Details for: PHKA2

Gene ID: 5256

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: PHKA2

Ensembl ID: ENSG00000044446

Description: phosphorylase kinase regulatory subunit alpha 2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • centrilobular region hepatocyte CL0019029
    CSI 6.28
    rCSI 16.39%
    PRS 81.96
  • kidney connecting tubule epithelial cell CL1000768
    CSI 5.26
    rCSI 13.35%
    PRS 76.1
  • hepatocyte CL0000182
    CSI 3.99
    rCSI 7.15%
    PRS 83.8
  • midzonal region hepatocyte CL0019028
    CSI 3.86
    rCSI 9.06%
    PRS 83.44
  • hepatic stellate cell CL0000632
    CSI 3.68
    rCSI 13.78%
    PRS 77.82
  • extravillous trophoblast CL0008036
    CSI 3.5
    rCSI 4.33%
    PRS 82.79
  • periportal region hepatocyte CL0019026
    CSI 3.47
    rCSI 13.5%
    PRS 82.84
  • granulocyte monocyte progenitor cell CL0000557
    CSI 3.35
    rCSI 2.9%
    PRS 87.86
  • common myeloid progenitor CL0000049
    CSI 3.25
    rCSI 2.63%
    PRS 86.63
  • melanocyte CL0000148
    CSI 3.04
    rCSI 2.25%
    PRS 78.88
  • cerebral cortex endothelial cell CL1001602
    CSI 2.95
    rCSI 5.1%
    PRS 76.91
  • Kupffer cell CL0000091
    CSI 2.88
    rCSI 6.59%
    PRS 85.38
  • vascular leptomeningeal cell CL4023051
    CSI 2.81
    rCSI 4.92%
    PRS 79.15
  • choroid plexus epithelial cell CL0000706
    CSI 2.52
    rCSI 4.13%
    PRS 75.19
  • stem cell CL0000034
    CSI 2.46
    rCSI 2.38%
    PRS 79.1
  • colon epithelial cell CL0011108
    CSI 2.45
    rCSI 2.57%
    PRS 82
  • chondrocyte CL0000138
    CSI 2.43
    rCSI 3.86%
    PRS 78.19
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.37
    rCSI 2.94%
    PRS 66.03
  • adipocyte CL0000136
    CSI 2.3
    rCSI 2.95%
    PRS 75.1
  • enterocyte CL0000584
    CSI 2.25
    rCSI 3.63%
    PRS 82.85
  • lung secretory cell CL1000272
    CSI 2.17
    rCSI 5.37%
    PRS 84.77
  • Mueller cell CL0000636
    CSI 2.17
    rCSI 4.94%
    PRS 76.6
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.15
    rCSI 1.94%
    PRS 83.07
  • cerebellar granule cell CL0001031
    CSI 2.12
    rCSI 3.11%
    PRS 78.06
  • goblet cell CL0000160
    CSI 2.08
    rCSI 1.97%
    PRS 82.67
  • cardiac muscle cell CL0000746
    CSI 2.01
    rCSI 2.89%
    PRS 75.14
  • endothelial cell of pericentral hepatic sinusoid CL0019022
    CSI 2
    rCSI 6.17%
    PRS 87.72
  • promyelocyte CL0000836
    CSI 1.99
    rCSI 2.87%
    PRS 88.83
  • VIP GABAergic cortical interneuron CL4023016
    CSI 1.98
    rCSI 2.36%
    PRS 68.24
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 1.83
    rCSI 4.73%
    PRS 80.53
  • sst GABAergic cortical interneuron CL4023017
    CSI 1.8
    rCSI 2.32%
    PRS 69.28
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.73
    rCSI 2.79%
    PRS 69.53
  • peripheral nervous system neuron CL2000032
    CSI 1.71
    rCSI 2.33%
    PRS 76.88
  • pancreatic acinar cell CL0002064
    CSI 1.69
    rCSI 2.25%
    PRS 89.07
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 1.61
    rCSI 1.24%
    PRS 87.78
  • retinal ganglion cell CL0000740
    CSI 1.59
    rCSI 3.52%
    PRS 71.5
  • astrocyte of the cerebral cortex CL0002605
    CSI 1.57
    rCSI 3.52%
    PRS 68.96
  • pulmonary alveolar type 1 cell CL0002062
    CSI 1.56
    rCSI 8.99%
    PRS 80.89
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.53
    rCSI 2.71%
    PRS 67.66
  • pancreatic ductal cell CL0002079
    CSI 1.52
    rCSI 2.96%
    PRS 87.23
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.52
    rCSI 3.69%
    PRS 65.92
  • parietal epithelial cell CL1000452
    CSI 1.47
    rCSI 3.93%
    PRS 77.22
  • promonocyte CL0000559
    CSI 1.37
    rCSI 2.34%
    PRS 88.93
  • blood vessel smooth muscle cell CL0019018
    CSI 1.33
    rCSI 10.79%
    PRS 79.61
  • direct pathway medium spiny neuron CL4023026
    CSI 1.26
    rCSI 30.05%
    PRS 65.94
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 1.24
    rCSI 3.86%
    PRS 71.83
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.2
    rCSI 28.98%
    PRS 66.42
  • regular atrial cardiac myocyte CL0002129
    CSI 1.16
    rCSI 3.75%
    PRS 81.19
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 0.98
    rCSI 1.65%
    PRS 68.1
  • type B pancreatic cell CL0000169
    CSI 0.98
    rCSI 2.16%
    PRS 84.31
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.74
    rCSI 2.3%
    PRS 69.6
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 0.6
    rCSI 2.25%
    PRS 68.53
  • regular ventricular cardiac myocyte CL0002131
    CSI 0.58
    rCSI 3.62%
    PRS 76.96
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.54
    rCSI 1.94%
    PRS 66.03
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 0.44
    rCSI 2.58%
    PRS 68.54
  • medium spiny neuron CL1001474
    CSI 0.29
    rCSI 2.49%
    PRS 73.63

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [PHKA2](/details-gene/5256) encodes the alpha-2 subunit of phosphorylase kinase (PhK), a key enzyme complex in carbohydrate metabolism. As the liver-specific isoform, [PHKA2](/details-gene/5256) is a regulatory component essential for the hormonal and calcium-mediated control of glycogenolysis. Its primary function is to integrate signals for the breakdown of glycogen into glucose-1-phosphate, a critical process for maintaining blood glucose homeostasis. Reflecting this role, the gene shows the highest expression significance in liver cells, particularly [hepatocytes](/details-cell/CL0000182). Clinically, loss-of-function mutations in [PHKA2](/details-gene/5256) are the cause of X-linked liver glycogenosis ([306000](https://omim.org/entry/306000)), a metabolic disorder characterized by hepatomegaly and hypoglycemia ([Link](https://pubmed.ncbi.nlm.nih.gov/7847371/)). ## Cellular Roles and Expression Landscape The expression profile of [PHKA2](/details-gene/5256) strongly underscores its central role in hepatic metabolism. **Overall**, the gene exhibits its highest significance in various subpopulations of [hepatocytes](/details-cell/CL0000182), including [centrilobular region hepatocytes](/details-cell/CL0019029) (CSI: 6.28), [midzonal region hepatocytes](/details-cell/CL0019028) (CSI: 3.86), and [periportal region hepatocytes](/details-cell/CL0019026) (CSI: 3.47). This widespread and high significance across all hepatic zones is consistent with the liver's primary responsibility for storing and mobilizing glucose from glycogen. Beyond hepatocytes, [PHKA2](/details-gene/5256) also shows notable significance in other liver-resident cells, such as [hepatic stellate cells](/details-cell/CL0000632) and [Kupffer cells](/details-cell/CL0000091), suggesting a broader role in the liver microenvironment than just glucose export. A high CSI score is also observed in [kidney connecting tubule epithelial cells](/details-cell/CL1000768) (CSI: 5.26), indicating a potentially important, though less characterized, role in glycogen metabolism within the kidney. Its expression in hematopoietic progenitors, such as [granulocyte monocyte progenitor cells](/details-cell/CL0000557) and [common myeloid progenitors](/details-cell/CL0000049), suggests a possible involvement in the energy metabolism of these highly proliferative cells. ## Pathways and Molecular Function The function of [PHKA2](/details-gene/5256) is intrinsically linked to energy regulation through carbohydrate metabolism. It is an integral component of the [Phosphorylase kinase complex](/details-go/GO:0005964), where it acts as a regulatory subunit. This complex is central to the [Glycogen breakdown (glycogenolysis)](https://reactome.org/content/detail/R-HSA-70221) pathway, where it phosphorylates and activates glycogen phosphorylase, the rate-limiting enzyme of this process. This functional annotation is consistent with its involvement in broader biological processes like the [Glycogen metabolic process](/details-go/GO:0005977) and the [Generation of precursor metabolites and energy](/details-go/GO:0006091). At the molecular level, [PHKA2](/details-gene/5256) is involved in [Phosphorylase kinase activity](/details-go/GO:0004689). A key feature of its regulatory function is its ability to bind calmodulin ([GO:0005516](https://www.ebi.ac.uk/QuickGO/term/GO:0005516)), which makes the PhK complex sensitive to intracellular calcium levels, thereby linking glycogenolysis to a wide array of signaling pathways. The gene's documented involvement in X-linked liver glycogenosis types I and II highlights the critical, non-redundant role of this specific subunit in hepatic glucose mobilization ([Link](https://doi.org/10.1086/302399)). ## Research Directions The well-established role of [PHKA2](/details-gene/5256) in X-linked liver glycogenosis provides a solid foundation for further research into its nuanced regulation and extra-hepatic functions. **Proposed Hypotheses:** 1. Given the high significance scores across different zones of the liver lobule, the regulatory control of [PHKA2](/details-gene/5256) expression or PhK complex activity may be zone-dependent. This differential regulation could contribute to the metabolic zonation of the liver, allowing for fine-tuned control of glycogenolysis in response to varying oxygen and nutrient gradients. 2. The high significance of [PHKA2](/details-gene/5256) in [kidney connecting tubule epithelial cells](/details-cell/CL1000768) suggests that localized glycogenolysis in this nephron segment is critical for specific renal functions, such as ion transport or pH balance. Dysregulation of this process could contribute to the subclinical renal abnormalities sometimes observed in patients with glycogen storage diseases. **Experimental Approach:** To test the hypothesis of zonal regulation in the liver, one could employ spatial transcriptomics combined with in situ proteomics on human liver tissue. This would allow for the simultaneous visualization and quantification of `PHKA2` mRNA and phosphorylated (active) PhK protein across the periportal-to-centrilobular axis. These spatial maps could then be correlated with the expression of key metabolic hormones and signaling molecules to determine if [PHKA2](/details-gene/5256) activity is differentially regulated by hormonal cues (e.g., insulin, glucagon) in different liver zones. **Therapeutic Potential:** Since X-linked liver glycogenosis is a monogenic, loss-of-function disorder, the therapeutic strategy would focus on functional restoration rather than inhibition. [PHKA2](/details-gene/5256) represents a promising target for gene replacement therapy. Due to the liver-specific nature of the disease and the natural tropism of adeno-associated viruses (AAVs) for [hepatocytes](/details-cell/CL0000182), an AAV-based vector carrying a functional copy of the `PHKA2` cDNA would be a direct and potentially curative approach. An alternative strategy for patients with specific missense mutations could involve the development of small-molecule pharmacological chaperones designed to stabilize the mutant protein and restore partial enzymatic activity.

Genular Protein ID: 2073681509

Symbol: KPB2_HUMAN

Name: Phosphorylase b kinase regulatory subunit alpha, liver isoform

UniProtKB Accession Codes:

P46019 A8K1T1 Q6LAJ5 Q7Z6W0 Q96CR3 Q9UDA1

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 42 Ensembl 1 GO 9 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 1 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 7847371

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

PubMed ID: 7847371

PubMed ID: 7549948

Title: Isolation of cDNA encoding the human liver phosphorylase kinase alpha subunit (PHKA2) and identification of a missense mutation of the PHKA2 gene in a family with liver phosphorylase kinase deficiency.

PubMed ID: 7549948

PubMed ID: 10330341

Title: Complete genomic structure and mutational spectrum of PHKA2 in patients with X-linked liver glycogenosis type I and II.

PubMed ID: 10330341

DOI: 10.1086/302399

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15772651

Title: The DNA sequence of the human X chromosome.

PubMed ID: 15772651

DOI: 10.1038/nature03440

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 9600238

Title: Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene.

PubMed ID: 9600238

DOI: 10.1007/s004390050715

PubMed ID: 8518797

Title: X-linked liver glycogenosis: localization and isolation of a candidate gene.

PubMed ID: 8518797

DOI: 10.1093/hmg/2.5.583

PubMed ID: 8226841

Title: The multiphosphorylation domain of the phosphorylase kinase alpha M and alpha L subunits is a hotspot of differential mRNA processing and of molecular evolution.

PubMed ID: 8226841

DOI: 10.1016/s0021-9258(19)49449-0

PubMed ID: 18691976

Title: Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.

PubMed ID: 18691976

DOI: 10.1016/j.molcel.2008.07.007

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 19413330

Title: Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.

PubMed ID: 19413330

DOI: 10.1021/ac9004309

PubMed ID: 19369195

Title: Large-scale proteomics analysis of the human kinome.

PubMed ID: 19369195

DOI: 10.1074/mcp.m800588-mcp200

PubMed ID: 19690332

Title: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.

PubMed ID: 19690332

DOI: 10.1126/scisignal.2000007

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 8733133

Title: X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase.

PubMed ID: 8733133

DOI: 10.1093/hmg/5.5.649

PubMed ID: 8733134

Title: Mutation hotspots in the PHKA2 gene in X-linked liver glycogenosis due to phosphorylase kinase deficiency with atypical activity in blood cells (XLG2).

PubMed ID: 8733134

DOI: 10.1093/hmg/5.5.653

PubMed ID: 17689125

Title: Glycogen storage disease type IX: High variability in clinical phenotype.

PubMed ID: 17689125

DOI: 10.1016/j.ymgme.2007.06.007

Sequence Information:

  • Length: 1235
  • Mass: 138408
  • Checksum: 6CA10CFFA86A582A
  • Sequence:
    • MRSRSNSGVR LDGYARLVQQ TILCYQNPVT GLLSASHEQK DAWVRDNIYS ILAVWGLGMA 
YRKNADRDED KAKAYELEQN VVKLMRGLLQ CMMRQVAKVE KFKHTQSTKD SLHAKYNTAT 
CGTVVGDDQW GHLQVDATSL FLLFLAQMTA SGLRIIFTLD EVAFIQNLVF YIEAAYKVAD 
YGMWERGDKT NQGIPELNAS SVGMAKAALE AIDELDLFGA HGGRKSVIHV LPDEVEHCQS 
ILFSMLPRAS TSKEIDAGLL SIISFPAFAV EDVNLVNVTK NEIISKLQGR YGCCRFLRDG 
YKTPREDPNR LHYDPAELKL FENIECEWPV FWTYFIIDGV FSGDAVQVQE YREALEGILI 
RGKNGIRLVP ELYAVPPNKV DEEYKNPHTV DRVPMGKVPH LWGQSLYILS SLLAEGFLAA 
GEIDPLNRRF STSVKPDVVV QVTVLAENNH IKDLLRKHGV NVQSIADIHP IQVQPGRILS 
HIYAKLGRNK NMNLSGRPYR HIGVLGTSKL YVIRNQIFTF TPQFTDQHHF YLALDNEMIV 
EMLRIELAYL CTCWRMTGRP TLTFPISRTM LTNDGSDIHS AVLSTIRKLE DGYFGGARVK 
LGNLSEFLTT SFYTYLTFLD PDCDEKLFDN ASEGTFSPDS DSDLVGYLED TCNQESQDEL 
DHYINHLLQS TSLRSYLPPL CKNTEDRHVF SAIHSTRDIL SVMAKAKGLE VPFVPMTLPT 
KVLSAHRKSL NLVDSPQPLL EKVPESDFQW PRDDHGDVDC EKLVEQLKDC SNLQDQADIL 
YILYVIKGPS WDTNLSGQHG VTVQNLLGEL YGKAGLNQEW GLIRYISGLL RKKVEVLAEA 
CTDLLSHQKQ LTVGLPPEPR EKIISAPLPP EELTKLIYEA SGQDISIAVL TQEIVVYLAM 
YVRAQPSLFV EMLRLRIGLI IQVMATELAR SLNCSGEEAS ESLMNLSPFD MKNLLHHILS 
GKEFGVERSV RPIHSSTSSP TISIHEVGHT GVTKTERSGI NRLRSEMKQM TRRFSADEQF 
FSVGQAASSS AHSSKSARSS TPSSPTGTSS SDSGGHHIGW GERQGQWLRR RRLDGAINRV 
PVGFYQRVWK ILQKCHGLSI DGYVLPSSTT REMTPHEIKF AVHVESVLNR VPQPEYRQLL 
VEAIMVLTLL SDTEMTSIGG IIHVDQIVQM ASQLFLQDQV SIGAMDTLEK DQATGICHFF 
YDSAPSGAYG TMTYLTRAVA SYLQELLPNS GCQMQ