2-dependent manner. supporting_text: >- an in vitro kinase assay shows that DrkA can phosphorylate STATa on Tyr702 in a STATa-SH2 (phosphotyrosine binding) domain-dependent manner - source_id: PMID:31002205 title: Analysis of DrkA kinase's role in STATa activation. statement: DrkA overexpression raises STATa phosphorylation in cells. supporting_text: >- Transient over-expression of DrkA increased STATa phosphorylation - source_id: PMID:31002205 title: Analysis of DrkA kinase's role in STATa activation. statement: The authors frame DrkA as a likely, not proven, direct STATa kinase. supporting_text: >- These observations strongly suggest that DrkA is one of the key regulators of STATa tyrosine phosphorylation and is consistent with it being the kinase that directly activates STATa. - order: 3 role: STATa nuclear transcriptional control node: id: stata_transcription label: STATa represses stalk genes and activates prestalk genes module_type: MOLECULAR_FUNCTION description: >- Tyrosine-phosphorylated STATa forms SH2-phosphotyrosine homodimers and binds TTGA-containing promoter elements. It represses ecmB, keeping tip prestalk cells from committing to stalk differentiation, and directly activates cudA in prestalk cells. Nuclear residence is shortened by GskA serine phosphorylation, which promotes export. annotons: - id: stata_transcription_factor label: STATa DNA-binding transcription factor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STATa term: id: UniProtKB:O00910 label: Signal transducer and activator of transcription A function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific description: >- Acts chiefly as a repressor of stalk genes and as an activator of cudA, following the statA review core function. targets: - preferred_term: ecmB repressor elements - preferred_term: cudA prestalk promoter element processes: - preferred_term: negative regulation of DNA-templated transcription term: id: GO:0045892 label: negative regulation of DNA-templated transcription - preferred_term: sorocarp stalk cell differentiation term: id: GO:0031149 label: sorocarp stalk cell differentiation locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus - preferred_term: cytoplasm term: id: GO:0005737 label: cytoplasm description: Latent pool before mound-stage activation. role_description: >- cAMP-activated STAT of the slug tip; repressor of stalk commitment and activator of the culmination factor cudA. evidence: - source_id: PMID:10393118 title: >- Evidence that the Dictyostelium Dd-STATa protein is a repressor that regulates commitment to stalk cell differentiation and is also required for efficient chemotaxis. statement: STATa binds stalk-gene repressor elements and represses ecmB. supporting_text: >- Dd-STATa binds these repressor elements in vitro and the ectopic expression of ecmB/lacZ in the null strain provides in vivo evidence that Dd-STATa is the repressor protein that regulates commitment to stalk cell differentiation. - source_id: PMID:15053873 title: Structure of an activated Dictyostelium STAT in its DNA-unbound form. statement: Phosphorylated STATa dimerizes through SH2-phosphotyrosine contacts. supporting_text: >- Dimerization is mediated by SH2 domain:phosphopeptide interactions and by a direct interaction between SH2 domains. - source_id: PMID:9200609 title: >- SH2 signaling in a lower eukaryote: a STAT protein that regulates stalk cell differentiation in dictyostelium. statement: STATa binds a mammalian ISRE. supporting_text: >- it will bind specifically to a mammalian interferon-stimulated response element - source_id: PMID:10821768 title: >- Analysis of the promoter of the cudA gene reveals novel mechanisms of Dictyostelium cell type differentiation. statement: STATa directly activates cudA in prestalk cells. supporting_text: >- Dd-STATa appears therefore to serve as a direct activator of cudA transcription in prestalk cells - id: gska_stata_export label: GskA promotes STATa nuclear export participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GskA term: id: UniProtKB:P51136 label: Glycogen synthase kinase-3 function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity targets: - preferred_term: STATa serine residues processes: - preferred_term: positive regulation of protein export from nucleus term: id: GO:0046827 label: positive regulation of protein export from nucleus locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus - preferred_term: cytoplasm term: id: GO:0005737 label: cytoplasm role_description: >- cAMP-regulated GSK-3 homologue that serine-phosphorylates STATa minutes after tyrosine phosphorylation and enhances its nuclear export, the second phase of a biphasic response. evidence: - source_id: PMID:11032815 title: Glycogen synthase kinase-3 enhances nuclear export of a Dictyostelium STAT protein. statement: GskA phosphorylation enhances STATa nuclear export. supporting_text: >- Phosphorylation by GskA enhances nuclear export of Dd-STATa. - source_id: PMID:11032815 title: Glycogen synthase kinase-3 enhances nuclear export of a Dictyostelium STAT protein. statement: cAMP first directs STATa import and then, via GskA, its export. supporting_text: >- extracellular cAMP initially directs nuclear import and then, via GskA, promotes its subsequent export connections: - source: gska_stata_export target: stata_transcription_factor connection_type: NEGATIVELY_REGULATES description: GskA serine phosphorylation promotes STATa nuclear export. - order: 4 role: transcription factor output for culmination node: id: stata_cuda_output label: CudA, a STATa target required for culmination module_type: BIOLOGICAL_PROCESS description: >- CudA is a nuclear transcription factor whose tip-specific expression is driven by STATa. It is the effector through which STATa supports culmination. annotons: - id: cuda_effector label: CudA transcription factor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CudA term: id: UniProtKB:O00841 label: Putative transcriptional regulator cudA function: preferred_term: sequence-specific DNA binding term: id: GO:0043565 label: sequence-specific DNA binding description: Follows the cudA review core function. processes: - preferred_term: culmination involved in sorocarp development term: id: GO:0031154 label: culmination involved in sorocarp development locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Downstream transcription factor of the STATa pathway in tip prestalk cells; required for culmination. evidence: - source_id: PMID:11356026 title: >- Adenylyl cyclase A expression is tip-specific in Dictyostelium slugs and directs StatA nuclear translocation and CudA gene expression. statement: STATa directs tip-specific expression of CudA, essential for culmination. supporting_text: >- the transcription factor StatA displays tip-specific nuclear translocation and directs tip-specific expression of the nuclear protein CudA, which is essential for culmination connections: - source: stata_car1_input target: stata_kinase connection_type: POSITIVELY_REGULATES description: >- cAR1 activation leads to STATa tyrosine phosphorylation. Whether cAR1 activates DrkA, and how, is unknown. - source: stata_kinase target: stata_transcription connection_type: POSITIVELY_REGULATES description: DrkA phosphorylation of STATa Tyr702 (in vitro evidence). - source: stata_transcription target: stata_cuda_output connection_type: CAUSES description: STATa binds the cudA prestalk promoter element and activates cudA. knowledge_gaps: - gap_statement: >- The receptor for DIF-1 and the stress sensor upstream of STATc are unknown, as is how Pyk2 and Pyk3 autophosphorylation increases under stress. boundary: >- DIF-1 and stress converge on PTP3 S747 phosphorylation and F-actin remodelling. cGMP (via GbpC) is proposed to act on the kinase arm and Ca2+ on the phosphatase arm, from pharmacology and mutants. The S448 kinase of PTP3 is unidentified. gap_kind: - BIOLOGY status: OPEN significance: >- Without a receptor, the STATc variant fits GO:0097696 only through its STAT core; whether DIF-1 acts at the cell surface is unresolved. resolution: >- Identify DIF-1-binding proteins; map the S448 kinase; test Pyk2/Pyk3 autophosphorylation in gbpC and Ca2+-signalling mutants. provenance: - reference_id: PMID:20159963 supporting_text: >- We propose that stress-induced cGMP signalling exerts its stimulatory effect by potentiating the activity of a semi-constitutive tyrosine kinase that phosphorylates STATc reference_section_type: ABSTRACT - gap_statement: >- The sign of Pyk3 action on STATc is disputed: one study reports prolonged DIF-1-induced STATc phosphorylation in pyk3 nulls, while later studies find reduced activation. boundary: >- The negative result was in an Ax3 background; the positive results were in Ax2, and the authors suggest strain dependence. gap_kind: - BIOLOGY status: OPEN significance: Determines whether Pyk3 is an activating kinase in all contexts or also a negative regulator in development. resolution: Compare pyk3 nulls in matched Ax2 and Ax3 backgrounds during development and after DIF-1. provenance: - reference_id: PMID:18657170 supporting_text: >- Dictyostelium DPYK3 negatively regulates STATc during development in response to DIF-1 signaling. reference_section_type: ABSTRACT - reference_id: PMID:25143406 supporting_text: >- However, this may be strain dependent because we are not able to reproduce the observation in Ax2 cells reference_section_type: INTRODUCTION - gap_statement: >- The STATa kinase is not established, and how cAR1 reaches it without G-beta is unknown. boundary: >- DrkA evidence is overexpression and in vitro phosphorylation; drkA overexpression is toxic and no null-mutant STATa phosphorylation data are reported. gap_kind: - BIOLOGY status: OPEN significance: Without it the STATa variant has no grounded kinase step. resolution: Test STATa Tyr702 phosphorylation and nuclear accumulation in drkA null or conditional mutants after cAMP stimulation. provenance: - reference_id: PMID:31002205 supporting_text: >- Although two tyrosine kinase-like (TKL) proteins, Pyk2 and Pyk3, have been definitively identified as STATc kinases, no kinase is known for STATa activation. reference_section_type: ABSTRACT - gap_statement: >- The inputs and activation mechanism of STATb and STATd are unknown. boundary: >- STATb is constitutively nuclear and dimeric even with its predicted phosphotyrosine replaced, and has a subtle growth role. STATd (dstD) has no characterization in the cached literature. gap_kind: - BIOLOGY status: OPEN significance: Two of the four Dictyostelium STATs cannot yet be placed in any pathway. resolution: Phenotype dstD nulls; identify STATb partners and targets. provenance: - reference_id: PMID:14701681 supporting_text: >- These observations suggest a non-canonical mode of activation of Dd-STATb that does not rely on orthodox SH2 domain:phosphotyrosine interactions. reference_section_type: ABSTRACT - gap_statement: >- Whether Dd-PIAS directly inhibits STATa, as PIAS proteins do metazoan STATs, is unknown. boundary: >- The link is genetic (overexpression phenocopies statA null; STATa target genes are up in the pisA null) and expression-pattern based. No binding or SUMOylation of STATa is shown in the cached abstract. gap_kind: - BIOLOGY status: OPEN significance: Would be a conserved negative-regulation layer of the canonical module retained without JAK. resolution: Test Dd-PIAS binding to and SUMOylation of STATa, and STATa DNA binding in pisA mutants. provenance: - reference_id: PMID:21933174 supporting_text: >- Our results suggest a functional interrelationship between Dd-PIAS and Dd-STATa that influences gene expression and development. reference_section_type: ABSTRACT