regA

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004115 3',5'-cyclic-AMP phosphodiesterase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of cAMP phosphodiesterase activity is correct and represents the core catalytic function of RegA, which harbors a class I PDE domain that hydrolyzes intracellular cAMP. Reason: RegA/DdPDE2 is directly demonstrated to be a cAMP-specific phosphodiesterase that degrades intracellular cAMP. The IBA annotation matches the experimentally established core function. Supporting Evidence: PMID:17040207 DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the cytosol of the cell where it degrades intracellular cAMP
GO:0047555 3',5'-cyclic-GMP phosphodiesterase activity	IBA GO_REF:0000033	REMOVE	Summary: RegA is a cAMP-specific phosphodiesterase with a cAMP/cGMP selectivity of ~200. cGMP phosphodiesterase activity is an over-propagation from the broader phosphodiesterase family and does not reflect the enzyme's demonstrated specificity. Reason: The IBA inference of cGMP phosphodiesterase activity conflicts with the experimentally established cAMP specificity of RegA (UniProt reports a cAMP/cGMP selectivity of 200, and characterization describes RegA/DdPDE2 as a cAMP-specific PDE). This electronic over-propagation from the general PDE family can be argued against on biochemical grounds. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN001682918 · PANTHER node for class-I cyclic-nucleotide phosphodiesterases SUPPORTS SOURCE BUT NOT TARGET cGMP-phosphodiesterase activity is a family-level property; RegA is experimentally cAMP-specific with a cAMP/cGMP selectivity near 200, so the cGMP activity does not transfer UniProtKB:O00408 · human PDE2A, a cGMP-stimulated phosphodiesterase SUPPORTS SOURCE BUT NOT TARGET Source enzyme hydrolyzes cGMP; RegA has diverged to cAMP specificity Supporting Evidence: PMID:17040207 DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the cytosol of the cell where it degrades intracellular cAMP
GO:0141162 negative regulation of cAMP/PKA signal transduction	IBA GO_REF:0000033	ACCEPT	Summary: By degrading intracellular cAMP, RegA lowers PKA activity, acting as a negative regulator of cAMP/PKA signaling. This is a well-supported core biological role. Reason: Genetic and biochemical evidence show that inhibition of the RegA phosphodiesterase increases PKA activity at a differentiation checkpoint, establishing RegA as a negative regulator of cAMP/PKA signal transduction. Supporting Evidence: PMID:9435289 inhibition of the phosphodiesterase results in an increase in the activity of PKA, which acts at a check point for terminal differentiation
GO:0030587 sorocarp development	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: RegA is required for normal fruiting body (sorocarp) development; loss of RegA causes rapid, precocious development. This is a genuine developmental role but downstream of the core cAMP-degrading function. Reason: The developmental role in sorocarp formation is well established across multiple experimental studies, but it is a consequence of RegA's control over intracellular cAMP/PKA rather than a distinct core molecular activity. Supporting Evidence: PMID:9435289 inhibition of the phosphodiesterase results in an increase in the activity of PKA, which acts at a check point for terminal differentiation
GO:0000160 phosphorelay signal transduction system	IEA GO_REF:0000002	ACCEPT	Summary: RegA is the response-regulator component of the RdeA-RegA His-Asp phosphorelay, a core aspect of its regulation. Correct annotation. Reason: RegA contains a receiver domain that accepts phosphate from RdeA in a His-Asp phosphorelay, directly supported by biochemical and genetic evidence. Supporting Evidence: PMID:10488068 The response regulator, RegA, is composed of an N-terminal receiver domain linked to a C-terminal cAMP-phosphodiesterase domain
GO:0004114 3',5'-cyclic-nucleotide phosphodiesterase activity	IEA GO_REF:0000002	MODIFY	Summary: This is the general parent term for the phosphodiesterase family. It is correct but less informative than the specific cAMP phosphodiesterase activity that represents RegA's actual demonstrated specificity. Reason: The general cyclic-nucleotide PDE activity is technically correct (EC 3.1.4.53), but RegA is cAMP-specific, so the specific child term GO:0004115 better captures the core function. Proposed replacements: 3',5'-cyclic-AMP phosphodiesterase activity Supporting Evidence: PMID:17040207 DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the cytosol of the cell where it degrades intracellular cAMP
GO:0004115 3',5'-cyclic-AMP phosphodiesterase activity	IEA GO_REF:0000120	ACCEPT	Summary: Correct core catalytic activity, consistent with direct experimental characterization of RegA as a cAMP-specific phosphodiesterase. Reason: This automated annotation agrees with the experimentally demonstrated cAMP phosphodiesterase activity of RegA. Supporting Evidence: PMID:17040207 DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the cytosol of the cell where it degrades intracellular cAMP
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: RegA is a cytosolic (internal) phosphodiesterase, consistent with its role in degrading intracellular cAMP. Correct localization. Reason: Subcellular location evidence and functional characterization place RegA in the cytosol where it degrades intracellular cAMP. Supporting Evidence: PMID:17040207 DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the cytosol of the cell where it degrades intracellular cAMP
GO:0007165 signal transduction	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: This is a very broad parent term. RegA does participate in signal transduction, but more specific terms (phosphorelay signal transduction system, negative regulation of cAMP/PKA signaling) are already present and far more informative. Reason: The generic signal transduction term adds little given the presence of specific and better annotations describing RegA's phosphorelay and cAMP/PKA regulatory roles. Supporting Evidence: PMID:10488068 The response regulator, RegA, is composed of an N-terminal receiver domain linked to a C-terminal cAMP-phosphodiesterase domain
GO:0008081 phosphoric diester hydrolase activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: General grandparent hydrolase term. Correct but far less informative than the specific cAMP phosphodiesterase activity. Reason: RegA is a phosphoric diester hydrolase, but the specific cAMP phosphodiesterase activity (GO:0004115) captures the core function; this broad term is retained only as a non-core ancestor. Supporting Evidence: PMID:17040207 DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the cytosol of the cell where it degrades intracellular cAMP
GO:0120320 lateral pseudopodium retraction	IMP PMID:10930471 The internal phosphodiesterase RegA is essential for the sup...	KEEP AS NON CORE	Summary: RegA is essential for suppressing lateral pseudopod formation during chemotaxis. This is a genuine experimentally-supported role but is downstream of the core cAMP-degrading activity. Reason: Direct mutant phenotype analysis shows RegA is required to suppress lateral pseudopods during chemotaxis, a cell-motility role secondary to its control of internal cAMP levels. Supporting Evidence: PMID:10930471 RegA is essential for specifically suppressing lateral pseudopod formation during the response to an increasing temporal gradient of cAMP
GO:0000160 phosphorelay signal transduction system	IMP PMID:10488068 The RdeA-RegA system, a eukaryotic phospho-relay controlling...	ACCEPT	Summary: Experimental evidence for RegA as the response regulator in the RdeA-RegA His-Asp phosphorelay. Core regulatory mechanism. Reason: Biochemical phospho-transfer between RdeA (His65) and RegA (Asp212) demonstrates RegA participation in a eukaryotic His-Asp phosphorelay. Supporting Evidence: PMID:10488068 Phosphorylation of RegA by a heterologous phospho-donor protein activates RegA phosphodiesterase activity at least 20-fold
GO:0005515 protein binding	IPI PMID:31730032 Mitogen-activated protein kinase regulation of the phosphodi...	MODIFY	Summary: This IPI annotation records the physical association between RegA and the MAP kinase Erk2. The bare protein binding term is uninformative; the more specific protein kinase binding term better captures the interaction. Reason: Co-immunoprecipitation shows RegA associates with the atypical MAPK Erk2, which downregulates RegA. Replacing bare protein binding with protein kinase binding conveys the nature of the interactor. Proposed replacements: protein kinase binding Supporting Evidence: PMID:31730032 Co-immunoprecipitation analysis indicated that Erk2 associates with both RegA
GO:0010225 response to UV-C	IDA PMID:25858552 Response of Dictyostelium discoideum to UV-C and involvement...	KEEP AS NON CORE	Summary: In this study regA was one of several developmentally regulated genes whose transcript levels were monitored by RT-PCR following UV-C exposure. This reflects a transcriptional/developmental response rather than a dedicated molecular function of RegA in UV-C response. Reason: The evidence is an expression change of regA among many developmental genes after UV-C irradiation, not a direct functional role of RegA in the UV-C response; retained as non-core. Supporting Evidence: PMID:25858552 regA, ctnA, ctnB, gp24, hspD and dsn were analysed using semiquantitative RT-PCR
GO:0005829 cytosol	TAS PMID:17040207 Seven Dictyostelium discoideum phosphodiesterases degrade th...	ACCEPT	Summary: RegA/DdPDE2 is described as localized in the cytosol where it degrades intracellular cAMP. Correct core localization. Reason: The cytosolic localization is explicitly stated and is consistent with RegA's function in degrading intracellular cAMP. Supporting Evidence: PMID:17040207 DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the cytosol of the cell where it degrades intracellular cAMP
GO:0061128 positive regulation of chemotaxis to cAMP by DIF-2	IMP PMID:26919666 Differentiation-inducing factor 2 modulates chemotaxis via t...	KEEP AS NON CORE	Summary: DIF-2 enhances chemotaxis in shallow cAMP gradients via RegA as part of the DhkC-RdeA-RegA two-component system. A specialized signaling role downstream of the core cAMP-degrading function. Reason: Mutant analysis places RegA in the DhkC-RdeA-RegA pathway through which DIF-2 enhances chemotaxis, a specific regulatory role that is not the core molecular function. Supporting Evidence: PMID:26919666 DIF-2 enhances chemotaxis under the same conditions via a phosphodiesterase, response regulator A (RegA)
GO:1904776 regulation of protein localization to cell cortex	IMP PMID:10930471 The internal phosphodiesterase RegA is essential for the sup...	KEEP AS NON CORE	Summary: In regA-null cells myosin II fails to localize normally to the cortex during a temporal cAMP gradient, indicating RegA influences cortical protein localization. A downstream cytoskeletal consequence of altered cAMP levels. Reason: The mutant phenotype links RegA to cortical myosin II localization, but this is a downstream effect of cAMP/PKA dysregulation rather than a core molecular function. Supporting Evidence: PMID:10930471 myosin II does not localize in a normal manner to the cortex
GO:0005515 protein binding	IPI PMID:9435289 A cAMP-phosphodiesterase controls PKA-dependent differentiat...	MODIFY	Summary: RegA phosphodiesterase is stimulated by binding to the regulatory subunit (PKA-R) of cAMP-dependent protein kinase. The bare protein binding term is uninformative; a specific protein kinase A regulatory subunit binding term is more appropriate. Reason: The interaction partner is the PKA regulatory subunit (PKA-R), so the specific term protein kinase A regulatory subunit binding conveys the identity of the interactor better than bare protein binding. Proposed replacements: protein kinase A regulatory subunit binding Supporting Evidence: PMID:9435289 stimulated by binding to the regulatory subunit of cAMP-dependent protein kinase, PKA-R
GO:0031288 sorocarp morphogenesis	IMP PMID:9435289 A cAMP-phosphodiesterase controls PKA-dependent differentiat...	KEEP AS NON CORE	Summary: RegA loss alters fruiting body morphogenesis (precocious/aberrant development). A genuine developmental phenotype downstream of cAMP/PKA control. Reason: The morphogenesis phenotype reflects RegA's control of the PKA differentiation checkpoint rather than a distinct core molecular activity. Supporting Evidence: PMID:9435289 inhibition of the phosphodiesterase results in an increase in the activity of PKA, which acts at a check point for terminal differentiation
GO:0000156 phosphorelay response regulator activity	IMP PMID:10488068 The RdeA-RegA system, a eukaryotic phospho-relay controlling...	ACCEPT	Summary: RegA's N-terminal receiver domain functions as a phosphorelay response regulator, accepting phosphate at Asp212 which activates the phosphodiesterase. This is a core molecular function. Reason: Phospho-transfer experiments demonstrate RegA acts as a response regulator whose receiver-domain phosphorylation activates its enzymatic output, a core function of the protein. Supporting Evidence: PMID:10488068 Phosphorylation of RegA by a heterologous phospho-donor protein activates RegA phosphodiesterase activity at least 20-fold
GO:0004114 3',5'-cyclic-nucleotide phosphodiesterase activity	IDA PMID:9582277 An intersection of the cAMP/PKA and two-component signal tra...	MODIFY	Summary: Direct biochemical characterization measured a cAMP phosphodiesterase activity (Km ~5 uM for cAMP). Since RegA is cAMP-specific, the specific child term is more precise than this general parent. Reason: The IDA measured cAMP-specific phosphodiesterase activity; the specific term GO:0004115 better represents the demonstrated substrate specificity than the general cyclic-nucleotide PDE term. Proposed replacements: 3',5'-cyclic-AMP phosphodiesterase activity Supporting Evidence: PMID:9582277 One domain is a cAMP phosphodiesterase (Km approximately 5 microM); the other is homologous to response regulators
GO:0048837 sorocarp sorus development	IMP PMID:24511612 Loss of cAMP-specific phosphodiesterase rescues spore develo...	KEEP AS NON CORE	Summary: Loss of RegA accelerates spore/sorus development and can rescue sporulation defects of certain G-protein mutants. A developmental role downstream of cAMP/PKA control. Reason: The spore/sorus developmental phenotype results from elevated cAMP/PKA activity when RegA is absent, a downstream consequence rather than a core molecular function. Supporting Evidence: PMID:24511612 Loss of RegA also results in accelerated spore development
GO:0030587 sorocarp development	HMP PMID:17659086 High-throughput analysis of spatio-temporal dynamics in Dict...	KEEP AS NON CORE	Summary: This high-throughput spatio-temporal phenotype screen catalogs many mutant clones. The cached abstract does not contain a regA-specific statement that I can quote to verify the developmental phenotype for this gene, though RegA's sorocarp role is well supported elsewhere. Reason: RegA's role in sorocarp development is well established from multiple dedicated studies; this high-throughput resource is consistent with that role but the abstract lacks a regA-specific quotable statement, so it is retained as non-core corroboration. Supporting Evidence: PMID:9435289 inhibition of the phosphodiesterase results in an increase in the activity of PKA, which acts at a check point for terminal differentiation
GO:0030435 sporulation resulting in formation of a cellular spore	IMP PMID:12796307 Genetic interactions of the E3 ubiquitin ligase component Fb...	KEEP AS NON CORE	Summary: regA mutations were recovered as suppressors that restore sporulation in an fbxA background, consistent with RegA restraining sporulation by lowering cAMP/PKA. A developmental role downstream of the core function. Reason: RegA influences sporulation through its control of intracellular cAMP/PKA; the suppressor genetics support a role in sporulation that is downstream of the core cAMP-degrading activity. Supporting Evidence: PMID:12796307 both suppressors also rescued substantially the culmination deficiency of the fbxA strain
GO:0030587 sorocarp development	IMP PMID:12796307 Genetic interactions of the E3 ubiquitin ligase component Fb...	KEEP AS NON CORE	Summary: regA and dhkA suppressor mutations rescue the culmination/fruiting deficiency of fbxA cells, linking RegA to sorocarp development downstream of cAMP/PKA control. Reason: The genetic suppression of a fruiting-body defect places RegA in sorocarp development, but as a downstream regulatory consequence rather than a core molecular activity. Supporting Evidence: PMID:12796307 both suppressors also rescued substantially the culmination deficiency of the fbxA strain
GO:0004115 3',5'-cyclic-AMP phosphodiesterase activity	IDA PMID:9435289 A cAMP-phosphodiesterase controls PKA-dependent differentiat...	ACCEPT	Summary: RegA is directly characterized as a cAMP-specific phosphodiesterase stimulated by PKA-R binding. Core catalytic function. Reason: Direct experimental evidence establishes RegA as a cAMP-specific phosphodiesterase, its core molecular function. Supporting Evidence: PMID:9435289 stimulated by binding to the regulatory subunit of cAMP-dependent protein kinase, PKA-R
GO:0006970 response to osmotic stress	TAS PMID:14718564 Adenylyl cyclase G is activated by an intramolecular osmosen...	KEEP AS NON CORE	Summary: Osmotic up-shift converts the histidine kinase DokA into a phosphatase, which inactivates RegA and leads to cortex fortification. RegA is thus a node in the osmotic-stress cAMP response, downstream of histidine kinase signaling. Reason: RegA participates in the osmotic-stress response as a target of DokA-mediated regulation of its phosphorelay input, a specialized regulatory context rather than a core molecular function. Supporting Evidence: PMID:14718564 This results in inactivation of the cAMP phosphodiesterase RegA and ultimately in fortification of the cell cortex
GO:0004115 3',5'-cyclic-AMP phosphodiesterase activity	IMP PMID:15752425 cAMP controls cytosolic Ca2+ levels in Dictyostelium discoid...	ACCEPT	Summary: A regA-null mutant devoid of the main cAMP phosphodiesterase displays altered cAMP metabolism, confirming RegA as the principal internal cAMP phosphodiesterase. Supports the core activity. Reason: The mutant phenotype confirms RegA is the main cAMP phosphodiesterase controlling intracellular cAMP, consistent with its core catalytic function. Supporting Evidence: PMID:15752425 a mutant that is devoid of the main cAMP-phosphodiesterase (PDE) RegA and displays an altered cAMP metabolism
GO:0051281 positive regulation of release of sequestered calcium ion into cytosol	IMP PMID:15752425 cAMP controls cytosolic Ca2+ levels in Dictyostelium discoid...	KEEP AS NON CORE	Summary: In regA-null cells the elevated intracellular cAMP is associated with augmented release of Ca2+ from internal stores, linking RegA-controlled cAMP to calcium store dynamics. A downstream physiological consequence. Reason: The calcium-release phenotype is an indirect consequence of altered intracellular cAMP in the regA mutant, not a core molecular function of RegA. Supporting Evidence: PMID:15752425 an augmented release of Ca2+ from stores in the mutant
GO:0051279 regulation of release of sequestered calcium ion into cytosol	IMP PMID:15752425 cAMP controls cytosolic Ca2+ levels in Dictyostelium discoid...	KEEP AS NON CORE	Summary: The general regulation-of-calcium-release term parallels the positive regulation annotation from the same study; a downstream consequence of RegA's control of intracellular cAMP. Reason: As with the positive-regulation term, this reflects an indirect effect of altered cAMP levels in the regA mutant on calcium store release rather than a core function. Supporting Evidence: PMID:15752425 an augmented release of Ca2+ from stores in the mutant
GO:0120320 lateral pseudopodium retraction	IMP PMID:15752425 cAMP controls cytosolic Ca2+ levels in Dictyostelium discoid...	KEEP AS NON CORE	Summary: This study also examined chemotactic/pseudopod behavior of regA-null cells, consistent with the well-established role of RegA in suppressing lateral pseudopods. A motility role downstream of cAMP control. Reason: The pseudopod/chemotaxis phenotype is downstream of RegA's regulation of intracellular cAMP; retained as non-core and corroborated by the dedicated Wessels et al. study. Supporting Evidence: PMID:15752425 a mutant that is devoid of the main cAMP-phosphodiesterase (PDE) RegA and displays an altered cAMP metabolism

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id: Q23917
gene_symbol: regA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: RegA (also known as PDE2/DdPDE2) is an intracellular, cytosolic
  cAMP-specific 3',5'-cyclic-nucleotide phosphodiesterase of Dictyostelium
  discoideum. It is a two-domain protein comprising an N-terminal response
  regulator (receiver) domain with a conserved phosphoacceptor aspartate
  (Asp212) and a C-terminal class I cyclic-nucleotide phosphodiesterase catalytic
  domain. RegA is the effector component of a His-Asp phosphorelay two-component
  system in which histidine kinases such as DhkA and DhkC feed phosphate through
  the histidine phosphotransfer protein RdeA to the RegA receiver domain, and
  phosphorylation of Asp212 activates the phosphodiesterase, increasing
  degradation of intracellular cAMP. By lowering intracellular cAMP, RegA
  restrains cAMP-dependent protein kinase (PKA) activity, thereby acting as a
  timing checkpoint for terminal differentiation. Loss of RegA elevates PKA
  activity and causes rapid, precocious development and sporulation, while RegA
  activity is required for orderly chemotaxis (suppression of lateral pseudopods)
  and for normal fruiting body (sorocarp) morphogenesis. RegA is developmentally
  regulated, expressed at low levels in vegetative cells and at high levels in
  prespore and prestalk cells, and its activity is further modulated by MAP
  kinase (Erk2) signaling and by osmotic-stress-driven changes in histidine
  kinase/phosphatase activity.
existing_annotations:
- term:
    id: GO:0004115
    label: 3',5'-cyclic-AMP phosphodiesterase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of cAMP phosphodiesterase activity is correct
      and represents the core catalytic function of RegA, which harbors a class I
      PDE domain that hydrolyzes intracellular cAMP.
    action: ACCEPT
    reason: RegA/DdPDE2 is directly demonstrated to be a cAMP-specific
      phosphodiesterase that degrades intracellular cAMP. The IBA annotation
      matches the experimentally established core function.
    supported_by:
    - reference_id: PMID:17040207
      supporting_text: DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the
        cytosol of the cell where it degrades intracellular cAMP
- term:
    id: GO:0047555
    label: 3',5'-cyclic-GMP phosphodiesterase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: RegA is a cAMP-specific phosphodiesterase with a cAMP/cGMP
      selectivity of ~200. cGMP phosphodiesterase activity is an over-propagation
      from the broader phosphodiesterase family and does not reflect the enzyme's
      demonstrated specificity.
    action: REMOVE
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: PANTHER:PTN001682918
        source_label: "PANTHER node for class-I cyclic-nucleotide phosphodiesterases"
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: "cGMP-phosphodiesterase activity is a family-level property; RegA is experimentally cAMP-specific with a cAMP/cGMP selectivity near 200, so the cGMP activity does not transfer"
      - source_id: UniProtKB:O00408
        source_label: "human PDE2A, a cGMP-stimulated phosphodiesterase"
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: "Source enzyme hydrolyzes cGMP; RegA has diverged to cAMP specificity"
    reason: The IBA inference of cGMP phosphodiesterase activity conflicts with
      the experimentally established cAMP specificity of RegA (UniProt reports a
      cAMP/cGMP selectivity of 200, and characterization describes RegA/DdPDE2 as
      a cAMP-specific PDE). This electronic over-propagation from the general
      PDE family can be argued against on biochemical grounds.
    supported_by:
    - reference_id: PMID:17040207
      supporting_text: DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the
        cytosol of the cell where it degrades intracellular cAMP
- term:
    id: GO:0141162
    label: negative regulation of cAMP/PKA signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: By degrading intracellular cAMP, RegA lowers PKA activity, acting as
      a negative regulator of cAMP/PKA signaling. This is a well-supported core
      biological role.
    action: ACCEPT
    reason: Genetic and biochemical evidence show that inhibition of the RegA
      phosphodiesterase increases PKA activity at a differentiation checkpoint,
      establishing RegA as a negative regulator of cAMP/PKA signal transduction.
    supported_by:
    - reference_id: PMID:9435289
      supporting_text: inhibition of the phosphodiesterase results in an increase
        in the activity of PKA, which acts at a check point for terminal
        differentiation
- term:
    id: GO:0030587
    label: sorocarp development
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: RegA is required for normal fruiting body (sorocarp) development;
      loss of RegA causes rapid, precocious development. This is a genuine
      developmental role but downstream of the core cAMP-degrading function.
    action: KEEP_AS_NON_CORE
    reason: The developmental role in sorocarp formation is well established
      across multiple experimental studies, but it is a consequence of RegA's
      control over intracellular cAMP/PKA rather than a distinct core molecular
      activity.
    supported_by:
    - reference_id: PMID:9435289
      supporting_text: inhibition of the phosphodiesterase results in an increase
        in the activity of PKA, which acts at a check point for terminal
        differentiation
- term:
    id: GO:0000160
    label: phosphorelay signal transduction system
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: RegA is the response-regulator component of the RdeA-RegA His-Asp
      phosphorelay, a core aspect of its regulation. Correct annotation.
    action: ACCEPT
    reason: RegA contains a receiver domain that accepts phosphate from RdeA in a
      His-Asp phosphorelay, directly supported by biochemical and genetic
      evidence.
    supported_by:
    - reference_id: PMID:10488068
      supporting_text: The response regulator, RegA, is composed of an N-terminal
        receiver domain linked to a C-terminal cAMP-phosphodiesterase domain
- term:
    id: GO:0004114
    label: 3',5'-cyclic-nucleotide phosphodiesterase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: This is the general parent term for the phosphodiesterase family.
      It is correct but less informative than the specific cAMP phosphodiesterase
      activity that represents RegA's actual demonstrated specificity.
    action: MODIFY
    reason: The general cyclic-nucleotide PDE activity is technically correct (EC
      3.1.4.53), but RegA is cAMP-specific, so the specific child term GO:0004115
      better captures the core function.
    proposed_replacement_terms:
    - id: GO:0004115
      label: 3',5'-cyclic-AMP phosphodiesterase activity
    supported_by:
    - reference_id: PMID:17040207
      supporting_text: DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the
        cytosol of the cell where it degrades intracellular cAMP
- term:
    id: GO:0004115
    label: 3',5'-cyclic-AMP phosphodiesterase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Correct core catalytic activity, consistent with direct experimental
      characterization of RegA as a cAMP-specific phosphodiesterase.
    action: ACCEPT
    reason: This automated annotation agrees with the experimentally demonstrated
      cAMP phosphodiesterase activity of RegA.
    supported_by:
    - reference_id: PMID:17040207
      supporting_text: DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the
        cytosol of the cell where it degrades intracellular cAMP
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: RegA is a cytosolic (internal) phosphodiesterase, consistent with
      its role in degrading intracellular cAMP. Correct localization.
    action: ACCEPT
    reason: Subcellular location evidence and functional characterization place
      RegA in the cytosol where it degrades intracellular cAMP.
    supported_by:
    - reference_id: PMID:17040207
      supporting_text: DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the
        cytosol of the cell where it degrades intracellular cAMP
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: This is a very broad parent term. RegA does participate in signal
      transduction, but more specific terms (phosphorelay signal transduction
      system, negative regulation of cAMP/PKA signaling) are already present and
      far more informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic signal transduction term adds little given the presence of
      specific and better annotations describing RegA's phosphorelay and
      cAMP/PKA regulatory roles.
    supported_by:
    - reference_id: PMID:10488068
      supporting_text: The response regulator, RegA, is composed of an N-terminal
        receiver domain linked to a C-terminal cAMP-phosphodiesterase domain
- term:
    id: GO:0008081
    label: phosphoric diester hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: General grandparent hydrolase term. Correct but far less informative
      than the specific cAMP phosphodiesterase activity.
    action: KEEP_AS_NON_CORE
    reason: RegA is a phosphoric diester hydrolase, but the specific cAMP
      phosphodiesterase activity (GO:0004115) captures the core function; this
      broad term is retained only as a non-core ancestor.
    supported_by:
    - reference_id: PMID:17040207
      supporting_text: DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the
        cytosol of the cell where it degrades intracellular cAMP
- term:
    id: GO:0120320
    label: lateral pseudopodium retraction
  evidence_type: IMP
  original_reference_id: PMID:10930471
  qualifier: acts_upstream_of_or_within
  review:
    summary: RegA is essential for suppressing lateral pseudopod formation during
      chemotaxis. This is a genuine experimentally-supported role but is
      downstream of the core cAMP-degrading activity.
    action: KEEP_AS_NON_CORE
    reason: Direct mutant phenotype analysis shows RegA is required to suppress
      lateral pseudopods during chemotaxis, a cell-motility role secondary to its
      control of internal cAMP levels.
    supported_by:
    - reference_id: PMID:10930471
      supporting_text: RegA is essential for specifically suppressing lateral
        pseudopod formation during the response to an increasing temporal
        gradient of cAMP
- term:
    id: GO:0000160
    label: phosphorelay signal transduction system
  evidence_type: IMP
  original_reference_id: PMID:10488068
  qualifier: involved_in
  review:
    summary: Experimental evidence for RegA as the response regulator in the
      RdeA-RegA His-Asp phosphorelay. Core regulatory mechanism.
    action: ACCEPT
    reason: Biochemical phospho-transfer between RdeA (His65) and RegA (Asp212)
      demonstrates RegA participation in a eukaryotic His-Asp phosphorelay.
    supported_by:
    - reference_id: PMID:10488068
      supporting_text: Phosphorylation of RegA by a heterologous phospho-donor
        protein activates RegA phosphodiesterase activity at least 20-fold
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31730032
  qualifier: enables
  review:
    summary: This IPI annotation records the physical association between RegA and
      the MAP kinase Erk2. The bare protein binding term is uninformative; the
      more specific protein kinase binding term better captures the interaction.
    action: MODIFY
    reason: Co-immunoprecipitation shows RegA associates with the atypical MAPK
      Erk2, which downregulates RegA. Replacing bare protein binding with protein
      kinase binding conveys the nature of the interactor.
    proposed_replacement_terms:
    - id: GO:0019901
      label: protein kinase binding
    supported_by:
    - reference_id: PMID:31730032
      supporting_text: Co-immunoprecipitation analysis indicated that Erk2
        associates with both RegA
- term:
    id: GO:0010225
    label: response to UV-C
  evidence_type: IDA
  original_reference_id: PMID:25858552
  qualifier: acts_upstream_of_or_within
  review:
    summary: In this study regA was one of several developmentally regulated genes
      whose transcript levels were monitored by RT-PCR following UV-C exposure.
      This reflects a transcriptional/developmental response rather than a
      dedicated molecular function of RegA in UV-C response.
    action: KEEP_AS_NON_CORE
    reason: The evidence is an expression change of regA among many developmental
      genes after UV-C irradiation, not a direct functional role of RegA in the
      UV-C response; retained as non-core.
    supported_by:
    - reference_id: PMID:25858552
      supporting_text: regA, ctnA, ctnB, gp24, hspD and dsn were analysed using
        semiquantitative RT-PCR
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: PMID:17040207
  qualifier: located_in
  review:
    summary: RegA/DdPDE2 is described as localized in the cytosol where it
      degrades intracellular cAMP. Correct core localization.
    action: ACCEPT
    reason: The cytosolic localization is explicitly stated and is consistent with
      RegA's function in degrading intracellular cAMP.
    supported_by:
    - reference_id: PMID:17040207
      supporting_text: DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the
        cytosol of the cell where it degrades intracellular cAMP
- term:
    id: GO:0061128
    label: positive regulation of chemotaxis to cAMP by DIF-2
  evidence_type: IMP
  original_reference_id: PMID:26919666
  qualifier: acts_upstream_of_or_within
  review:
    summary: DIF-2 enhances chemotaxis in shallow cAMP gradients via RegA as part
      of the DhkC-RdeA-RegA two-component system. A specialized signaling role
      downstream of the core cAMP-degrading function.
    action: KEEP_AS_NON_CORE
    reason: Mutant analysis places RegA in the DhkC-RdeA-RegA pathway through which
      DIF-2 enhances chemotaxis, a specific regulatory role that is not the core
      molecular function.
    supported_by:
    - reference_id: PMID:26919666
      supporting_text: DIF-2 enhances chemotaxis under the same conditions via a
        phosphodiesterase, response regulator A (RegA)
- term:
    id: GO:1904776
    label: regulation of protein localization to cell cortex
  evidence_type: IMP
  original_reference_id: PMID:10930471
  qualifier: acts_upstream_of_or_within
  review:
    summary: In regA-null cells myosin II fails to localize normally to the cortex
      during a temporal cAMP gradient, indicating RegA influences cortical
      protein localization. A downstream cytoskeletal consequence of altered cAMP
      levels.
    action: KEEP_AS_NON_CORE
    reason: The mutant phenotype links RegA to cortical myosin II localization, but
      this is a downstream effect of cAMP/PKA dysregulation rather than a core
      molecular function.
    supported_by:
    - reference_id: PMID:10930471
      supporting_text: myosin II does not localize in a normal manner to the
        cortex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9435289
  qualifier: enables
  review:
    summary: RegA phosphodiesterase is stimulated by binding to the regulatory
      subunit (PKA-R) of cAMP-dependent protein kinase. The bare protein binding
      term is uninformative; a specific protein kinase A regulatory subunit
      binding term is more appropriate.
    action: MODIFY
    reason: The interaction partner is the PKA regulatory subunit (PKA-R), so the
      specific term protein kinase A regulatory subunit binding conveys the
      identity of the interactor better than bare protein binding.
    proposed_replacement_terms:
    - id: GO:0034237
      label: protein kinase A regulatory subunit binding
    supported_by:
    - reference_id: PMID:9435289
      supporting_text: stimulated by binding to the regulatory subunit of
        cAMP-dependent protein kinase, PKA-R
- term:
    id: GO:0031288
    label: sorocarp morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:9435289
  qualifier: acts_upstream_of_or_within
  review:
    summary: RegA loss alters fruiting body morphogenesis (precocious/aberrant
      development). A genuine developmental phenotype downstream of cAMP/PKA
      control.
    action: KEEP_AS_NON_CORE
    reason: The morphogenesis phenotype reflects RegA's control of the PKA
      differentiation checkpoint rather than a distinct core molecular activity.
    supported_by:
    - reference_id: PMID:9435289
      supporting_text: inhibition of the phosphodiesterase results in an increase
        in the activity of PKA, which acts at a check point for terminal
        differentiation
- term:
    id: GO:0000156
    label: phosphorelay response regulator activity
  evidence_type: IMP
  original_reference_id: PMID:10488068
  qualifier: enables
  review:
    summary: RegA's N-terminal receiver domain functions as a phosphorelay
      response regulator, accepting phosphate at Asp212 which activates the
      phosphodiesterase. This is a core molecular function.
    action: ACCEPT
    reason: Phospho-transfer experiments demonstrate RegA acts as a response
      regulator whose receiver-domain phosphorylation activates its enzymatic
      output, a core function of the protein.
    supported_by:
    - reference_id: PMID:10488068
      supporting_text: Phosphorylation of RegA by a heterologous phospho-donor
        protein activates RegA phosphodiesterase activity at least 20-fold
- term:
    id: GO:0004114
    label: 3',5'-cyclic-nucleotide phosphodiesterase activity
  evidence_type: IDA
  original_reference_id: PMID:9582277
  qualifier: enables
  review:
    summary: Direct biochemical characterization measured a cAMP phosphodiesterase
      activity (Km ~5 uM for cAMP). Since RegA is cAMP-specific, the specific
      child term is more precise than this general parent.
    action: MODIFY
    reason: The IDA measured cAMP-specific phosphodiesterase activity; the
      specific term GO:0004115 better represents the demonstrated substrate
      specificity than the general cyclic-nucleotide PDE term.
    proposed_replacement_terms:
    - id: GO:0004115
      label: 3',5'-cyclic-AMP phosphodiesterase activity
    supported_by:
    - reference_id: PMID:9582277
      supporting_text: One domain is a cAMP phosphodiesterase (Km approximately 5
        microM); the other is homologous to response regulators
- term:
    id: GO:0048837
    label: sorocarp sorus development
  evidence_type: IMP
  original_reference_id: PMID:24511612
  qualifier: acts_upstream_of_or_within
  review:
    summary: Loss of RegA accelerates spore/sorus development and can rescue
      sporulation defects of certain G-protein mutants. A developmental role
      downstream of cAMP/PKA control.
    action: KEEP_AS_NON_CORE
    reason: The spore/sorus developmental phenotype results from elevated cAMP/PKA
      activity when RegA is absent, a downstream consequence rather than a core
      molecular function.
    supported_by:
    - reference_id: PMID:24511612
      supporting_text: Loss of RegA also results in accelerated spore development
- term:
    id: GO:0030587
    label: sorocarp development
  evidence_type: HMP
  original_reference_id: PMID:17659086
  qualifier: acts_upstream_of_or_within
  review:
    summary: This high-throughput spatio-temporal phenotype screen catalogs many
      mutant clones. The cached abstract does not contain a regA-specific
      statement that I can quote to verify the developmental phenotype for this
      gene, though RegA's sorocarp role is well supported elsewhere.
    action: KEEP_AS_NON_CORE
    reason: RegA's role in sorocarp development is well established from multiple
      dedicated studies; this high-throughput resource is consistent with that
      role but the abstract lacks a regA-specific quotable statement, so it is
      retained as non-core corroboration.
    supported_by:
    - reference_id: PMID:9435289
      supporting_text: inhibition of the phosphodiesterase results in an increase
        in the activity of PKA, which acts at a check point for terminal
        differentiation
- term:
    id: GO:0030435
    label: sporulation resulting in formation of a cellular spore
  evidence_type: IMP
  original_reference_id: PMID:12796307
  qualifier: acts_upstream_of_or_within
  review:
    summary: regA mutations were recovered as suppressors that restore sporulation
      in an fbxA background, consistent with RegA restraining sporulation by
      lowering cAMP/PKA. A developmental role downstream of the core function.
    action: KEEP_AS_NON_CORE
    reason: RegA influences sporulation through its control of intracellular
      cAMP/PKA; the suppressor genetics support a role in sporulation that is
      downstream of the core cAMP-degrading activity.
    supported_by:
    - reference_id: PMID:12796307
      supporting_text: both suppressors also rescued substantially the culmination
        deficiency of the fbxA strain
- term:
    id: GO:0030587
    label: sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:12796307
  qualifier: acts_upstream_of_or_within
  review:
    summary: regA and dhkA suppressor mutations rescue the culmination/fruiting
      deficiency of fbxA cells, linking RegA to sorocarp development downstream of
      cAMP/PKA control.
    action: KEEP_AS_NON_CORE
    reason: The genetic suppression of a fruiting-body defect places RegA in
      sorocarp development, but as a downstream regulatory consequence rather than
      a core molecular activity.
    supported_by:
    - reference_id: PMID:12796307
      supporting_text: both suppressors also rescued substantially the culmination
        deficiency of the fbxA strain
- term:
    id: GO:0004115
    label: 3',5'-cyclic-AMP phosphodiesterase activity
  evidence_type: IDA
  original_reference_id: PMID:9435289
  qualifier: enables
  review:
    summary: RegA is directly characterized as a cAMP-specific phosphodiesterase
      stimulated by PKA-R binding. Core catalytic function.
    action: ACCEPT
    reason: Direct experimental evidence establishes RegA as a cAMP-specific
      phosphodiesterase, its core molecular function.
    supported_by:
    - reference_id: PMID:9435289
      supporting_text: stimulated by binding to the regulatory subunit of
        cAMP-dependent protein kinase, PKA-R
- term:
    id: GO:0006970
    label: response to osmotic stress
  evidence_type: TAS
  original_reference_id: PMID:14718564
  qualifier: acts_upstream_of_or_within
  review:
    summary: Osmotic up-shift converts the histidine kinase DokA into a
      phosphatase, which inactivates RegA and leads to cortex fortification. RegA
      is thus a node in the osmotic-stress cAMP response, downstream of histidine
      kinase signaling.
    action: KEEP_AS_NON_CORE
    reason: RegA participates in the osmotic-stress response as a target of
      DokA-mediated regulation of its phosphorelay input, a specialized
      regulatory context rather than a core molecular function.
    supported_by:
    - reference_id: PMID:14718564
      supporting_text: This results in inactivation of the cAMP phosphodiesterase
        RegA and ultimately in fortification of the cell cortex
- term:
    id: GO:0004115
    label: 3',5'-cyclic-AMP phosphodiesterase activity
  evidence_type: IMP
  original_reference_id: PMID:15752425
  qualifier: enables
  review:
    summary: A regA-null mutant devoid of the main cAMP phosphodiesterase displays
      altered cAMP metabolism, confirming RegA as the principal internal cAMP
      phosphodiesterase. Supports the core activity.
    action: ACCEPT
    reason: The mutant phenotype confirms RegA is the main cAMP phosphodiesterase
      controlling intracellular cAMP, consistent with its core catalytic
      function.
    supported_by:
    - reference_id: PMID:15752425
      supporting_text: a mutant that is devoid of the main cAMP-phosphodiesterase
        (PDE) RegA and displays an altered cAMP metabolism
- term:
    id: GO:0051281
    label: positive regulation of release of sequestered calcium ion into cytosol
  evidence_type: IMP
  original_reference_id: PMID:15752425
  qualifier: acts_upstream_of_or_within
  review:
    summary: In regA-null cells the elevated intracellular cAMP is associated with
      augmented release of Ca2+ from internal stores, linking RegA-controlled cAMP
      to calcium store dynamics. A downstream physiological consequence.
    action: KEEP_AS_NON_CORE
    reason: The calcium-release phenotype is an indirect consequence of altered
      intracellular cAMP in the regA mutant, not a core molecular function of
      RegA.
    supported_by:
    - reference_id: PMID:15752425
      supporting_text: an augmented release of Ca2+ from stores in the mutant
- term:
    id: GO:0051279
    label: regulation of release of sequestered calcium ion into cytosol
  evidence_type: IMP
  original_reference_id: PMID:15752425
  qualifier: acts_upstream_of_or_within
  review:
    summary: The general regulation-of-calcium-release term parallels the positive
      regulation annotation from the same study; a downstream consequence of
      RegA's control of intracellular cAMP.
    action: KEEP_AS_NON_CORE
    reason: As with the positive-regulation term, this reflects an indirect effect
      of altered cAMP levels in the regA mutant on calcium store release rather
      than a core function.
    supported_by:
    - reference_id: PMID:15752425
      supporting_text: an augmented release of Ca2+ from stores in the mutant
- term:
    id: GO:0120320
    label: lateral pseudopodium retraction
  evidence_type: IMP
  original_reference_id: PMID:15752425
  qualifier: acts_upstream_of_or_within
  review:
    summary: This study also examined chemotactic/pseudopod behavior of regA-null
      cells, consistent with the well-established role of RegA in suppressing
      lateral pseudopods. A motility role downstream of cAMP control.
    action: KEEP_AS_NON_CORE
    reason: The pseudopod/chemotaxis phenotype is downstream of RegA's regulation
      of intracellular cAMP; retained as non-core and corroborated by the
      dedicated Wessels et al. study.
    supported_by:
    - reference_id: PMID:15752425
      supporting_text: a mutant that is devoid of the main cAMP-phosphodiesterase
        (PDE) RegA and displays an altered cAMP metabolism
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10488068
  title: The RdeA-RegA system, a eukaryotic phospho-relay controlling cAMP breakdown.
  findings:
  - statement: RegA is a two-domain response regulator with an N-terminal receiver
      domain and a C-terminal cAMP-phosphodiesterase domain.
    supporting_text: The response regulator, RegA, is composed of an N-terminal
      receiver domain linked to a C-terminal cAMP-phosphodiesterase domain
  - statement: Phosphorylation of the RegA receiver domain activates its
      phosphodiesterase activity at least 20-fold.
    supporting_text: Phosphorylation of RegA by a heterologous phospho-donor
      protein activates RegA phosphodiesterase activity at least 20-fold
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the RdeA-RegA His-Asp phosphorelay and that receiver
      domain phosphorylation activates the phosphodiesterase; core mechanism.
- id: PMID:10930471
  title: The internal phosphodiesterase RegA is essential for the suppression of lateral
    pseudopods during Dictyostelium chemotaxis.
  findings:
  - statement: RegA is required to suppress lateral pseudopod formation during
      chemotaxis in increasing temporal cAMP gradients.
    supporting_text: RegA is essential for specifically suppressing lateral
      pseudopod formation during the response to an increasing temporal gradient
      of cAMP
  - statement: In regA-null cells myosin II fails to localize normally to the
      cortex.
    supporting_text: myosin II does not localize in a normal manner to the cortex
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; directly supports the chemotaxis/pseudopod
      and cortical myosin localization annotations.
- id: PMID:12796307
  title: Genetic interactions of the E3 ubiquitin ligase component FbxA with cyclic
    AMP metabolism and a histidine kinase signaling pathway during Dictyostelium discoideum
    development.
  findings:
  - statement: regA (and dhkA) suppressor mutations rescue the culmination
      deficiency of fbxA cells.
    supporting_text: both suppressors also rescued substantially the culmination
      deficiency of the fbxA strain
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports RegA's developmental (sporulation/culmination) role via
      suppressor genetics linked to cAMP metabolism.
- id: PMID:14718564
  title: Adenylyl cyclase G is activated by an intramolecular osmosensor.
  findings:
  - statement: Osmotic up-shift converts DokA to a phosphatase that inactivates
      RegA, leading to cell cortex fortification.
    supporting_text: This results in inactivation of the cAMP phosphodiesterase
      RegA and ultimately in fortification of the cell cortex
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Primarily about ACG, but the introduction traces RegA's role in
      the osmotic-stress cAMP response, supporting the osmotic-stress annotation.
- id: PMID:15752425
  title: cAMP controls cytosolic Ca2+ levels in Dictyostelium discoideum.
  findings:
  - statement: The regA-null mutant lacks the main cAMP phosphodiesterase and shows
      altered cAMP metabolism.
    supporting_text: a mutant that is devoid of the main cAMP-phosphodiesterase
      (PDE) RegA and displays an altered cAMP metabolism
  - statement: Loss of RegA is associated with augmented release of Ca2+ from
      internal stores.
    supporting_text: an augmented release of Ca2+ from stores in the mutant
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Links RegA-controlled intracellular cAMP to cytosolic calcium
      regulation; calcium effects are downstream of the core PDE function.
- id: PMID:17040207
  title: Seven Dictyostelium discoideum phosphodiesterases degrade three pools of
    cAMP and cGMP.
  findings:
  - statement: RegA (DdPDE2) is a cAMP-specific PDE localized in the cytosol that
      degrades intracellular cAMP and is regulated by histidine kinase/phosphorelay.
    supporting_text: DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the
      cytosol of the cell where it degrades intracellular cAMP
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Authoritative statement of RegA's cAMP specificity, cytosolic
      localization, and phosphorelay regulation; grounds the core function and the
      cGMP-activity REMOVE.
- id: PMID:17659086
  title: High-throughput analysis of spatio-temporal dynamics in Dictyostelium.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: High-throughput phenotype screen; abstract does not contain a
      regA-specific statement, so this reference only corroborates the
      well-established sorocarp-development role indirectly.
- id: PMID:24511612
  title: Loss of cAMP-specific phosphodiesterase rescues spore development in G protein
    mutant in dictyostelium.
  findings:
  - statement: Loss of RegA accelerates spore development, consistent with elevated
      cAMP/PKA driving precocious differentiation.
    supporting_text: Loss of RegA also results in accelerated spore development
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports RegA's role in restraining spore development downstream
      of cAMP/PKA signaling.
- id: PMID:25858552
  title: Response of Dictyostelium discoideum to UV-C and involvement of poly (ADP-ribose)
    polymerase.
  findings:
  - statement: regA was among developmentally regulated genes monitored by RT-PCR
      after UV-C exposure.
    supporting_text: regA, ctnA, ctnB, gp24, hspD and dsn were analysed using
      semiquantitative RT-PCR
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: regA appears only as one of several developmental marker genes in
      an expression assay; provides weak, non-core support for a UV-C response
      role.
- id: PMID:26919666
  title: Differentiation-inducing factor 2 modulates chemotaxis via the histidine
    kinase DhkC-dependent pathway in Dictyostelium discoideum.
  findings:
  - statement: DIF-2 enhances chemotaxis in shallow cAMP gradients via RegA within
      the DhkC-RdeA-RegA two-component system.
    supporting_text: DIF-2 enhances chemotaxis under the same conditions via a
      phosphodiesterase, response regulator A (RegA)
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only but directly supports RegA's role in DIF-2-modulated
      chemotaxis via the DhkC-RdeA-RegA pathway.
- id: PMID:31730032
  title: Mitogen-activated protein kinase regulation of the phosphodiesterase RegA
    in early Dictyostelium development.
  findings:
  - statement: The MAP kinase Erk2 physically associates with RegA and
      downregulates its function.
    supporting_text: Co-immunoprecipitation analysis indicated that Erk2
      associates with both RegA
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Documents the RegA-Erk2 physical interaction underpinning the
      protein-binding (protein kinase binding) annotation.
- id: PMID:9435289
  title: A cAMP-phosphodiesterase controls PKA-dependent differentiation.
  findings:
  - statement: RegA phosphodiesterase is stimulated by binding to the PKA
      regulatory subunit (PKA-R).
    supporting_text: stimulated by binding to the regulatory subunit of
      cAMP-dependent protein kinase, PKA-R
  - statement: Inhibition of RegA increases PKA activity at a terminal
      differentiation checkpoint.
    supporting_text: inhibition of the phosphodiesterase results in an increase in
      the activity of PKA, which acts at a check point for terminal
      differentiation
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes RegA as the cAMP phosphodiesterase controlling
      PKA-dependent differentiation and its stimulation by PKA-R binding.
- id: PMID:9582277
  title: An intersection of the cAMP/PKA and two-component signal transduction systems
    in Dictyostelium.
  findings:
  - statement: RegA has a cAMP phosphodiesterase domain (Km ~5 uM) and a
      response-regulator domain; phosphotransfer depends on Asp212.
    supporting_text: One domain is a cAMP phosphodiesterase (Km approximately 5
      microM); the other is homologous to response regulators
  - statement: Phosphotransfer to RegA is dependent on Asp212, the predicted
      phosphoacceptor.
    supporting_text: with transfer dependent on Asp212, the predicted
      phosphoacceptor
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines the two-domain architecture and the Asp212 phosphoacceptor
      that activates the phosphodiesterase.
core_functions:
- description: RegA is a cytosolic cAMP-specific 3',5'-cyclic-nucleotide
    phosphodiesterase that degrades intracellular cAMP, thereby limiting PKA
    activity and acting as a negative regulator of cAMP/PKA signaling that times
    terminal differentiation.
  molecular_function:
    id: GO:0004115
    label: 3',5'-cyclic-AMP phosphodiesterase activity
  locations:
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0141162
    label: negative regulation of cAMP/PKA signal transduction
  supported_by:
  - reference_id: PMID:17040207
    supporting_text: DdPDE2 (RegA) encodes a cAMP-specific PDE localized in the
      cytosol of the cell where it degrades intracellular cAMP
  - reference_id: PMID:9435289
    supporting_text: inhibition of the phosphodiesterase results in an increase in
      the activity of PKA, which acts at a check point for terminal
      differentiation
- description: RegA's N-terminal receiver domain functions as a phosphorelay
    response regulator, accepting phosphate at Asp212 from the histidine
    phosphotransfer protein RdeA within a His-Asp two-component phosphorelay;
    phosphorylation of this domain activates the C-terminal phosphodiesterase.
  molecular_function:
    id: GO:0000156
    label: phosphorelay response regulator activity
  directly_involved_in:
  - id: GO:0000160
    label: phosphorelay signal transduction system
  supported_by:
  - reference_id: PMID:10488068
    supporting_text: The response regulator, RegA, is composed of an N-terminal
      receiver domain linked to a C-terminal cAMP-phosphodiesterase domain
  - reference_id: PMID:10488068
    supporting_text: Phosphorylation of RegA by a heterologous phospho-donor
      protein activates RegA phosphodiesterase activity at least 20-fold

Gene Description

Existing Annotations Review

Core Functions

RegA is a cytosolic cAMP-specific 3',5'-cyclic-nucleotide phosphodiesterase that degrades intracellular cAMP, thereby limiting PKA activity and acting as a negative regulator of cAMP/PKA signaling that times terminal differentiation.

RegA's N-terminal receiver domain functions as a phosphorelay response regulator, accepting phosphate at Asp212 from the histidine phosphotransfer protein RdeA within a His-Asp two-component phosphorelay; phosphorylation of this domain activates the C-terminal phosphodiesterase.

References

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