Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Phosphorylase kinase is a cytosolic enzyme, so a cytoplasm localization is correct. The gene is separately and more precisely annotated to cytosol (GO:0005829, IDA/TAS), which is the accurate subcellular compartment for glycogenolysis. Reason: Correct but general cellular-component annotation; PhK acts in the cytosol where glycogen breakdown occurs. Retained; the more specific cytosol term is the core location. Supporting Evidence: Reactome:R-HSA-71588 The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL).
GO:0005964 phosphorylase kinase complex	IBA GO_REF:0000033	ACCEPT	Summary: PHKG2 is the catalytic gamma subunit of the phosphorylase kinase holoenzyme, a hexadecamer of four (alpha-beta-gamma-delta) protomers. Being part of the phosphorylase kinase complex is a defining structural property of this gene product. Reason: Well-supported by holoenzyme biochemistry; the gamma subunit is an integral catalytic component of the phosphorylase kinase complex. Supporting Evidence: PMID:10487978 one catalytic (gamma) subunit and three different regulatory (alpha, beta, and file:human/PHKG2/PHKG2-uniprot.txt Alpha (PHKA1 or PHKA2) and beta (PHKB)
GO:0005977 glycogen metabolic process	IBA GO_REF:0000033	ACCEPT	Summary: PhK is a regulatory enzyme of glycogen metabolism; by phosphorylating glycogen phosphorylase it controls glycogen breakdown. Glycogen metabolic process is a correct but broad parent of the more specific glycogen catabolic process. Reason: Accurate high-level BP; the specific role is in glycogen catabolism (GO:0005980), which is separately annotated. Retained as the broader process term. Supporting Evidence: PMID:8896567 phosphorylase kinase (Phk), a regulatory enzyme of
GO:0007165 signal transduction	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phosphorylase kinase integrates Ca2+ (via calmodulin/delta) and cAMP/PKA (phosphorylation of alpha/beta) signals to trigger glycogenolysis, so it functions as a signalling node. However, this is a broad process term and not the core molecular role of PHKG2. Reason: Defensible but generic; PhK does transduce hormonal/Ca2+ signals to glycogen breakdown, but the informative annotations are its kinase activity and role in glycogen catabolism. Kept as non-core. Supporting Evidence: PMID:10487978 Ca2+ relieves inhibition via the delta subunit
GO:0004689 phosphorylase kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phosphorylase kinase activity is the defining molecular function of PHKG2, the catalytic gamma subunit. This IBA annotation is consistent with experimental evidence in human (PMID:35549678) and the phylogenetic conservation of the gamma subunit. Reason: Core molecular function, phylogenetically inferred and experimentally supported. Supporting Evidence: PMID:35549678 the catalytic gamma subunit, which is an active site of PhK enzyme
GO:0004672 protein kinase activity	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based annotation to the general protein kinase activity term. PHKG2 is a protein kinase, so this is correct though broader than the specific phosphorylase kinase activity (GO:0004689) and protein serine/threonine kinase activity (GO:0004674) it is separately annotated to. Reason: Correct broad parent MF from the protein kinase domain (residues 24-291); acceptable as a more general IEA. Supporting Evidence: PMID:2948189 shares 72% identity with rabbit
GO:0004689 phosphorylase kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation (ARBA/EC 2.7.11.19) to phosphorylase kinase activity, the core function of PHKG2. Consistent with the experimental and phylogenetic evidence. Reason: Correct core MF; duplicate of the experimentally and phylogenetically supported phosphorylase kinase activity annotation. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt Reaction=2 ATP + phosphorylase b = 2 ADP + phosphorylase a.
GO:0005516 calmodulin binding	IEA GO_REF:0000120	ACCEPT	Summary: The gamma subunit contains two calmodulin-binding regions (residues 306-330 and 346-370). Within the holoenzyme the delta subunit is calmodulin, and Ca2+/calmodulin relieves regulatory inhibition of the gamma catalytic subunit. Calmodulin binding is therefore a bona fide molecular function of PHKG2. Reason: Supported by UniProt calmodulin-binding regions and the established Ca2+/calmodulin regulation of PhK; retained. Supporting Evidence: PMID:10487978 Ca2+ relieves inhibition via the delta subunit file:human/PHKG2/PHKG2-uniprot.txt Calmodulin-binding (domain-N)
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: PHKG2 is an ATP-dependent protein kinase with a glycine-rich ATP-binding P-loop (residues 30-38) and further ATP-binding residues; ATP binding is required for its phosphotransferase activity. Reason: Correct; supported by the ATP-binding motif in the kinase domain and the catalytic reaction (2 ATP + phosphorylase b -> 2 ADP + phosphorylase a). Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt Reaction=2 ATP + phosphorylase b = 2 ADP + phosphorylase a.
GO:0005964 phosphorylase kinase complex	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation to the phosphorylase kinase complex, of which PHKG2 is the catalytic gamma subunit. Duplicate of the IBA/TAS complex annotations. Reason: Correct core cellular component; PHKG2 is an integral subunit of the PhK holoenzyme. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt Alpha (PHKA1 or PHKA2) and beta (PHKB)
GO:0005977 glycogen metabolic process	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation to glycogen metabolic process, matching the IBA/TAS annotations. PhK regulates glycogen metabolism via activation of glycogen phosphorylase. Reason: Correct broad BP; the specific role is in glycogen catabolism (separately annotated). Supporting Evidence: PMID:8896567 phosphorylase kinase (Phk), a regulatory enzyme of
GO:0005515 protein binding	IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein...	MARK AS OVER ANNOTATED	Summary: High-throughput AP-MS interaction study. The recorded partner (UniProtKB:P46019) is PHKA2, the alpha regulatory subunit of the phosphorylase kinase holoenzyme, so this interaction reflects assembly of the PhK complex. The generic protein binding term is uninformative and the meaningful relationship is already captured by the phosphorylase kinase complex annotation (GO:0005964). Reason: Bare protein binding provides no specific functional information; the biologically meaningful partner (PHKA2) is subsumed by the complex annotation. Retained (experimental IPI) but flagged as over-annotated per curation policy rather than removed. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt P15735; P46019: PHKA2; NbExp=11
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	MARK AS OVER ANNOTATED	Summary: Large-scale interactome study; the recorded partner (UniProtKB:P46019) is PHKA2, the alpha regulatory subunit of PhK, consistent with holoenzyme assembly. The generic protein binding term is uninformative. Reason: Uninformative bare protein binding; PHKA2 interaction is captured by the phosphorylase kinase complex annotation. Retained but flagged as over-annotated. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt P15735; P46019: PHKA2; NbExp=11
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Interactome-mapping study; partner UniProtKB:P46019 (PHKA2) is the alpha regulatory subunit of the PhK holoenzyme. The generic protein binding term is uninformative. Reason: Bare protein binding is uninformative; the PHKA2 interaction is subsumed by the complex annotation. Retained but flagged as over-annotated. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt P15735; P46019: PHKA2; NbExp=11
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Binary interactome (HuRI) study; the recorded partner here is UniProtKB:P43356 (MAGEA2B), a MAGE family protein. This is a single high-throughput binary interaction of unclear functional significance for glycogenolysis; the generic protein binding term is uninformative. Reason: Bare protein binding with a high-throughput partner (MAGEA2B) of unknown relevance to PHKG2 function; uninformative. Retained (experimental IPI) but flagged as over-annotated per policy. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt P15735; P43356: MAGEA2B; NbExp=3
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Second interaction row from the HuRI binary interactome study; partner UniProtKB:P46019 (PHKA2), the alpha regulatory subunit of PhK, consistent with holoenzyme assembly. The generic protein binding term is uninformative. Reason: Bare protein binding is uninformative; the PHKA2 interaction is captured by the complex annotation. Retained but flagged as over-annotated. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt P15735; P46019: PHKA2; NbExp=11
GO:0005515 protein binding	IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro...	MARK AS OVER ANNOTATED	Summary: Kinase interaction network study; partner UniProtKB:P46019 (PHKA2) is the alpha regulatory subunit of PhK. The generic protein binding term is uninformative. Reason: Uninformative bare protein binding; PHKA2 interaction subsumed by the complex annotation. Retained but flagged as over-annotated. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt P15735; P46019: PHKA2; NbExp=11
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Proteome-scale interactome (BioPlex) study; partner UniProtKB:P46019 (PHKA2) is the alpha regulatory subunit of PhK, consistent with holoenzyme assembly. The generic protein binding term is uninformative. Reason: Bare protein binding is uninformative; the PHKA2 interaction is captured by the complex annotation. Retained but flagged as over-annotated. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt P15735; P46019: PHKA2; NbExp=11
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: OpenCell endogenous-tagging interactome study; partner UniProtKB:P46019 (PHKA2), the alpha regulatory subunit of PhK. The generic protein binding term is uninformative. Reason: Uninformative bare protein binding; the PHKA2 interaction is subsumed by the complex annotation. Retained but flagged as over-annotated. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt P15735; P46019: PHKA2; NbExp=11
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Multimodal cell-map interactome study; partner UniProtKB:P46019 (PHKA2), the alpha regulatory subunit of PhK. The generic protein binding term is uninformative. Reason: Bare protein binding is uninformative; the PHKA2 interaction is captured by the complex annotation. Retained but flagged as over-annotated. Supporting Evidence: file:human/PHKG2/PHKG2-uniprot.txt P15735; P46019: PHKA2; NbExp=11
GO:0005980 glycogen catabolic process	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation to glycogen catabolic process. This is the specific biological process in which PhK acts: by activating glycogen phosphorylase it drives glycogen breakdown (glycogenolysis). This is a core biological process for PHKG2. Reason: Correct and specific BP; matches the Reactome TAS annotation to the same term. Supporting Evidence: Reactome:R-HSA-71588 The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL).
GO:0019899 enzyme binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl ortholog-transfer annotation to the generic enzyme binding term (from rat ortholog P31325). While PHKG2 binds its substrate glycogen phosphorylase and the other PhK subunits, enzyme binding is an uninformative parent that adds little beyond the more specific kinase-substrate and complex annotations. Reason: Generic, uninformative MF; the meaningful interactions (substrate glycogen phosphorylase; PhK subunits) are better captured by phosphorylase kinase activity and the complex annotation. Flagged as over-annotated. Supporting Evidence: Reactome:R-HSA-71588 catalyzes the phosphorylation of glycogen phosphorylase (PYGL)
GO:0045819 positive regulation of glycogen catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: By phosphorylating and activating glycogen phosphorylase (converting phosphorylase b to the active phosphorylase a), PhK positively regulates glycogen catabolism. This is an accurate regulatory BP for PHKG2. Reason: Correct; PhK activation of phosphorylase is a positive regulatory step in glycogenolysis. Matches the TAS annotation to the same term. Supporting Evidence: PMID:10487978 kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase.
GO:0005980 glycogen catabolic process	TAS Reactome:R-HSA-70221	ACCEPT	Summary: Reactome traceable annotation placing PHKG2 in glycogen breakdown (glycogenolysis). Glycogen phosphorylase, activated by phosphorylase kinase, catalyzes glucose release from glycogen; PHKG2 provides the catalytic activity that switches phosphorylase on. Reason: Correct core BP; well-supported by the Reactome glycogenolysis pathway. Supporting Evidence: Reactome:R-HSA-70221 Glycogen phosphorylase, which can be activated by phosphorylase kinase, catalyzes
GO:0004689 phosphorylase kinase activity	EXP PMID:12930917 Severe phenotype of phosphorylase kinase-deficient liver gly...	ACCEPT	Summary: Experimental annotation (via Reactome) associated with functional characterization of PHKG2 GSD9C variants (E157K, D215N, W300X, H89fs) in liver PhK deficiency. Confirms phosphorylase kinase activity as the function of PHKG2. Reason: Experimental support for the core phosphorylase kinase activity; PHKG2 disease variants impair PhK function. Supporting Evidence: PMID:12930917 manifests in infancy with
GO:0004689 phosphorylase kinase activity	EXP PMID:7847371 X-linked liver phosphorylase kinase deficiency is associated...	ACCEPT	Summary: Experimental annotation (via Reactome) for the phosphorylase kinase holoenzyme activity. This reference concerns the PhK alpha (PHKA2) subunit in X-linked liver PhK deficiency and is used by Reactome as one line of evidence for the liver PhK complex, of which PHKG2 is the catalytic gamma subunit. Reason: Supports phosphorylase kinase activity of the liver PhK complex that contains PHKG2. The paper's primary focus is the alpha subunit, so its direct relevance to PHKG2 catalysis is indirect; retained as consistent with the core function (defer to Reactome curation, do not remove an experimental annotation). Supporting Evidence: Reactome:R-HSA-71588 consisting of four copies each of PHKA2 (alpha regulatory) (van den Berg et al. 1995), PHKB (beta regulatory)
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence (HPA) evidence localizing PHKG2 to the cytosol. This is the correct and specific subcellular location where phosphorylase kinase acts on glycogen phosphorylase during glycogenolysis. Reason: Core cellular component; experimentally supported and consistent with the cytosolic site of glycogen breakdown. Supporting Evidence: Reactome:R-HSA-71588 The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL).
GO:0004689 phosphorylase kinase activity	EXP PMID:35549678 A very rare case report of glycogen storage disease type IXc...	ACCEPT	Summary: Experimental characterization of human PHKG2: recombinant wild-type and GSD9C-variant gamma subunits were assayed for PhK enzyme activity, with the F233S and R320DfsX5 disease variants strongly reducing activity, directly demonstrating phosphorylase kinase activity for PHKG2. UniProt cites this paper for the catalytic activity and EC 2.7.11.19. Reason: Strongest direct experimental evidence for the core molecular function; human PHKG2 catalyzes the phosphorylase kinase reaction. Supporting Evidence: PMID:35549678 The PhK enzyme activity of both the F233S and R320DfsX5 mutants was deficient PMID:35549678 the catalytic gamma subunit, which is an active site of PhK enzyme
GO:0005829 cytosol	TAS Reactome:R-HSA-71588	ACCEPT	Summary: Reactome traceable annotation to cytosol, where the phosphorylase kinase complex phosphorylates glycogen phosphorylase. Consistent with the HPA IDA cytosol annotation. Reason: Correct core cellular component; matches the IDA cytosol annotation. Supporting Evidence: Reactome:R-HSA-71588 The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL).
GO:0004674 protein serine/threonine kinase activity	TAS PMID:10487978 Phosphorylase kinase: the complexity of its regulation is re...	ACCEPT	Summary: PHKG2 belongs to the CAMK Ser/Thr protein kinase family and phosphorylates serine/threonine residues (Ser14 of glycogen phosphorylase). Protein serine/threonine kinase activity is a correct but broader parent of phosphorylase kinase activity (GO:0004689). Reason: Correct broader MF; PHKG2 is a Ser/Thr protein kinase. The specific phosphorylase kinase activity term is separately annotated as the core function. Supporting Evidence: PMID:10487978 regulatory subunits inhibit the phosphotransferase activity of the gamma
GO:0004689 phosphorylase kinase activity	TAS PMID:10487978 Phosphorylase kinase: the complexity of its regulation is re...	ACCEPT	Summary: Traceable annotation to phosphorylase kinase activity from the Brushia & Walsh review of PhK structure/function, which describes the gamma subunit as the catalytic subunit that phosphorylates and activates glycogen phosphorylase. Reason: Core molecular function, supported by a review of PhK biochemistry. Supporting Evidence: PMID:10487978 kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase.
GO:0005964 phosphorylase kinase complex	TAS PMID:10487978 Phosphorylase kinase: the complexity of its regulation is re...	ACCEPT	Summary: Traceable annotation placing PHKG2 in the phosphorylase kinase complex; the review describes PhK as having one catalytic gamma subunit and three regulatory subunits per protomer. Reason: Correct core cellular component; PHKG2 is the catalytic subunit of the PhK complex. Supporting Evidence: PMID:10487978 one catalytic (gamma) subunit and three different regulatory (alpha, beta, and
GO:0045819 positive regulation of glycogen catabolic process	TAS PMID:10487978 Phosphorylase kinase: the complexity of its regulation is re...	ACCEPT	Summary: By phosphorylating and thereby activating glycogen phosphorylase, PhK positively regulates glycogen catabolism. Traceable from the Brushia & Walsh review. Reason: Correct regulatory BP; PhK activation of phosphorylase is a positive regulatory step in glycogenolysis. Supporting Evidence: PMID:10487978 kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase.
GO:0050321 tau-protein kinase activity	TAS PMID:8999860 The regulatory Ser262 of microtubule-associated protein tau ...	MARK AS OVER ANNOTATED	Summary: This annotation derives from a study showing that phosphorylase kinase purified from rabbit skeletal muscle phosphorylates microtubule-associated protein tau in vitro (Km 6.9 uM), with the authors suggesting PhK may participate in tau phosphorylation in neurons. The assayed enzyme is muscle PhK (i.e. the PHKG1 gamma isoform / muscle holoenzyme), not the liver/testis PHKG2 gamma-2 isoform, and tau is a much poorer substrate than phosphorylase. This is an in-vitro cross-reactivity, not a physiological function of PHKG2. Reason: Retained as an experimental TAS annotation per curation policy (not removed), but flagged as an over-annotation: the demonstrated tau kinase activity is an in-vitro activity of muscle phosphorylase kinase, tau is a poor substrate relative to glycogen phosphorylase, and there is no evidence this reflects a physiological role of the liver/testis PHKG2 isoform. Supporting Evidence: PMID:8999860 Phosphorylase kinase, purified from rabbit skeletal muscle
GO:0004689 phosphorylase kinase activity	TAS PMID:2948189 Homology probing: identification of cDNA clones encoding mem...	ACCEPT	Summary: Traceable annotation from the original homology-cloning paper that identified the cDNA (PSK-C3) encoding a Ser/Thr kinase 72% identical to rabbit muscle phosphorylase kinase gamma subunit, i.e. the initial molecular identification of PHKG2. Reason: Supports the phosphorylase kinase / Ser-Thr kinase identity of the gene product. Supporting Evidence: PMID:2948189 shares 72% identity with rabbit
GO:0005977 glycogen metabolic process	TAS PMID:8896567 Mutations in the testis/liver isoform of the phosphorylase k...	ACCEPT	Summary: Traceable annotation to glycogen metabolic process; PhK is described as a regulatory enzyme of glycogen metabolism whose deficiency causes glycogen storage disease. Reason: Correct broad BP; the specific role is glycogen catabolism (separately annotated). Supporting Evidence: PMID:8896567 phosphorylase kinase (Phk), a regulatory enzyme of
GO:0006091 generation of precursor metabolites and energy	TAS PMID:8896567 Mutations in the testis/liver isoform of the phosphorylase k...	KEEP AS NON CORE	Summary: By driving glycogenolysis, PhK contributes to the mobilization of glucose from glycogen stores used to maintain blood-glucose homeostasis and supply energy. This is a broad metabolic process term, not the core molecular role of PHKG2. Reason: Defensible but very general BP; the informative annotations are phosphorylase kinase activity and glycogen catabolism. Kept as non-core. Supporting Evidence: PMID:8896567 phosphorylase kinase (Phk), a regulatory enzyme of
GO:0006468 protein phosphorylation	TAS PMID:2948189 Homology probing: identification of cDNA clones encoding mem...	ACCEPT	Summary: PHKG2 is a protein kinase that phosphorylates glycogen phosphorylase. Protein phosphorylation is a correct but generic biological process; the specific, informative process is glycogen catabolism / its positive regulation. Reason: Correct broad BP consistent with the kinase activity; retained as a general process term. The specific catabolic/regulatory processes are separately annotated as core. Supporting Evidence: PMID:2948189 shares 72% identity with rabbit

Core Functions

Catalytic gamma-2 subunit of phosphorylase kinase; an ATP-dependent protein serine/threonine kinase (EC 2.7.11.19) that phosphorylates and activates glycogen phosphorylase (b to a), driving glycogen breakdown in the cytosol as part of the phosphorylase kinase holoenzyme.

Molecular Function:

phosphorylase kinase activity

Directly Involved In:

glycogen catabolic process

Cellular Locations:

cytosol

In Complex:

phosphorylase kinase complex

Supporting Evidence:

PMID:35549678
the catalytic gamma subunit, which is an active site of PhK enzyme
PMID:10487978
kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase.

Positive regulation of glycogenolysis: by phosphorylating and activating glycogen phosphorylase in response to Ca2+/calmodulin and cAMP/PKA signalling, PHKG2 (within the PhK holoenzyme) positively regulates glycogen catabolism.

Molecular Function:

phosphorylase kinase activity

Directly Involved In:

positive regulation of glycogen catabolic process

Cellular Locations:

cytosol

Supporting Evidence:

PMID:10487978
kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase.
PMID:10487978
Ca2+ relieves inhibition via the delta subunit

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

file:human/PHKG2/PHKG2-uniprot.txt

UniProtKB entry P15735 (PHKG2_HUMAN), phosphorylase b kinase gamma catalytic chain, liver/testis isoform

PMID:10487978

Phosphorylase kinase: the complexity of its regulation is reflected in the complexity of its structure.

PMID:12930917

Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene.

PMID:23455922

Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:2948189

Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32707033

Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:35549678

A very rare case report of glycogen storage disease type IXc with novel PHKG2 variants.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:7847371

X-linked liver phosphorylase kinase deficiency is associated with mutations in the human liver phosphorylase kinase alpha subunit.

PMID:8896567

Mutations in the testis/liver isoform of the phosphorylase kinase gamma subunit (PHKG2) cause autosomal liver glycogenosis in the gsd rat and in humans.

PMID:8999860

The regulatory Ser262 of microtubule-associated protein tau is phosphorylated by phosphorylase kinase.

Reactome:R-HSA-70221

Glycogen breakdown (glycogenolysis)

Reactome:R-HSA-71588

glycogen phosphorylase (PYGL) dimer b + 2 ATP => glycogen phosphorylase (PYGL) dimer a + 2 ADP

📚 Additional Documentation

Notes

(PHKG2-notes.md)

PHKG2 (Homo sapiens) — review notes

UniProtKB:P15735. HGNC:8931. Gene: PHKG2. 406 aa. Chromosome 16.

Identity / core biology

PHKG2 = "Phosphorylase b kinase gamma catalytic chain, liver/testis isoform"
(PHK-gamma-LT / PHK-gamma-T / PSK-C3 / phosphorylase kinase subunit gamma-2).
EC 2.7.11.19.

It is the catalytic (gamma) subunit of phosphorylase kinase (PhK). PhK is a
huge (~1.3 MDa) hexadecamer, (alpha-beta-gamma-delta)4. Gamma carries all catalytic
activity; alpha (PHKA1/PHKA2) and beta (PHKB) are regulatory, delta is calmodulin.
PMID:10487978
Function: activates glycogenolysis by phosphorylating and thereby activating glycogen
phosphorylase (converts phosphorylase b -> a). Couples Ca2+ (via calmodulin/delta) and
cAMP/PKA (phosphorylation of alpha/beta) signalling to glycogen breakdown.
[PMID:10487978 "phosphorylase b kinase (Phk), which phosphorylates and thereby
activates glycogen phosphorylase"; "Ca2+ relieves inhibition via the delta subunit...
Phosphorylation of the alpha and beta subunits by the ... (cAMP)-dependent protein
kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the
enzyme."]
UniProt FUNCTION: "Catalytic subunit of the phosphorylase b kinase (PHK), which
mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by
phosphorylating and thereby activating glycogen phosphorylase. May regulate
glycogeneolysis in the testis. In vitro, phosphorylates PYGM (PubMed:35549678)."
PHKG2 is the predominant catalytic-gamma isoform in liver, testis, erythrocytes (and
possibly other non-muscle tissues), whereas PHKG1 is the muscle isoform.
PMID:8896567

Structure / features (UniProt)

Protein kinase domain 24..291; active site (proton acceptor) at 153; ATP binding 30..38
and 53. CAMK Ser/Thr protein kinase family.
Two calmodulin-binding regions: 306..330 (domain-N) and 346..370 (domain-C).
Crystal structure 2Y7J (residues 6-293, kinase domain).
Catalytic activity: 2 ATP + phosphorylase b = 2 ADP + phosphorylase a (EC 2.7.11.19),
ECO experimental from PMID:35549678.

Disease

Glycogen storage disease type IXc (GSD9C / GSD-IXc, OMIM 613027): autosomal recessive
liver PhK deficiency. Infantile hepatomegaly, growth retardation, hypotonia, liver
dysfunction, elevated aminotransferases and lipids; can progress to hepatic
fibrosis/cirrhosis (more severe than the X-linked PHKA2 form).
[PMID:8896567; PMID:12930917; PMID:35549678; PMID:9245685]
PHKG2 GSD9C variants (V106E, G189E, E157K, D215N, F233S, H89fs, R320DfsX5, etc.)
reduce PhK enzyme activity. Functional assays: D215N and F233S markedly decrease PhK
activity; S253G polymorphism has no impact. [PMID:35549678; PMID:12930917; PMID:8896567]

GO annotation review decisions (summary)

Core, accept:
- GO:0004689 phosphorylase kinase activity (MF) — this IS the gene's function. Multiple
EXP (Reactome PMID:12930917, PMID:7847371, UniProt PMID:35549678), TAS, IBA, IEA.
ACCEPT the IBA/EXP(35549678); the others accepted/kept.
- GO:0005964 phosphorylase kinase complex (CC part_of) — subunit of the holoenzyme. IBA +
TAS + IEA. ACCEPT.
- GO:0005829 cytosol (CC) — IDA (HPA) + Reactome TAS. ACCEPT. (glycogenolysis is cytosolic)
- GO:0005980 glycogen catabolic process (BP) — TAS Reactome + IEA. This is the specific
process; accept as the core BP.
- GO:0045819 positive regulation of glycogen catabolic process (BP) — kinase activation of
phosphorylase = positive regulation of glycogen catabolism. ACCEPT (TAS + IEA).
- GO:0005516 calmodulin binding (MF) — gamma subunit has 2 CaM-binding regions; delta =
CaM; IEA. ACCEPT (supported by UniProt features + PMID:10487978 regulation).
- GO:0005524 ATP binding (MF) — kinase; ATP-binding P-loop 30..38. ACCEPT.

Generalize / less-specific (MODIFY or ACCEPT-as-broad-parent):
- GO:0005737 cytoplasm (IBA is_active_in) — correct but cytosol (0005829) is more specific
and separately annotated. KEEP (IBA, is_active_in) but note cytosol is more precise.
- GO:0004672 protein kinase activity (IEA InterPro) — true but generic parent of 0004689.
ACCEPT as broader IEA (allowed to be broader).
- GO:0004674 protein serine/threonine kinase activity (TAS) — true (CAMK Ser/Thr family)
but parent of phosphorylase kinase activity. ACCEPT (broader, correct branch).
- GO:0006468 protein phosphorylation (BP TAS PMID:2948189) — generic; the specific act is
phosphorylating glycogen phosphorylase within glycogenolysis. KEEP (correct but generic).
- GO:0005977 glycogen metabolic process (BP) — parent of glycogen catabolic process; the
activity drives catabolism specifically. ACCEPT as broader (IBA/TAS/IEA).

Non-core / peripheral:
- GO:0007165 signal transduction (BP IBA) — PhK is a node coupling Ca2+/cAMP signals to
glycogenolysis, so "signal transduction" is defensible but broad and not the core MF.
KEEP_AS_NON_CORE.
- GO:0006091 generation of precursor metabolites and energy (BP TAS PMID:8896567) — broad
metabolic role (glycogenolysis yields glucose/energy). KEEP_AS_NON_CORE.
- GO:0050321 tau-protein kinase activity (MF TAS PMID:8999860) — PMID:8999860 shows RABBIT
SKELETAL MUSCLE PhK (i.e. PHKG1 holoenzyme) phosphorylates tau in vitro; it is not about
the liver/testis PHKG2 gamma-2 isoform, and is an in-vitro promiscuous activity, not the
physiological function of PHKG2. MARK_AS_OVER_ANNOTATED (in-vitro, wrong isoform/tissue,
not core). Do NOT remove (experimental TAS; defer but flag as over-annotation).

Protein binding IPIs (GO:0005515, 8 rows): all bare protein binding. With/from is mostly
PHKA2 (P46019, the alpha regulatory subunit — a genuine PhK partner) and one MAGEA2B
(P43356). Per policy, bare protein binding is uninformative; MARK_AS_OVER_ANNOTATED, note
the informative interaction (PHKA2 = holoenzyme assembly, captured by 0005964). Do not
REMOVE (IPI experimental). Supporting evidence = UniProt INTERACTION section.

GO:0019899 enzyme binding (IEA Ensembl, ortholog rat P31325) — generic; the meaningful
partner is glycogen phosphorylase (substrate) / PHKA2. MARK_AS_OVER_ANNOTATED (generic,
uninformative parent of protein binding).

References about the ALPHA subunit (note)

PMID:7847371 (van den Berg 1995): about the PhK alpha (alphaL/PHKA2) subunit, X-linked
liver PhK deficiency. Reactome uses it as one evidence for PhK-holoenzyme phosphorylase
kinase activity (R-HSA-71588). It supports the holoenzyme activity, not PHKG2 catalysis
specifically. Keep the annotation (EXP on holoenzyme activity) but relevance to PHKG2
gene function is MEDIUM.
PMID:2948189 (Hanks 1987): homology cloning; identified a Ser/Thr kinase 72% identical to
rabbit muscle phosphorylase kinase gamma — this is the original PSK-C3/PHKG2 cDNA
identification. Supports Ser/Thr kinase + phosphorylase kinase identity.

core_functions

MF GO:0004689 phosphorylase kinase activity; directly_involved_in GO:0005980 glycogen
catabolic process (and its positive regulation, GO:0045819); location GO:0005829 cytosol;
in_complex GO:0005964 phosphorylase kinase complex.

📄 View Raw YAML

id: P15735
gene_symbol: PHKG2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PHKG2 encodes the liver/testis isoform of the catalytic gamma subunit of phosphorylase
  kinase (PhK), an ATP-dependent protein serine/threonine kinase (EC 2.7.11.19). PhK is a
  large ~1.3 MDa (alpha-beta-gamma-delta)4 hexadecameric holoenzyme in which the gamma
  subunit (PHKG1 in muscle, PHKG2 in liver/testis and other non-muscle tissues) carries all
  the catalytic activity while alpha (PHKA1/PHKA2) and beta (PHKB) are regulatory and delta
  is calmodulin. PhK activates glycogenolysis by phosphorylating Ser14 of glycogen
  phosphorylase, converting the less-active phosphorylase b to the active phosphorylase a,
  thereby coupling hormonal (cAMP/PKA) and Ca2+/calmodulin signalling to glycogen
  breakdown. The gamma subunit has an N-terminal protein kinase domain and C-terminal
  calmodulin-binding regions and binds ATP. PHKG2 acts in the cytosol. Loss-of-function
  variants cause autosomal recessive glycogen storage disease type IXc (GSD9C, liver PhK
  deficiency), presenting in infancy with hepatomegaly, hypoglycaemia, growth retardation
  and elevated aminotransferases and lipids, and potentially progressing to hepatic
  fibrosis or cirrhosis.
alternative_products:
- name: '1'
  id: P15735-1
- name: '2'
  id: P15735-2
  sequence_note: VSP_041858, VSP_041859
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phosphorylase kinase is a cytosolic enzyme, so a cytoplasm localization is correct.
      The gene is separately and more precisely annotated to cytosol (GO:0005829, IDA/TAS),
      which is the accurate subcellular compartment for glycogenolysis.
    action: ACCEPT
    reason: >-
      Correct but general cellular-component annotation; PhK acts in the cytosol where
      glycogen breakdown occurs. Retained; the more specific cytosol term is the core
      location.
    supported_by:
    - reference_id: Reactome:R-HSA-71588
      supporting_text: "The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL)."
- term:
    id: GO:0005964
    label: phosphorylase kinase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      PHKG2 is the catalytic gamma subunit of the phosphorylase kinase holoenzyme, a
      hexadecamer of four (alpha-beta-gamma-delta) protomers. Being part of the
      phosphorylase kinase complex is a defining structural property of this gene product.
    action: ACCEPT
    reason: >-
      Well-supported by holoenzyme biochemistry; the gamma subunit is an integral catalytic
      component of the phosphorylase kinase complex.
    supported_by:
    - reference_id: PMID:10487978
      supporting_text: one catalytic (gamma) subunit and three different regulatory (alpha, beta, and
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: Alpha (PHKA1 or PHKA2) and beta (PHKB)
- term:
    id: GO:0005977
    label: glycogen metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      PhK is a regulatory enzyme of glycogen metabolism; by phosphorylating glycogen
      phosphorylase it controls glycogen breakdown. Glycogen metabolic process is a correct
      but broad parent of the more specific glycogen catabolic process.
    action: ACCEPT
    reason: >-
      Accurate high-level BP; the specific role is in glycogen catabolism (GO:0005980),
      which is separately annotated. Retained as the broader process term.
    supported_by:
    - reference_id: PMID:8896567
      supporting_text: phosphorylase kinase (Phk), a regulatory enzyme of
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phosphorylase kinase integrates Ca2+ (via calmodulin/delta) and cAMP/PKA
      (phosphorylation of alpha/beta) signals to trigger glycogenolysis, so it functions as
      a signalling node. However, this is a broad process term and not the core molecular
      role of PHKG2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Defensible but generic; PhK does transduce hormonal/Ca2+ signals to glycogen
      breakdown, but the informative annotations are its kinase activity and role in
      glycogen catabolism. Kept as non-core.
    supported_by:
    - reference_id: PMID:10487978
      supporting_text: Ca2+ relieves inhibition via the delta subunit
- term:
    id: GO:0004689
    label: phosphorylase kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phosphorylase kinase activity is the defining molecular function of PHKG2, the
      catalytic gamma subunit. This IBA annotation is consistent with experimental evidence
      in human (PMID:35549678) and the phylogenetic conservation of the gamma subunit.
    action: ACCEPT
    reason: >-
      Core molecular function, phylogenetically inferred and experimentally supported.
    supported_by:
    - reference_id: PMID:35549678
      supporting_text: the catalytic gamma subunit, which is an active site of PhK enzyme
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based annotation to the general protein kinase activity term. PHKG2 is a
      protein kinase, so this is correct though broader than the specific phosphorylase
      kinase activity (GO:0004689) and protein serine/threonine kinase activity
      (GO:0004674) it is separately annotated to.
    action: ACCEPT
    reason: >-
      Correct broad parent MF from the protein kinase domain (residues 24-291); acceptable
      as a more general IEA.
    supported_by:
    - reference_id: PMID:2948189
      supporting_text: shares 72% identity with rabbit
- term:
    id: GO:0004689
    label: phosphorylase kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (ARBA/EC 2.7.11.19) to phosphorylase kinase activity, the core
      function of PHKG2. Consistent with the experimental and phylogenetic evidence.
    action: ACCEPT
    reason: >-
      Correct core MF; duplicate of the experimentally and phylogenetically supported
      phosphorylase kinase activity annotation.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: Reaction=2 ATP + phosphorylase b = 2 ADP + phosphorylase a.
- term:
    id: GO:0005516
    label: calmodulin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      The gamma subunit contains two calmodulin-binding regions (residues 306-330 and
      346-370). Within the holoenzyme the delta subunit is calmodulin, and Ca2+/calmodulin
      relieves regulatory inhibition of the gamma catalytic subunit. Calmodulin binding is
      therefore a bona fide molecular function of PHKG2.
    action: ACCEPT
    reason: >-
      Supported by UniProt calmodulin-binding regions and the established Ca2+/calmodulin
      regulation of PhK; retained.
    supported_by:
    - reference_id: PMID:10487978
      supporting_text: Ca2+ relieves inhibition via the delta subunit
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: Calmodulin-binding (domain-N)
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      PHKG2 is an ATP-dependent protein kinase with a glycine-rich ATP-binding P-loop
      (residues 30-38) and further ATP-binding residues; ATP binding is required for its
      phosphotransferase activity.
    action: ACCEPT
    reason: >-
      Correct; supported by the ATP-binding motif in the kinase domain and the catalytic
      reaction (2 ATP + phosphorylase b -> 2 ADP + phosphorylase a).
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: Reaction=2 ATP + phosphorylase b = 2 ADP + phosphorylase a.
- term:
    id: GO:0005964
    label: phosphorylase kinase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: >-
      Electronic annotation to the phosphorylase kinase complex, of which PHKG2 is the
      catalytic gamma subunit. Duplicate of the IBA/TAS complex annotations.
    action: ACCEPT
    reason: >-
      Correct core cellular component; PHKG2 is an integral subunit of the PhK holoenzyme.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: Alpha (PHKA1 or PHKA2) and beta (PHKB)
- term:
    id: GO:0005977
    label: glycogen metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to glycogen metabolic process, matching the IBA/TAS annotations.
      PhK regulates glycogen metabolism via activation of glycogen phosphorylase.
    action: ACCEPT
    reason: >-
      Correct broad BP; the specific role is in glycogen catabolism (separately annotated).
    supported_by:
    - reference_id: PMID:8896567
      supporting_text: phosphorylase kinase (Phk), a regulatory enzyme of
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23455922
  qualifier: enables
  review:
    summary: >-
      High-throughput AP-MS interaction study. The recorded partner (UniProtKB:P46019) is
      PHKA2, the alpha regulatory subunit of the phosphorylase kinase holoenzyme, so this
      interaction reflects assembly of the PhK complex. The generic protein binding term is
      uninformative and the meaningful relationship is already captured by the phosphorylase
      kinase complex annotation (GO:0005964).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding provides no specific functional information; the biologically
      meaningful partner (PHKA2) is subsumed by the complex annotation. Retained (experimental
      IPI) but flagged as over-annotated per curation policy rather than removed.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: "P15735; P46019: PHKA2; NbExp=11"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: >-
      Large-scale interactome study; the recorded partner (UniProtKB:P46019) is PHKA2, the
      alpha regulatory subunit of PhK, consistent with holoenzyme assembly. The generic
      protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative bare protein binding; PHKA2 interaction is captured by the phosphorylase
      kinase complex annotation. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: "P15735; P46019: PHKA2; NbExp=11"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Interactome-mapping study; partner UniProtKB:P46019 (PHKA2) is the alpha regulatory
      subunit of the PhK holoenzyme. The generic protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding is uninformative; the PHKA2 interaction is subsumed by the complex
      annotation. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: "P15735; P46019: PHKA2; NbExp=11"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Binary interactome (HuRI) study; the recorded partner here is UniProtKB:P43356
      (MAGEA2B), a MAGE family protein. This is a single high-throughput binary interaction
      of unclear functional significance for glycogenolysis; the generic protein binding
      term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding with a high-throughput partner (MAGEA2B) of unknown relevance to
      PHKG2 function; uninformative. Retained (experimental IPI) but flagged as
      over-annotated per policy.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: "P15735; P43356: MAGEA2B; NbExp=3"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Second interaction row from the HuRI binary interactome study; partner
      UniProtKB:P46019 (PHKA2), the alpha regulatory subunit of PhK, consistent with
      holoenzyme assembly. The generic protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding is uninformative; the PHKA2 interaction is captured by the complex
      annotation. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: "P15735; P46019: PHKA2; NbExp=11"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  qualifier: enables
  review:
    summary: >-
      Kinase interaction network study; partner UniProtKB:P46019 (PHKA2) is the alpha
      regulatory subunit of PhK. The generic protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative bare protein binding; PHKA2 interaction subsumed by the complex
      annotation. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: "P15735; P46019: PHKA2; NbExp=11"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Proteome-scale interactome (BioPlex) study; partner UniProtKB:P46019 (PHKA2) is the
      alpha regulatory subunit of PhK, consistent with holoenzyme assembly. The generic
      protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding is uninformative; the PHKA2 interaction is captured by the complex
      annotation. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: "P15735; P46019: PHKA2; NbExp=11"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: >-
      OpenCell endogenous-tagging interactome study; partner UniProtKB:P46019 (PHKA2), the
      alpha regulatory subunit of PhK. The generic protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative bare protein binding; the PHKA2 interaction is subsumed by the complex
      annotation. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: "P15735; P46019: PHKA2; NbExp=11"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      Multimodal cell-map interactome study; partner UniProtKB:P46019 (PHKA2), the alpha
      regulatory subunit of PhK. The generic protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding is uninformative; the PHKA2 interaction is captured by the complex
      annotation. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: file:human/PHKG2/PHKG2-uniprot.txt
      supporting_text: "P15735; P46019: PHKA2; NbExp=11"
- term:
    id: GO:0005980
    label: glycogen catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to glycogen catabolic process. This is the specific biological
      process in which PhK acts: by activating glycogen phosphorylase it drives glycogen
      breakdown (glycogenolysis). This is a core biological process for PHKG2.
    action: ACCEPT
    reason: >-
      Correct and specific BP; matches the Reactome TAS annotation to the same term.
    supported_by:
    - reference_id: Reactome:R-HSA-71588
      supporting_text: "The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL)."
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl ortholog-transfer annotation to the generic enzyme binding term (from rat
      ortholog P31325). While PHKG2 binds its substrate glycogen phosphorylase and the other
      PhK subunits, enzyme binding is an uninformative parent that adds little beyond the
      more specific kinase-substrate and complex annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic, uninformative MF; the meaningful interactions (substrate glycogen
      phosphorylase; PhK subunits) are better captured by phosphorylase kinase activity and
      the complex annotation. Flagged as over-annotated.
    supported_by:
    - reference_id: Reactome:R-HSA-71588
      supporting_text: catalyzes the phosphorylation of glycogen phosphorylase (PYGL)
- term:
    id: GO:0045819
    label: positive regulation of glycogen catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      By phosphorylating and activating glycogen phosphorylase (converting phosphorylase b
      to the active phosphorylase a), PhK positively regulates glycogen catabolism. This is
      an accurate regulatory BP for PHKG2.
    action: ACCEPT
    reason: >-
      Correct; PhK activation of phosphorylase is a positive regulatory step in
      glycogenolysis. Matches the TAS annotation to the same term.
    supported_by:
    - reference_id: PMID:10487978
      supporting_text: kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase.
- term:
    id: GO:0005980
    label: glycogen catabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70221
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable annotation placing PHKG2 in glycogen breakdown (glycogenolysis).
      Glycogen phosphorylase, activated by phosphorylase kinase, catalyzes glucose release
      from glycogen; PHKG2 provides the catalytic activity that switches phosphorylase on.
    action: ACCEPT
    reason: >-
      Correct core BP; well-supported by the Reactome glycogenolysis pathway.
    supported_by:
    - reference_id: Reactome:R-HSA-70221
      supporting_text: Glycogen phosphorylase, which can be activated by phosphorylase kinase, catalyzes
- term:
    id: GO:0004689
    label: phosphorylase kinase activity
  evidence_type: EXP
  original_reference_id: PMID:12930917
  qualifier: enables
  review:
    summary: >-
      Experimental annotation (via Reactome) associated with functional characterization of
      PHKG2 GSD9C variants (E157K, D215N, W300X, H89fs) in liver PhK deficiency. Confirms
      phosphorylase kinase activity as the function of PHKG2.
    action: ACCEPT
    reason: >-
      Experimental support for the core phosphorylase kinase activity; PHKG2 disease
      variants impair PhK function.
    supported_by:
    - reference_id: PMID:12930917
      supporting_text: manifests in infancy with
- term:
    id: GO:0004689
    label: phosphorylase kinase activity
  evidence_type: EXP
  original_reference_id: PMID:7847371
  qualifier: enables
  review:
    summary: >-
      Experimental annotation (via Reactome) for the phosphorylase kinase holoenzyme
      activity. This reference concerns the PhK alpha (PHKA2) subunit in X-linked liver PhK
      deficiency and is used by Reactome as one line of evidence for the liver PhK complex,
      of which PHKG2 is the catalytic gamma subunit.
    action: ACCEPT
    reason: >-
      Supports phosphorylase kinase activity of the liver PhK complex that contains PHKG2.
      The paper's primary focus is the alpha subunit, so its direct relevance to PHKG2
      catalysis is indirect; retained as consistent with the core function (defer to
      Reactome curation, do not remove an experimental annotation).
    supported_by:
    - reference_id: Reactome:R-HSA-71588
      supporting_text: consisting of four copies each of PHKA2 (alpha regulatory) (van den Berg et al. 1995), PHKB (beta regulatory)
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence (HPA) evidence localizing PHKG2 to the cytosol. This is the correct
      and specific subcellular location where phosphorylase kinase acts on glycogen
      phosphorylase during glycogenolysis.
    action: ACCEPT
    reason: >-
      Core cellular component; experimentally supported and consistent with the cytosolic
      site of glycogen breakdown.
    supported_by:
    - reference_id: Reactome:R-HSA-71588
      supporting_text: "The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL)."
- term:
    id: GO:0004689
    label: phosphorylase kinase activity
  evidence_type: EXP
  original_reference_id: PMID:35549678
  qualifier: enables
  review:
    summary: >-
      Experimental characterization of human PHKG2: recombinant wild-type and GSD9C-variant
      gamma subunits were assayed for PhK enzyme activity, with the F233S and R320DfsX5
      disease variants strongly reducing activity, directly demonstrating phosphorylase
      kinase activity for PHKG2. UniProt cites this paper for the catalytic activity and
      EC 2.7.11.19.
    action: ACCEPT
    reason: >-
      Strongest direct experimental evidence for the core molecular function; human PHKG2
      catalyzes the phosphorylase kinase reaction.
    supported_by:
    - reference_id: PMID:35549678
      supporting_text: The PhK enzyme activity of both the F233S and R320DfsX5 mutants was deficient
    - reference_id: PMID:35549678
      supporting_text: the catalytic gamma subunit, which is an active site of PhK enzyme
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71588
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to cytosol, where the phosphorylase kinase complex
      phosphorylates glycogen phosphorylase. Consistent with the HPA IDA cytosol annotation.
    action: ACCEPT
    reason: >-
      Correct core cellular component; matches the IDA cytosol annotation.
    supported_by:
    - reference_id: Reactome:R-HSA-71588
      supporting_text: "The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL)."
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: TAS
  original_reference_id: PMID:10487978
  qualifier: enables
  review:
    summary: >-
      PHKG2 belongs to the CAMK Ser/Thr protein kinase family and phosphorylates
      serine/threonine residues (Ser14 of glycogen phosphorylase). Protein
      serine/threonine kinase activity is a correct but broader parent of phosphorylase
      kinase activity (GO:0004689).
    action: ACCEPT
    reason: >-
      Correct broader MF; PHKG2 is a Ser/Thr protein kinase. The specific phosphorylase
      kinase activity term is separately annotated as the core function.
    supported_by:
    - reference_id: PMID:10487978
      supporting_text: regulatory subunits inhibit the phosphotransferase activity of the gamma
- term:
    id: GO:0004689
    label: phosphorylase kinase activity
  evidence_type: TAS
  original_reference_id: PMID:10487978
  qualifier: enables
  review:
    summary: >-
      Traceable annotation to phosphorylase kinase activity from the Brushia & Walsh review
      of PhK structure/function, which describes the gamma subunit as the catalytic subunit
      that phosphorylates and activates glycogen phosphorylase.
    action: ACCEPT
    reason: >-
      Core molecular function, supported by a review of PhK biochemistry.
    supported_by:
    - reference_id: PMID:10487978
      supporting_text: kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase.
- term:
    id: GO:0005964
    label: phosphorylase kinase complex
  evidence_type: TAS
  original_reference_id: PMID:10487978
  qualifier: part_of
  review:
    summary: >-
      Traceable annotation placing PHKG2 in the phosphorylase kinase complex; the review
      describes PhK as having one catalytic gamma subunit and three regulatory subunits per
      protomer.
    action: ACCEPT
    reason: >-
      Correct core cellular component; PHKG2 is the catalytic subunit of the PhK complex.
    supported_by:
    - reference_id: PMID:10487978
      supporting_text: one catalytic (gamma) subunit and three different regulatory (alpha, beta, and
- term:
    id: GO:0045819
    label: positive regulation of glycogen catabolic process
  evidence_type: TAS
  original_reference_id: PMID:10487978
  qualifier: involved_in
  review:
    summary: >-
      By phosphorylating and thereby activating glycogen phosphorylase, PhK positively
      regulates glycogen catabolism. Traceable from the Brushia & Walsh review.
    action: ACCEPT
    reason: >-
      Correct regulatory BP; PhK activation of phosphorylase is a positive regulatory step
      in glycogenolysis.
    supported_by:
    - reference_id: PMID:10487978
      supporting_text: kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase.
- term:
    id: GO:0050321
    label: tau-protein kinase activity
  evidence_type: TAS
  original_reference_id: PMID:8999860
  qualifier: enables
  review:
    summary: >-
      This annotation derives from a study showing that phosphorylase kinase purified from
      rabbit skeletal muscle phosphorylates microtubule-associated protein tau in vitro (Km
      6.9 uM), with the authors suggesting PhK may participate in tau phosphorylation in
      neurons. The assayed enzyme is muscle PhK (i.e. the PHKG1 gamma isoform / muscle
      holoenzyme), not the liver/testis PHKG2 gamma-2 isoform, and tau is a much poorer
      substrate than phosphorylase. This is an in-vitro cross-reactivity, not a
      physiological function of PHKG2.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Retained as an experimental TAS annotation per curation policy (not removed), but
      flagged as an over-annotation: the demonstrated tau kinase activity is an in-vitro
      activity of muscle phosphorylase kinase, tau is a poor substrate relative to glycogen
      phosphorylase, and there is no evidence this reflects a physiological role of the
      liver/testis PHKG2 isoform.
    supported_by:
    - reference_id: PMID:8999860
      supporting_text: Phosphorylase kinase, purified from rabbit skeletal muscle
- term:
    id: GO:0004689
    label: phosphorylase kinase activity
  evidence_type: TAS
  original_reference_id: PMID:2948189
  qualifier: enables
  review:
    summary: >-
      Traceable annotation from the original homology-cloning paper that identified the
      cDNA (PSK-C3) encoding a Ser/Thr kinase 72% identical to rabbit muscle phosphorylase
      kinase gamma subunit, i.e. the initial molecular identification of PHKG2.
    action: ACCEPT
    reason: >-
      Supports the phosphorylase kinase / Ser-Thr kinase identity of the gene product.
    supported_by:
    - reference_id: PMID:2948189
      supporting_text: shares 72% identity with rabbit
- term:
    id: GO:0005977
    label: glycogen metabolic process
  evidence_type: TAS
  original_reference_id: PMID:8896567
  qualifier: involved_in
  review:
    summary: >-
      Traceable annotation to glycogen metabolic process; PhK is described as a regulatory
      enzyme of glycogen metabolism whose deficiency causes glycogen storage disease.
    action: ACCEPT
    reason: >-
      Correct broad BP; the specific role is glycogen catabolism (separately annotated).
    supported_by:
    - reference_id: PMID:8896567
      supporting_text: phosphorylase kinase (Phk), a regulatory enzyme of
- term:
    id: GO:0006091
    label: generation of precursor metabolites and energy
  evidence_type: TAS
  original_reference_id: PMID:8896567
  qualifier: involved_in
  review:
    summary: >-
      By driving glycogenolysis, PhK contributes to the mobilization of glucose from
      glycogen stores used to maintain blood-glucose homeostasis and supply energy. This is
      a broad metabolic process term, not the core molecular role of PHKG2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Defensible but very general BP; the informative annotations are phosphorylase kinase
      activity and glycogen catabolism. Kept as non-core.
    supported_by:
    - reference_id: PMID:8896567
      supporting_text: phosphorylase kinase (Phk), a regulatory enzyme of
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: TAS
  original_reference_id: PMID:2948189
  qualifier: involved_in
  review:
    summary: >-
      PHKG2 is a protein kinase that phosphorylates glycogen phosphorylase. Protein
      phosphorylation is a correct but generic biological process; the specific,
      informative process is glycogen catabolism / its positive regulation.
    action: ACCEPT
    reason: >-
      Correct broad BP consistent with the kinase activity; retained as a general process
      term. The specific catabolic/regulatory processes are separately annotated as core.
    supported_by:
    - reference_id: PMID:2948189
      supporting_text: shares 72% identity with rabbit
core_functions:
- description: >-
    Catalytic gamma-2 subunit of phosphorylase kinase; an ATP-dependent protein
    serine/threonine kinase (EC 2.7.11.19) that phosphorylates and activates glycogen
    phosphorylase (b to a), driving glycogen breakdown in the cytosol as part of the
    phosphorylase kinase holoenzyme.
  molecular_function:
    id: GO:0004689
    label: phosphorylase kinase activity
  directly_involved_in:
  - id: GO:0005980
    label: glycogen catabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  in_complex:
    id: GO:0005964
    label: phosphorylase kinase complex
  supported_by:
  - reference_id: PMID:35549678
    supporting_text: the catalytic gamma subunit, which is an active site of PhK enzyme
  - reference_id: PMID:10487978
    supporting_text: kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase.
- description: >-
    Positive regulation of glycogenolysis: by phosphorylating and activating glycogen
    phosphorylase in response to Ca2+/calmodulin and cAMP/PKA signalling, PHKG2 (within
    the PhK holoenzyme) positively regulates glycogen catabolism.
  molecular_function:
    id: GO:0004689
    label: phosphorylase kinase activity
  directly_involved_in:
  - id: GO:0045819
    label: positive regulation of glycogen catabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:10487978
    supporting_text: kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase.
  - reference_id: PMID:10487978
    supporting_text: Ca2+ relieves inhibition via the delta 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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/PHKG2/PHKG2-uniprot.txt
  title: UniProtKB entry P15735 (PHKG2_HUMAN), phosphorylase b kinase gamma catalytic
    chain, liver/testis isoform
  findings: []
- id: PMID:10487978
  title: 'Phosphorylase kinase: the complexity of its regulation is reflected in the
    complexity of its structure.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Authoritative review of phosphorylase kinase structure/function; establishes the
      gamma subunit as the sole catalytic subunit and the Ca2+/cAMP regulation of PhK.
- id: PMID:12930917
  title: Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with
    mutations in the PHKG2 gene.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      GSD9C PHKG2 variant characterization (E157K, D215N, W300X, H89fs); establishes PHKG2
      as the cause of severe liver PhK deficiency.
- id: PMID:23455922
  title: Interlaboratory reproducibility of large-scale human protein-complex analysis
    by standardized AP-MS.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput AP-MS; source of a PHKG2-PHKA2 interaction underlying a bare protein
      binding annotation.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome; source of a bare protein binding (PHKA2) annotation.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Interactome map; source of a bare protein binding (PHKA2) annotation.
- id: PMID:2948189
  title: 'Homology probing: identification of cDNA clones encoding members of the
    protein-serine kinase family.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Original cloning of PSK-C3/PHKG2 cDNA; Ser/Thr kinase 72% identical to muscle
      phosphorylase kinase gamma subunit.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI binary interactome; source of bare protein binding annotations (PHKA2, MAGEA2B).
- id: PMID:32707033
  title: Kinase Interaction Network Expands Functional and Disease Roles of Human
    Kinases.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Kinase interaction network; source of a bare protein binding (PHKA2) annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex proteome-scale interactome; source of a bare protein binding (PHKA2) annotation.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: OpenCell endogenous-tagging interactome; source of a bare protein binding (PHKA2) annotation.
- id: PMID:35549678
  title: A very rare case report of glycogen storage disease type IXc with novel PHKG2
    variants.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct experimental PhK activity assays of human wild-type and GSD9C-variant PHKG2
      (F233S, R320DfsX5, D215N); UniProt cites it for the catalytic activity / EC 2.7.11.19.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; source of a bare protein binding (PHKA2) annotation.
- id: PMID:7847371
  title: X-linked liver phosphorylase kinase deficiency is associated with mutations
    in the human liver phosphorylase kinase alpha subunit.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      About the PhK alpha (PHKA2) subunit; used by Reactome as evidence for the liver PhK
      holoenzyme (which contains PHKG2) rather than PHKG2 catalysis directly.
- id: PMID:8896567
  title: Mutations in the testis/liver isoform of the phosphorylase kinase gamma subunit
    (PHKG2) cause autosomal liver glycogenosis in the gsd rat and in humans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identifies PHKG2 mutations as the cause of autosomal liver PhK deficiency (GSD9C) in
      humans and the gsd rat; PHKG2 is the predominant catalytic gamma isoform in
      liver/testis/erythrocytes.
- id: PMID:8999860
  title: The regulatory Ser262 of microtubule-associated protein tau is phosphorylated
    by phosphorylase kinase.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Demonstrates in-vitro tau phosphorylation by rabbit skeletal muscle phosphorylase
      kinase (muscle PHKG1 holoenzyme), not the liver/testis PHKG2 isoform; supports an
      over-annotated, non-physiological activity for PHKG2.
- id: Reactome:R-HSA-70221
  title: Glycogen breakdown (glycogenolysis)
  findings: []
- id: Reactome:R-HSA-71588
  title: glycogen phosphorylase (PYGL) dimer b + 2 ATP => glycogen phosphorylase (PYGL)
    dimer a + 2 ADP
  findings: []

PHKG2

Gene Description