Affinage

PRKG2

cGMP-dependent protein kinase 2 · UniProt Q13237

Length
762 aa
Mass
87.4 kDa
Annotated
2026-06-10
31 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRKG2 (cGKII) is a cGMP-activated serine/threonine protein kinase that transduces nitric oxide/cGMP signals into substrate phosphorylation across neuronal, epithelial, and skeletal tissues (PMID:18031684, PMID:25480791). In neurons, cGMP-activated cGKII binds the GluA1/GluR1 C-terminus adjacent to its catalytic site and phosphorylates GluR1 at Ser845 to drive AMPA receptor surface expression and synaptic potentiation, a mechanism that also modulates epileptic excitatory transmission (PMID:18031684, PMID:29587280), and it acts presynaptically to maintain the homeostatic balance of synaptic vesicle exocytosis and endocytosis in cerebellar granule cells (PMID:29084181). In retinal development, cGKII serves as an obligate relay between NO/cGMP and AKT/CREB signaling, controlling stage-specific cell death and survival decisions (PMID:24531539, PMID:32360667). In epithelia, cGKII phosphorylates the NHE3 Na+/H+ exchanger at three required sites to drive its internalization and inhibit exchange activity (PMID:25480791). A major role is in chondrocyte biology and skeletal growth: the cGKII kinase domain is required to regulate SOX9-driven collagen gene expression (COL2A1/COL10A1) and to phosphorylate c-Raf1 at Ser43 for FGF2-dependent ERK activation, and loss-of-function truncating mutations cause disproportionate dwarfism in cattle and humans (PMID:19887637, PMID:33106379). cGKII also phosphorylates the oligodendrocyte transcription factor MYRF at Ser259 to repress myelin genes (PMID:32270922), and its abundance is controlled by SMURF1-mediated ubiquitination and proteasomal degradation under diabetic conditions (PMID:40682619).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2007 High

    Established a direct mechanistic link between cGKII and synaptic plasticity by showing it binds and phosphorylates an AMPA receptor subunit to control receptor trafficking.

    Evidence Reciprocal Co-IP from brain, in vitro binding and phosphorylation assays, surface biotinylation, and LTP electrophysiology in hippocampal slices

    PMID:18031684

    Open questions at the time
    • Does not resolve whether cGKII acts at synaptic vs only extrasynaptic GluR1 pools in vivo
    • Upstream guanylyl cyclase source generating cGMP not defined
  2. 2008 Medium

    Characterized a PRKG2-PDGFRB fusion in which the PRKG2 5' portion drives a constitutively active PDGFRβ, defining a disease-causing rearrangement of the locus.

    Evidence FISH, fusion transcript cloning, cell-based transformation and kinase activity assays

    PMID:18166785

    Open questions at the time
    • The fusion reflects PDGFRβ activity, not native PRKG2 kinase function
    • Contribution of the PRKG2 sequence beyond providing a promoter/dimerization element not dissected
  3. 2009 Medium

    Demonstrated that the PRKG2 kinase domain is required for normal regulation of SOX9-driven collagen genes, linking kinase loss-of-function to dwarfism.

    Evidence Genetic fine-mapping and sequencing in cattle plus WT vs R678X overexpression with COL2/COL10 qPCR

    PMID:19887637

    Open questions at the time
    • Direct substrate connecting cGKII to SOX9 not identified in this study
    • Mechanism of collagen gene dysregulation downstream of kinase activity unresolved
  4. 2010 Medium

    Identified an Nkx homeodomain element controlling stage-specific PRKG2 transcription, explaining its induction at the prehypertrophic chondrocyte transition.

    Evidence Promoter deletion/mutagenesis and reporter assays in differentiating ATDC5 chondrocytes

    PMID:20057151

    Open questions at the time
    • The specific Nkx factor binding in vivo not identified
    • Link between transcriptional induction and downstream chondrocyte phenotype not tested
  5. 2014 High

    Defined the epithelial substrate code by showing cGKII inhibits NHE3 via simultaneous phosphorylation of three sites driving exchanger internalization.

    Evidence iTRAQ/LC-MS/MS phosphoproteomics, mutagenesis of all three sites, NHE3 activity and surface biotinylation in cell lines and mouse ileum

    PMID:25480791

    Open questions at the time
    • Physiological context driving cGMP/cGKII activation of this pathway not defined
    • How Ser663 serves both cGKII-inhibitory and dexamethasone-stimulatory roles mechanistically unclear
  6. 2014 Medium

    Placed cGKII as a stage-dependent switch in NO/cGMP control of retinal cell death versus survival through AKT and CREB.

    Evidence shRNA knockdown in vivo/in vitro, phospho-CREB immunostaining, AKT inhibition, caspase assays in chick retina

    PMID:24531539

    Open questions at the time
    • Direct cGKII substrate upstream of AKT not identified
    • Molecular basis for opposing E6 vs E8 outcomes unresolved
  7. 2017 Medium

    Revealed a presynaptic role for cGKII in maintaining the exo/endocytosis balance of synaptic vesicles.

    Evidence cGKII knockout mouse, live vesicle-cycling imaging, EM ultrastructure, KT5823 inhibition in cerebellar granule cells

    PMID:29084181

    Open questions at the time
    • Presynaptic substrate(s) of cGKII not identified
    • Whether the structural synapse changes are direct kinase effects unclear
  8. 2018 Medium

    Extended the GluA1/Ser845 mechanism to disease by linking cGKII activity to epileptic excitatory transmission.

    Evidence Pharmacological cGKII gain/loss-of-function in pilocarpine rat model with behavior, electrophysiology, phospho-Ser845 immunoblotting

    PMID:29587280

    Open questions at the time
    • Pharmacological agents may have off-target effects on related kinases
    • Genetic confirmation in epilepsy model not provided
  9. 2020 Medium

    Identified MYRF Ser259 as a cGKII-dependent phosphorylation site coupling cGKII to myelin gene repression in Huntington disease.

    Evidence Phospho-specific immunoblotting, PRKG2 shRNA knockdown in HD mice, MYRF/mutant huntingtin Co-IP, myelin gene expression

    PMID:32270922

    Open questions at the time
    • Direct cGKII-MYRF phosphorylation not demonstrated in vitro
    • Whether effect is specific to HD context or general to oligodendrocytes unclear
  10. 2020 Medium

    Confirmed cGKII as an obligate relay from NO/cGMP to AKT in retinal cells using both knockdown and knockout.

    Evidence cGKII shRNA and knockout mouse retinas, soluble guanylyl cyclase inhibition, phospho-AKT/ERK immunoblotting

    PMID:32360667

    Open questions at the time
    • Direct kinase target between cGKII and AKT not identified
    • Generalizability beyond retina untested
  11. 2020 Medium

    Identified c-Raf1 Ser43 as a cGKII substrate explaining how kinase loss-of-function impairs FGF2-ERK signaling and SOX9-mediated collagen regulation in human dwarfism.

    Evidence Exome sequencing of patients, expression of truncated mutants, phospho-Raf1/ERK immunoblotting, COL10A1/COL2A1 analysis

    PMID:33106379

    Open questions at the time
    • Direct in vitro cGKII phosphorylation of c-Raf1 Ser43 not isolated from cellular context
    • How c-Raf1/ERK output converges on SOX9 transcription not fully mapped
  12. 2021 Low

    Proposed a PKG2-PLCβ1 interaction by which PKG2 suppresses calcium-dependent ER stress in diabetic osteoblasts.

    Evidence Co-IP, proteomic identification, lentiviral overexpression, calcium and ER stress marker assays in rat osteoblasts

    PMID:34221234

    Open questions at the time
    • Single Co-IP/proteomic identification without reciprocal or in vitro validation of direct binding
    • Whether PKG2 phosphorylates PLCβ1 not tested
  13. 2025 Medium

    Established that PKG2 protein abundance is controlled by SMURF1-mediated ubiquitination and proteasomal degradation under diabetic conditions, affecting osteogenic differentiation.

    Evidence Co-IP, ubiquitination assay, MG132 rescue, SMURF1 overexpression with PKG2 rescue in BMSCs and diabetic rat implant model

    PMID:40682619

    Open questions at the time
    • Ubiquitination site(s) on PKG2 not mapped
    • Whether SMURF1 directly ubiquitinates PKG2 vs via adaptor unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified picture of how cGKII selects among its diverse substrates in different tissues, and the upstream cues controlling its compartmentalized activation, remains unresolved.
  • No structural model of substrate-specific docking across GluR1, NHE3, MYRF, c-Raf1
  • Tissue-specific determinants of cGKII signaling output not defined
  • Mechanism connecting kinase activity to SOX9 transcriptional control not fully established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
GRIA1MYRFNHE3PLCB1RAF1SMURF1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 PRKG2 (cGKII) binds directly to the GluR1 (GluA1) C-terminal domain adjacent to the kinase catalytic site; this interaction is increased when cGKII is activated by cGMP. Within the complex, cGKII phosphorylates GluR1 at Ser845. Activation of cGKII by cGMP increases surface expression of AMPARs at extrasynaptic sites, and inhibition of cGKII blocks GluR1 surface increase during chemLTP and reduces LTP in hippocampal slices. Co-immunoprecipitation from brain tissue, in vitro binding assays, phosphorylation assays, surface biotinylation, pharmacological inhibition in hippocampal slice electrophysiology Neuron High 18031684
2014 cGKII inhibits NHE3 Na+/H+ exchanger activity by phosphorylating it at three sites (rabbit Ser554, Ser607, Ser663; mouse Ser552, Ser605, Ser659), all of which must be simultaneously present for cGMP/cGKII-mediated inhibition. This phosphorylation is associated with reduced NHE3 surface expression (internalization). Ser663 phosphorylation is also required for dexamethasone-stimulated NHE3 activity and surface expression, representing a multifunctional phosphorylation site. iTRAQ/LC-MS/MS phosphoproteomics with TiO2 enrichment, site-directed mutagenesis, surface biotinylation, fluorometric NHE3 activity assay in PS120/NHERF2 and Caco-2/Bbe cells and mouse ileum The Journal of biological chemistry High 25480791
2009 A nonsense mutation (R678X) in PRKG2 truncates 85 C-terminal amino acids including most of the kinase domain and causes dwarfism in Angus cattle. The R678X mutant protein fails to regulate COL2A1 expression normally (COL2 and COL10 mRNA are overexpressed), establishing that the PRKG2 kinase domain is required for its regulation of collagen gene expression downstream of SOX9. Genetic fine-mapping, sequencing, cell culture overexpression of WT vs. R678X PRKG2, real-time PCR for COL2 and COL10 mRNA Proceedings of the National Academy of Sciences of the United States of America Medium 19887637
2008 PRKG2 is fused to PDGFRB via t(4;5)(q21.1;q31.3), incorporating the first two exons of PRKG2 fused to truncated exon 12 of PDGFRB, disrupting the juxtamembrane auto-inhibitory domain of PDGFRβ. Functional studies confirmed that the transforming and kinase activity of the PRKG2-PDGFRβ fusion protein depends on disruption of this auto-inhibitory domain. FISH, molecular cloning of fusion transcript, functional cell-based transformation and kinase activity assays Haematologica Medium 18166785
2020 PRKG2 promotes phosphorylation of the oligodendrocyte transcription factor MYRF at Ser259. This phosphorylation increases MYRF binding to mutant huntingtin and reduces expression of myelin-associated genes. Knockdown of PRKG2 in HD mice decreased MYRF Ser259 phosphorylation and increased myelin-associated protein expression, placing PRKG2 upstream of MYRF in a demyelination pathway. Phospho-specific immunoblotting, PRKG2 shRNA knockdown in HD mouse model, co-immunoprecipitation of MYRF and mutant huntingtin, myelin gene expression analysis EMBO reports Medium 32270922
2014 In developing chick retina, cGKII mediates NO/cGMP-dependent cell death (E6) and cell survival (E8) via opposing regulation of nuclear AKT activation and downstream CREB1 phosphorylation. shRNA knockdown of cGKII prevented NO-induced cell death at E6 and cell survival at E8, and abrogated CREB phosphorylation changes at both stages; AKT inhibition blocked cGKII-dependent CREB regulation. shRNA-mediated cGKII knockdown in vivo and in vitro, phospho-CREB immunostaining, AKT pharmacological inhibition, caspase activation assay Cell death and differentiation Medium 24531539
2020 In retinal cells, cGKII is required for NO-induced AKT activation and nuclear AKT accumulation downstream of soluble guanylyl cyclase. Knockdown of cGKII prevented cycloheximide/anisomycin-induced AKT phosphorylation, and cGKII knockout mice showed no AKT enhancement upon cycloheximide treatment, establishing cGKII as an obligate relay between NO/cGMP signaling and AKT activation. cGKII shRNA knockdown, cGKII knockout mouse retinas, pharmacological inhibition of soluble guanylyl cyclase, immunoblotting for phospho-AKT and phospho-ERK Biochimica et biophysica acta. Molecular cell research Medium 32360667
2020 Truncated PRKG2 mutant proteins lacking most or all of the kinase domain (nonsense and frameshift variants identified in human patients) fail to phosphorylate c-Raf1 at Ser43, resulting in reduced ERK1/2 activation in response to FGF2, and alter downstream MAPK signaling. These mutant proteins also dysregulate SOX9-mediated transcription by downregulating COL10A1 and upregulating COL2A1. Exome sequencing, functional expression of truncated mutant PRKG2 in cells, phospho-Raf1 and phospho-ERK1/2 immunoblotting, COL10A1/COL2A1 expression analysis Journal of medical genetics Medium 33106379
2018 cGKII regulates epileptic seizure activity by phosphorylating GluA1 at Ser845, thereby modulating GluA1 expression and function at the postsynaptic membrane. Pharmacological activation of cGKII in vivo increased epileptic behaviors and AMPAR-mediated excitatory synaptic transmission, while inhibition reduced them. Pharmacological cGKII activation/inhibition in pilocarpine-induced rat model, behavioral analysis, electrophysiology, immunoblotting for GluA1 and phospho-Ser845 Cellular physiology and biochemistry Medium 29587280
2017 cGKII plays a presynaptic role in controlling the homeostatic balance of synaptic vesicle exocytosis and endocytosis in cerebellar granule cells. Genetic knockout of cGKII slows endocytosis in a subset of boutons under strong stimulation and causes structural changes to synapses in cultured cells and cerebellar cortex in vivo. cGKII knockout mouse model, live imaging of vesicle cycling, electron microscopy ultrastructural analysis, pharmacological inhibition with KT5823 International journal of molecular sciences Medium 29084181
2010 Transcription of the cGKII (PRKG2) gene in chondrocytes is regulated by an Nkx homeodomain binding site located between -292 and -286 bp upstream of the transcription start site. Deletion or mutagenesis of this site markedly reduced promoter activity, and cGKII mRNA expression increased dramatically at the prehypertrophic stage of ATDC5 chondrogenic differentiation. 5'-flanking region cloning and deletion analysis, site-directed mutagenesis of Nkx-binding site, promoter-reporter assays in ATDC5 cells during chondrogenic differentiation Bioscience, biotechnology, and biochemistry Medium 20057151
2021 PKG2 interacts with PLCβ1 (phospholipase Cβ1) as identified by proteomic analysis. Upregulation of PKG2 (by lentiviral overexpression or cinaciguat) inhibits PLCβ1 activation, thereby reducing intracellular calcium overload and suppressing endoplasmic reticulum stress in osteoblasts under diabetic conditions. Co-immunoprecipitation, proteomic analysis, lentiviral PKG2 overexpression, calcium measurement, ER stress marker immunoblotting in primary rat osteoblasts Oxidative medicine and cellular longevity Low 34221234
2025 SMURF1 (an E3 ubiquitin ligase) ubiquitinates PKG2 and targets it for proteasomal degradation in the context of high-glucose/diabetic conditions. Co-immunoprecipitation confirmed the interaction between SMURF1 and PKG2; proteasome inhibitor MG132 restored PKG2 levels reduced by SMURF1 overexpression; SMURF1 overexpression reduced osteogenic differentiation in a PKG2-dependent manner. Co-immunoprecipitation of SMURF1 and PKG2, ubiquitination assay, proteasome inhibitor (MG132) treatment, SMURF1 overexpression with PKG2 expression rescue, osteogenic differentiation assays in BMSCs and diabetic rat implant model Applied biochemistry and biotechnology Medium 40682619
2019 PKG2 overexpression in ovarian cancer cells (SKOV3) inhibits phosphorylation of AKT and ERK in the EGFR downstream signaling pathway and suppresses EGFR expression, while PKG2 siRNA knockdown has the opposite effect, establishing PKG2 as a negative regulator of EGFR/AKT/ERK signaling in this context. PKG2 plasmid overexpression and siRNA knockdown in SKOV3 cells, western blot for phospho-AKT, phospho-ERK, EGFR Journal of B.U.ON. Low 32521860

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 A GluR1-cGKII interaction regulates AMPA receptor trafficking. Neuron 145 18031684
2014 Cyclic GMP kinase II (cGKII) inhibits NHE3 by altering its trafficking and phosphorylating NHE3 at three required sites: identification of a multifunctional phosphorylation site. The Journal of biological chemistry 48 25480791
2009 A nonsense mutation in cGMP-dependent type II protein kinase (PRKG2) causes dwarfism in American Angus cattle. Proceedings of the National Academy of Sciences of the United States of America 41 19887637
1999 Pkg2, a novel transmembrane protein Ser/Thr kinase of Streptomyces granaticolor. Journal of bacteriology 41 9864307
2008 Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion. Haematologica 39 18166785
2008 Fusion of PRKG2 and SPTBN1 to the platelet-derived growth factor receptor beta gene (PDGFRB) in imatinib-responsive atypical myeloproliferative disorders. Cancer genetics and cytogenetics 27 18262053
2020 Phosphorylation of myelin regulatory factor by PRKG2 mediates demyelination in Huntington's disease. EMBO reports 25 32270922
2014 The nitric oxide-cGKII system relays death and survival signals during embryonic retinal development via AKT-induced CREB1 activation. Cell death and differentiation 22 24531539
2020 Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia. Journal of medical genetics 15 33106379
2015 Transcriptional profiling of PRKG2-null growth plate identifies putative down-stream targets of PRKG2. BMC research notes 11 25924610
2008 Phenotypic characterization of the Komeda miniature rat Ishikawa, an animal model of dwarfism caused by a mutation in Prkg2. Comparative medicine 11 19149413
2023 Polymorphism detection of PRKG2 gene and its association with the number of thoracolumbar vertebrae and carcass traits in Dezhou donkey. BMC genomic data 9 36600198
2022 Prkg2 regulates alveolar type 2-mediated re-alveolarization. Stem cell research & therapy 9 35313961
2021 PRKG2 Splice Site Variant in Dogo Argentino Dogs with Disproportionate Dwarfism. Genes 8 34680883
2022 RNA Sequencing of the Pituitary Gland and Association Analyses Reveal PRKG2 as a Candidate Gene for Growth and Carcass Traits in Chinese Ningdu Yellow Chickens. Frontiers in veterinary science 7 35782572
2020 Protein synthesis inhibition promotes nitric oxide generation and activation of CGKII-dependent downstream signaling pathways in the retina. Biochimica et biophysica acta. Molecular cell research 6 32360667
2021 Pharmic Activation of PKG2 Alleviates Diabetes-Induced Osteoblast Dysfunction by Suppressing PLCβ1-Ca2+-Mediated Endoplasmic Reticulum Stress. Oxidative medicine and cellular longevity 5 34221234
2010 Transcriptional regulation of cGMP-dependent protein kinase II (cGK-II) in chondrocytes. Bioscience, biotechnology, and biochemistry 5 20057151
2020 Expression of PKG2 in ovarian cancer and its effect on epidermal growth factor receptor. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 4 32521860
2014 Common variants of cGKII/PRKG2 are not associated with gout susceptibility. The Journal of rheumatology 4 24882840
2024 Aggressive systemic mastocytosis with the co-occurrence of PRKG2::PDGFRB, KAT6A::NCOA2, and RXRA::NOTCH1 fusion transcripts and a heterozygous RUNX1 frameshift mutation. Cancer genetics 3 38471404
2021 Generation of induced pluripotent stem cell line (IGIBi007-A) from a patient with a novel acromesomelic dysplasia, PRKG2 type (AMDP). Stem cell research 3 33887582
2018 Inhibition of Cgkii Suppresses Seizure Activity and Hippocampal Excitation by Regulating the Postsynaptic Delivery of Glua1. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 3 29587280
2017 Altered Synaptic Membrane Retrieval after Strong Stimulation of Cerebellar Granule Neurons in Cyclic GMP-Dependent Protein Kinase II (cGKII) Knockout Mice. International journal of molecular sciences 3 29084181
2015 Polymorphism of rs7688672 and rs10033237 in cGKII/PRKG2 and gout susceptibility of Han population in northern China. Gene 3 25688884
2005 Effect of phosphate on the expression of protein-Ser/Thr kinase pkg2 in Streptomyces granaticolor. Folia microbiologica 2 16681148
2024 ELOVL2, PRKG2, and EDARADD DNA Methylation Strongly Estimate Indonesian Adolescents. Diagnostics (Basel, Switzerland) 1 39202255
2026 Case Report: Dual pathogenic mechanism of a PRKG2 missense variant underlies an attenuated phenotype of acromesomelic dysplasia. Frontiers in genetics 0 41574272
2025 SMURF1 Affects Dental Implant Integration in Diabetes By Regulating PKG2 Expression. Applied biochemistry and biotechnology 0 40682619
2025 A nonsense mutation in the PRKG2 gene in dalmatian dogs with chondrodysplasia. PloS one 0 41296694
2023 Diagnostic exome identifies a novel PRKG2 mutation in a proband with skeletal dysplasia. Clinical genetics 0 38072398

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