pkaR

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005829 cytosol	IBA GO_REF:0000033	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:26485773 the rest is recovered in the form of dissociated regulatory and catalytic subunits
GO:0005952 cAMP-dependent protein kinase complex	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:26485773 holoenzyme is a dimer consisting of one regulatory and one catalytic subunit
GO:0030552 cAMP binding	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:16453431 The protein is highly specific for cAMP and has a dissociation constant of 4 nM
GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway	IBA GO_REF:0000033	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:1728597 are defective in cAMP relay, the production of cAMP in response to extracellular cAMP stimulation
GO:0004862 cAMP-dependent protein kinase inhibitor activity	IBA GO_REF:0000033	ACCEPT	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. Reason: The R subunit inhibits catalytic-subunit activity in a cAMP-reversible manner, which is its central molecular function. Supporting Evidence: PMID:16453431 This subunit inhibits the activity of purified catalytic subunit from beef heart protein kinase; the inhibition is reversed upon addition of cAMP
GO:0034236 protein kinase A catalytic subunit binding	IBA GO_REF:0000033	ACCEPT	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. Reason: The R subunit physically associates with the catalytic subunit to form the holoenzyme; this binding is the physical basis of its inhibitory function. Supporting Evidence: PMID:8373760 It is physically associated with the regulatory subunit, and this association results in an inhibition of the catalytic activity which is reverted by cAMP
GO:0005952 cAMP-dependent protein kinase complex	IEA GO_REF:0000120	ACCEPT	Summary: InterPro/ARBA electronic annotation to the PKA complex, redundant with the IBA and IDA annotations to the same term. Correct. Reason: Consistent with the direct experimental evidence that PKA-R is part of the cAMP-dependent protein kinase holoenzyme. Supporting Evidence: PMID:26485773 holoenzyme is a dimer consisting of one regulatory and one catalytic subunit
GO:0008603 cAMP-dependent protein kinase regulator activity	IEA GO_REF:0000002	ACCEPT	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. Reason: The R subunit is the regulator of PKA activity; regulator activity is correct and directly supported experimentally. Supporting Evidence: PMID:2450571 the ability to inhibit the catalytic (C) subunit through protein-protein interaction
GO:0010628 positive regulation of gene expression	IEA GO_REF:0000117	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:7713325 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
GO:0045595 regulation of cell differentiation	IEA GO_REF:0000117	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:1312226 Inactivation of this protein results in the unrestrained activity of the catalytic subunit, so prematurely triggering terminal cell differentiation
GO:0010468 regulation of gene expression	IMP PMID:8565818 Induction of terminal differentiation of Dictyostelium by cA...	KEEP AS NON CORE	Summary: IMP annotation reflecting that PKA activity induces terminal differentiation and cell-type gene expression. Valid developmental process but general and 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. Supporting Evidence: PMID:8565818 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
GO:0010628 positive regulation of gene expression	IDA PMID:7713325 Protein kinase A is a positive regulator of spore coat gene ...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:7713325 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
GO:0008603 cAMP-dependent protein kinase regulator activity	IMP PMID:1728597 Multiple roles for cAMP-dependent protein kinase during Dict...	ACCEPT	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. Reason: Structure-function mutagenesis of the R subunit confirms it regulates catalytic-subunit activity; this is a core function. Supporting Evidence: PMID:1728597 we have constructed mutants of the R subunit that are defective in cAMP binding, in inhibition of the C subunit, or in both functions
GO:0030552 cAMP binding	IDA PMID:1728597 Multiple roles for cAMP-dependent protein kinase during Dict...	ACCEPT	Summary: Direct demonstration of cAMP binding by the R subunit via mutants specifically defective in cAMP binding. Core molecular function. Reason: cAMP binding by the R subunit is directly demonstrated and is a core sensing function. Supporting Evidence: PMID:1728597 we have constructed mutants of the R subunit that are defective in cAMP binding, in inhibition of the C subunit, or in both functions
GO:0005813 centrosome	TAS PMID:15548420 Molecular and functional analysis of the dictyostelium centr...	KEEP AS NON CORE	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. 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.
GO:0005829 cytosol	TAS PMID:15473840 Chemoattractant signaling in dictyostelium discoideum.	KEEP AS NON CORE	Summary: TAS cytosolic localization from a chemoattractant-signaling review, consistent with PKA being a soluble cytosolic kinase. Correct but non-core. Reason: Cytosolic localization is consistent with the soluble PKA holoenzyme but is a location annotation, not the core molecular function.
GO:0005952 cAMP-dependent protein kinase complex	IDA PMID:26485773 An unusual adenosine cyclic 3',5'-phosphate-dependent protei...	ACCEPT	Summary: Direct biochemical evidence that the Dictyostelium PKA holoenzyme is a dimer of one regulatory and one catalytic subunit. Core structural annotation. Reason: The R subunit is a direct component of the purified PKA holoenzyme complex. Supporting Evidence: PMID:26485773 holoenzyme is a dimer consisting of one regulatory and one catalytic subunit
GO:0010628 positive regulation of gene expression	IMP PMID:1728597 Multiple roles for cAMP-dependent protein kinase during Dict...	KEEP AS NON CORE	Summary: IMP evidence that PKA activity is required for expression of postaggregative genes. Valid downstream developmental process, 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. Supporting Evidence: PMID:1728597 a number of postaggregative genes are not expressed in PKA- cells
GO:0010628 positive regulation of gene expression	IMP PMID:28057864 Adenylate cyclase A acting on PKA mediates induction of stal...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:28057864 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
GO:0106070 regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	IMP PMID:1728597 Multiple roles for cAMP-dependent protein kinase during Dict...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:1728597 are defective in cAMP relay, the production of cAMP in response to extracellular cAMP stimulation
GO:0004862 cAMP-dependent protein kinase inhibitor activity	IDA PMID:2450571 Expression and properties of the regulatory subunit of Dicty...	ACCEPT	Summary: Recombinant R subunit directly inhibits the catalytic subunit through protein-protein interaction. Core molecular function. Reason: Direct biochemical demonstration of catalytic-subunit inhibition by the R subunit; this is a core function. Supporting Evidence: PMID:2450571 the ability to inhibit the catalytic (C) subunit through protein-protein interaction
GO:0005515 protein binding	IPI PMID:8373760 An unusual catalytic subunit for the cAMP-dependent protein ...	MODIFY	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. 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 replacements: protein kinase A catalytic subunit binding Supporting Evidence: PMID:8373760 It is physically associated with the regulatory subunit, and this association results in an inhibition of the catalytic activity which is reverted by cAMP
GO:0005515 protein binding	IPI PMID:9435289 A cAMP-phosphodiesterase controls PKA-dependent differentiat...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:9435289 A cAMP-specific phosphodiesterase was found that is stimulated by binding to the regulatory subunit of cAMP-dependent protein kinase, PKA-R
GO:0008603 cAMP-dependent protein kinase regulator activity	IMP PMID:1312226 Mutation of protein kinase A causes heterochronic developmen...	ACCEPT	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. Reason: Genetic inactivation of the R subunit causes unrestrained catalytic-subunit activity, confirming its role as the PKA regulator. Supporting Evidence: PMID:1312226 Inactivation of this protein results in the unrestrained activity of the catalytic subunit, so prematurely triggering terminal cell differentiation
GO:0008603 cAMP-dependent protein kinase regulator activity	IDA PMID:26485773 An unusual adenosine cyclic 3',5'-phosphate-dependent protei...	ACCEPT	Summary: Purified R subunit inhibits the catalytic subunit in a cAMP-reversible manner, directly demonstrating regulator activity. Core molecular function. Reason: Direct biochemical evidence of the R subunit regulating PKA activity. Supporting Evidence: PMID:26485773 The regulatory subunit is a monomeric protein of M, 42 000 that carries only one cAMP binding site
GO:0030552 cAMP binding	IMP PMID:1312226 Mutation of protein kinase A causes heterochronic developmen...	ACCEPT	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. Reason: The R subunit's cAMP-binding activity is genetically established and is a core sensing function. Supporting Evidence: PMID:1312226 We have traced the lesion in one class of these mutants to the regulatory subunit of cyclic AMP-dependent protein kinase
GO:0030552 cAMP binding	IDA PMID:16453431 A cAMP-dependent protein kinase is present in differentiatin...	ACCEPT	Summary: Purified R subunit binds cAMP with high specificity and a dissociation constant of 4 nM. Core molecular function. Reason: Direct biochemical measurement of high-affinity cAMP binding by the R subunit. Supporting Evidence: PMID:16453431 The protein is highly specific for cAMP and has a dissociation constant of 4 nM
GO:0030552 cAMP binding	IDA PMID:2450571 Expression and properties of the regulatory subunit of Dicty...	ACCEPT	Summary: Recombinant R subunit retains high-affinity cAMP-binding activity. Core molecular function. Reason: Directly demonstrated high-affinity cAMP binding by the recombinant R subunit. Supporting Evidence: PMID:2450571 retained high-affinity cAMP-binding activity and the capacity to interact with the catalytic subunit
GO:0061939 c-di-GMP signaling	IMP PMID:28057864 Adenylate cyclase A acting on PKA mediates induction of stal...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:28057864 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
GO:0034236 protein kinase A catalytic subunit binding	IPI PMID:26485773 An unusual adenosine cyclic 3',5'-phosphate-dependent protei...	ACCEPT	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. Reason: Direct interaction of the R subunit with the PKA catalytic subunit is well established and is a core function. Supporting Evidence: PMID:26485773 holoenzyme is a dimer consisting of one regulatory and one catalytic subunit
GO:1904643 response to curcumin	IMP PMID:29135990 Curcumin affects gene expression and reactive oxygen species...	KEEP AS NON CORE	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. Reason: PKA activity mediates part of the cellular response to curcumin, but this is a highly specific experimental context and not a core function. Supporting Evidence: PMID:29135990 a protein kinase A dependent decrease in catalase A and three superoxide dismutase enzymes
GO:0031154 culmination involved in sorocarp development	IMP PMID:1586944 Culmination in Dictyostelium is regulated by the cAMP-depend...	KEEP AS NON CORE	Summary: PKA activity is required for culmination and for the differentiation of prestalk cells into stalk cells. Valid developmental process, 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. Supporting Evidence: PMID:1586944 the activity of PKA is necessary for the altered pattern of movement of prestalk cells at culmination and their differentiation into stalk cells
GO:0031288 sorocarp morphogenesis	IMP PMID:9435289 A cAMP-phosphodiesterase controls PKA-dependent differentiat...	KEEP AS NON CORE	Summary: PKA activity, controlled by the RegA phosphodiesterase acting on PKA-R, gates terminal differentiation and fruiting-body morphogenesis. Valid developmental process, 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. Supporting Evidence: PMID:9435289 inhibition of the phosphodiesterase results in an increase in the activity of PKA, which acts at a check point for terminal differentiation
GO:0031156 regulation of sorocarp development	IMP PMID:1728597 Multiple roles for cAMP-dependent protein kinase during Dict...	KEEP AS NON CORE	Summary: PKA has multiple roles across Dictyostelium development, including the late multicellular stages. Valid but general developmental process, 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. Supporting Evidence: PMID:1728597 The cAMP-dependent protein kinase (PKA) holoenzyme of Dictyostelium comprises a single regulatory (R) and catalytic (C) subunit
GO:0031285 regulation of sorocarp stalk cell differentiation	IGI PMID:12455979 CulB, a putative ubiquitin ligase subunit, regulates prestal...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:12455979 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
GO:0030435 sporulation resulting in formation of a cellular spore	IMP PMID:14695060 Surrogate hosts: protozoa and invertebrates as models for st...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:9435289 inhibition of the phosphodiesterase results in an increase in the activity of PKA, which acts at a check point for terminal differentiation

Gene Description

Existing Annotations Review

Core Functions

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.

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.

pkaR physically binds the PKA catalytic subunit (pkaC), the interaction that both assembles the holoenzyme and mediates inhibition of catalytic activity.

References

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