carD

UniProt ID: Q9TX43
Organism: Dictyostelium discoideum
Review Status: COMPLETE
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Gene Description

Cyclic AMP receptor 4 (CAR4/cAR4, encoded by carD) is one of four serpentine seven-transmembrane G protein-coupled cAMP receptors of Dictyostelium discoideum. It is a low-affinity cAMP receptor and the latest-expressed member of the cAR family, with transcript first appearing during tip elongation and accumulating through culmination. CAR4 is expressed predominantly in the anterior prestalk zone of the migrating pseudoplasmodium, a center where extracellular cAMP organizes cell-type patterning. Acting through heterotrimeric G proteins, CAR4 transduces extracellular cAMP signals that establish anteroposterior polarity, promoting prestalk gene expression and restricting prespore differentiation to the appropriate spatial domain. Downstream, CAR4 signaling activates a protein tyrosine phosphatase that inhibits GSK3, a mechanism paralleling metazoan Wnt/Frizzled-GSK3 pathways in controlling cell-fate choice. Loss of CAR4 does not perturb early aggregation but causes major axial patterning defects and aberrant cellular differentiation during late (slug and culmination) development. CAR4 is a paralog of the aggregation-stage receptor cAR1 (CAR1), and the four cARs are deployed in a stage-specific developmental sequence.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004930 G protein-coupled receptor activity
IBA
GO_REF:0000033 		ACCEPT
Summary: CAR4 is a bona fide seven-transmembrane G protein-coupled receptor of the Dictyostelium cAR family, and its signaling is mediated by G proteins. Phylogenetic inference to GPCR activity is correct and represents a core molecular function.
Reason: The primary literature explicitly describes CAR4 as a cell-surface, G protein-linked cAMP receptor whose activity is mediated by G proteins, and the UniProt topology confirms a canonical 7TM architecture. GPCR activity is a correct and central molecular function.
Supporting Evidence:
PMID:7958880
the gene for a new cell-surface, G protein-linked cAMP receptor
GO:0005886 plasma membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: As a cell-surface GPCR, CAR4 is active at the plasma membrane. This is a correct core localization.
Reason: CAR4 is described as a cell-surface receptor and is predicted to be a multi-pass membrane protein; the plasma membrane is where a chemoattractant cAMP receptor acts.
Supporting Evidence:
PMID:7958880
the gene for a new cell-surface, G protein-linked cAMP receptor
GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: This IBA term propagates the adenylate-cyclase-activating signaling role of aggregation-stage cAR paralogs (notably cAR1) to CAR4. The characterized signaling output of CAR4 is regulation of a tyrosine phosphatase that inhibits GSK3 during late-development patterning, not activation of adenylate cyclase. There is no direct evidence that CAR4 couples to adenylate cyclase activation.
Reason: cAR1-4 are stage-specific paralogs and this IBA is a likely over-propagation from receptors that do activate adenylate cyclase. CAR4's documented downstream pathway operates through a protein tyrosine phosphatase/GSK3 axis controlling cell fate, so the specific adenylate-cyclase-activating claim is not supported for this paralog.
Propagation Review
Root cause: PROPAGATION BAD
Failure modes: WRONG ORTHOLOG OR PARALOG
Sources checked:
PANTHER:PTN000560943 · PANTHER node for the Dictyostelium cAMP-receptor (cAR) family SUPPORTS SOURCE BUT NOT TARGET
Adenylate-cyclase-activating role is a property of aggregation-stage cAR1, not of the late-development paralog CAR4 which signals through a tyrosine-phosphatase/GSK3 axis
dictyBase:DDB_G0273397 · Dictyostelium cAR1-type paralog SUPPORTS SOURCE BUT NOT TARGET
cAR1 activates adenylate cyclase, but this function does not transfer to the divergent CAR4 paralog
Supporting Evidence:
PMID:12408804
We now show that CAR4 regulates a tyrosine phosphatase that inhibits GSK3 activity
GO:0004888 transmembrane signaling receptor activity
IEA
GO_REF:0000002 		ACCEPT
Summary: A correct but general parent term for CAR4's receptor activity. The more specific cAMP receptor activity (GO:0001646) better captures the ligand specificity.
Reason: CAR4 is a transmembrane signaling receptor; the term is accurate. It is a general ancestor of the more informative cAMP receptor activity annotation, which is also present.
Supporting Evidence:
PMID:7958880
the gene for a new cell-surface, G protein-linked cAMP receptor
GO:0004930 G protein-coupled receptor activity
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based GPCR activity annotation, consistent with the IBA annotation and the experimental characterization of CAR4 as a G protein-linked cAMP receptor.
Reason: Correct core molecular function, supported by both the GPCR domain architecture and the primary literature describing G protein-linked signaling.
Supporting Evidence:
PMID:7958880
the gene for a new cell-surface, G protein-linked cAMP receptor
GO:0007165 signal transduction
IEA
GO_REF:0000117 		ACCEPT
Summary: Correct but very general process term. CAR4 transduces extracellular cAMP signals; more specific GPCR signaling pathway terms are also annotated.
Reason: CAR4 is a signal-transducing receptor. The term is accurate though general; the more specific GPCR signaling pathway annotation is preferable for capturing the mechanism.
Supporting Evidence:
PMID:2722797
the cell surface receptors participate in the transduction of the cAMP signal during chemotaxis and cell differentiation
GO:0007166 cell surface receptor signaling pathway
IEA
GO_REF:0000002 		ACCEPT
Summary: CAR4 is a cell-surface receptor that initiates intracellular signaling in response to extracellular cAMP. Correct process annotation.
Reason: Accurate for a cell-surface cAMP GPCR; this is a parent of the more specific G protein-coupled receptor signaling pathway term.
Supporting Evidence:
PMID:7958880
the gene for a new cell-surface, G protein-linked cAMP receptor
GO:0007186 G protein-coupled receptor signaling pathway
IEA
GO_REF:0000002 		ACCEPT
Summary: CAR4 signals through heterotrimeric G proteins, making this the most appropriate specific process term for its signaling role.
Reason: The activity of the receptor is explicitly mediated by G proteins, so GPCR signaling pathway is the correct core process.
Supporting Evidence:
PMID:7958880
the gene for a new cell-surface, G protein-linked cAMP receptor
GO:0016020 membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: Correct but general localization. CAR4 is a multi-pass membrane protein; the more specific plasma membrane annotation is also present.
Reason: CAR4 is predicted to be a multi-pass membrane protein and is a cell-surface receptor. Membrane is accurate; plasma membrane is the more informative term.
Supporting Evidence:
PMID:7958880
the gene for a new cell-surface, G protein-linked cAMP receptor
GO:0030552 cAMP binding
IEA
GO_REF:0000002 		ACCEPT
Summary: cAMP binding is the defining ligand-recognition activity of the cAR receptor family and is a core molecular function of CAR4.
Reason: The receptor binds extracellular cAMP as its ligand; this activity is supported by both the InterPro domain and direct biochemical study of the cell surface cAMP receptors.
Supporting Evidence:
PMID:2722797
cAMP is probably bound to the surface receptors in the anti conformation in a hydrophobic cleft of the receptor
GO:0035589 G protein-coupled purinergic nucleotide receptor signaling pathway
IEA
GO_REF:0000108 		REMOVE
Summary: This term was assigned by an automated inter-ontology logical inference (ECO:0000364) from cAMP receptor activity. Purinergic nucleotide receptor signaling refers to P2-type receptors for extracellular ATP/ADP/UTP, which is a distinct signaling system. Dictyostelium cAMP receptor signaling is not purinergic receptor signaling, so this is a spurious mapping.
Reason: The annotation is an automated logical-inference artifact that misplaces cAMP receptor signaling into the purinergic (P2 receptor) branch. It is biologically incorrect for a cAR-family cAMP receptor and should be removed.
GO:0008160 protein tyrosine phosphatase activator activity
TAS
PMID:12408804
Receptor-dependent and tyrosine phosphatase-mediated inhibit... 		KEEP AS NON CORE
Summary: CAR4 signaling activates a protein tyrosine phosphatase that inhibits GSK3 to control cell-fate choice. This captures a real, receptor-dependent regulatory relationship, but as a direct molecular function of the receptor it is an over-interpretation, because CAR4 regulates the phosphatase indirectly through G protein signaling rather than acting as a direct enzyme activator.
Reason: The essence is supported by the primary paper (CAR4 regulates a tyrosine phosphatase that inhibits GSK3), and it is an important downstream mechanism for patterning. However, this is a signaling-mediated regulatory role rather than a direct catalytic-activator molecular function of the receptor, so it is retained as non-core.
Supporting Evidence:
PMID:12408804
We now show that CAR4 regulates a tyrosine phosphatase that inhibits GSK3 activity
GO:0005886 plasma membrane
TAS
PMID:15473840
Chemoattractant signaling in dictyostelium discoideum. 		ACCEPT
Summary: Plasma membrane localization of the cAMP chemoattractant receptors, consistent with the IBA plasma membrane annotation and CAR4's cell-surface character.
Reason: CAR4 is a cell-surface cAMP receptor; the plasma membrane is the correct core localization.
Supporting Evidence:
PMID:7958880
the gene for a new cell-surface, G protein-linked cAMP receptor
GO:0010628 positive regulation of gene expression
IMP
PMID:7958880
The cAMP receptor CAR4 regulates axial patterning and cellul... 		KEEP AS NON CORE
Summary: car4 null mutants show significantly reduced prestalk gene expression, indicating CAR4 normally promotes expression of prestalk-specific genes during late development. This is a downstream developmental regulatory role.
Reason: Supported by the loss-of-function phenotype (reduced prestalk gene expression in car4 nulls). This is a pleiotropic downstream developmental consequence of CAR4 signaling, not the receptor's core molecular function, so it is retained as non-core.
Supporting Evidence:
PMID:7958880
Prestalk gene expression is significantly reduced in car4 nulls, whereas prespore-specific markers are overexpressed and detected in zones normally restricted to prestalk cells
GO:0010629 negative regulation of gene expression
IMP
PMID:7958880
The cAMP receptor CAR4 regulates axial patterning and cellul... 		KEEP AS NON CORE
Summary: In car4 nulls, prespore-specific markers are overexpressed and appear in zones normally restricted to prestalk cells, indicating CAR4 normally restricts (negatively regulates) prespore gene expression in the prestalk domain. A downstream developmental regulatory role.
Reason: Supported by the loss-of-function phenotype (ectopic overexpression of prespore markers in car4 nulls). This is a spatial patterning consequence of CAR4 signaling rather than the core molecular function.
Supporting Evidence:
PMID:7958880
Prestalk gene expression is significantly reduced in car4 nulls, whereas prespore-specific markers are overexpressed and detected in zones normally restricted to prestalk cells
GO:0001646 cAMP receptor activity
ISS
PMID:7958880
The cAMP receptor CAR4 regulates axial patterning and cellul... 		ACCEPT
Summary: cAMP receptor activity is the defining, core molecular function of CAR4, inferred by sequence similarity to the founding cAR1 receptor (P13773) and consistent with its experimental characterization.
Reason: CAR4 is a member of the cAR family of cAMP receptors and was characterized as a cell-surface cAMP receptor; cAMP receptor activity is the correct and central molecular function.
Supporting Evidence:
PMID:7958880
the gene for a new cell-surface, G protein-linked cAMP receptor
GO:0030552 cAMP binding
ISS
PMID:7958880
The cAMP receptor CAR4 regulates axial patterning and cellul... 		ACCEPT
Summary: cAMP binding, inferred by similarity to cAR1, is the ligand-recognition component of CAR4's receptor function and is a core molecular activity.
Reason: Ligand binding is intrinsic to cAMP receptor activity; the annotation is correct and complements the cAMP receptor activity term.
Supporting Evidence:
PMID:2722797
cAMP is probably bound to the surface receptors in the anti conformation in a hydrophobic cleft of the receptor
GO:0007165 signal transduction
TAS
PMID:15473840
Chemoattractant signaling in dictyostelium discoideum. 		ACCEPT
Summary: General signal transduction annotation from a chemoattractant-signaling review. Correct but less informative than the GPCR signaling pathway terms.
Reason: CAR4 transduces extracellular cAMP signals; the term is accurate though general.
Supporting Evidence:
PMID:2722797
the cell surface receptors participate in the transduction of the cAMP signal during chemotaxis and cell differentiation
GO:0030552 cAMP binding
IDA
PMID:2722797
The cyclic nucleotide specificity of eight cAMP-binding prot... 		ACCEPT
Summary: Direct biochemical study of the Dictyostelium cell-surface cAMP receptors demonstrated cAMP binding in a hydrophobic cleft. cAMP binding is a core molecular activity of CAR4 as a cAMP receptor.
Reason: Experimental (IDA) support for cAMP binding by the cell-surface receptors. This ligand-binding activity is intrinsic to CAR4's core function as a cAMP receptor.
Supporting Evidence:
PMID:2722797
cAMP is probably bound to the surface receptors in the anti conformation in a hydrophobic cleft of the receptor
GO:0030154 cell differentiation
IMP
PMID:7958880
The cAMP receptor CAR4 regulates axial patterning and cellul... 		KEEP AS NON CORE
Summary: car4 null cells exhibit aberrant cellular differentiation during late development, with mis-patterned prestalk and prespore cell types. CAR4 signaling acts upstream of cell-type differentiation.
Reason: Supported by the loss-of-function phenotype; this is a genuine but downstream, pleiotropic developmental role of CAR4 signaling rather than its core molecular function.
Supporting Evidence:
PMID:7958880
cAMP signaling is required for pattern formation and cellular differentiation during late Dictyostelium development
GO:0031154 culmination involved in sorocarp development
IMP
PMID:7958880
The cAMP receptor CAR4 regulates axial patterning and cellul... 		KEEP AS NON CORE
Summary: CAR4 is expressed from tip elongation through culmination and car4 nulls show patterning defects that persist in terminally differentiated fruiting bodies, consistent with a role in late (culmination-stage) morphogenesis.
Reason: Supported by expression timing and the terminal-stage patterning phenotype. This is a downstream developmental role of CAR4 rather than its core molecular function.
Supporting Evidence:
PMID:7958880
CAR4 mRNA is initially expressed during tip elongation and continues to accumulate into culmination
GO:0001646 cAMP receptor activity
TAS
PMID:15473840
Chemoattractant signaling in dictyostelium discoideum. 		ACCEPT
Summary: cAMP receptor activity annotation from a chemoattractant-signaling review, consistent with the ISS annotation. Core molecular function.
Reason: cAMP receptor activity is the defining, core molecular function of CAR4.
Supporting Evidence:
PMID:7958880
the gene for a new cell-surface, G protein-linked cAMP receptor
GO:0030552 cAMP binding
TAS
PMID:15473840
Chemoattractant signaling in dictyostelium discoideum. 		ACCEPT
Summary: cAMP binding annotation from a chemoattractant-signaling review; consistent with the direct and inferred cAMP binding annotations. Core ligand-recognition activity.
Reason: Ligand binding is intrinsic to CAR4's cAMP receptor function; the annotation is correct.
Supporting Evidence:
PMID:2722797
cAMP is probably bound to the surface receptors in the anti conformation in a hydrophobic cleft of the receptor

Core Functions

CAR4 is a seven-transmembrane G protein-coupled receptor that binds extracellular cAMP at the plasma membrane and, through heterotrimeric G proteins, transduces the cAMP signal to control late-development cell-type patterning and differentiation.

Molecular Function:
cAMP receptor activity
Directly Involved In:
G protein-coupled receptor signaling pathway cell differentiation
Cellular Locations:
plasma membrane
Supporting Evidence:
  • PMID:7958880
    the gene for a new cell-surface, G protein-linked cAMP receptor
  • PMID:7958880
    cAMP signaling is required for pattern formation and cellular differentiation during late Dictyostelium development
  • PMID:2722797
    cAMP is probably bound to the surface receptors in the anti conformation in a hydrophobic cleft of the receptor

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000108
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:7958880
The cAMP receptor CAR4 regulates axial patterning and cellular differentiation during late development of Dictyostelium.
  • CAR4 is a cell-surface, G protein-linked cAMP receptor.
    "the gene for a new cell-surface, G protein-linked cAMP receptor"
  • CAR4 is maximally expressed in the prestalk-rich anterior of the pseudoplasmodium, a center for extracellular cAMP signaling and patterning.
    "CAR4 is maximally expressed in pseudoplasmodia anteriors which are centers for extracellular cAMP signaling and for organization of cellular patterning"
  • car4 nulls progress through early development but show major anteroposterior patterning defects during late development.
    "Although car4 null cells progress unperturbed through early development, they exhibit major patterning aberrations as the anteroposterior axis becomes established"
  • CAR4 promotes prestalk gene expression and restricts prespore differentiation to the appropriate spatial domain.
    "Prestalk gene expression is significantly reduced in car4 nulls, whereas prespore-specific markers are overexpressed and detected in zones normally restricted to prestalk cells"
PMID:2722797
The cyclic nucleotide specificity of eight cAMP-binding proteins in Dictyostelium discoideum is correlated into three groups.
  • The Dictyostelium cell-surface cAMP receptors bind cAMP in a hydrophobic cleft and transduce the cAMP signal during chemotaxis and differentiation.
    "cAMP is probably bound to the surface receptors in the anti conformation in a hydrophobic cleft of the receptor"
PMID:12408804
Receptor-dependent and tyrosine phosphatase-mediated inhibition of GSK3 regulates cell fate choice.
  • CAR4 regulates a protein tyrosine phosphatase that inhibits GSK3 activity, controlling cell-fate choice in a manner paralleling Wnt/Frizzled-GSK3 signaling.
    "We now show that CAR4 regulates a tyrosine phosphatase that inhibits GSK3 activity"
PMID:15473840
Chemoattractant signaling in dictyostelium discoideum.
  • Review of Dictyostelium chemoattractant (cAMP) receptor signaling modules including cyclic AMP signaling.
    "signaling via chemoattractant receptors"

📄 View Raw YAML

 
id: Q9TX43
gene_symbol: carD
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: Cyclic AMP receptor 4 (CAR4/cAR4, encoded by carD) is one of four
  serpentine seven-transmembrane G protein-coupled cAMP receptors of Dictyostelium
  discoideum. It is a low-affinity cAMP receptor and the latest-expressed member of
  the cAR family, with transcript first appearing during tip elongation and
  accumulating through culmination. CAR4 is expressed predominantly in the anterior
  prestalk zone of the migrating pseudoplasmodium, a center where extracellular cAMP
  organizes cell-type patterning. Acting through heterotrimeric G proteins, CAR4
  transduces extracellular cAMP signals that establish anteroposterior polarity,
  promoting prestalk gene expression and restricting prespore differentiation to the
  appropriate spatial domain. Downstream, CAR4 signaling activates a protein
  tyrosine phosphatase that inhibits GSK3, a mechanism paralleling metazoan
  Wnt/Frizzled-GSK3 pathways in controlling cell-fate choice. Loss of CAR4 does not
  perturb early aggregation but causes major axial patterning defects and aberrant
  cellular differentiation during late (slug and culmination) development. CAR4 is a
  paralog of the aggregation-stage receptor cAR1 (CAR1), and the four cARs are
  deployed in a stage-specific developmental sequence.
existing_annotations:
- term:
    id: GO:0004930
    label: G protein-coupled receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: CAR4 is a bona fide seven-transmembrane G protein-coupled receptor of
      the Dictyostelium cAR family, and its signaling is mediated by G proteins.
      Phylogenetic inference to GPCR activity is correct and represents a core
      molecular function.
    action: ACCEPT
    reason: The primary literature explicitly describes CAR4 as a cell-surface, G
      protein-linked cAMP receptor whose activity is mediated by G proteins, and the
      UniProt topology confirms a canonical 7TM architecture. GPCR activity is a
      correct and central molecular function.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: the gene for a new cell-surface, G protein-linked cAMP
        receptor
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: As a cell-surface GPCR, CAR4 is active at the plasma membrane. This is
      a correct core localization.
    action: ACCEPT
    reason: CAR4 is described as a cell-surface receptor and is predicted to be a
      multi-pass membrane protein; the plasma membrane is where a chemoattractant
      cAMP receptor acts.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: the gene for a new cell-surface, G protein-linked cAMP
        receptor
- term:
    id: GO:0007189
    label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: This IBA term propagates the adenylate-cyclase-activating signaling
      role of aggregation-stage cAR paralogs (notably cAR1) to CAR4. The
      characterized signaling output of CAR4 is regulation of a tyrosine phosphatase
      that inhibits GSK3 during late-development patterning, not activation of
      adenylate cyclase. There is no direct evidence that CAR4 couples to adenylate
      cyclase activation.
    action: MARK_AS_OVER_ANNOTATED
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - WRONG_ORTHOLOG_OR_PARALOG
      source_entities:
      - source_id: PANTHER:PTN000560943
        source_label: "PANTHER node for the Dictyostelium cAMP-receptor (cAR) family"
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: "Adenylate-cyclase-activating role is a property of aggregation-stage cAR1, not of the late-development paralog CAR4 which signals through a tyrosine-phosphatase/GSK3 axis"
      - source_id: dictyBase:DDB_G0273397
        source_label: "Dictyostelium cAR1-type paralog"
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: "cAR1 activates adenylate cyclase, but this function does not transfer to the divergent CAR4 paralog"
    reason: cAR1-4 are stage-specific paralogs and this IBA is a likely
      over-propagation from receptors that do activate adenylate cyclase. CAR4's
      documented downstream pathway operates through a protein tyrosine
      phosphatase/GSK3 axis controlling cell fate, so the specific
      adenylate-cyclase-activating claim is not supported for this paralog.
    supported_by:
    - reference_id: PMID:12408804
      supporting_text: We now show that CAR4 regulates a tyrosine phosphatase that
        inhibits GSK3 activity
- term:
    id: GO:0004888
    label: transmembrane signaling receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: A correct but general parent term for CAR4's receptor activity. The
      more specific cAMP receptor activity (GO:0001646) better captures the ligand
      specificity.
    action: ACCEPT
    reason: CAR4 is a transmembrane signaling receptor; the term is accurate. It is
      a general ancestor of the more informative cAMP receptor activity annotation,
      which is also present.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: the gene for a new cell-surface, G protein-linked cAMP
        receptor
- term:
    id: GO:0004930
    label: G protein-coupled receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based GPCR activity annotation, consistent with the IBA
      annotation and the experimental characterization of CAR4 as a G protein-linked
      cAMP receptor.
    action: ACCEPT
    reason: Correct core molecular function, supported by both the GPCR domain
      architecture and the primary literature describing G protein-linked signaling.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: the gene for a new cell-surface, G protein-linked cAMP
        receptor
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Correct but very general process term. CAR4 transduces extracellular
      cAMP signals; more specific GPCR signaling pathway terms are also annotated.
    action: ACCEPT
    reason: CAR4 is a signal-transducing receptor. The term is accurate though
      general; the more specific GPCR signaling pathway annotation is preferable for
      capturing the mechanism.
    supported_by:
    - reference_id: PMID:2722797
      supporting_text: the cell surface receptors participate in the transduction of
        the cAMP signal during chemotaxis and cell differentiation
- term:
    id: GO:0007166
    label: cell surface receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: CAR4 is a cell-surface receptor that initiates intracellular signaling
      in response to extracellular cAMP. Correct process annotation.
    action: ACCEPT
    reason: Accurate for a cell-surface cAMP GPCR; this is a parent of the more
      specific G protein-coupled receptor signaling pathway term.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: the gene for a new cell-surface, G protein-linked cAMP
        receptor
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: CAR4 signals through heterotrimeric G proteins, making this the most
      appropriate specific process term for its signaling role.
    action: ACCEPT
    reason: The activity of the receptor is explicitly mediated by G proteins, so
      GPCR signaling pathway is the correct core process.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: the gene for a new cell-surface, G protein-linked cAMP
        receptor
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Correct but general localization. CAR4 is a multi-pass membrane
      protein; the more specific plasma membrane annotation is also present.
    action: ACCEPT
    reason: CAR4 is predicted to be a multi-pass membrane protein and is a
      cell-surface receptor. Membrane is accurate; plasma membrane is the more
      informative term.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: the gene for a new cell-surface, G protein-linked cAMP
        receptor
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: cAMP binding is the defining ligand-recognition activity of the cAR
      receptor family and is a core molecular function of CAR4.
    action: ACCEPT
    reason: The receptor binds extracellular cAMP as its ligand; this activity is
      supported by both the InterPro domain and direct biochemical study of the cell
      surface cAMP receptors.
    supported_by:
    - reference_id: PMID:2722797
      supporting_text: cAMP is probably bound to the surface receptors in the anti
        conformation in a hydrophobic cleft of the receptor
- term:
    id: GO:0035589
    label: G protein-coupled purinergic nucleotide receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: This term was assigned by an automated inter-ontology logical inference
      (ECO:0000364) from cAMP receptor activity. Purinergic nucleotide receptor
      signaling refers to P2-type receptors for extracellular ATP/ADP/UTP, which is
      a distinct signaling system. Dictyostelium cAMP receptor signaling is not
      purinergic receptor signaling, so this is a spurious mapping.
    action: REMOVE
    reason: The annotation is an automated logical-inference artifact that misplaces
      cAMP receptor signaling into the purinergic (P2 receptor) branch. It is
      biologically incorrect for a cAR-family cAMP receptor and should be removed.
- term:
    id: GO:0008160
    label: protein tyrosine phosphatase activator activity
  evidence_type: TAS
  original_reference_id: PMID:12408804
  qualifier: enables
  review:
    summary: CAR4 signaling activates a protein tyrosine phosphatase that inhibits
      GSK3 to control cell-fate choice. This captures a real, receptor-dependent
      regulatory relationship, but as a direct molecular function of the receptor it
      is an over-interpretation, because CAR4 regulates the phosphatase indirectly
      through G protein signaling rather than acting as a direct enzyme activator.
    action: KEEP_AS_NON_CORE
    reason: The essence is supported by the primary paper (CAR4 regulates a tyrosine
      phosphatase that inhibits GSK3), and it is an important downstream mechanism
      for patterning. However, this is a signaling-mediated regulatory role rather
      than a direct catalytic-activator molecular function of the receptor, so it is
      retained as non-core.
    supported_by:
    - reference_id: PMID:12408804
      supporting_text: We now show that CAR4 regulates a tyrosine phosphatase that
        inhibits GSK3 activity
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: located_in
  review:
    summary: Plasma membrane localization of the cAMP chemoattractant receptors,
      consistent with the IBA plasma membrane annotation and CAR4's cell-surface
      character.
    action: ACCEPT
    reason: CAR4 is a cell-surface cAMP receptor; the plasma membrane is the correct
      core localization.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: the gene for a new cell-surface, G protein-linked cAMP
        receptor
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:7958880
  qualifier: acts_upstream_of_or_within
  review:
    summary: car4 null mutants show significantly reduced prestalk gene expression,
      indicating CAR4 normally promotes expression of prestalk-specific genes during
      late development. This is a downstream developmental regulatory role.
    action: KEEP_AS_NON_CORE
    reason: Supported by the loss-of-function phenotype (reduced prestalk gene
      expression in car4 nulls). This is a pleiotropic downstream developmental
      consequence of CAR4 signaling, not the receptor's core molecular function, so
      it is retained as non-core.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: Prestalk gene expression is significantly reduced in car4
        nulls, whereas prespore-specific markers are overexpressed and detected in
        zones normally restricted to prestalk cells
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:7958880
  qualifier: acts_upstream_of_or_within
  review:
    summary: In car4 nulls, prespore-specific markers are overexpressed and appear
      in zones normally restricted to prestalk cells, indicating CAR4 normally
      restricts (negatively regulates) prespore gene expression in the prestalk
      domain. A downstream developmental regulatory role.
    action: KEEP_AS_NON_CORE
    reason: Supported by the loss-of-function phenotype (ectopic overexpression of
      prespore markers in car4 nulls). This is a spatial patterning consequence of
      CAR4 signaling rather than the core molecular function.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: Prestalk gene expression is significantly reduced in car4
        nulls, whereas prespore-specific markers are overexpressed and detected in
        zones normally restricted to prestalk cells
- term:
    id: GO:0001646
    label: cAMP receptor activity
  evidence_type: ISS
  original_reference_id: PMID:7958880
  qualifier: enables
  review:
    summary: cAMP receptor activity is the defining, core molecular function of
      CAR4, inferred by sequence similarity to the founding cAR1 receptor (P13773)
      and consistent with its experimental characterization.
    action: ACCEPT
    reason: CAR4 is a member of the cAR family of cAMP receptors and was
      characterized as a cell-surface cAMP receptor; cAMP receptor activity is the
      correct and central molecular function.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: the gene for a new cell-surface, G protein-linked cAMP
        receptor
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: ISS
  original_reference_id: PMID:7958880
  qualifier: enables
  review:
    summary: cAMP binding, inferred by similarity to cAR1, is the ligand-recognition
      component of CAR4's receptor function and is a core molecular activity.
    action: ACCEPT
    reason: Ligand binding is intrinsic to cAMP receptor activity; the annotation is
      correct and complements the cAMP receptor activity term.
    supported_by:
    - reference_id: PMID:2722797
      supporting_text: cAMP is probably bound to the surface receptors in the anti
        conformation in a hydrophobic cleft of the receptor
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: acts_upstream_of_or_within
  review:
    summary: General signal transduction annotation from a chemoattractant-signaling
      review. Correct but less informative than the GPCR signaling pathway terms.
    action: ACCEPT
    reason: CAR4 transduces extracellular cAMP signals; the term is accurate though
      general.
    supported_by:
    - reference_id: PMID:2722797
      supporting_text: the cell surface receptors participate in the transduction of
        the cAMP signal during chemotaxis and cell differentiation
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: IDA
  original_reference_id: PMID:2722797
  qualifier: enables
  review:
    summary: Direct biochemical study of the Dictyostelium cell-surface cAMP
      receptors demonstrated cAMP binding in a hydrophobic cleft. cAMP binding is a
      core molecular activity of CAR4 as a cAMP receptor.
    action: ACCEPT
    reason: Experimental (IDA) support for cAMP binding by the cell-surface
      receptors. This ligand-binding activity is intrinsic to CAR4's core function
      as a cAMP receptor.
    supported_by:
    - reference_id: PMID:2722797
      supporting_text: cAMP is probably bound to the surface receptors in the anti
        conformation in a hydrophobic cleft of the receptor
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:7958880
  qualifier: acts_upstream_of_or_within
  review:
    summary: car4 null cells exhibit aberrant cellular differentiation during late
      development, with mis-patterned prestalk and prespore cell types. CAR4
      signaling acts upstream of cell-type differentiation.
    action: KEEP_AS_NON_CORE
    reason: Supported by the loss-of-function phenotype; this is a genuine but
      downstream, pleiotropic developmental role of CAR4 signaling rather than its
      core molecular function.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: cAMP signaling is required for pattern formation and cellular
        differentiation during late Dictyostelium development
- term:
    id: GO:0031154
    label: culmination involved in sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:7958880
  qualifier: acts_upstream_of_or_within
  review:
    summary: CAR4 is expressed from tip elongation through culmination and car4
      nulls show patterning defects that persist in terminally differentiated
      fruiting bodies, consistent with a role in late (culmination-stage)
      morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Supported by expression timing and the terminal-stage patterning
      phenotype. This is a downstream developmental role of CAR4 rather than its
      core molecular function.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: CAR4 mRNA is initially expressed during tip elongation and
        continues to accumulate into culmination
- term:
    id: GO:0001646
    label: cAMP receptor activity
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: enables
  review:
    summary: cAMP receptor activity annotation from a chemoattractant-signaling
      review, consistent with the ISS annotation. Core molecular function.
    action: ACCEPT
    reason: cAMP receptor activity is the defining, core molecular function of CAR4.
    supported_by:
    - reference_id: PMID:7958880
      supporting_text: the gene for a new cell-surface, G protein-linked cAMP
        receptor
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: enables
  review:
    summary: cAMP binding annotation from a chemoattractant-signaling review;
      consistent with the direct and inferred cAMP binding annotations. Core
      ligand-recognition activity.
    action: ACCEPT
    reason: Ligand binding is intrinsic to CAR4's cAMP receptor function; the
      annotation is correct.
    supported_by:
    - reference_id: PMID:2722797
      supporting_text: cAMP is probably bound to the surface receptors in the anti
        conformation in a hydrophobic cleft of the receptor
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:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:7958880
  title: The cAMP receptor CAR4 regulates axial patterning and cellular differentiation
    during late development of Dictyostelium.
  findings:
  - statement: CAR4 is a cell-surface, G protein-linked cAMP receptor.
    supporting_text: the gene for a new cell-surface, G protein-linked cAMP receptor
  - statement: CAR4 is maximally expressed in the prestalk-rich anterior of the
      pseudoplasmodium, a center for extracellular cAMP signaling and patterning.
    supporting_text: CAR4 is maximally expressed in pseudoplasmodia anteriors which
      are centers for extracellular cAMP signaling and for organization of cellular
      patterning
  - statement: car4 nulls progress through early development but show major
      anteroposterior patterning defects during late development.
    supporting_text: Although car4 null cells progress unperturbed through early
      development, they exhibit major patterning aberrations as the anteroposterior
      axis becomes established
  - statement: CAR4 promotes prestalk gene expression and restricts prespore
      differentiation to the appropriate spatial domain.
    supporting_text: Prestalk gene expression is significantly reduced in car4 nulls,
      whereas prespore-specific markers are overexpressed and detected in zones
      normally restricted to prestalk cells
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding CAR4/carD characterization paper (Louis, Ginsburg, Kimmel
      1994). PubMed-verified; the abstract directly supports the receptor, expression,
      localization, and loss-of-function patterning phenotypes cited. Full text not
      cached (abstract-only).
- id: PMID:2722797
  title: The cyclic nucleotide specificity of eight cAMP-binding proteins in Dictyostelium
    discoideum is correlated into three groups.
  findings:
  - statement: The Dictyostelium cell-surface cAMP receptors bind cAMP in a
      hydrophobic cleft and transduce the cAMP signal during chemotaxis and
      differentiation.
    supporting_text: cAMP is probably bound to the surface receptors in the anti
      conformation in a hydrophobic cleft of the receptor
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Biochemical characterization of cAMP-binding proteins including the
      cell-surface cAMP receptors; predates cloning of CAR4 (1994) so supports
      receptor-class cAMP binding rather than CAR4-specific data. Abstract-only.
- id: PMID:12408804
  title: Receptor-dependent and tyrosine phosphatase-mediated inhibition of GSK3 regulates
    cell fate choice.
  findings:
  - statement: CAR4 regulates a protein tyrosine phosphatase that inhibits GSK3
      activity, controlling cell-fate choice in a manner paralleling Wnt/Frizzled-GSK3
      signaling.
    supporting_text: We now show that CAR4 regulates a tyrosine phosphatase that
      inhibits GSK3 activity
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Directly establishes the CAR4 downstream signaling mechanism (PTP
      activation inhibiting GSK3). Supports the tyrosine-phosphatase-activator
      annotation as a signaling-mediated (indirect) role. Abstract-only.
- id: PMID:15473840
  title: Chemoattractant signaling in dictyostelium discoideum.
  findings:
  - statement: Review of Dictyostelium chemoattractant (cAMP) receptor signaling
      modules including cyclic AMP signaling.
    supporting_text: signaling via chemoattractant receptors
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review of cAMP chemoattractant signaling; source of several TAS
      annotations. General rather than CAR4-specific. Abstract-only.
core_functions:
- description: CAR4 is a seven-transmembrane G protein-coupled receptor that binds
    extracellular cAMP at the plasma membrane and, through heterotrimeric G proteins,
    transduces the cAMP signal to control late-development cell-type patterning and
    differentiation.
  molecular_function:
    id: GO:0001646
    label: cAMP receptor activity
  locations:
  - id: GO:0005886
    label: plasma membrane
  directly_involved_in:
  - id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  - id: GO:0030154
    label: cell differentiation
  supported_by:
  - reference_id: PMID:7958880
    supporting_text: the gene for a new cell-surface, G protein-linked cAMP receptor
  - reference_id: PMID:7958880
    supporting_text: cAMP signaling is required for pattern formation and cellular
      differentiation during late Dictyostelium development
  - reference_id: PMID:2722797
    supporting_text: cAMP is probably bound to the surface receptors in the anti
      conformation in a hydrophobic cleft of the receptor