PHKG2

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

Gene Description

Existing Annotations Review

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.

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.

References

📚 Additional Documentation

Notes

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