gcA

id: Q553Y7
gene_symbol: gcA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: gcA encodes GCA (DdGCA), a large membrane-bound guanylyl cyclase of
  Dictyostelium discoideum that catalyzes the synthesis of the second messenger
  cGMP from GTP. Unusually for a membrane guanylyl cyclase, GCA has the topology of
  a metazoan membrane adenylyl cyclase, with 12 transmembrane-spanning regions and
  two intramolecular cyclase domains (arranged in transposed order relative to
  adenylyl cyclases) that fold into a single catalytic center. It requires Mg2+,
  is inhibited by calcium, and is activated in vitro by GTPgammaS, apparently
  through a monomeric G protein. In vivo the enzyme is activated by extracellular
  cAMP acting through a G-protein-coupled cAMP receptor. GCA is one of two guanylyl
  cyclases in Dictyostelium (the other being the soluble sGC/sgcA); the two are
  partially redundant, and only the double null loses all detectable guanylyl
  cyclase activity. GCA is expressed mainly during growth and later multicellular
  development, whereas sGC predominates during aggregation. The cGMP produced by
  these cyclases acts as a diffusible second messenger that promotes cortical
  myosin II filament assembly in the rear and sides of chemotaxing cells,
  suppressing lateral pseudopodia and thereby refining directional movement during
  cAMP-mediated chemotaxis, cell streaming, and electrotaxis.
existing_annotations:
- term:
    id: GO:0004383
    label: guanylate cyclase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of guanylate cyclase activity is correct and is
      strongly corroborated by direct biochemical evidence for GCA. This is the
      core molecular function of the gene product.
    action: ACCEPT
    reason: GCA is a bona fide guanylyl cyclase demonstrated experimentally to
      synthesize cGMP from GTP. The IBA inference agrees with the direct assays.
    supported_by:
    - reference_id: PMID:11237875
      supporting_text: DdGCA expressed in Dictyostelium exhibits high guanylate
        cyclase activity and no detectable adenylate cyclase activity
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: GCA is an integral, multi-pass membrane protein that is exclusively
      membrane-bound. Plasma membrane localization is consistent with its
      activation downstream of the plasma-membrane cAMP receptor and with its
      localization to the leading-edge membrane.
    action: ACCEPT
    reason: The enzyme is membrane-bound with 12 transmembrane spans; activation by
      the plasma-membrane cAMP GPCR and leading-edge localization support a plasma
      membrane site of action.
    supported_by:
    - reference_id: PMID:11777934
      supporting_text: GCA is exclusively membrane-bound and is active mainly with
        Mg(2+)
    - reference_id: PMID:11237875
      supporting_text: We have cloned a Dictyostelium gene, DdGCA, encoding a
        protein with 12 transmembrane spanning regions and two cyclase domains
- term:
    id: GO:0006182
    label: cGMP biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: cGMP biosynthesis is the core biological process carried out by GCA
      and is well supported by direct enzymology.
    action: ACCEPT
    reason: GCA synthesizes cGMP from GTP; the double gca/sgc null loses all
      detectable guanylyl cyclase activity, confirming these enzymes are the source
      of cGMP.
    supported_by:
    - reference_id: PMID:11777934
      supporting_text: all detectable GC activity is lost in a cell line in which
        both genes have been inactivated
- term:
    id: GO:0007168
    label: receptor guanylyl cyclase signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: This IBA transfers the metazoan receptor-guanylyl-cyclase signaling
      role (as in natriuretic peptide receptors NPR-A/B) to GCA. GCA is not a
      receptor guanylyl cyclase. Metazoan receptor GCs have a single transmembrane
      span and one cyclase domain and are directly activated by extracellular
      peptide ligand binding, whereas GCA has 12 transmembrane spans and two
      cyclase domains (adenylyl-cyclase topology) and is activated indirectly,
      downstream of a G-protein-coupled cAMP receptor. The inference does not
      transfer to this divergent enzyme.
    action: REMOVE
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: PANTHER:PTN000229249
        source_label: "PANTHER node for the guanylyl cyclase family"
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: "The receptor-guanylyl-cyclase signaling role reflects metazoan single-pass receptor GCs in the family; GCA is a 12-transmembrane, G-protein-activated cyclase and does not use this receptor mechanism"
      - source_id: UniProtKB:P16066
        source_label: "human guanylyl cyclase GUCY2C (heat-stable enterotoxin/guanylin receptor)"
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: "GUCY2C is a genuine peptide-activated receptor guanylyl cyclase; this signaling-pathway role does not transfer to the topologically distinct GCA"
    reason: GCA does not act in a receptor guanylyl cyclase signaling pathway. It
      is a G-protein-activated 12-transmembrane cyclase, not a ligand-binding
      receptor cyclase; the phylogenetic inference from metazoan peptide-receptor
      guanylyl cyclases is a mis-propagation to a structurally and mechanistically
      distinct enzyme.
    supported_by:
    - reference_id: PMID:11237875
      supporting_text: membrane-bound guanylate cyclase activity is induced after
        cAMP stimulation; a G-protein-coupled cAMP receptor and G-proteins are
        essential for this activation
    - reference_id: PMID:11522784
      supporting_text: DdGCA is a Dictyostelium guanylyl cyclase with a topology
        typical for mammalian adenylyl cyclases containing 12 transmembrane-spanning
        regions and two cyclase domain
- term:
    id: GO:0001653
    label: peptide receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: This IBA transfers peptide receptor activity from metazoan receptor
      guanylyl cyclases (natriuretic peptide receptors) to GCA. GCA has no ligand-
      binding ectodomain of a peptide receptor; it is a 12-transmembrane,
      adenylyl-cyclase-topology enzyme activated indirectly via a G-protein, not by
      direct peptide binding.
    action: REMOVE
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: PANTHER:PTN000229249
        source_label: "PANTHER node for the guanylyl cyclase family"
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: "Peptide receptor activity reflects metazoan single-pass receptor guanylyl cyclases (natriuretic/guanylin receptors) in the family; GCA has no peptide-receptor ectodomain"
      - source_id: UniProtKB:P20594
        source_label: "human natriuretic peptide receptor NPR2 (guanylyl cyclase)"
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: "NPR2 is a bona fide peptide-binding receptor guanylyl cyclase; this ligand-receptor activity does not transfer to the G-protein-activated 12-transmembrane GCA"
    reason: GCA is not a peptide receptor. The inference derives from mammalian
      single-pass receptor guanylyl cyclases that bind natriuretic peptides; this
      function does not transfer to a G-protein-activated 12-transmembrane cyclase.
    supported_by:
    - reference_id: PMID:11522784
      supporting_text: DdGCA is a Dictyostelium guanylyl cyclase with a topology
        typical for mammalian adenylyl cyclases containing 12 transmembrane-spanning
        regions and two cyclase domain
    - reference_id: PMID:11522784
      supporting_text: GTPgammaS activation is not mediated by a heterotrimeric
        G-protein but possibly by a monomeric G-protein
- term:
    id: GO:0004383
    label: guanylate cyclase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated EC-to-GO mapping (EC 4.6.1.2) for guanylate cyclase
      activity. Correct and consistent with the direct biochemical evidence.
    action: ACCEPT
    reason: GCA catalyzes GTP to 3',5'-cyclic GMP (EC 4.6.1.2), matching this
      annotation.
    supported_by:
    - reference_id: PMID:11237875
      supporting_text: DdGCA expressed in Dictyostelium exhibits high guanylate
        cyclase activity and no detectable adenylate cyclase activity
- term:
    id: GO:0009190
    label: cyclic nucleotide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO inference from the adenylyl/guanylyl cyclase domain. It is
      correct but general; the more specific cGMP biosynthetic process is captured
      by another annotation.
    action: ACCEPT
    reason: GCA produces the cyclic nucleotide cGMP, so cyclic nucleotide
      biosynthetic process is a correct (if general) parent term.
    supported_by:
    - reference_id: PMID:11237875
      supporting_text: DdGCA expressed in Dictyostelium exhibits high guanylate
        cyclase activity and no detectable adenylate cyclase activity
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt subcellular-location mapping to membrane. Correct; GCA is a
      multi-pass integral membrane protein and is exclusively membrane-bound.
    action: ACCEPT
    reason: GCA is an integral membrane protein (12 transmembrane spans) that is
      exclusively membrane-bound, so the membrane annotation is accurate.
    supported_by:
    - reference_id: PMID:11777934
      supporting_text: GCA is exclusively membrane-bound and is active mainly with
        Mg(2+)
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO inference. GCA produces the intracellular second messenger
      cGMP downstream of receptor activation, so participation in intracellular
      signal transduction is correct, though general.
    action: ACCEPT
    reason: cGMP synthesis by GCA is an intracellular signal transduction event
      downstream of the cAMP receptor; the term is correct at a general level.
    supported_by:
    - reference_id: PMID:11237875
      supporting_text: membrane-bound guanylate cyclase activity is induced after
        cAMP stimulation; a G-protein-coupled cAMP receptor and G-proteins are
        essential for this activation
- term:
    id: GO:0007168
    label: receptor guanylyl cyclase signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: acts_upstream_of_or_within
  review:
    summary: This term implies GCA is a ligand-binding receptor guanylyl cyclase,
      which it is not. GCA participates in cGMP signaling downstream of the cAMP
      GPCR, but the specific receptor-guanylyl-cyclase term is a misnomer for this
      12-transmembrane, G-protein-activated enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: GCA functions in cGMP-mediated signaling downstream of a G-protein-
      coupled cAMP receptor, not as a receptor guanylyl cyclase. The term over-
      specifies a receptor-cyclase mechanism that does not apply; the genuine
      signaling role is better captured by cGMP biosynthetic process and the
      chemotaxis/myosin annotations.
    supported_by:
    - reference_id: PMID:11522784
      supporting_text: DdGCA is a Dictyostelium guanylyl cyclase with a topology
        typical for mammalian adenylyl cyclases containing 12 transmembrane-spanning
        regions and two cyclase domain
- term:
    id: GO:0019722
    label: calcium-mediated signaling
  evidence_type: IGI
  original_reference_id: PMID:40295210
  qualifier: acts_upstream_of_or_within
  negated: true
  review:
    summary: NOT annotation. In gca/sgc double-null cells, the intracellular
      calcium response to external calcium is only slightly delayed rather than
      abolished, indicating that GCA (and cGMP synthesis) is not required for
      calcium-mediated signaling. The negation is supported.
    action: ACCEPT
    reason: The genetic evidence shows the calcium response persists (merely
      delayed) without GCA/sGC, so GCA does not act within calcium-mediated
      signaling. The negated annotation correctly records this non-requirement.
    supported_by:
    - reference_id: PMID:40295210
      supporting_text: gca/sgc-null cells showed a slightly delayed response
    - reference_id: PMID:40295210
      supporting_text: Although calcium signaling is not strictly necessary for
        chemotaxis
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: located_in
  review:
    summary: Membrane localization of GCA. Correct; the enzyme is an integral
      multi-pass membrane protein.
    action: ACCEPT
    reason: GCA is exclusively membrane-bound, consistent with a membrane
      localization annotation.
    supported_by:
    - reference_id: PMID:11777934
      supporting_text: GCA is exclusively membrane-bound and is active mainly with
        Mg(2+)
- term:
    id: GO:0004383
    label: guanylate cyclase activity
  evidence_type: IDA
  original_reference_id: PMID:11522784
  qualifier: enables
  review:
    summary: Direct assay of GCA guanylyl cyclase activity, including GTPgammaS
      stimulation and mutagenesis of catalytic residues. This is core, well-
      supported experimental evidence.
    action: ACCEPT
    reason: Roelofs et al. directly measured GCA guanylyl cyclase activity and its
      regulation, firmly establishing the catalytic function.
    supported_by:
    - reference_id: PMID:11522784
      supporting_text: guanylyl cyclase activity is strongly stimulated by
        guanosine 5'-3-O-(thio) triphosphate (GTPgammaS)
- term:
    id: GO:0031252
    label: cell leading edge
  evidence_type: IDA
  original_reference_id: PMID:19346484
  qualifier: located_in
  review:
    summary: Components of the guanylyl-cyclase-dependent signaling pathway
      localize to the leading edge of migrating cells in an actin-dependent manner.
      As a membrane cyclase in this pathway, GCA at the leading edge is consistent
      with the data, though leading-edge enrichment is best characterized for the
      soluble sGC.
    action: KEEP_AS_NON_CORE
    reason: Leading-edge localization is a context-dependent property tied to
      directed migration rather than the core catalytic function; it is supported
      for the GCase-dependent signaling components in migrating cells.
    supported_by:
    - reference_id: PMID:19346484
      supporting_text: Molecular components of the GCase- and PI3K-dependent
        signaling pathways localized at the leading edge of migrating cells during
        electrotaxis in an actin-dependent manner
- term:
    id: GO:0051602
    label: response to electrical stimulus
  evidence_type: IGI
  original_reference_id: PMID:19346484
  qualifier: acts_upstream_of_or_within
  review:
    summary: Genetic modulation of the guanylyl cyclases (with cGMP-binding GbpC and
      PI3K) reverses the preferred direction of electrotaxis, implicating the GCase
      pathway in the response to a direct-current electric field. This is a valid
      accessory role, not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: GCA contributes, via cGMP, to directional bias during electrotaxis, an
      accessory physiological process downstream of its catalytic activity.
    supported_by:
    - reference_id: PMID:19346484
      supporting_text: the preferential direction of migration during electrotaxis
        in Dictyostelium cells can be reversed by genetically modulating both
        guanylyl cyclases (GCases)
- term:
    id: GO:0004383
    label: guanylate cyclase activity
  evidence_type: IDA
  original_reference_id: PMID:11237875
  qualifier: enables
  review:
    summary: Direct demonstration that expressed DdGCA has high guanylyl cyclase
      activity and no detectable adenylyl cyclase activity. Core experimental
      evidence for the molecular function.
    action: ACCEPT
    reason: This is the original biochemical characterization establishing GCA as a
      guanylyl cyclase.
    supported_by:
    - reference_id: PMID:11237875
      supporting_text: DdGCA expressed in Dictyostelium exhibits high guanylate
        cyclase activity and no detectable adenylate cyclase activity
- term:
    id: GO:0004383
    label: guanylate cyclase activity
  evidence_type: IMP
  original_reference_id: PMID:11777934
  qualifier: enables
  review:
    summary: Gene-inactivation evidence from characterizing GCA in sgc-null cells
      and the loss of all guanylyl cyclase activity in the gca/sgc double null
      confirms GCA guanylyl cyclase activity in vivo. Core function.
    action: ACCEPT
    reason: The double-null result (all detectable GC activity lost) and single-
      null characterization firmly attribute guanylyl cyclase activity to GCA.
    supported_by:
    - reference_id: PMID:11777934
      supporting_text: all detectable GC activity is lost in a cell line in which
        both genes have been inactivated
- term:
    id: GO:0050920
    label: regulation of chemotaxis
  evidence_type: IGI
  original_reference_id: PMID:22081140
  qualifier: acts_upstream_of_or_within
  review:
    summary: The guanylyl cyclase pathway (sGC/GCA-derived cGMP) is one of several
      accessory signaling enzymes that are not required for the basal Ras module
      but improve orientation and sensitivity of chemotaxis in shallow gradients.
      This is a modulatory, non-core role.
    action: KEEP_AS_NON_CORE
    reason: cGMP signaling amplifies and refines chemotaxis rather than being
      essential; GCA's contribution here is downstream of its catalytic function
      and is redundant with sGC.
    supported_by:
    - reference_id: PMID:22081140
      supporting_text: The signalling enzymes PI3K, TorC2, PLA2 and sGC are not
        required for Ras activation and chemotaxis to folate or to steep gradients
        of cAMP, but they provide a memory of direction and improved orientation of
        the cell
- term:
    id: GO:0006935
    label: chemotaxis
  evidence_type: IGI
  original_reference_id: PMID:18073238
  qualifier: acts_upstream_of_or_within
  review:
    summary: cGMP signaling controls the quiescent rear of the cell during cAMP-
      wave chemotaxis and cell streaming. GCA-derived cGMP contributes to this
      process, an accessory role downstream of catalysis.
    action: KEEP_AS_NON_CORE
    reason: Chemotaxis is a downstream physiological process supported by cGMP; it
      is a valid but non-core role for GCA, which is redundant with sGC.
    supported_by:
    - reference_id: PMID:18073238
      supporting_text: Wild-type cells efficiently retract pseudopodia in the rear
        of the cell during the rising flank of the cAMP wave and have a quiescent
        cell posterior
- term:
    id: GO:0120320
    label: lateral pseudopodium retraction
  evidence_type: IGI
  original_reference_id: PMID:18073238
  qualifier: acts_upstream_of_or_within
  review:
    summary: cGMP suppresses pseudopod formation in the rear and sides of the cell
      by promoting cortical myosin, so lateral pseudopodia are retracted. GCA-
      derived cGMP contributes to this rear/side response.
    action: KEEP_AS_NON_CORE
    reason: Suppression/retraction of lateral pseudopodia is a downstream effect of
      cGMP signaling; a valid non-core role for GCA.
    supported_by:
    - reference_id: PMID:18073238
      supporting_text: a quiescent rear of the cell increases the efficiency of
        directional movement and is essential to maintain stable cell-cell contacts
    - reference_id: PMID:16790492
      supporting_text: cGMP suppresses pseudopod formation in the back of the cell,
        whereas the sGC protein refines pseudopod formation at the leading edge
- term:
    id: GO:0031033
    label: myosin filament organization
  evidence_type: IGI
  original_reference_id: PMID:16790492
  qualifier: acts_upstream_of_or_within
  review:
    summary: cGMP mediates the formation of cortical myosin II filaments in
      response to a cAMP stimulus, organizing myosin in the back of the cell. GCA-
      derived cGMP contributes to this, downstream of its catalytic activity.
    action: KEEP_AS_NON_CORE
    reason: Regulation of myosin filament organization is a key downstream effect
      of the cGMP produced by GCA, but is not GCA's core molecular function.
    supported_by:
    - reference_id: PMID:16790492
      supporting_text: One of the second messengers used during Dictyostelium
        chemotaxis is cGMP, which mediates the formation of myosin filaments in
        response to a cAMP stimulus
    - reference_id: PMID:16790492
      supporting_text: In a cAMP gradient, myosin is mostly found in the back of
        the cell, where it increases the cortical tension and suppress pseudopod
        extension
- term:
    id: GO:0031037
    label: myosin II filament disassembly
  evidence_type: TAS
  original_reference_id: PMID:14710184
  qualifier: acts_upstream_of_or_within
  review:
    summary: The cGMP-signaling cascade regulates cortical myosin II filament
      dynamics in the posterior of the cell. The cited review emphasizes cGMP-
      driven myosin filament formation in the rear; the specific disassembly
      framing is one side of the assembly/disassembly regulation attributed to this
      pathway.
    action: KEEP_AS_NON_CORE
    reason: Regulation of cortical myosin II filament dynamics is a downstream role
      of GCA-derived cGMP. The annotation captures a real regulatory role, though
      the primary reported effect of the cGMP cascade is promotion of myosin
      filament formation in the posterior.
    supported_by:
    - reference_id: PMID:14710184
      supporting_text: a cyclic-GMP-signalling cascade has been identified that
        regulates myosin filament formation in the posterior of the cell, thereby
        inhibiting the formation of lateral pseudopodia that could misdirect the
        cell
- term:
    id: GO:0120320
    label: lateral pseudopodium retraction
  evidence_type: TAS
  original_reference_id: PMID:14710184
  qualifier: acts_upstream_of_or_within
  review:
    summary: The cGMP cascade inhibits formation of lateral pseudopodia (favoring
      their retraction) by promoting posterior myosin. GCA-derived cGMP contributes
      to this rear/side function.
    action: KEEP_AS_NON_CORE
    reason: Suppression/retraction of lateral pseudopodia is a downstream effect of
      cGMP signaling; a valid non-core role for GCA.
    supported_by:
    - reference_id: PMID:14710184
      supporting_text: a cyclic-GMP-signalling cascade has been identified that
        regulates myosin filament formation in the posterior of the cell, thereby
        inhibiting the formation of lateral pseudopodia that could misdirect the
        cell
- term:
    id: GO:0006935
    label: chemotaxis
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: acts_upstream_of_or_within
  review:
    summary: cGMP signaling contributes to the cortical-myosin module that
      underlies cAMP chemotaxis in Dictyostelium. GCA-derived cGMP participates in
      chemotaxis as an accessory role.
    action: KEEP_AS_NON_CORE
    reason: Chemotaxis is a downstream physiological process to which GCA
      contributes via cGMP; it is valid but non-core and redundant with sGC.
    supported_by:
    - reference_id: PMID:16790492
      supporting_text: One of the second messengers used during Dictyostelium
        chemotaxis is cGMP, which mediates the formation of myosin filaments in
        response to a cAMP stimulus
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:11237875
  title: Guanylate cyclase in Dictyostelium discoideum with the topology of mammalian
    adenylate cyclase.
  findings:
  - statement: DdGCA encodes a protein with 12 transmembrane spanning regions and
      two cyclase domains, unlike single-pass metazoan receptor guanylyl cyclases.
    supporting_text: We have cloned a Dictyostelium gene, DdGCA, encoding a protein
      with 12 transmembrane spanning regions and two cyclase domains
  - statement: Expressed DdGCA has high guanylate cyclase activity and no detectable
      adenylate cyclase activity.
    supporting_text: DdGCA expressed in Dictyostelium exhibits high guanylate
      cyclase activity and no detectable adenylate cyclase activity
  - statement: DdGCA deletion is not essential for chemotaxis, and a second guanylyl
      cyclase remains active in the knockout.
    supporting_text: The knock-out strain still exhibits substantial guanylate
      cyclase activity, demonstrating that Dictyostelium contains at least one other
      guanylate cyclase
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Original cloning and characterization of DdGCA; PubMed-verified,
      establishes topology, catalytic activity, and redundancy with a second
      guanylyl cyclase.
- id: PMID:11522784
  title: GTPgammaS regulation of a 12-transmembrane guanylyl cyclase is retained after
    mutation to an adenylyl cyclase.
  findings:
  - statement: DdGCA is a 12-transmembrane guanylyl cyclase with adenylyl-cyclase
      topology, activated by GTPgammaS possibly via a monomeric G protein.
    supporting_text: GTPgammaS activation is not mediated by a heterotrimeric
      G-protein but possibly by a monomeric G-protein
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct assay of GCA activity and regulation; supports the
      guanylate cyclase MF (IDA) annotation.
- id: PMID:11777934
  title: Characterization of two unusual guanylyl cyclases from dictyostelium.
  findings:
  - statement: GCA and sGC are the two Dictyostelium guanylyl cyclases; the double
      null loses all detectable GC activity.
    supporting_text: all detectable GC activity is lost in a cell line in which both
      genes have been inactivated
  - statement: GCA is exclusively membrane-bound and active mainly with Mg2+, and is
      expressed mainly during growth and multicellular development.
    supporting_text: GCA is expressed mainly during growth and multicellular
      development, whereas sGC is expressed mainly during cell aggregation
  - statement: Both enzymes are activated in vivo by extracellular cAMP via a
      G-protein-coupled receptor and inhibited by calcium.
    supporting_text: Ca(2+) inhibits both GCA and sGC with K(i) of about 50 and 200
      nm, respectively
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines GCA versus sGC redundancy, membrane localization,
      expression pattern, and calcium inhibition.
- id: PMID:14710184
  title: 'Chemotaxis: signalling modules join hands at front and tail.'
  findings:
  - statement: A cGMP-signalling cascade regulates myosin filament formation in the
      posterior of the cell and inhibits lateral pseudopod formation.
    supporting_text: a cyclic-GMP-signalling cascade has been identified that
      regulates myosin filament formation in the posterior of the cell, thereby
      inhibiting the formation of lateral pseudopodia that could misdirect the cell
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review framing the cGMP/rear module of chemotaxis; supports
      downstream myosin and pseudopod annotations.
- id: PMID:15473840
  title: Chemoattractant signaling in dictyostelium discoideum.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Broad review of chemoattractant signaling modules; the TAS
      receptor-guanylyl-cyclase pathway annotation derived from it over-specifies
      GCA's mechanism.
- id: PMID:16790492
  title: Guanylyl cyclase protein and cGMP product independently control front and
    back of chemotaxing Dictyostelium cells.
  findings:
  - statement: cGMP mediates cortical myosin II filament formation and suppresses
      pseudopod formation in the back of the cell during chemotaxis.
    supporting_text: cGMP suppresses pseudopod formation in the back of the cell,
      whereas the sGC protein refines pseudopod formation at the leading edge
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Focuses on sGC but establishes the cGMP-myosin rear module to
      which GCA-derived cGMP contributes.
- id: PMID:18073238
  title: The role of cGMP and the rear of the cell in Dictyostelium chemotaxis and
    cell streaming.
  findings:
  - statement: A quiescent, cGMP-controlled rear increases directional movement
      efficiency and maintains cell-cell contacts during streaming.
    supporting_text: a quiescent rear of the cell increases the efficiency of
      directional movement and is essential to maintain stable cell-cell contacts
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports the chemotaxis and lateral pseudopodium retraction
      annotations via the cGMP rear module.
- id: PMID:19346484
  title: Switching direction in electric-signal-induced cell migration by cyclic guanosine
    monophosphate and phosphatidylinositol signaling.
  findings:
  - statement: Genetically modulating both guanylyl cyclases (and GbpC/PI3K)
      reverses the preferred direction of electrotaxis.
    supporting_text: the preferential direction of migration during electrotaxis in
      Dictyostelium cells can be reversed by genetically modulating both guanylyl
      cyclases (GCases)
  - statement: GCase-dependent signaling components localize to the leading edge of
      migrating cells in an actin-dependent manner.
    supporting_text: Molecular components of the GCase- and PI3K-dependent signaling
      pathways localized at the leading edge of migrating cells during electrotaxis
      in an actin-dependent manner
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports the electrotaxis and leading-edge annotations for the
      GCase pathway.
- id: PMID:22081140
  title: 'Dictyostelium chemotaxis: essential Ras activation and accessory signalling
    pathways for amplification.'
  findings:
  - statement: sGC/cGMP signaling is an accessory pathway that is not required for
      basal Ras-driven chemotaxis but improves orientation and sensitivity in
      shallow gradients.
    supporting_text: The signalling enzymes PI3K, TorC2, PLA2 and sGC are not
      required for Ras activation and chemotaxis to folate or to steep gradients of
      cAMP, but they provide a memory of direction and improved orientation of the
      cell
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Places the guanylyl cyclase pathway as accessory/amplifying for
      chemotaxis; supports the regulation of chemotaxis non-core call.
- id: PMID:40295210
  title: Intracellular Calcium Responses to External Calcium Stimuli in Dictyostelium.
  findings:
  - statement: gca/sgc double-null cells still respond to external calcium (only
      slightly delayed), indicating GCA/cGMP is not required for calcium-mediated
      signaling.
    supporting_text: gca/sgc-null cells showed a slightly delayed response
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Genetic-interaction basis for the NOT calcium-mediated signaling
      annotation.
core_functions:
- description: GCA is a membrane-bound guanylyl cyclase that synthesizes the second
    messenger cGMP from GTP at the plasma membrane. It has an adenylyl-cyclase-like
    topology (12 transmembrane spans and two intramolecular cyclase domains),
    requires Mg2+, is inhibited by calcium, and is activated in vivo by
    extracellular cAMP acting through a G-protein-coupled cAMP receptor. The cGMP it
    produces acts as a diffusible second messenger that promotes cortical myosin II
    assembly in the rear of chemotaxing cells; GCA is partially redundant with the
    soluble guanylyl cyclase sGC.
  molecular_function:
    id: GO:0004383
    label: guanylate cyclase activity
  locations:
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0016020
    label: membrane
  directly_involved_in:
  - id: GO:0006182
    label: cGMP biosynthetic process
  supported_by:
  - reference_id: PMID:11237875
    supporting_text: DdGCA expressed in Dictyostelium exhibits high guanylate
      cyclase activity and no detectable adenylate cyclase activity
  - reference_id: PMID:11777934
    supporting_text: GCA is exclusively membrane-bound and is active mainly with
      Mg(2+)
  - reference_id: PMID:11522784
    supporting_text: DdGCA is a Dictyostelium guanylyl cyclase with a topology
      typical for mammalian adenylyl cyclases containing 12 transmembrane-spanning
      regions and two cyclase domain