ctnA

id: Q86IV5
gene_symbol: ctnA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: Countin-1 (CtnA) is a secreted, glycosylated protein of the social
  amoeba Dictyostelium discoideum and the principal bioactive component of counting
  factor (CF), a ~450 kDa multi-subunit extracellular complex (also containing CF50,
  CF45-1 and CF60) that regulates the size of the multicellular structures formed
  during development. When cells starve they aggregate into streams that break up
  into groups of roughly 2x10^4 cells, each of which becomes a fruiting body;
  secreted CF reports local cell number, and high CF levels promote stream breakup
  so that fewer cells accumulate per group. CtnA carries a saposin B-type domain,
  is exported through a signal peptide after N-glycosylation, and binds a small
  number of high-affinity cell-surface sites to trigger rapid signal transduction.
  Through this signaling it represses cell-cell adhesion, increases cell motility
  and F-actin polymerization, lowers intracellular glucose by inhibiting
  glucose-6-phosphatase, and modulates the cAMP and cGMP relay pulses. Loss of CtnA
  abolishes detectable CF activity, so aggregation streams fail to break up and
  cells form abnormally few, very large aggregates and fruiting bodies.
existing_annotations:
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: CtnA is a secreted protein exported via an N-terminal signal peptide,
      so extracellular localization is correct. This is a core aspect of its
      function as the diffusible component of counting factor.
    action: ACCEPT
    reason: The secreted/extracellular location is directly established
      experimentally and is essential to CtnA's role as an extracellular
      size-regulating signal.
    supported_by:
    - reference_id: PMID:10444594
      supporting_text: The predicted protein, which we have named countin, is
        hydrophilic, has a potential signal sequence upstream of where we observe
        the amino terminus of the secreted protein
- term:
    id: GO:0006971
    label: hypotonic response
  evidence_type: IDA
  original_reference_id: PMID:38986731
  qualifier: involved_in
  review:
    summary: This IDA annotation derives from a trafficking study whose full text
      is not available. The cached abstract describes CtnA localization,
      glycosylation and secretion pathways but does not mention any hypotonic or
      osmotic response for CtnA, so the supporting evidence cannot be verified.
    action: UNDECIDED
    reason: Full text is unavailable and the abstract does not cover a hypotonic
      response. Per policy, an experimental annotation that cannot be verified from
      the accessible text is left UNDECIDED rather than removed.
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IDA
  original_reference_id: PMID:38986731
  qualifier: located_in
  review:
    summary: Before secretion, intracellular CtnA localizes to cytoplasmic vesicles
      and punctae, as directly shown in the trafficking study. This is a valid
      subcellular localization reflecting the secretory route of the protein.
    action: ACCEPT
    reason: The abstract explicitly states CtnA localizes to cytoplasmic vesicles
      during growth and starvation, supporting this located_in annotation.
    supported_by:
    - reference_id: PMID:38986731
      supporting_text: During growth and starvation, CtnA localizes to cytoplasmic
        vesicles and punctae
- term:
    id: GO:0140582
    label: adenylate cyclase-activating G protein-coupled cAMP receptor signaling
      pathway
  evidence_type: IDA
  original_reference_id: PMID:37921687
  qualifier: involved_in
  review:
    summary: This annotation comes from a single-cell transcriptomics study of
      collective cAMP signalling in which ctnA is one of many genes whose
      expression responds to cAMP oscillations. The paper does not present CtnA as
      a component that acts within the adenylate cyclase-activating cAMP receptor
      pathway; rather ctnA expression is downstream of that signalling. Treating a
      cAMP-responsive marker gene as involved_in the pathway over-interprets the
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: In PMID:37921687 ctnA is a cAMP-regulated expression marker, not a
      demonstrated participant in the adenylate cyclase-activating cAMP receptor
      signaling pathway. CtnA's genuine modulation of cAMP relay is captured
      separately by the annotations from PMID:11371560.
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IMP
  original_reference_id: PMID:16606621
  qualifier: involved_in
  review:
    summary: Counting factor (whose bioactivity resides in countin) represses
      internal glucose levels by increasing the Km of glucose-6-phosphatase, which
      hydrolyzes glucose-6-phosphate. This is a genuine downstream effect of CtnA
      signal transduction rather than a core molecular function of the protein.
    action: KEEP_AS_NON_CORE
    reason: The link to glucose-6-phosphate metabolism is a downstream consequence
      of CtnA signaling on glucose-6-phosphatase, established by IMP, but it is not
      the core evolved function of the secreted signal.
    supported_by:
    - reference_id: PMID:16606621
      supporting_text: The CF signal transduction pathway involves CF-repressing
        internal glucose levels by increasing the K(m) of glucose-6-phosphatase
- term:
    id: GO:0001678
    label: intracellular glucose homeostasis
  evidence_type: IMP
  original_reference_id: PMID:15643062
  qualifier: involved_in
  review:
    summary: A brief exposure of cells to recombinant countin decreases
      intracellular glucose, part of the CF signal transduction pathway that
      lowers internal glucose. This is a downstream signaling effect, not the
      core function.
    action: KEEP_AS_NON_CORE
    reason: CtnA signaling lowers intracellular glucose (via glucose-6-phosphatase
      inhibition), a supported downstream effect that is peripheral to the core
      size-counting function.
    supported_by:
    - reference_id: PMID:15643062
      supporting_text: an 8-min exposure of cells to recombinant countin decreases
        intracellular glucose levels
- term:
    id: GO:0031157
    label: regulation of aggregate size involved in sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:10444594
  qualifier: involved_in
  review:
    summary: This is the central, well-established function of CtnA. Disrupting the
      countin gene abolishes CF secretion so aggregation streams do not break up
      and cells form huge aggregates and fruiting bodies. This term precisely
      captures CtnA's core role.
    action: ACCEPT
    reason: Loss-of-function directly demonstrates that CtnA regulates the size of
      aggregates during fruiting-body (sorocarp) development; this is the core
      function of the gene.
    supported_by:
    - reference_id: PMID:10444594
      supporting_text: there is no detectable secretion of counting factor, and the
        aggregation streams do not break up
    - reference_id: PMID:10444594
      supporting_text: it behaves as a complex of polypeptides with an effective
        molecular mass of 450 kD
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: IMP
  original_reference_id: PMID:12912898
  qualifier: involved_in
  review:
    summary: Cells lacking countin have elevated cytosolic glucose, showing CtnA
      contributes to glucose homeostasis. This is a downstream physiological effect
      of CtnA signaling rather than its core function.
    action: KEEP_AS_NON_CORE
    reason: The glucose homeostasis phenotype of countin-null cells is a supported
      downstream effect of CF signaling, secondary to the core aggregate-size
      counting role.
    supported_by:
    - reference_id: PMID:12912898
      supporting_text: cells lacking countin or CF50 have higher glucose levels,
        higher cell-cell adhesion, and lower motilities
- term:
    id: GO:0040015
    label: negative regulation of multicellular organism growth
  evidence_type: IMP
  original_reference_id: PMID:10444594
  qualifier: acts_upstream_of_or_within
  review:
    summary: Countin disruption produces considerably larger fruiting bodies,
      consistent with CtnA limiting the size of the multicellular structure. This
      overlaps with the more precise aggregate-size term and is a broader
      restatement of the same size-limiting role.
    action: KEEP_AS_NON_CORE
    reason: The larger-structure phenotype supports a size-limiting role, but
      GO:0031157 (regulation of aggregate size) more precisely captures the core
      function; this broader growth term is retained as non-core.
    supported_by:
    - reference_id: PMID:10444594
      supporting_text: these were considerably larger than those of the parental
        cells
- term:
    id: GO:0098727
    label: maintenance of cell number
  evidence_type: IDA
  original_reference_id: PMID:11371560
  qualifier: involved_in
  review:
    summary: Counting factor regulates the number of cells per group/fruiting body.
      This IDA reflects CtnA's role in setting group cell number, which is closely
      related to but broader than the specific aggregate-size term, so it is kept
      as non-core.
    action: KEEP_AS_NON_CORE
    reason: CtnA sets the number of cells per group, supporting this annotation,
      but the size-counting role is more precisely captured by GO:0031157; retained
      as a non-core aspect.
    supported_by:
    - reference_id: PMID:11371560
      supporting_text: A secreted counting factor (CF), regulates the size of
        Dictyostelium discoideum fruiting bodies in part by regulating cell-cell
        adhesion
- term:
    id: GO:0106071
    label: positive regulation of adenylate cyclase-activating G protein-coupled receptor
      signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:11371560
  qualifier: acts_upstream_of_or_within
  review:
    summary: A brief exposure of cells to purified CF increases the cAMP-induced
      cAMP pulse, i.e. it positively modulates the adenylate cyclase-activating
      cAMP relay. This is a supported downstream signaling effect of CtnA/CF.
    action: KEEP_AS_NON_CORE
    reason: CF increases the cAMP-induced cAMP pulse, supporting positive regulation
      of the adenylate cyclase-activating pathway; this is one of several signaling
      outputs of CtnA and is non-core relative to size counting.
    supported_by:
    - reference_id: PMID:11371560
      supporting_text: A 1-min exposure of cells to purified CF increases the
        cAMP-induced cAMP pulse
- 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 ctnA is one of several developmental marker genes whose
      mRNA level was measured by RT-PCR after UV-C irradiation, and ctnA expression
      was markedly reduced. This shows ctnA expression responds to UV-C, not that
      CtnA mediates the UV-C response; annotating the protein as involved in the
      UV-C response over-interprets an expression readout.
    action: MARK_AS_OVER_ANNOTATED
    reason: ctnA is used as a downstream expression marker of UV-C-induced
      developmental defects; its reduced transcription does not establish a
      functional role for CtnA in the UV-C response.
    supported_by:
    - reference_id: PMID:25858552
      supporting_text: expression of csA and ctnA was markedly reduced
- term:
    id: GO:0048870
    label: cell motility
  evidence_type: IDA
  original_reference_id: PMID:12070154
  qualifier: acts_upstream_of_or_within
  review:
    summary: Recombinant countin increases cell motility, one of the rapid cellular
      responses it evokes as a secreted signal. This is a downstream effect of
      CtnA signaling rather than the protein's own core molecular function.
    action: KEEP_AS_NON_CORE
    reason: CtnA increases cell motility as part of its signaling output, supported
      by direct assay of recombinant countin; this is a non-core downstream effect.
    supported_by:
    - reference_id: PMID:12070154
      supporting_text: Recombinant countin increases cell motility, decreases
        cell-cell adhesion
- term:
    id: GO:0010754
    label: negative regulation of receptor guanylyl cyclase signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:11371560
  qualifier: acts_upstream_of_or_within
  review:
    summary: CF slowly down-regulates the cAMP-induced cGMP pulse by inhibiting
      guanylyl cyclase activity, a supported signaling output of CtnA/CF. This is
      a downstream regulatory effect and is non-core relative to size counting.
    action: KEEP_AS_NON_CORE
    reason: The inhibition of the cAMP-induced cGMP pulse via guanylyl cyclase is a
      documented CF signaling effect, one of several parallel outputs and not the
      core function.
    supported_by:
    - reference_id: PMID:11371560
      supporting_text: down-regulates the cAMP-induced cGMP pulse by inhibiting
        guanylyl cyclase
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:10444594
  qualifier: located_in
  review:
    summary: Direct evidence establishes that countin is secreted; it is purified
      from conditioned medium and its secretion is lost on gene disruption. The
      extracellular location is core to its function as a diffusible signal.
    action: ACCEPT
    reason: CtnA is directly shown to be secreted into the extracellular medium, a
      core feature of its role as the diffusible counting-factor signal.
    supported_by:
    - reference_id: PMID:10444594
      supporting_text: there is no detectable secretion of counting factor, and the
        aggregation streams do not break up
- term:
    id: GO:0007162
    label: negative regulation of cell adhesion
  evidence_type: IMP
  original_reference_id: PMID:11090633
  qualifier: acts_upstream_of_or_within
  review:
    summary: Counting factor regulates group size by repressing cell-cell adhesion;
      high CF (and thus low adhesion) causes streams to break into small groups.
      This adhesion-repressing activity is a principal mechanism by which CtnA
      controls group size.
    action: ACCEPT
    reason: Repression of cell-cell adhesion is a central, well-supported mechanism
      of CtnA/CF action on group size.
    supported_by:
    - reference_id: PMID:11090633
      supporting_text: CF regulates group size by repressing cell-cell adhesion
- term:
    id: GO:0007162
    label: negative regulation of cell adhesion
  evidence_type: IDA
  original_reference_id: PMID:12070154
  qualifier: involved_in
  review:
    summary: Recombinant countin directly decreases cell-cell adhesion, confirming
      by direct assay the adhesion-repressing activity inferred from CF. This is a
      key mechanistic output of CtnA signaling.
    action: ACCEPT
    reason: Direct assay of recombinant countin shows it decreases cell-cell
      adhesion, supporting this annotation and the mechanism of group-size control.
    supported_by:
    - reference_id: PMID:12070154
      supporting_text: Recombinant countin increases cell motility, decreases
        cell-cell adhesion
- term:
    id: GO:0030041
    label: actin filament polymerization
  evidence_type: IDA
  original_reference_id: PMID:12070154
  qualifier: involved_in
  review:
    summary: A brief exposure to countin causes an increase in F-actin
      polymerization, part of the rapid cytoskeletal signal-transduction response
      it triggers. This is a downstream cellular effect rather than the core
      function of the secreted protein.
    action: KEEP_AS_NON_CORE
    reason: The increase in F-actin polymerization is a rapid downstream response
      to CtnA signaling, supported by direct assay but peripheral to the core
      size-counting role.
    supported_by:
    - reference_id: PMID:12070154
      supporting_text: causes an increase in F-actin polymerization
references:
- 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: PMID:10444594
  title: A cell-counting factor regulating structure size in Dictyostelium.
  findings:
  - statement: Countin is a ~40 kDa secreted, hydrophilic protein with a signal
      sequence, purified as part of a ~450 kDa counting-factor complex.
    supporting_text: The predicted protein, which we have named countin, is
      hydrophilic, has a potential signal sequence upstream of where we observe the
      amino terminus of the secreted protein
  - statement: Disrupting the countin gene abolishes counting-factor secretion so
      aggregation streams do not break up, giving huge fruiting bodies.
    supporting_text: there is no detectable secretion of counting factor, and the
      aggregation streams do not break up
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational paper identifying countin and its gene-disruption
      phenotype; PMC full text confirms the secreted, size-limiting role.
- id: PMID:11090633
  title: A precise group size in Dictyostelium is generated by a cell-counting factor
    modulating cell-cell adhesion.
  findings:
  - statement: Counting factor sets group size by repressing cell-cell adhesion.
    supporting_text: CF regulates group size by repressing cell-cell adhesion
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only cache; abstract directly supports the
      adhesion-repression mechanism of CF/countin.
- id: PMID:11371560
  title: A cell number-counting factor regulates group size in Dictyostelium by differentially
    modulating cAMP-induced cAMP and cGMP pulse sizes.
  findings:
  - statement: CF increases the cAMP-induced cAMP pulse and inhibits the
      cAMP-induced cGMP pulse via guanylyl cyclase.
    supporting_text: down-regulates the cAMP-induced cGMP pulse by inhibiting
      guanylyl cyclase
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only cache; supports the parallel cAMP/cGMP pulse
      modulation outputs of counting factor.
- id: PMID:12070154
  title: Cells respond to and bind countin, a component of a multisubunit cell number
    counting factor.
  findings:
  - statement: Recombinant countin binds ~53 high-affinity cell-surface sites and
      triggers rapid responses including increased motility, decreased adhesion and
      increased F-actin polymerization.
    supporting_text: Recombinant countin increases cell motility, decreases
      cell-cell adhesion
  - statement: Cells have a small number of high-affinity countin-binding sites.
    supporting_text: vegetative and developing cells have approximately 53
      cell-surface sites that bind countin
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only cache; establishes countin as a ligand binding
      cell-surface sites and driving the CF cellular responses.
- id: PMID:12912898
  title: CF45-1, a secreted protein which participates in Dictyostelium group size
    regulation.
  findings:
  - statement: Countin-null cells have elevated cytosolic glucose, higher adhesion
      and lower motility, forming large groups.
    supporting_text: cells lacking countin or CF50 have higher glucose levels,
      higher cell-cell adhesion, and lower motilities
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Primarily about CF45-1 but full text documents the countin-null
      glucose/adhesion/motility phenotype used here.
- id: PMID:15643062
  title: Exposure of cells to a cell number-counting factor decreases the activity
    of glucose-6-phosphatase to decrease intracellular glucose levels in Dictyostelium
    discoideum.
  findings:
  - statement: Brief exposure to recombinant countin lowers intracellular glucose.
    supporting_text: an 8-min exposure of cells to recombinant countin decreases
      intracellular glucose levels
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only cache; supports the glucose-lowering downstream
      effect of countin signaling.
- id: PMID:16606621
  title: A protein in crude cytosol regulates glucose-6-phosphatase activity in crude
    microsomes to regulate group size in Dictyostelium.
  findings:
  - statement: CF represses internal glucose by increasing the Km of
      glucose-6-phosphatase.
    supporting_text: The CF signal transduction pathway involves CF-repressing
      internal glucose levels by increasing the K(m) of glucose-6-phosphatase
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text supports CF/countin regulation of glucose-6-phosphatase
      as a downstream signaling effect.
- id: PMID:25858552
  title: Response of Dictyostelium discoideum to UV-C and involvement of poly (ADP-ribose)
    polymerase.
  findings:
  - statement: ctnA is used as a developmental marker gene; its expression is
      markedly reduced after UV-C irradiation.
    supporting_text: expression of csA and ctnA was markedly reduced
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: ctnA appears only as an expression marker reduced by UV-C; the
      paper does not show CtnA functions in the UV-C response, so the response
      to UV-C annotation over-interprets this readout.
- id: PMID:37921687
  title: Collective signalling drives rapid jumping between cell states.
  findings:
  - statement: Developmental gene expression jumps are driven by collective cAMP
      oscillations; ctnA is among cAMP-responsive genes but is not shown to act
      within the cAMP receptor pathway.
    supporting_text: the jump coincides with the onset of collective oscillations
      of cAMP
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: ctnA is a cAMP-responsive expression marker here; the paper does
      not establish CtnA as a participant in the adenylate cyclase-activating cAMP
      receptor signaling pathway.
- id: PMID:38986731
  title: Trafficking of adhesion and aggregation-modulating proteins during the early
    stages of Dictyostelium development.
  findings:
  - statement: CtnA localizes to cytoplasmic vesicles and punctae and is secreted
      in a glycosylation- and signal-peptide-dependent manner.
    supporting_text: During growth and starvation, CtnA localizes to cytoplasmic
      vesicles and punctae
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only cache; supports cytoplasmic-vesicle localization
      and the glycosylation-dependent secretion of CtnA.
core_functions:
- description: CtnA is the principal secreted subunit of counting factor, a
    multi-subunit extracellular signal that limits the number of cells per
    aggregate during Dictyostelium development. Secreted CtnA binds a small number
    of high-affinity cell-surface sites and triggers rapid signal transduction that
    represses cell-cell adhesion and increases motility, causing aggregation
    streams to break up into appropriately sized groups; loss of CtnA abolishes CF
    activity and yields abnormally large aggregates.
  molecular_function:
    id: GO:0005102
    label: signaling receptor binding
  directly_involved_in:
  - id: GO:0031157
    label: regulation of aggregate size involved in sorocarp development
  - id: GO:0007162
    label: negative regulation of cell adhesion
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:12070154
    supporting_text: vegetative and developing cells have approximately 53
      cell-surface sites that bind countin
  - reference_id: PMID:11090633
    supporting_text: CF regulates group size by repressing cell-cell adhesion
  - reference_id: PMID:10444594
    supporting_text: there is no detectable secretion of counting factor, and the
      aggregation streams do not break up