Affinage

PRKACB

cAMP-dependent protein kinase catalytic subunit beta · UniProt P22694

Length
351 aa
Mass
40.6 kDa
Annotated
2026-06-10
25 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRKACB encodes the catalytic subunit beta of cAMP-dependent protein kinase A, which assembles with regulatory subunits into holoenzymes whose activation threshold is set by cAMP, and which phosphorylates downstream substrates to control cell proliferation, differentiation, and inflammatory output (PMID:29669941, PMID:41851075). Holoenzyme assembly and regulatory control depend on specific residues: the Ser54 position is critical for type I holoenzyme formation, and pathogenic missense variants shift the holoenzyme toward heightened cAMP sensitivity and elevated basal activity, while a K286del variant acts by destabilizing the protein and increasing signaling (PMID:29669941, PMID:33055300). Catalytically, PRKACB drives the canonical PKA/CREB axis—phosphorylating CREB at Ser133 to support cell survival, anti-apoptotic, and anti-inflammatory programs in chondrocytes (PMID:41684158)—and also directly binds and phosphorylates RhoA at Ser188, thereby inhibiting RhoA/ROCK1/FAK signaling and suppressing migration, invasion, and EMT (PMID:41851075). Consistent with this restraining role, gain of PRKACB function suppresses tumor-cell growth and invasion, whereas its loss or weakened substrate engagement promotes metastasis and amplifies macrophage cytokine release (PMID:41851075, PMID:23833645). Constitutive activation of PRKACB through germline or mosaic missense variants produces developmental defects via aberrant inhibition of hedgehog signaling, and recurrent ATP1B1-PRKACB gene fusions act as driver events in intraductal oncocytic papillary neoplasms of the pancreas and bile duct (PMID:33058759, PMID:31678302). PRKACB is transcriptionally regulated by TAL1/RUNX1/GATA1 and HOXC13 at its promoter and post-transcriptionally repressed by miR-200a-3p, which couples its expression to megakaryocytic differentiation and to tau hyperphosphorylation states (PMID:29069738, PMID:31379578, PMID:38381512).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2013 Medium

    Established a cellular phenotype for PRKACB before its molecular mechanism was placed, showing it restrains rather than drives transformed cell behavior.

    Evidence PRKACB overexpression in LTEP-A2 NSCLC cells with proliferation, colony, invasion, and apoptosis assays

    PMID:23833645

    Open questions at the time
    • No pathway or substrate placement for the growth-suppressive effect
    • Gain-of-function only; no loss-of-function comparison
  2. 2017 Medium

    Defined how PRKACB expression is set during hematopoietic differentiation, addressing transcriptional control of an isoform.

    Evidence Strep-CP, ChIP-seq, and reporter assays showing TAL1/RUNX1/GATA1 binding and coactivator-to-corepressor exchange at the Cβ3 promoter in K562 and CD34+ cells

    PMID:29069738

    Open questions at the time
    • Isoform-specific function of Cβ3 not characterized
    • Mechanism limited to megakaryocytic context
  3. 2018 High

    Resolved how a somatic mutation perturbs PKA regulation, identifying a residue critical for holoenzyme assembly and cAMP control.

    Evidence Whole-exome sequencing of cortisol-producing adenoma plus BRET, SPR, and in vitro kinase assays on the p.S54L variant with recombinant proteins

    PMID:29669941

    Open questions at the time
    • Substrate specificity changes downstream of altered activation not mapped
    • In vivo tumor causation not directly demonstrated
  4. 2019 High

    Connected PRKACB to a Mendelian developmental phenotype through a specific signaling output, linking heightened cAMP sensitivity to hedgehog suppression.

    Evidence Whole-exome sequencing, cAMP-sensitivity assays, and hedgehog reporter assays in NIH 3T3 fibroblasts expressing PRKACB variants

    PMID:33058759

    Open questions at the time
    • Direct molecular link between PKA activity and the hedgehog node not detailed
    • Tissue-specific basis of distinct malformations unresolved
  5. 2019 Medium

    Established PRKACB rearrangement as a cancer driver, indicating activation of catalytic activity via fusion in a defined neoplasm.

    Evidence RNA-based targeted fusion sequencing with RT-PCR validation across pancreatobiliary neoplasms and 126 controls

    PMID:31678302

    Open questions at the time
    • Biochemical proof that the fusion elevates PKA activity not shown directly
    • Mechanism of regulatory-subunit escape unresolved
  6. 2019 Medium

    Demonstrated post-transcriptional control of PRKACB and its consequence for tau phosphorylation, defining a miRNA-PKA-tau axis.

    Evidence Dual-luciferase 3'UTR validation, Western blot, and PRKACB overexpression rescue in an AD cell model

    PMID:31379578

    Open questions at the time
    • Direct PRKACB phosphorylation of tau not shown biochemically
    • Relevance beyond cell model not established
  7. 2020 Medium

    Distinguished mechanisms of pathogenic variants, showing protein destabilization as an alternative route to increased PKA signaling.

    Evidence Protein stability and PKA signaling assays on p.K286del and p.T300M variants in cell-based systems

    PMID:33055300

    Open questions at the time
    • Pathogenicity of p.T300M unresolved
    • Limited methodological detail; single study
  8. 2023 Medium

    Identified an additional transcriptional repressor of PRKACB and a developmental phenotype, extending promoter-level control beyond hematopoiesis.

    Evidence ChIP-Seq, dual-luciferase reporter, and functional assays in rabbit dermal papilla cells with HOXC13

    PMID:38381512

    Open questions at the time
    • Conservation of HOXC13 regulation in human cells not shown
    • Link between PRKACB and WNT effectors mechanistically unmapped
  9. 2025 Low

    Probed PRKACB's role in myeloid inflammation, indicating it suppresses cytokine output.

    Evidence PRKACB knockdown in THP-1 macrophages with cytokine ELISA and viability assays

    PMID:41624837

    Open questions at the time
    • Single knockdown in one cell line; not independently confirmed
    • No pathway mechanism linking PRKACB to cytokine regulation
  10. 2025 Low

    Placed PRKACB in a microbe-induced pro-metastatic pathway, an unusual assignment as a pattern recognition receptor.

    Evidence P. gingivalis EV stimulation, JNK/NFATC2 pathway analysis, and migration/invasion plus in vivo metastasis assays in ESCC

    PMID:41419976

    Open questions at the time
    • Pattern recognition receptor claim not biochemically validated
    • Direct PRKACB-JNK linkage not demonstrated
  11. 2026 High

    Defined a direct substrate-level mechanism by which PRKACB restrains metastasis, the strongest mechanistic placement in the corpus.

    Evidence Co-IP, GST pull-down, PLA, Ser188 phosphorylation biochemistry, and peritoneal metastasis model with RhoA mutants in diffuse-type gastric cancer

    PMID:41851075

    Open questions at the time
    • Whether RhoA Ser188 phosphorylation is cAMP-dependent in vivo not established
    • Generality across cancer types beyond DGC unknown
  12. 2026 Medium

    Confirmed the PKA/CREB axis as the effector route for PRKACB's anti-apoptotic and anti-inflammatory function via pharmacological dependency.

    Evidence PRKACB overexpression plus H89 inhibitor rescue with apoptosis, matrix protein, and cytokine readouts in IL-1β-treated chondrocytes

    PMID:41684158

    Open questions at the time
    • Direct CREB Ser133 phosphorylation by PRKACB not shown in this system
    • Single cell-based model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PRKACB substrate selection (RhoA versus CREB versus tau) is partitioned across tissues, and whether its tumor-suppressive versus tumor-driving roles depend on holoenzyme context, remain unresolved.
  • No unified model reconciling growth-suppressive and oncogenic-fusion roles
  • Tissue-specific regulatory subunit pairing not characterized in the corpus
  • Direct kinetic substrate hierarchy not measured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3
Partners
PRKAR1ARHOA
Complex memberships
PKA holoenzyme

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 The somatic PRKACB p.S54L mutation (identified by whole-exome sequencing in a cortisol-producing adenoma) impairs formation of type I PKA holoenzymes and makes these holoenzymes highly sensitive to cAMP activation. The mutant enzyme shows higher basal PKA activity but lower maximal activity compared to wild-type, as measured by bioluminescence resonance energy transfer, surface plasmon resonance, and phosphorylation of a synthetic substrate in cell lysates and with recombinant proteins. This establishes Ser54 as a residue critical for holoenzyme assembly and regulatory control. Whole-exome sequencing, BRET, surface plasmon resonance, in vitro kinase assay (recombinant proteins and cell lysates), active-site variant functional analysis JCI insight High 29669941
2020 Germline or mosaic missense variants in PRKACB (and PRKACA) cause PKA holoenzymes that are more sensitive to activation by cAMP than wild-type. Expression of PRKACB variants in NIH 3T3 fibroblasts inhibits hedgehog signaling, providing a mechanistic basis for developmental defects (atrioventricular septal defect, polydactyly, skeletal abnormalities) seen in affected individuals. Whole-exome sequencing, computational structural analysis, functional cAMP-sensitivity assays, hedgehog signaling reporter assays in NIH 3T3 fibroblasts with PRKACB variant overexpression American journal of human genetics High 33058759
2020 The PRKACB p.K286del variant destabilizes the PRKACB protein and leads to increased PKA signaling. In contrast, the p.T300M variant did not affect protein stability or cAMP response, and its pathogenicity remains uncertain. Functional studies with recombinant/expressed variants: protein stability assays and PKA signaling assays in cell-based systems Endocrine-related cancer Medium 33055300
2017 TAL1 together with hematopoietic transcription factors RUNX1 and GATA1 binds the promoter of the PRKACB Cβ3 isoform. During megakaryocytic differentiation, a coactivator complex (including WDR5 and p300) on the Cβ3 promoter is replaced with a corepressor complex, removing activating chromatin modifications and reducing PRKACB-Cβ3 isoform expression. Streptavidin/biotin-based chromatin precipitation (Strep-CP), ChIP promoter arrays, ChIP-seq, reporter assays in K562 cells and primary human CD34+ cells Oncotarget Medium 29069738
2019 miR-200a-3p directly targets the 3' UTR of PRKACB (confirmed by dual-luciferase assay), reducing PRKACB/PKA activity and thereby decreasing tau hyperphosphorylation at PKA-preferred epitopes (Thr205, Ser202, Ser214, Ser396, Ser356). Overexpression of PRKACB reverses the effects of miR-200a-3p on tau phosphorylation and cell apoptosis in an AD cell model. Dual-luciferase reporter assay, Western blot, ELISA, flow cytometry, PRKACB overexpression rescue experiments in cell culture Frontiers in pharmacology Medium 31379578
2022 Aluminium exposure increases miR-200a-3p expression, which targets and downregulates PRKACB, reducing PKA/CREB signaling activity and causing abnormal tau hyperphosphorylation in PC12 nerve cells. PRKACB phosphorylates CREB at Ser-133 as part of the PKA/CREB pathway. miRNA target prediction (TargetScan), Western blot, RT-PCR, miRNA overexpression/inhibition in PC12 cells Neurotoxicity research Low 36459375
2026 PRKACB physically interacts with RhoA and promotes RhoA phosphorylation at Ser188, thereby inhibiting RhoA signaling and its downstream effectors ROCK1 and FAK, suppressing cell migration, invasion, pseudopodia formation, and EMT in diffuse-type gastric cancer. Common DGC RhoA mutations (V38G and N41K) weaken the PRKACB–RhoA interaction, reducing Ser188 phosphorylation and enhancing metastatic potential. Co-immunoprecipitation, GST pull-down assay, in situ proximity ligation assay, PRKACB knockdown/overexpression, mouse peritoneal metastasis model, RhoA inhibitor rescue Cell death & disease High 41851075
2026 PRKACB overexpression in IL-1β-treated human chondrocytes activates the PKA/CREB signaling pathway (increased p-PKA and p-CREB), reduces apoptosis, restores collagen II and aggrecan expression, and suppresses TNF-α, IL-6, and IL-8 secretion. A PKA inhibitor (H89) reverses these protective effects, confirming that PRKACB acts through the PKA/CREB axis. PRKACB plasmid transfection, MTT assay, flow cytometry apoptosis, Western blot (p-PKA, p-CREB, caspase-3, collagen II, aggrecan), ELISA (cytokines), H89 pharmacological inhibition Immunity, inflammation and disease Medium 41684158
2013 Overexpression of PRKACB in LTEP-A2 non-small cell lung cancer cells decreases cell proliferation, colony formation, and invasion while increasing apoptosis, establishing a functional role for PRKACB in suppressing NSCLC cell growth and invasive behavior. PRKACB plasmid transfection, MTT assay, colony formation, flow cytometry, Transwell invasion assay Oncology letters Medium 23833645
2025 PRKACB knockdown in THP-1 macrophages significantly upregulates TNF-α and IL-1β release and decreases cell viability, indicating that PRKACB suppresses macrophage inflammatory output and maintains cell viability in the context of sepsis-related myeloid biology. PRKACB knockdown, ELISA (TNF-α, IL-1β), cell viability assay in THP-1 macrophages Frontiers in immunology Low 41624837
2023 HOXC13 binds the PRKACB promoter region (−1596 to −1107 bp) and inhibits its transcription, as validated by dual-luciferase reporter assay. PRKACB overexpression in rabbit dermal papilla cells inhibits proliferation and promotes apoptosis, and modulates BCL2, WNT2, LEF1, and SFRP2 expression relevant to hair follicle development. ChIP-Seq, dual-luciferase reporter assay, RT-qPCR, CCK-8, flow cytometry in rabbit dermal papilla cells Gene Medium 38381512
2019 Recurrent gene fusions involving PRKACB (specifically ATP1B1-PRKACB) are found in intraductal oncocytic papillary neoplasms of the pancreas and bile duct, and are present in corresponding invasive carcinomas; these fusions are absent from 126 control pancreatobiliary lesions, establishing PRKACB rearrangements as driver events in these neoplasms. RNA-based targeted sequencing panel (fusion gene detection), RT-PCR validation, analysis of matched cyst fluid and bile duct brushings Gastroenterology Medium 31678302
2025 Porphyromonas gingivalis-derived extracellular vesicles induce PRKACB expression, which activates the JNK pathway, resulting in upregulation of NFATC2 and enhanced ESCC cell migration and invasion. PRKACB is identified as functioning as a pattern recognition receptor in this context. 16S rRNA sequencing, FISH, bioinformatics, in vitro migration/invasion assays, in vivo metastasis model, Western blot, mechanistic pathway analysis Journal of nanobiotechnology Low 41419976

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct. Gastroenterology 131 31678302
2019 MicroRNA-200a-3p Mediates Neuroprotection in Alzheimer-Related Deficits and Attenuates Amyloid-Beta Overproduction and Tau Hyperphosphorylation via Coregulating BACE1 and PRKACB. Frontiers in pharmacology 75 31379578
2018 Activating PRKACB somatic mutation in cortisol-producing adenomas. JCI insight 49 29669941
2020 Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome. American journal of human genetics 42 33058759
2013 PRKACB is downregulated in non-small cell lung cancer and exogenous PRKACB inhibits proliferation and invasion of LTEP-A2 cells. Oncology letters 33 23833645
2014 Upregulation of miR-23b enhances the autologous therapeutic potential for degenerative arthritis by targeting PRKACB in synovial fluid-derived mesenchymal stem cells from patients. Molecules and cells 32 24916040
2020 MicroRNA-384 Inhibits the Progression of Papillary Thyroid Cancer by Targeting PRKACB. BioMed research international 18 31998791
2023 Gene Rearrangement and Expression of PRKACA and PRKACB Govern Morphobiology of Pancreatobiliary Oncocytic Neoplasms. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 16 37871652
2022 Investigation of -PRKACA/-PRKACB fusion genes in oncocytic tumors of the pancreatobiliary and other systems. Virchows Archiv : an international journal of pathology 16 36152045
2020 CircRAD18 Accelerates the Progression of Acute Myeloid Leukemia by Modulation of miR-206/PRKACB Axis. Cancer management and research 16 33154668
1994 Localization of the IGHG, PRKACB, and TNP2 genes in pigs by in situ hybridization. Mammalian genome : official journal of the International Mammalian Genome Society 13 8012108
2021 Novel implications of a strictly monomorphic (GCC) repeat in the human PRKACB gene. Scientific reports 11 34667254
2020 PRKACB variants in skeletal disease or adrenocortical hyperplasia: effects on protein kinase A. Endocrine-related cancer 11 33055300
2022 miR-200a-3p Regulates PRKACB and Participates in Aluminium-Induced Tau Phosphorylation in PC12 Cells. Neurotoxicity research 9 36459375
2017 Hematopoietic transcription factors and differential cofactor binding regulate PRKACB isoform expression. Oncotarget 6 29069738
2024 PRKACB is a novel imprinted gene in marsupials. Epigenetics & chromatin 5 39342354
2025 FENDRR Affects COAD Biological Behavior by Inhibiting the DUSP4/CREB/PRKACB Pathway. International journal of genomics 2 40630642
2026 PRKACB Attenuates Chondrocyte Loss and Inflammation in Osteoarthritis. Immunity, inflammation and disease 1 41684158
2023 ChIP-Seq analysis reveals PRKACB as a target gene of HOXC13 involved in rabbit hair follicle development. Gene 1 38381512
2026 Multi-omics machine learning identifies diagnostic gene signatures and functionally supports PRKACB involvement in macrophage inflammatory responses in sepsis. Frontiers in immunology 0 41624837
2026 Loss of PRKACB facilitates metastasis of diffuse-type gastric cancer through RhoA signaling activation. Cell death & disease 0 41851075
2025 Knockdown of ARHGDIB promotes autophagy and reduces inflammation in LPS-induced alveolar epithelial cells via the PRKACB/NF-κB pathway. Allergologia et immunopathologia 0 40923418
2025 CircANKRD52 Augments the Growth and Invasion of Melanoma Cells by Sponging miR-141-3p and Upregulating PRKACB. Journal of cellular and molecular medicine 0 41173801
2025 Porphyromonas gingivalis extracellular vesicles promotes tumor metastasis in esophageal squamous cell carcinoma by inducing PRKACB/JNK/ NFATC2 axis. Journal of nanobiotechnology 0 41419976
2025 A novel PRKACB variant associated with bilateral postaxial polydactyly and intrauterine growth restriction: A case report and literature review. Global medical genetics 0 41488747

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