pkaR

id: P05987
gene_symbol: pkaR
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: pkaR encodes the single regulatory (R) subunit of cAMP-dependent
  protein kinase (PKA) in Dictyostelium discoideum. It binds the catalytic
  subunit pkaC to form the inactive PKA holoenzyme, which in this organism is an
  unusual R-C dimer rather than the R2C2 tetramer of most eukaryotes, because the
  R subunit lacks the N-terminal dimerization domain. The R subunit carries a
  single high-affinity cAMP-binding site (Kd in the low nanomolar range); binding
  of cAMP releases the active catalytic subunit. Through this cAMP-gated
  inhibition of pkaC, pkaR is the intracellular cAMP sensor that gates PKA
  activity throughout the Dictyostelium developmental program, including
  aggregation and cAMP relay, prespore and prestalk/stalk cell differentiation,
  culmination, and sporulation. Loss-of-function or inhibitor-defective mutations
  in the R subunit, such as the rdeC allele, cause premature heterochronic
  terminal differentiation by unleashing constitutive catalytic-subunit activity.
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference of cytosolic localization. PKA-R is a soluble
      subunit of the cytosolic PKA holoenzyme, and biochemical purification
      recovers it as a soluble protein, so this is a correct but non-core
      localization annotation.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization is consistent with the biochemistry of the
      soluble PKA holoenzyme and is corroborated by a separate TAS annotation.
      It is a valid location but not the core molecular function of the gene.
    supported_by:
    - reference_id: PMID:26485773
      supporting_text: the rest is recovered in the form of dissociated
        regulatory and catalytic subunits
- term:
    id: GO:0005952
    label: cAMP-dependent protein kinase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: PKA-R is part of the cAMP-dependent protein kinase holoenzyme. In
      Dictyostelium this holoenzyme is an R-C dimer. This is a core structural
      annotation and is corroborated by direct experimental evidence.
    action: ACCEPT
    reason: The regulatory subunit is by definition a component of the PKA
      complex; direct biochemical evidence shows the Dictyostelium holoenzyme is
      a dimer of one R and one C subunit.
    supported_by:
    - reference_id: PMID:26485773
      supporting_text: holoenzyme is a dimer consisting of one regulatory and one
        catalytic subunit
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: cAMP binding is a core molecular function of the regulatory subunit,
      well supported by direct experimental measurement of a high-affinity
      cAMP-binding site.
    action: ACCEPT
    reason: The R subunit carries a high-affinity cAMP-binding site (Kd in the
      low nanomolar range); cAMP binding is the sensing event that gates PKA
      activation. This is a core function.
    supported_by:
    - reference_id: PMID:16453431
      supporting_text: The protein is highly specific for cAMP and has a
        dissociation constant of 4 nM
- 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: Phylogenetic inference placing PKA-R in the adenylate
      cyclase/cAMP signaling cascade. In Dictyostelium PKA acts downstream of
      cAMP and is required for cAMP relay, so participation in this signaling
      pathway is defensible but represents a broad pathway-level annotation
      rather than the core function.
    action: KEEP_AS_NON_CORE
    reason: PKA activity is required for the cAMP relay that drives aggregation,
      linking it to adenylate cyclase-based signaling. The annotation is
      biologically reasonable at the pathway level but is not the core molecular
      role of the R subunit.
    supported_by:
    - reference_id: PMID:1728597
      supporting_text: are defective in cAMP relay, the production of cAMP in
        response to extracellular cAMP stimulation
- term:
    id: GO:0004862
    label: cAMP-dependent protein kinase inhibitor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: cAMP-dependent protein kinase inhibitor activity is the defining
      core function of the R subunit. It binds and inhibits the catalytic
      subunit, an inhibition relieved by cAMP. Strongly supported by direct
      experimental evidence.
    action: ACCEPT
    reason: The R subunit inhibits catalytic-subunit activity in a
      cAMP-reversible manner, which is its central molecular function.
    supported_by:
    - reference_id: PMID:16453431
      supporting_text: This subunit inhibits the activity of purified catalytic
        subunit from beef heart protein kinase; the inhibition is reversed upon
        addition of cAMP
- term:
    id: GO:0034236
    label: protein kinase A catalytic subunit binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Binding to the PKA catalytic subunit is a core function of the R
      subunit and is directly supported by co-purification and reconstitution
      studies with pkaC.
    action: ACCEPT
    reason: The R subunit physically associates with the catalytic subunit to
      form the holoenzyme; this binding is the physical basis of its inhibitory
      function.
    supported_by:
    - reference_id: PMID:8373760
      supporting_text: It is physically associated with the regulatory subunit,
        and this association results in an inhibition of the catalytic activity
        which is reverted by cAMP
- term:
    id: GO:0005952
    label: cAMP-dependent protein kinase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: InterPro/ARBA electronic annotation to the PKA complex, redundant
      with the IBA and IDA annotations to the same term. Correct.
    action: ACCEPT
    reason: Consistent with the direct experimental evidence that PKA-R is part
      of the cAMP-dependent protein kinase holoenzyme.
    supported_by:
    - reference_id: PMID:26485773
      supporting_text: holoenzyme is a dimer consisting of one regulatory and one
        catalytic subunit
- term:
    id: GO:0008603
    label: cAMP-dependent protein kinase regulator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO electronic annotation to PKA regulator activity. This is
      a correct parent-level molecular function; the more specific
      cAMP-dependent protein kinase inhibitor activity is also annotated with
      experimental evidence.
    action: ACCEPT
    reason: The R subunit is the regulator of PKA activity; regulator activity is
      correct and directly supported experimentally.
    supported_by:
    - reference_id: PMID:2450571
      supporting_text: the ability to inhibit the catalytic (C) subunit through
        protein-protein interaction
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA electronic annotation. PKA activity does positively regulate
      developmental gene expression such as spore coat genes, a role better
      captured by the experimentally supported annotations to this term. As a
      family-level electronic inference it is a downstream process rather than a
      core function.
    action: KEEP_AS_NON_CORE
    reason: The PKA pathway positively regulates prespore/spore gene expression,
      but for the R subunit this is a downstream developmental process, not its
      core molecular function.
    supported_by:
    - reference_id: PMID:7713325
      supporting_text: expression of a dominant inhibitor of the cAMP dependent
        protein kinase (PKA) in prespore cells greatly reduces the transcription
        rates of the cotB and cotC genes
- term:
    id: GO:0045595
    label: regulation of cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA electronic annotation. PKA is a master regulator of cell-type
      differentiation in Dictyostelium, so this general process term is
      biologically valid but broad and non-core.
    action: KEEP_AS_NON_CORE
    reason: PKA activity controls prestalk/prespore and terminal differentiation;
      the term is correct at a general level but is a downstream developmental
      process, not the core molecular function of the R subunit.
    supported_by:
    - reference_id: PMID:1312226
      supporting_text: Inactivation of this protein results in the unrestrained
        activity of the catalytic subunit, so prematurely triggering terminal
        cell differentiation
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:8565818
  qualifier: involved_in
  review:
    summary: IMP annotation reflecting that PKA activity induces terminal
      differentiation and cell-type gene expression. Valid developmental process
      but general and non-core.
    action: KEEP_AS_NON_CORE
    reason: Manipulation of PKA activity alters cell-type-specific gene
      expression during terminal differentiation. This is a downstream role of
      the PKA pathway rather than the core molecular function of the R subunit.
    supported_by:
    - reference_id: PMID:8565818
      supporting_text: Expression of the catalytic (C) subunit of the
        cAMP-dependent protein kinase (PKA) of Dictyostelium under the control of
        heterologous, cell-type-specific promoters causes ectopic terminal
        differentiation
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IDA
  original_reference_id: PMID:7713325
  qualifier: involved_in
  review:
    summary: PKA is a positive regulator of spore coat (cot) gene transcription;
      expression of a dominant PKA inhibitor reduces cotB/cotC transcription.
      Well-supported developmental process, kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: Directly supported role of PKA in positively regulating spore coat
      gene transcription. This is a downstream developmental output of the PKA
      pathway rather than the core molecular function of the R subunit.
    supported_by:
    - reference_id: PMID:7713325
      supporting_text: expression of a dominant inhibitor of the cAMP dependent
        protein kinase (PKA) in prespore cells greatly reduces the transcription
        rates of the cotB and cotC genes
- term:
    id: GO:0008603
    label: cAMP-dependent protein kinase regulator activity
  evidence_type: IMP
  original_reference_id: PMID:1728597
  qualifier: enables
  review:
    summary: Mutational analysis of the R subunit (defective in cAMP binding
      and/or C-subunit inhibition) directly demonstrates its regulator activity
      toward PKA. Core molecular function.
    action: ACCEPT
    reason: Structure-function mutagenesis of the R subunit confirms it regulates
      catalytic-subunit activity; this is a core function.
    supported_by:
    - reference_id: PMID:1728597
      supporting_text: we have constructed mutants of the R subunit that are
        defective in cAMP binding, in inhibition of the C subunit, or in both
        functions
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: IDA
  original_reference_id: PMID:1728597
  qualifier: enables
  review:
    summary: Direct demonstration of cAMP binding by the R subunit via mutants
      specifically defective in cAMP binding. Core molecular function.
    action: ACCEPT
    reason: cAMP binding by the R subunit is directly demonstrated and is a core
      sensing function.
    supported_by:
    - reference_id: PMID:1728597
      supporting_text: we have constructed mutants of the R subunit that are
        defective in cAMP binding, in inhibition of the C subunit, or in both
        functions
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: TAS
  original_reference_id: PMID:15548420
  qualifier: located_in
  review:
    summary: TAS annotation to centrosome from a review of the Dictyostelium
      centrosome proteome. A plausible anchored pool of PKA, but a secondary
      localization rather than the core function.
    action: KEEP_AS_NON_CORE
    reason: Centrosomal localization is reported at the level of the centrosome
      proteome review; it represents a minor/anchored pool and is not the core
      molecular function of the gene.
    supported_by: []
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: located_in
  review:
    summary: TAS cytosolic localization from a chemoattractant-signaling review,
      consistent with PKA being a soluble cytosolic kinase. Correct but non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization is consistent with the soluble PKA holoenzyme
      but is a location annotation, not the core molecular function.
    supported_by: []
- term:
    id: GO:0005952
    label: cAMP-dependent protein kinase complex
  evidence_type: IDA
  original_reference_id: PMID:26485773
  qualifier: part_of
  review:
    summary: Direct biochemical evidence that the Dictyostelium PKA holoenzyme is
      a dimer of one regulatory and one catalytic subunit. Core structural
      annotation.
    action: ACCEPT
    reason: The R subunit is a direct component of the purified PKA holoenzyme
      complex.
    supported_by:
    - reference_id: PMID:26485773
      supporting_text: holoenzyme is a dimer consisting of one regulatory and one
        catalytic subunit
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:1728597
  qualifier: involved_in
  review:
    summary: IMP evidence that PKA activity is required for expression of
      postaggregative genes. Valid downstream developmental process, non-core.
    action: KEEP_AS_NON_CORE
    reason: PKA activity is required for postaggregative gene expression; this is
      a downstream developmental output rather than the core molecular function
      of the R subunit.
    supported_by:
    - reference_id: PMID:1728597
      supporting_text: a number of postaggregative genes are not expressed in
        PKA- cells
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:28057864
  qualifier: involved_in
  review:
    summary: PKA activity mediates c-di-GMP-induced stalk gene expression at the
      organizer; PKA activation bypasses the c-di-GMP requirement. Valid
      developmental process, non-core.
    action: KEEP_AS_NON_CORE
    reason: PKA positively regulates stalk gene transcription downstream of
      c-di-GMP; this is a downstream developmental output rather than the core
      molecular function of the R subunit.
    supported_by:
    - reference_id: PMID:28057864
      supporting_text: knockdown of cAMP-dependent protein kinase (PKA) activity
        in prestalk cells reduced stalk gene induction by c-di-GMP, whereas PKA
        activation bypassed the c-di-GMP requirement for stalk gene expression
- term:
    id: GO:0106070
    label: regulation of adenylate cyclase-activating G protein-coupled receptor signaling
      pathway
  evidence_type: IMP
  original_reference_id: PMID:1728597
  qualifier: involved_in
  review:
    summary: PKA-defective cells are defective in cAMP relay (production of cAMP
      in response to extracellular cAMP), indicating PKA regulates the adenylate
      cyclase-based signaling pathway. Valid pathway-level regulation, non-core.
    action: KEEP_AS_NON_CORE
    reason: PKA activity is required for the cAMP relay and thus feeds back on the
      adenylate cyclase signaling pathway; this is a pathway-level developmental
      role rather than the core molecular function.
    supported_by:
    - reference_id: PMID:1728597
      supporting_text: are defective in cAMP relay, the production of cAMP in
        response to extracellular cAMP stimulation
- term:
    id: GO:0004862
    label: cAMP-dependent protein kinase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:2450571
  qualifier: enables
  review:
    summary: Recombinant R subunit directly inhibits the catalytic subunit
      through protein-protein interaction. Core molecular function.
    action: ACCEPT
    reason: Direct biochemical demonstration of catalytic-subunit inhibition by
      the R subunit; this is a core function.
    supported_by:
    - reference_id: PMID:2450571
      supporting_text: the ability to inhibit the catalytic (C) subunit through
        protein-protein interaction
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8373760
  qualifier: enables
  review:
    summary: IPI protein-binding annotation with the catalytic subunit pkaC
      (UniProtKB:P34099) as partner. The bare protein binding term is
      uninformative; the interaction is specifically with the PKA catalytic
      subunit, captured by the more specific GO:0034236.
    action: MODIFY
    reason: The interactor is the PKA catalytic subunit, so the specific term
      protein kinase A catalytic subunit binding is more informative than the
      generic protein binding.
    proposed_replacement_terms:
    - id: GO:0034236
      label: protein kinase A catalytic subunit binding
    supported_by:
    - reference_id: PMID:8373760
      supporting_text: It is physically associated with the regulatory subunit,
        and this association results in an inhibition of the catalytic activity
        which is reverted by cAMP
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9435289
  qualifier: enables
  review:
    summary: IPI protein-binding annotation with the RegA cAMP-phosphodiesterase
      (UniProtKB:Q23917) as partner. RegA is stimulated by binding to PKA-R.
      This is a real, functionally meaningful interaction, but the bare protein
      binding term is uninformative and there is no specific MF child term for
      phosphodiesterase binding.
    action: KEEP_AS_NON_CORE
    reason: The interaction with the RegA phosphodiesterase is genuine and
      functionally relevant to the PKA/RegA regulatory circuit, but the generic
      protein binding term is uninformative and this is not the core molecular
      function.
    supported_by:
    - reference_id: PMID:9435289
      supporting_text: A cAMP-specific phosphodiesterase was found that is
        stimulated by binding to the regulatory subunit of cAMP-dependent protein
        kinase, PKA-R
- term:
    id: GO:0008603
    label: cAMP-dependent protein kinase regulator activity
  evidence_type: IMP
  original_reference_id: PMID:1312226
  qualifier: enables
  review:
    summary: The rdeC mutation in the R subunit unleashes constitutive catalytic
      activity, directly demonstrating the R subunit's regulator activity toward
      PKA. Core molecular function.
    action: ACCEPT
    reason: Genetic inactivation of the R subunit causes unrestrained
      catalytic-subunit activity, confirming its role as the PKA regulator.
    supported_by:
    - reference_id: PMID:1312226
      supporting_text: Inactivation of this protein results in the unrestrained
        activity of the catalytic subunit, so prematurely triggering terminal
        cell differentiation
- term:
    id: GO:0008603
    label: cAMP-dependent protein kinase regulator activity
  evidence_type: IDA
  original_reference_id: PMID:26485773
  qualifier: enables
  review:
    summary: Purified R subunit inhibits the catalytic subunit in a
      cAMP-reversible manner, directly demonstrating regulator activity. Core
      molecular function.
    action: ACCEPT
    reason: Direct biochemical evidence of the R subunit regulating PKA activity.
    supported_by:
    - reference_id: PMID:26485773
      supporting_text: The regulatory subunit is a monomeric protein of M, 42 000
        that carries only one cAMP binding site
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: IMP
  original_reference_id: PMID:1312226
  qualifier: enables
  review:
    summary: The rdeC mutant R subunit still binds cAMP but poorly inhibits the C
      subunit, dissociating the cAMP-binding and inhibitory functions and
      confirming cAMP binding as an R-subunit property. Core molecular function.
    action: ACCEPT
    reason: The R subunit's cAMP-binding activity is genetically established and
      is a core sensing function.
    supported_by:
    - reference_id: PMID:1312226
      supporting_text: We have traced the lesion in one class of these mutants to
        the regulatory subunit of cyclic AMP-dependent protein kinase
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: IDA
  original_reference_id: PMID:16453431
  qualifier: enables
  review:
    summary: Purified R subunit binds cAMP with high specificity and a
      dissociation constant of 4 nM. Core molecular function.
    action: ACCEPT
    reason: Direct biochemical measurement of high-affinity cAMP binding by the R
      subunit.
    supported_by:
    - reference_id: PMID:16453431
      supporting_text: The protein is highly specific for cAMP and has a
        dissociation constant of 4 nM
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: IDA
  original_reference_id: PMID:2450571
  qualifier: enables
  review:
    summary: Recombinant R subunit retains high-affinity cAMP-binding activity.
      Core molecular function.
    action: ACCEPT
    reason: Directly demonstrated high-affinity cAMP binding by the recombinant R
      subunit.
    supported_by:
    - reference_id: PMID:2450571
      supporting_text: retained high-affinity cAMP-binding activity and the
        capacity to interact with the catalytic subunit
- term:
    id: GO:0061939
    label: c-di-GMP signaling
  evidence_type: IMP
  original_reference_id: PMID:28057864
  qualifier: involved_in
  review:
    summary: PKA acts downstream of c-di-GMP to induce stalk formation at the
      organizer; c-di-GMP raises cAMP which activates PKA. Valid participation in
      the c-di-GMP-to-PKA signaling relay, non-core.
    action: KEEP_AS_NON_CORE
    reason: PKA is a downstream effector in the c-di-GMP-induced stalk-formation
      pathway; this is a signaling/developmental role rather than the core
      molecular function of the R subunit.
    supported_by:
    - reference_id: PMID:28057864
      supporting_text: knockdown of cAMP-dependent protein kinase (PKA) activity
        in prestalk cells reduced stalk gene induction by c-di-GMP, whereas PKA
        activation bypassed the c-di-GMP requirement for stalk gene expression
- term:
    id: GO:0034236
    label: protein kinase A catalytic subunit binding
  evidence_type: IPI
  original_reference_id: PMID:26485773
  qualifier: enables
  review:
    summary: The R subunit physically associates with the catalytic subunit
      (pkaC, UniProtKB:P34099) to form the holoenzyme. Core molecular function
      and the physical basis of its inhibitory activity.
    action: ACCEPT
    reason: Direct interaction of the R subunit with the PKA catalytic subunit is
      well established and is a core function.
    supported_by:
    - reference_id: PMID:26485773
      supporting_text: holoenzyme is a dimer consisting of one regulatory and one
        catalytic subunit
- term:
    id: GO:1904643
    label: response to curcumin
  evidence_type: IMP
  original_reference_id: PMID:29135990
  qualifier: acts_upstream_of_or_within
  review:
    summary: Curcumin's effects on gene expression and reactive oxygen species
      (decreased catalase A and superoxide dismutases) occur through a PKA-
      dependent mechanism. A narrow, condition-specific process annotation,
      non-core.
    action: KEEP_AS_NON_CORE
    reason: PKA activity mediates part of the cellular response to curcumin, but
      this is a highly specific experimental context and not a core function.
    supported_by:
    - reference_id: PMID:29135990
      supporting_text: a protein kinase A dependent decrease in catalase A and
        three superoxide dismutase enzymes
- term:
    id: GO:0031154
    label: culmination involved in sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:1586944
  qualifier: acts_upstream_of_or_within
  review:
    summary: PKA activity is required for culmination and for the differentiation
      of prestalk cells into stalk cells. Valid developmental process, non-core.
    action: KEEP_AS_NON_CORE
    reason: PKA controls the switch from slug migration to culmination and stalk
      cell differentiation; this is a downstream developmental process, not the
      core molecular function of the R subunit.
    supported_by:
    - reference_id: PMID:1586944
      supporting_text: the activity of PKA is necessary for the altered pattern
        of movement of prestalk cells at culmination and their differentiation
        into stalk cells
- term:
    id: GO:0031288
    label: sorocarp morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:9435289
  qualifier: acts_upstream_of_or_within
  review:
    summary: PKA activity, controlled by the RegA phosphodiesterase acting on
      PKA-R, gates terminal differentiation and fruiting-body morphogenesis.
      Valid developmental process, non-core.
    action: KEEP_AS_NON_CORE
    reason: PKA acts at a checkpoint for terminal differentiation and sorocarp
      morphogenesis; this is a downstream developmental process rather than the
      core molecular function.
    supported_by:
    - reference_id: PMID:9435289
      supporting_text: inhibition of the phosphodiesterase results in an increase
        in the activity of PKA, which acts at a check point for terminal
        differentiation
- term:
    id: GO:0031156
    label: regulation of sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:1728597
  qualifier: acts_upstream_of_or_within
  review:
    summary: PKA has multiple roles across Dictyostelium development, including
      the late multicellular stages. Valid but general developmental process,
      non-core.
    action: KEEP_AS_NON_CORE
    reason: The R subunit, via its control of PKA activity, regulates
      developmental progression; this is a general developmental process rather
      than the core molecular function.
    supported_by:
    - reference_id: PMID:1728597
      supporting_text: The cAMP-dependent protein kinase (PKA) holoenzyme of
        Dictyostelium comprises a single regulatory (R) and catalytic (C) subunit
- term:
    id: GO:0031285
    label: regulation of sorocarp stalk cell differentiation
  evidence_type: IGI
  original_reference_id: PMID:12455979
  qualifier: acts_upstream_of_or_within
  review:
    summary: Genetic interaction, activating PKA by disrupting pkaR enhances the
      prestalk/stalk differentiation phenotype of culB mutants, implicating PKA
      in stalk cell differentiation control. Valid developmental process,
      non-core.
    action: KEEP_AS_NON_CORE
    reason: PKA activation (via pkaR disruption) modulates stalk cell
      differentiation in genetic-interaction experiments; this is a downstream
      developmental process rather than the core molecular function.
    supported_by:
    - reference_id: PMID:12455979
      supporting_text: Activation of cyclic AMP-dependent protein kinase (PKA) by
        disruption of the regulatory subunit gene (pkaR) or by overexpression of
        the catalytic subunit gene (pkaC) enhances the prestalk/stalk cell
        differentiation phenotype of the culB mutant
- term:
    id: GO:0030435
    label: sporulation resulting in formation of a cellular spore
  evidence_type: IMP
  original_reference_id: PMID:14695060
  qualifier: acts_upstream_of_or_within
  review:
    summary: PKA activation drives terminal differentiation and sporulation in
      Dictyostelium, a well-established role. However, the cited reference is a
      review of protozoan/invertebrate surrogate hosts for pathogen studies and
      does not document a pkaR sporulation phenotype; it appears to be a
      mis-attributed citation. The underlying biology is sound and is supported
      by other work on the PKA terminal-differentiation checkpoint.
    action: KEEP_AS_NON_CORE
    reason: PKA activity is required for and drives sporulation as part of
      terminal differentiation, a downstream developmental process rather than
      the core molecular function. The specific cited reference does not support
      the claim and is flagged in reference_review, but the process itself is
      well established.
    supported_by:
    - reference_id: PMID:9435289
      supporting_text: inhibition of the phosphodiesterase results in an increase
        in the activity of PKA, which acts at a check point for terminal
        differentiation
core_functions:
- description: pkaR is the cAMP-dependent protein kinase inhibitor/regulatory
    subunit. It binds the PKA catalytic subunit (pkaC) to form the inactive
    holoenzyme and inhibits catalytic activity in a manner that is reversed by
    cAMP, making it the switch that keeps PKA off until cAMP levels rise.
  molecular_function:
    id: GO:0004862
    label: cAMP-dependent protein kinase inhibitor activity
  locations:
  - id: GO:0005829
    label: cytosol
  in_complex:
    id: GO:0005952
    label: cAMP-dependent protein kinase complex
  supported_by:
  - reference_id: PMID:16453431
    supporting_text: This subunit inhibits the activity of purified catalytic
      subunit from beef heart protein kinase; the inhibition is reversed upon
      addition of cAMP
  - reference_id: PMID:1312226
    supporting_text: Inactivation of this protein results in the unrestrained
      activity of the catalytic subunit, so prematurely triggering terminal cell
      differentiation
- description: pkaR is the intracellular cAMP sensor of the PKA holoenzyme,
    carrying a single high-affinity cAMP-binding site. cAMP binding triggers
    dissociation of the holoenzyme and release of the active catalytic subunit,
    coupling intracellular cAMP levels to PKA activation.
  molecular_function:
    id: GO:0030552
    label: cAMP binding
  locations:
  - id: GO:0005829
    label: cytosol
  in_complex:
    id: GO:0005952
    label: cAMP-dependent protein kinase complex
  supported_by:
  - reference_id: PMID:16453431
    supporting_text: The protein is highly specific for cAMP and has a
      dissociation constant of 4 nM
  - reference_id: PMID:2450571
    supporting_text: retained high-affinity cAMP-binding activity and the
      capacity to interact with the catalytic subunit
- description: pkaR physically binds the PKA catalytic subunit (pkaC), the
    interaction that both assembles the holoenzyme and mediates inhibition of
    catalytic activity.
  molecular_function:
    id: GO:0034236
    label: protein kinase A catalytic subunit binding
  in_complex:
    id: GO:0005952
    label: cAMP-dependent protein kinase complex
  supported_by:
  - reference_id: PMID:8373760
    supporting_text: It is physically associated with the regulatory subunit, and
      this association results in an inhibition of the catalytic activity which is
      reverted by cAMP
  - reference_id: PMID:26485773
    supporting_text: holoenzyme is a dimer consisting of one regulatory and one
      catalytic subunit
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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning
    models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple Source Sequence Data
  findings: []
- id: PMID:12455979
  title: CulB, a putative ubiquitin ligase subunit, regulates prestalk cell differentiation
    and morphogenesis in Dictyostelium spp.
  findings:
  - statement: Activating PKA by disrupting the pkaR regulatory subunit gene
      enhances prestalk/stalk cell differentiation, implicating PKA in stalk cell
      fate control.
    supporting_text: Activation of cyclic AMP-dependent protein kinase (PKA) by
      disruption of the regulatory subunit gene (pkaR) or by overexpression of
      the catalytic subunit gene (pkaC) enhances the prestalk/stalk cell
      differentiation phenotype of the culB mutant
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; genetic-interaction evidence that pkaR
      disruption (PKA activation) promotes stalk differentiation.
- id: PMID:1312226
  title: Mutation of protein kinase A causes heterochronic development of Dictyostelium.
  findings:
  - statement: The rde/rdeC lesion maps to the PKA regulatory subunit;
      inactivating it unleashes constitutive catalytic-subunit activity and
      premature terminal differentiation.
    supporting_text: Inactivation of this protein results in the unrestrained
      activity of the catalytic subunit, so prematurely triggering terminal cell
      differentiation
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Key genetic evidence that the R subunit inhibits the catalytic
      subunit; source of the rdeC mutant.
- id: PMID:14695060
  title: 'Surrogate hosts: protozoa and invertebrates as models for studying pathogen-host
    interactions.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: This review of protozoan/invertebrate surrogate hosts does not
      document a pkaR sporulation phenotype and does not appear to support the
      GO:0030435 sporulation annotation it is cited for; likely a mis-attributed
      reference.
- id: PMID:15473840
  title: Chemoattractant signaling in dictyostelium discoideum.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Signaling review; source of the TAS cytosol localization,
      contextual rather than gene-specific.
- id: PMID:15548420
  title: Molecular and functional analysis of the dictyostelium centrosome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Centrosome proteome review supporting the TAS centrosome
      localization; secondary localization.
- id: PMID:1586944
  title: Culmination in Dictyostelium is regulated by the cAMP-dependent protein kinase.
  findings:
  - statement: PKA activity is required for the movement of prestalk cells at
      culmination and their differentiation into stalk cells.
    supporting_text: the activity of PKA is necessary for the altered pattern of
      movement of prestalk cells at culmination and their differentiation into
      stalk cells
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the PKA requirement for culmination and stalk cell
      differentiation.
- id: PMID:16453431
  title: A cAMP-dependent protein kinase is present in differentiating Dictyostelium
    discoideum cells.
  findings:
  - statement: The purified regulatory subunit inhibits catalytic-subunit
      activity in a cAMP-reversible manner and binds cAMP with high specificity
      (Kd 4 nM).
    supporting_text: This subunit inhibits the activity of purified catalytic
      subunit from beef heart protein kinase; the inhibition is reversed upon
      addition of cAMP
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Biochemical demonstration of high-affinity cAMP binding and
      cAMP-reversible inhibition of the catalytic subunit.
- id: PMID:1728597
  title: Multiple roles for cAMP-dependent protein kinase during Dictyostelium development.
  findings:
  - statement: The Dictyostelium PKA holoenzyme is a single R plus single C
      subunit, and R-subunit mutants dissect the cAMP-binding and C-inhibition
      functions.
    supporting_text: we have constructed mutants of the R subunit that are
      defective in cAMP binding, in inhibition of the C subunit, or in both
      functions
  - statement: PKA-deficient cells are defective in cAMP relay and fail to
      express postaggregative genes.
    supporting_text: a number of postaggregative genes are not expressed in PKA-
      cells
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structure-function mutagenesis of the R subunit and multiple
      developmental roles of PKA.
- id: PMID:2450571
  title: Expression and properties of the regulatory subunit of Dictyostelium cAMP-dependent
    protein kinase encoded by lambda gt11 cDNA clones.
  findings:
  - statement: Recombinant R subunit retains high-affinity cAMP binding and the
      ability to inhibit the catalytic subunit through protein-protein
      interaction.
    supporting_text: the ability to inhibit the catalytic (C) subunit through
      protein-protein interaction
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Recombinant expression confirms cAMP binding and
      catalytic-subunit inhibition are intrinsic R-subunit properties.
- id: PMID:26485773
  title: An unusual adenosine cyclic 3',5'-phosphate-dependent protein kinase from
    Dictyostelium discoideum.
  findings:
  - statement: The Dictyostelium PKA holoenzyme is an unusual dimer of one
      regulatory and one catalytic subunit, and the R subunit carries a single
      high-affinity cAMP-binding site.
    supporting_text: holoenzyme is a dimer consisting of one regulatory and one
      catalytic subunit
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Original biochemical characterization of the unusual R-C dimeric
      holoenzyme and single cAMP-binding site.
- id: PMID:28057864
  title: Adenylate cyclase A acting on PKA mediates induction of stalk formation by
    cyclic diguanylate at the Dictyostelium organizer.
  findings:
  - statement: PKA acts downstream of c-di-GMP to induce stalk gene expression;
      PKA activation bypasses the c-di-GMP requirement.
    supporting_text: knockdown of cAMP-dependent protein kinase (PKA) activity in
      prestalk cells reduced stalk gene induction by c-di-GMP, whereas PKA
      activation bypassed the c-di-GMP requirement for stalk gene expression
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Places PKA as a downstream effector in the c-di-GMP stalk
      induction pathway.
- id: PMID:29135990
  title: Curcumin affects gene expression and reactive oxygen species via a PKA dependent
    mechanism in Dictyostelium discoideum.
  findings:
  - statement: Curcumin causes a PKA-dependent decrease in catalase A and
      superoxide dismutases, increasing reactive oxygen species.
    supporting_text: a protein kinase A dependent decrease in catalase A and three
      superoxide dismutase enzymes
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Narrow condition-specific PKA-dependent response to curcumin.
- id: PMID:7713325
  title: Protein kinase A is a positive regulator of spore coat gene transcription
    in Dictyostelium.
  findings:
  - statement: A dominant PKA inhibitor in prespore cells reduces transcription of
      the spore coat genes cotB and cotC, showing PKA positively regulates spore
      coat gene expression.
    supporting_text: expression of a dominant inhibitor of the cAMP dependent
      protein kinase (PKA) in prespore cells greatly reduces the transcription
      rates of the cotB and cotC genes
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct evidence that PKA positively regulates spore coat gene
      transcription.
- id: PMID:8373760
  title: An unusual catalytic subunit for the cAMP-dependent protein kinase of Dictyostelium
    discoideum.
  findings:
  - statement: The pkaC catalytic subunit is physically associated with the
      regulatory subunit, and this association inhibits catalytic activity in a
      cAMP-reversible manner.
    supporting_text: It is physically associated with the regulatory subunit, and
      this association results in an inhibition of the catalytic activity which is
      reverted by cAMP
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Characterizes the catalytic subunit pkaC and confirms R-C
      physical association and cAMP-reversible inhibition.
- id: PMID:8565818
  title: Induction of terminal differentiation of Dictyostelium by cAMP-dependent
    protein kinase and opposing effects of intracellulr and extracellular cAMP on
    stalk cell differentiation.
  findings:
  - statement: Ectopic expression of the PKA catalytic subunit under cell-type
      promoters causes ectopic terminal differentiation, demonstrating PKA drives
      terminal differentiation and gene expression.
    supporting_text: Expression of the catalytic (C) subunit of the cAMP-dependent
      protein kinase (PKA) of Dictyostelium under the control of heterologous,
      cell-type-specific promoters causes ectopic terminal differentiation
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PKA activity drives terminal differentiation and cell-type gene
      expression.
- id: PMID:9435289
  title: A cAMP-phosphodiesterase controls PKA-dependent differentiation.
  findings:
  - statement: The RegA cAMP-phosphodiesterase is stimulated by binding the PKA
      regulatory subunit (PKA-R), and PKA activity acts at a checkpoint for
      terminal differentiation.
    supporting_text: A cAMP-specific phosphodiesterase was found that is
      stimulated by binding to the regulatory subunit of cAMP-dependent protein
      kinase, PKA-R
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the RegA-PKA-R interaction and the PKA terminal-
      differentiation checkpoint.