gbpC

id: Q8MVR1
gene_symbol: gbpC
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: GbpC (cyclic GMP-binding protein C, also called GefT/RasGEFT and Roco1)
  is a very large (2631 aa) multidomain Roco-family protein and the principal
  intracellular effector of the second messenger cGMP in Dictyostelium discoideum.
  Its domain arrangement comprises N-terminal leucine-rich repeats, a Ras-like Roc
  GTPase domain, a COR domain, a MAP3K-like serine/threonine protein kinase domain,
  a RasGEF (CDC25) domain with an N-terminal RasGEF-N and DEP module, a GRAM domain,
  and two tandem cyclic-nucleotide-binding (cGMP-binding) domains. GbpC accounts for
  essentially all high-affinity cGMP binding in the soluble fraction of the cell.
  It operates as a self-contained intramolecular signaling cascade in which cGMP binding
  to the cyclic-nucleotide-binding domains stimulates the internal RasGEF domain to
  catalyze GDP/GTP exchange on the Roc domain, and GTP-loaded Roc in turn activates
  the C-terminal MAP3K-like kinase, whose phosphorylation of downstream targets is
  the functional output. GbpC is largely cytoplasmic in resting cells and translocates
  via its GRAM (phospholipid-binding) domain to the plasma membrane and F-actin-rich
  cell cortex upon chemoattractant (cAMP) stimulation. Functionally it governs the
  cGMP branch of chemotactic signaling, controlling myosin II regulation, cell
  polarity and the cell-rear/retraction response, and it contributes to electrotaxis
  directionality and to regulation of bleb-based motility.
existing_annotations:
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: GbpC contains a MAP3K-like serine/threonine protein kinase domain that
      constitutes the functional output of the protein. A kinase-dead mutant fails
      to rescue chemotaxis, confirming catalytic relevance. This is a core molecular
      function, though the more specific serine/threonine child term is preferable.
    action: ACCEPT
    reason: The kinase domain is experimentally essential for GbpC activity in vivo,
      making protein kinase activity a genuine core function of this Roco protein.
    supported_by:
    - reference_id: PMID:18703517
      supporting_text: Mutants that lack a functional guanine exchange factor (GEF),
        Roc, or kinase domain are inactive in vivo
    - reference_id: PMID:18703517
      supporting_text: 'a four-step intramolecular activation mechanism of the Roco
        protein GbpC: cGMP binding to the cyclic nucleotide-binding domains, activation
        of the GEF domain, GDP/GTP exchange of Roc, and activation of the MAPKKK domain'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: GbpC is predominantly cytoplasmic in resting cells and only translocates
      to the cell boundary upon stimulation. Cytoplasmic localization is well supported
      by direct evidence for this gene product.
    action: ACCEPT
    reason: Direct experimental data show GbpC resides in the cytoplasm of resting
      cells, consistent with the IBA inference.
    supported_by:
    - reference_id: PMID:22119747
      supporting_text: In resting cells, the protein is present in the cytoplasm,
        but GbpC rapidly translocates to the cell boundary upon stimulation with the
        chemoattractant cAMP
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: GbpC is a bona fide signal transducer (the cGMP effector of chemotactic
      signaling), so this annotation is correct but very general. More specific child
      terms (intracellular signal transduction, regulation of chemotaxis) capture
      its role better.
    action: KEEP_AS_NON_CORE
    reason: The term is accurate but too high-level to represent the specific cGMP
      signaling role; retained as non-core in favor of more precise process terms.
    supported_by:
    - reference_id: PMID:22119747
      supporting_text: cGMP-mediated GbpC activation is essential for the proper regulation
        of myosin II during chemotaxis
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based inference of protein kinase activity from the kinase domain.
      Redundant with the IBA annotation but consistent with the experimentally validated
      MAP3K-like kinase domain.
    action: ACCEPT
    reason: The protein kinase domain is present and functionally essential; the IEA
      inference is correct.
    supported_by:
    - reference_id: PMID:18703517
      supporting_text: Mutants that lack a functional guanine exchange factor (GEF),
        Roc, or kinase domain are inactive in vivo
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    summary: The GbpC kinase domain is a serine/threonine (MAP3K-like, TKL family)
      kinase per UniProt EC 2.7.11.1 and domain analysis. This more specific MF term
      accurately captures the catalytic output of GbpC.
    action: ACCEPT
    reason: Serine/threonine protein kinase activity is the precise molecular function
      of the GbpC kinase domain and a core function of the protein.
    supported_by:
    - reference_id: PMID:12011437
      supporting_text: 'GbpC contains the following nine domains (in order): leucine-rich
        repeats, Ras, MEK kinase, Ras guanine nucleotide exchange factor N-terminal
        (RasGEF-N), DEP, RasGEF, cGMP-binding, GRAM, and a second cGMP-binding domain'
    - reference_id: PMID:18703517
      supporting_text: 'a four-step intramolecular activation mechanism of the Roco
        protein GbpC: cGMP binding to the cyclic nucleotide-binding domains, activation
        of the GEF domain, GDP/GTP exchange of Roc, and activation of the MAPKKK domain'
- term:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: GbpC contains a RasGEF (CDC25) domain that has been directly shown to
      accelerate GDP/GTP exchange on its own Roc domain. The IEA inference is confirmed
      by direct biochemical evidence.
    action: ACCEPT
    reason: GEF activity is a core, experimentally demonstrated molecular function
      of the internal RasGEF domain of GbpC.
    supported_by:
    - reference_id: PMID:18703517
      supporting_text: the RasGEF domain of GbpC specifically accelerates the GDP/GTP
        exchange of the Roc domain
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ATP binding is inferred from the kinase domain. It is a correct supporting
      molecular function underlying the kinase activity but is not itself a distinctive
      core function.
    action: KEEP_AS_NON_CORE
    reason: ATP binding is a generic cofactor-binding activity intrinsic to the kinase
      domain; correct but subsidiary to the kinase activity annotation.
    supported_by:
    - reference_id: PMID:18703517
      supporting_text: Mutants that lack a functional guanine exchange factor (GEF),
        Roc, or kinase domain are inactive in vivo
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: ARBA machine-learning inference of cytoplasmic localization, consistent
      with direct evidence that GbpC is cytoplasmic in resting cells.
    action: ACCEPT
    reason: Cytoplasmic localization is well established for GbpC by direct experimental
      evidence.
    supported_by:
    - reference_id: PMID:22119747
      supporting_text: In resting cells, the protein is present in the cytoplasm,
        but GbpC rapidly translocates to the cell boundary upon stimulation with the
        chemoattractant cAMP
- term:
    id: GO:0007264
    label: small GTPase-mediated signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: GbpC harbors a Ras-like Roc GTPase domain that cycles between GDP- and
      GTP-bound states within its intramolecular cascade, so small GTPase-mediated
      signaling is mechanistically relevant. This is an accurate but mechanistic sub-aspect
      rather than the top-level function.
    action: KEEP_AS_NON_CORE
    reason: The intramolecular Roc GTPase switch is central to GbpC mechanism, but
      this process term is best retained as non-core relative to the cGMP/kinase output.
    supported_by:
    - reference_id: PMID:18703517
      supporting_text: the RasGEF domain of GbpC specifically accelerates the GDP/GTP
        exchange of the Roc domain
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: GbpC transduces the intracellular cGMP signal, so intracellular signal
      transduction is an appropriate process annotation.
    action: KEEP_AS_NON_CORE
    reason: Correct and more informative than bare signal transduction, but still
      a general process term relative to the specific chemotaxis/polarity roles.
    supported_by:
    - reference_id: PMID:22119747
      supporting_text: cGMP-mediated GbpC activation is essential for the proper regulation
        of myosin II during chemotaxis
- term:
    id: GO:0106310
    label: protein serine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: Rhea/EC-based inference of serine kinase activity, consistent with the
      Ser/Thr kinase (EC 2.7.11.1) MAP3K-like domain of GbpC.
    action: ACCEPT
    reason: Serine kinase activity accurately reflects the catalytic activity of the
      GbpC kinase domain.
    supported_by:
    - reference_id: PMID:18703517
      supporting_text: 'a four-step intramolecular activation mechanism of the Roco
        protein GbpC: cGMP binding to the cyclic nucleotide-binding domains, activation
        of the GEF domain, GDP/GTP exchange of Roc, and activation of the MAPKKK domain'
- term:
    id: GO:0019887
    label: protein kinase regulator activity
  evidence_type: IMP
  original_reference_id: PMID:16546177
  qualifier: enables
  review:
    summary: Loss of GbpC (or of cGMP) abrogates chemotaxis-induced activation of
      myosin light chain kinase A (MLCK-A). GbpC is thus genetically required for
      MLCK-A activation, but this is most likely an upstream/indirect effect (via
      the GbpC kinase cascade) rather than GbpC directly acting as a kinase-regulator
      module.
    action: KEEP_AS_NON_CORE
    reason: The IMP evidence supports a requirement of GbpC for MLCK-A activation,
      but the relationship is upstream and probably indirect; retained as non-core
      rather than a direct core molecular function.
    supported_by:
    - reference_id: PMID:16546177
      supporting_text: MLCK-A activation during chemotaxis is highly responsive to
        cellular cGMP levels and the cGMP-binding protein GbpC
- term:
    id: GO:0007163
    label: establishment or maintenance of cell polarity
  evidence_type: IMP
  original_reference_id: PMID:15827084
  qualifier: involved_in
  review:
    summary: gbpC-null cells fail to polarize effectively in a chemoattractant gradient,
      establishing a direct role for GbpC in chemotactic cell polarity through myosin
      II.
    action: ACCEPT
    reason: Strong loss-of-function evidence directly links GbpC to establishment
      of cell polarity during chemotaxis; a core biological role.
    supported_by:
    - reference_id: PMID:15827084
      supporting_text: gbpC-null cells display strongly reduced chemotaxis, because
        they are unable to polarise effectively in a chemotactic gradient
    - reference_id: PMID:15827084
      supporting_text: cGMP activates GbpC, mediating the chemoattractant-induced
        establishment of cell polarity through myosin
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22119747
  qualifier: located_in
  review:
    summary: Direct localization evidence shows GbpC is present in the cytoplasm of
      resting cells before chemoattractant-induced translocation.
    action: ACCEPT
    reason: Direct imaging demonstrates cytoplasmic localization of GbpC in resting
      cells.
    supported_by:
    - reference_id: PMID:22119747
      supporting_text: In resting cells, the protein is present in the cytoplasm,
        but GbpC rapidly translocates to the cell boundary upon stimulation with the
        chemoattractant cAMP
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IMP
  original_reference_id: PMID:22119747
  qualifier: located_in
  review:
    summary: Upon cAMP stimulation or osmotic shock GbpC translocates to the plasma
      membrane via its GRAM domain; GRAM-domain mutations disrupt membrane association
      and GbpC function. This is a genuine stimulus-dependent localization.
    action: ACCEPT
    reason: Both localization and GRAM-domain mutant analysis support plasma-membrane
      association as a functionally important localization of GbpC.
    supported_by:
    - reference_id: PMID:22119747
      supporting_text: the protein localizes toward the plasma membrane and actin
        cytoskeleton
    - reference_id: PMID:22119747
      supporting_text: cAMP induces a GRAM-dependent translocation of GbpC toward
        the plasma membrane and cell cortex
- term:
    id: GO:0005938
    label: cell cortex
  evidence_type: IDA
  original_reference_id: PMID:22119747
  qualifier: located_in
  review:
    summary: After stimulation GbpC enriches in the F-actin-rich cell cortex, where
      it is thought to phosphorylate effector proteins. Directly supported localization.
    action: ACCEPT
    reason: Direct evidence places stimulated GbpC at the cell cortex, consistent
      with its role in cortical myosin regulation.
    supported_by:
    - reference_id: PMID:22119747
      supporting_text: cAMP induces a GRAM-dependent translocation of GbpC toward
        the plasma membrane and cell cortex
- term:
    id: GO:0031252
    label: cell leading edge
  evidence_type: IDA
  original_reference_id: PMID:19346484
  qualifier: located_in
  review:
    summary: This paper reports that GCase- and PI3K-pathway signaling components localize
      at the leading edge during electrotaxis, but the cached text does not explicitly
      document GbpC-specific leading-edge localization (GbpC is classically associated
      with the cell rear/retraction). Cannot verify the GbpC-specific claim from the
      available text.
    action: UNDECIDED
    reason: The full text may contain GbpC-specific localization imaging not captured
      in the cached article; leading-edge localization is not clearly attributable
      to GbpC from the accessible text, so no confident action is taken.
- term:
    id: GO:0032060
    label: bleb assembly
  evidence_type: IGI
  original_reference_id: PMID:26317626
  qualifier: acts_upstream_of_or_within
  review:
    summary: In a genetic (mutant) blebbing screen, gbpC/gbpD-deficient cells extended
      blebs more frequently than wild type, indicating GbpC acts within the regulation
      of bleb-based protrusion. A specialized, non-core process role.
    action: KEEP_AS_NON_CORE
    reason: Genetic evidence supports GbpC involvement in regulating blebbing, but
      this is a peripheral process relative to the core cGMP/kinase signaling function.
    supported_by:
    - reference_id: PMID:26317626
      supporting_text: cells deficient in gbpC-/gbpD (guanylate cyclases), pkgB (serine/threonine-protein
        kinase), iplA (Ca2+ channel), or pi3k (phosphatidylinositol 3-kinase) extended
        blebs more frequently than wild type cells
- term:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  evidence_type: IDA
  original_reference_id: PMID:18703517
  qualifier: enables
  review:
    summary: Direct in vitro nucleotide-exchange assays show the isolated GbpC RasGEF
      domain specifically accelerates GDP/GTP exchange on its own Roc domain (and
      not on other Ras/Rap proteins). This is the strongest evidence for the GEF core
      function.
    action: ACCEPT
    reason: Direct biochemical demonstration of specific GEF activity toward the Roc
      domain; a core molecular function of GbpC.
    supported_by:
    - reference_id: PMID:18703517
      supporting_text: the RasGEF domain of GbpC specifically accelerates the GDP/GTP
        exchange of the Roc domain
- term:
    id: GO:0051602
    label: response to electrical stimulus
  evidence_type: IMP
  original_reference_id: PMID:19346484
  qualifier: acts_upstream_of_or_within
  review:
    summary: Genetic modulation of GbpC (with guanylyl cyclases) can reverse the preferred
      migration direction during electrotaxis, implicating GbpC in the cellular response
      to a direct-current electric field. A specialized process role.
    action: KEEP_AS_NON_CORE
    reason: GbpC contributes to electrotaxis directionality via the cGMP pathway,
      but this is a context-specific process rather than a core function.
    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) and the cyclic guanosine monophosphate (cGMP)-binding protein
        C (GbpC)
- term:
    id: GO:0030553
    label: cGMP binding
  evidence_type: IMP
  original_reference_id: PMID:12011437
  qualifier: enables
  review:
    summary: Disruption of gbpC eliminates all high-affinity cGMP-binding activity
      in the soluble cell fraction, establishing GbpC as the principal high-affinity
      cGMP receptor in Dictyostelium. This is a defining core molecular function.
    action: ACCEPT
    reason: GbpC accounts for the cell's high-affinity cGMP binding; cGMP binding
      is the central input function of this cGMP effector.
    supported_by:
    - reference_id: PMID:12011437
      supporting_text: Disruption of the gbpC gene results in loss of all high-affinity
        cGMP-binding activity present in the soluble cellular fraction
    - reference_id: PMID:18703517
      supporting_text: Because GbpC is the only high affinity cGMP-target in Dictyostelium
- term:
    id: GO:0005543
    label: phospholipid binding
  evidence_type: IDA
  original_reference_id: PMID:22119747
  qualifier: enables
  review:
    summary: The GbpC GRAM domain binds various phospholipids in vitro and mediates
      membrane association. A real molecular function underlying stimulus-dependent
      membrane targeting, but subsidiary to the cGMP/kinase signaling core.
    action: KEEP_AS_NON_CORE
    reason: Phospholipid binding by the GRAM domain is directly demonstrated and functionally
      relevant for localization, but serves the membrane-targeting mechanism rather
      than being a top-level output function.
    supported_by:
    - reference_id: PMID:22119747
      supporting_text: the GRAM domain itself associates with cellular membranes and
        binds various phospholipids in vitro
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IDA
  original_reference_id: PMID:22119747
  qualifier: enables
  review:
    summary: The Ras-like Roc domain of GbpC binds GTP; GTP-agarose pulldowns and
      P-loop (K342N) mutagenesis confirmed that GTP binding is mediated by the Roc
      domain. Intrinsic to the intramolecular Roc GTPase switch.
    action: ACCEPT
    reason: Direct evidence shows GbpC binds GTP through its Roc domain, a core mechanistic
      activity of this Roco protein.
    supported_by:
    - reference_id: PMID:18703517
      supporting_text: confirming that GTP binding is mediated by the Roc domain
- term:
    id: GO:0030553
    label: cGMP binding
  evidence_type: IDA
  original_reference_id: PMID:18673369
  qualifier: enables
  review:
    summary: cGMP binding is a well-established core function of GbpC (it is the only
      high-affinity cGMP target in Dictyostelium). However, the cited reference PMID:18673369
      is a Legionella pneumophila SidC study unrelated to GbpC, so the identifier
      appears mis-attributed. The function itself is correct and supported by the
      GbpC literature.
    action: ACCEPT
    reason: The cGMP-binding function is genuine and central; the annotation is retained
      but the original reference is mis-cited (see reference_review for PMID:18673369).
      Support is provided from the correct GbpC literature.
    supported_by:
    - reference_id: PMID:18703517
      supporting_text: Because GbpC is the only high affinity cGMP-target in Dictyostelium
    - reference_id: PMID:12011437
      supporting_text: Disruption of the gbpC gene results in loss of all high-affinity
        cGMP-binding activity present in the soluble cellular fraction
- term:
    id: GO:0046579
    label: positive regulation of Ras protein signal transduction
  evidence_type: IDA
  original_reference_id: PMID:18703517
  qualifier: involved_in
  review:
    summary: The GbpC RasGEF domain positively regulates the GbpC Ras-like Roc domain
      by catalyzing GDP/GTP exchange, driving it into the active GTP-bound state.
      A directly demonstrated regulatory role in (intramolecular) Ras-type signaling.
    action: ACCEPT
    reason: Direct evidence shows GbpC GEF activity positively regulates its Roc (Ras-like)
      GTPase, consistent with this process term.
    supported_by:
    - reference_id: PMID:18703517
      supporting_text: the RasGEF domain of GbpC specifically accelerates the GDP/GTP
        exchange of the Roc domain
- term:
    id: GO:0050920
    label: regulation of chemotaxis
  evidence_type: IMP
  original_reference_id: PMID:18673369
  qualifier: acts_upstream_of_or_within
  review:
    summary: GbpC is a key regulator of Dictyostelium chemotaxis via the cGMP pathway,
      a well-supported function. The cited reference PMID:18673369, however, is a
      Legionella SidC paper unrelated to GbpC and appears mis-attributed; the same
      function is properly supported by PMID:15827084.
    action: ACCEPT
    reason: Regulation of chemotaxis is a genuine core process for GbpC; the annotation
      is retained but the original reference is mis-cited (see reference_review for
      PMID:18673369), with support drawn from the correct GbpC study.
    supported_by:
    - reference_id: PMID:15827084
      supporting_text: gbpC-null cells display strongly reduced chemotaxis, because
        they are unable to polarise effectively in a chemotactic gradient
- term:
    id: GO:0031589
    label: cell-substrate adhesion
  evidence_type: IMP
  original_reference_id: PMID:15827084
  qualifier: acts_upstream_of_or_within
  review:
    summary: In this paper the increased-adhesion / substrate-attached-pseudopod phenotype
      is attributed to GbpD (and its overexpression), not to GbpC, whose phenotype
      is reduced chemotaxis/polarity. The cached abstract does not document a GbpC-specific
      adhesion phenotype, so this annotation cannot be verified from the accessible text.
    action: UNDECIDED
    reason: The adhesion phenotype in this study is associated with the paralog GbpD;
      a GbpC-specific cell-substrate adhesion role is not verifiable from the available
      text. Per policy the experimental IMP annotation is not overruled, but it is
      left undecided pending full-text confirmation.
- term:
    id: GO:0050920
    label: regulation of chemotaxis
  evidence_type: IMP
  original_reference_id: PMID:15827084
  qualifier: acts_upstream_of_or_within
  review:
    summary: gbpC-null cells show strongly reduced chemotaxis due to failed polarization,
      directly demonstrating that GbpC regulates chemotaxis through the cGMP/myosin II
      pathway. A core biological role.
    action: ACCEPT
    reason: Loss-of-function evidence firmly establishes GbpC as a regulator of chemotaxis.
    supported_by:
    - reference_id: PMID:15827084
      supporting_text: gbpC-null cells display strongly reduced chemotaxis, because
        they are unable to polarise effectively in a chemotactic gradient
    - reference_id: PMID:22119747
      supporting_text: cGMP-mediated GbpC activation is essential for the proper regulation
        of myosin II during chemotaxis
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:12011437
  title: Identification of four candidate cGMP targets in Dictyostelium.
  findings:
  - statement: GbpC is a nine-domain protein containing leucine-rich repeats, a Ras
      (Roc) domain, a MEK/MAP3K-like kinase, RasGEF-N, DEP, RasGEF, and two cGMP-binding
      domains flanking a GRAM domain.
    supporting_text: 'GbpC contains the following nine domains (in order): leucine-rich
      repeats, Ras, MEK kinase, Ras guanine nucleotide exchange factor N-terminal
      (RasGEF-N), DEP, RasGEF, cGMP-binding, GRAM, and a second cGMP-binding domain'
  - statement: Disruption of gbpC removes all high-affinity cGMP-binding activity
      in the soluble fraction, identifying GbpC as the principal cGMP receptor.
    supporting_text: Disruption of the gbpC gene results in loss of all high-affinity
      cGMP-binding activity present in the soluble cellular fraction
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Original identification of GbpC and its domain architecture; abstract
      confirms it is the dominant high-affinity cGMP-binding protein.
- id: PMID:15827084
  title: RasGEF-containing proteins GbpC and GbpD have differential effects on cell
    polarity and chemotaxis in Dictyostelium.
  findings:
  - statement: gbpC-null cells display strongly reduced chemotaxis because they cannot
      polarize in a chemotactic gradient.
    supporting_text: gbpC-null cells display strongly reduced chemotaxis, because
      they are unable to polarise effectively in a chemotactic gradient
  - statement: cGMP activates GbpC to mediate chemoattractant-induced cell polarity
      through myosin, whereas GbpD promotes substrate attachment.
    supporting_text: cGMP activates GbpC, mediating the chemoattractant-induced establishment
      of cell polarity through myosin
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes GbpC's role in chemotactic polarity via myosin; the
      adhesion phenotype in this paper belongs to the paralog GbpD, not GbpC.
- id: PMID:16546177
  title: Myosin light chain kinase A is activated by cGMP-dependent and cGMP-independent
    pathways.
  findings:
  - statement: Activation of myosin light chain kinase A during chemotaxis depends
      on cGMP levels and on GbpC.
    supporting_text: MLCK-A activation during chemotaxis is highly responsive to cellular
      cGMP levels and the cGMP-binding protein GbpC
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Places GbpC upstream of MLCK-A activation in the chemotaxis myosin
      pathway; supports an indirect kinase-regulatory role.
- id: PMID:18673369
  title: The Legionella pneumophila phosphatidylinositol-4 phosphate-binding type
    IV substrate SidC recruits endoplasmic reticulum vesicles to a replication-permissive
    vacuole.
  findings: []
  reference_review:
    relevance: NONE
    correctness: WRONG_IDENTIFIER
    review_notes: This PMID is a Legionella pneumophila SidC effector study with no
      relation to GbpC or cGMP binding. It is cited in GOA as the reference for GbpC
      cGMP binding (IDA) and regulation of chemotaxis (IMP); those functions are genuine
      but the identifier is mis-attributed. The correct GbpC references are PMID:12011437,
      PMID:18703517 and PMID:15827084.
- id: PMID:18703517
  title: Intramolecular activation mechanism of the Dictyostelium LRRK2 homolog Roco
    protein GbpC.
  findings:
  - statement: The GbpC RasGEF domain specifically accelerates GDP/GTP exchange on
      its own Roc domain and on no other tested Ras/Rap GTPase.
    supporting_text: the RasGEF domain of GbpC specifically accelerates the GDP/GTP
      exchange of the Roc domain
  - statement: cGMP binding stimulates GbpC binding to GTP-agarose, indicating cGMP-stimulated
      GDP/GTP exchange at the Roc domain.
    supporting_text: cGMP binding to GbpC strongly stimulates the binding of GbpC
      to GTP-agarose
  - statement: GbpC operates as a four-step intramolecular cascade from cGMP binding
      through GEF activation and Roc exchange to MAP3K activation.
    supporting_text: 'a four-step intramolecular activation mechanism of the Roco protein
      GbpC: cGMP binding to the cyclic nucleotide-binding domains, activation of the
      GEF domain, GDP/GTP exchange of Roc, and activation of the MAPKKK domain'
  - statement: GbpC is the only high-affinity cGMP target in Dictyostelium; functional
      GEF, Roc, and kinase domains are all required in vivo.
    supporting_text: Mutants that lack a functional guanine exchange factor (GEF),
      Roc, or kinase domain are inactive in vivo
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full-text PMC article; directly demonstrates the intramolecular
      cGMP to GEF to Roc to kinase signaling cascade underpinning several core molecular
      functions.
- id: PMID:19346484
  title: Switching direction in electric-signal-induced cell migration by cyclic guanosine
    monophosphate and phosphatidylinositol signaling.
  findings:
  - statement: Genetic modulation of GbpC together with guanylyl cyclases can reverse
      the direction of migration during electrotaxis.
    supporting_text: the preferential direction of migration during electrotaxis in
      Dictyostelium cells can be reversed by genetically modulating both guanylyl
      cyclases (GCases) and the cyclic guanosine monophosphate (cGMP)-binding protein
      C (GbpC)
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports a GbpC role in electrotaxis directionality; the cached
      text does not clearly document GbpC-specific leading-edge localization.
- id: PMID:22119747
  title: Multiple regulatory mechanisms for the Dictyostelium Roco protein GbpC.
  findings:
  - statement: GbpC is cytoplasmic in resting cells and translocates to the cell boundary
      upon cAMP stimulation.
    supporting_text: In resting cells, the protein is present in the cytoplasm, but
      GbpC rapidly translocates to the cell boundary upon stimulation with the chemoattractant
      cAMP
  - statement: The GRAM domain binds phospholipids and mediates GbpC translocation
      to the plasma membrane and cell cortex.
    supporting_text: cAMP induces a GRAM-dependent translocation of GbpC toward the
      plasma membrane and cell cortex
  - statement: cGMP-mediated GbpC activation is essential for proper regulation of
      myosin II during chemotaxis.
    supporting_text: cGMP-mediated GbpC activation is essential for the proper regulation
      of myosin II during chemotaxis
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full-text PMC article; establishes the GRAM-dependent membrane/cortex
      localization and phospholipid-binding activity of GbpC.
- id: PMID:26317626
  title: Microtubule-Mediated Inositol Lipid Signaling Plays Critical Roles in Regulation
    of Blebbing.
  findings:
  - statement: gbpC/gbpD-deficient cells extend blebs more frequently than wild type,
      implicating GbpC in regulation of blebbing.
    supporting_text: cells deficient in gbpC-/gbpD (guanylate cyclases), pkgB (serine/threonine-protein
      kinase), iplA (Ca2+ channel), or pi3k (phosphatidylinositol 3-kinase) extended
      blebs more frequently than wild type cells
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Genetic blebbing screen; note the paper parenthetically mislabels
      gbpC/gbpD as guanylate cyclases, but the mutant blebbing phenotype is the basis
      for the IGI annotation.
suggested_questions:
- question: >-
    What is the physiological in vivo substrate of the GbpC MAP3K-like kinase
    domain that links cGMP binding to myosin II regulation at the cell rear
    during chemotaxis?
core_functions:
- description: GbpC is the principal high-affinity intracellular cGMP receptor in
    Dictyostelium; cGMP binding to its tandem cyclic-nucleotide-binding domains is
    the sensing event that initiates the intramolecular signaling cascade controlling
    chemotaxis.
  molecular_function:
    id: GO:0030553
    label: cGMP binding
  directly_involved_in:
  - id: GO:0035556
    label: intracellular signal transduction
  - id: GO:0050920
    label: regulation of chemotaxis
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:12011437
    supporting_text: Disruption of the gbpC gene results in loss of all high-affinity
      cGMP-binding activity present in the soluble cellular fraction
  - reference_id: PMID:18703517
    supporting_text: Because GbpC is the only high affinity cGMP-target in Dictyostelium
- description: GbpC contains an internal RasGEF (CDC25) domain that specifically catalyzes
    GDP/GTP exchange on its own Ras-like Roc GTPase domain, converting the cGMP-binding
    signal into activation of the Roc GTPase within a single polypeptide.
  molecular_function:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  directly_involved_in:
  - id: GO:0046579
    label: positive regulation of Ras protein signal transduction
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:18703517
    supporting_text: the RasGEF domain of GbpC specifically accelerates the GDP/GTP
      exchange of the Roc domain
- description: The C-terminal MAP3K-like serine/threonine protein kinase domain is
    the catalytic output of GbpC; activated downstream of the Roc GTPase, it phosphorylates
    effector proteins to control myosin II regulation, cell polarity and the cell-rear
    retraction response during chemotaxis. The kinase domain is essential for GbpC
    function in vivo.
  molecular_function:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  directly_involved_in:
  - id: GO:0050920
    label: regulation of chemotaxis
  - id: GO:0007163
    label: establishment or maintenance of cell polarity
  locations:
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0005938
    label: cell cortex
  supported_by:
  - reference_id: PMID:18703517
    supporting_text: 'a four-step intramolecular activation mechanism of the Roco protein
      GbpC: cGMP binding to the cyclic nucleotide-binding domains, activation of the
      GEF domain, GDP/GTP exchange of Roc, and activation of the MAPKKK domain'
  - reference_id: PMID:18703517
    supporting_text: Mutants that lack a functional guanine exchange factor (GEF),
      Roc, or kinase domain are inactive in vivo
  - reference_id: PMID:22119747
    supporting_text: cGMP-mediated GbpC activation is essential for the proper regulation
      of myosin II during chemotaxis