Affinage

PRKACB

cAMP-dependent protein kinase catalytic subunit beta · UniProt P22694

Round 2 corrected
Length
351 aa
Mass
40.6 kDa
Annotated
2026-04-28
55 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRKACB encodes the catalytic subunit beta (Cβ) of cAMP-dependent protein kinase A (PKA), a serine/threonine kinase that is released from regulatory subunits upon cAMP binding to phosphorylate diverse substrates in signaling, inflammation, neurodegeneration, and cardiac function (PMID:2342480, PMID:10830164). Cβ phosphorylates RhoA at Ser188 to suppress RhoA/ROCK1/FAK-mediated cell migration and invasion, and phosphorylates tau at multiple sites via the PKA/CREB axis, linking its activity to both metastasis suppression and neurodegenerative tau pathology (PMID:41851075, PMID:31379578). Gain-of-function missense mutations (e.g., p.S54L) impair type I holoenzyme assembly and increase cAMP sensitivity, causing developmental phenotypes including congenital heart defects and polydactyly, while oncogenic ATP1B1–PRKACB fusions drive intraductal oncocytic papillary neoplasms of the pancreas and bile duct (PMID:29669941, PMID:33058759, PMID:31678302). PRKACB expression is regulated transcriptionally by a TAL1/RUNX1/GATA1 complex during hematopoietic differentiation and post-transcriptionally by miR-200a-3p targeting its 3′-UTR (PMID:29069738, PMID:36459375).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1990 High

    Molecular cloning of PRKACB established it as one of two mammalian catalytic subunit genes of PKA, resolving the question of how many distinct catalytic isoforms constitute the PKA holoenzyme in mammals.

    Evidence cDNA cloning and sequence analysis showing 93% amino acid identity with Cα

    PMID:2342480

    Open questions at the time
    • No functional distinction between Cα and Cβ established
    • Tissue-specific roles of Cβ versus Cα unknown
  2. 2000 High

    Demonstration that PKA catalytic subunits phosphorylate the cardiac ryanodine receptor RyR2, dissociating FKBP12.6 and altering channel gating, provided the first link between PKA catalytic activity and a specific disease-relevant substrate complex in heart failure.

    Evidence Cosedimentation, co-immunoprecipitation, and single-channel recordings showing PKA-dependent RyR2 hyperphosphorylation in failing hearts

    PMID:10830164

    Open questions at the time
    • Relative contribution of PRKACB versus PRKACA to RyR2 phosphorylation not resolved
    • AKAP-mediated compartmentalization of Cβ at the SR not directly tested
  3. 2013 Medium

    Overexpression of PRKACB in NSCLC cells suppressed proliferation and invasion, establishing a context-dependent tumor-suppressive role for the catalytic subunit.

    Evidence Plasmid overexpression in LTEP-A2 cells assessed by MTT, colony formation, Transwell invasion, and apoptosis assays

    PMID:23833645

    Open questions at the time
    • No downstream pathway or substrate identified
    • Single cell line without in vivo validation
  4. 2017 Medium

    Identification of TAL1/RUNX1/GATA1 binding at the PRKACB Cβ3 isoform promoter revealed that hematopoietic transcription factor complexes regulate isoform-specific expression, with a coactivator-to-corepressor switch during megakaryocytic differentiation.

    Evidence Strep-CP, ChIP-Seq, and chromatin modification analysis during K562 megakaryocytic differentiation

    PMID:29069738

    Open questions at the time
    • Functional consequence of Cβ3 downregulation for megakaryocyte biology not demonstrated
    • Whether this regulatory mechanism operates in primary megakaryocytes is untested
  5. 2018 High

    Biochemical characterization of the somatic p.S54L mutation showed that Ser54 is critical for type I holoenzyme assembly, resolving how a single residue change can produce constitutive PKA activity and excessive cAMP sensitivity.

    Evidence BRET, surface plasmon resonance, and in vitro kinase assays with recombinant wild-type and S54L PRKACB

    PMID:29669941

    Open questions at the time
    • Whether Ser54 mutations occur somatically in contexts beyond the reported case
    • Structural basis of impaired RI binding not resolved at atomic level
  6. 2019 High

    Discovery of recurrent ATP1B1–PRKACB fusions as the defining genetic event in intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct established PRKACB gene rearrangement as a bona fide oncogenic driver.

    Evidence RNA-based targeted sequencing, RT-PCR, and DNA sequencing across >20 IOPNs with matched controls

    PMID:31678302

    Open questions at the time
    • Mechanism by which the fusion activates cAMP-independent kinase activity not biochemically defined
    • Whether fusion-targeted therapy is feasible remains unknown
  7. 2019 Medium

    Validation that miR-200a-3p directly targets the PRKACB 3′-UTR and that PRKACB mediates tau hyperphosphorylation at multiple AD-relevant sites (Thr205, Ser202/214/396/356) connected post-transcriptional regulation of PRKACB to Alzheimer's disease-associated tau pathology.

    Evidence Dual-luciferase reporter assays, PRKACB rescue experiments, Western blot and ELISA for phospho-tau in AD cell model

    PMID:31379578 PMID:36459375

    Open questions at the time
    • In vivo relevance of miR-200a-3p/PRKACB axis in AD brain tissue not demonstrated
    • Whether PRKACB directly phosphorylates tau or acts through an intermediate kinase is unresolved
  8. 2020 High

    Germline PRKACB variants causing increased cAMP sensitivity of PKA holoenzymes were linked to congenital heart defects and polydactyly through inhibition of hedgehog signaling, establishing PRKACB as a Mendelian disease gene.

    Evidence cAMP sensitivity assays and hedgehog reporter assays in NIH 3T3 fibroblasts expressing patient-derived variants

    PMID:33055300 PMID:33058759

    Open questions at the time
    • Which hedgehog pathway components are directly phosphorylated by Cβ is not established
    • Genotype–phenotype correlation across different PRKACB variants remains incomplete
  9. 2025 Medium

    Knockdown studies in macrophages demonstrated that PRKACB restrains inflammatory cytokine output (TNF-α, IL-1β), defining an anti-inflammatory function in myeloid cells.

    Evidence Gene knockdown in THP-1 macrophages, ELISA cytokine measurement, single-cell RNA-seq confirming myeloid expression

    PMID:41624837

    Open questions at the time
    • Downstream signaling pathway by which PRKACB suppresses cytokine release not defined
    • Single knockdown approach without rescue or in vivo corroboration
  10. 2026 High

    Identification of direct PRKACB–RhoA interaction and Ser188 phosphorylation resolved a long-standing question of how PKA suppresses RhoA-driven metastasis, and showed that common DGC-associated RhoA mutations evade this phosphorylation.

    Evidence Co-IP, GST pull-down, proximity ligation assay, in vivo peritoneal metastasis model in mice

    PMID:41851075

    Open questions at the time
    • Whether PRKACA also phosphorylates RhoA S188 with comparable efficiency not compared
    • Whether therapeutic reactivation of PRKACB–RhoA signaling is feasible in DGC is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the non-redundant roles of PRKACB versus PRKACA in specific tissues, the structural basis for isoform-specific holoenzyme assembly, and whether PRKACB directly phosphorylates tau or acts through intermediate kinases in neurodegeneration.
  • No systematic comparison of Cα versus Cβ substrate specificity in vivo
  • No high-resolution structure of Cβ in complex with type I regulatory subunits
  • Direct versus indirect role in tau phosphorylation not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-1266738 Developmental Biology 1
Partners
CREB1FKBP1BPRKAR1APRKAR1BRHOARYR2TAL1
Complex memberships
PKA holoenzyme (type I and type II)RyR2/FKBP12.6/PKA/mAKAP macromolecular complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 A somatic missense mutation p.S54L in PRKACB impairs formation of type I PKA holoenzymes and renders them highly sensitive to cAMP. The mutant enzyme shows higher basal PKA activity but lower maximal activity compared to wild-type, as measured by BRET, surface plasmon resonance, and phosphorylation of a synthetic substrate, demonstrating that residue Ser54 is critical for holoenzyme assembly and regulation. Bioluminescence resonance energy transfer (BRET), surface plasmon resonance, in vitro PKA activity assay with recombinant proteins JCI insight High 29669941
2020 Heterozygous germline or mosaic missense variants in PRKACB lead to PKA holoenzymes with increased sensitivity to activation by cAMP. Expression of PRKACB variants in NIH 3T3 fibroblasts inhibited hedgehog signaling, providing a mechanistic basis for the developmental defects (atrioventricular septal defect, postaxial polydactyly) observed in affected individuals. Structural and functional analysis of variants, cAMP-sensitivity assays, hedgehog signaling reporter assay in NIH 3T3 fibroblasts American journal of human genetics High 33058759
2020 PRKACB variants p.K286del and p.T300M were identified in subjects with unusual bone and endocrine phenotypes. The p.K286del variant affected PRKACB protein stability and led to increased PKA signaling, while p.T300M did not affect protein stability or response to cAMP. Functional studies of recombinant variants: protein stability assays, PKA signaling assays Endocrine-related cancer Medium 33055300
2019 PRKACB forms recurrent fusion genes (ATP1B1-PRKACB) in intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct, and these fusions are also present in corresponding invasive carcinomas, establishing PRKACB gene rearrangement as a driver event in these tumors. RNA-based targeted sequencing, RT-PCR, DNA sequencing Gastroenterology High 31678302
2013 Overexpression of PRKACB in NSCLC cell line LTEP-A2 decreased proliferation, colony formation, and invasion while increasing apoptosis, establishing PRKACB as a functional suppressor of tumor cell growth in this context. Plasmid transfection/overexpression, MTT assay, colony formation assay, flow cytometry, Transwell invasion assay Oncology letters Medium 23833645
2017 TAL1 together with hematopoietic transcription factors RUNX1 and GATA1 binds the promoter of the PRKACB isoform 3 (Cβ3) to regulate its expression. During megakaryocytic differentiation, a coactivator complex including WDR5 and p300 is replaced by a corepressor complex, removing activating chromatin modifications and reducing Cβ3 isoform expression. Chromatin precipitation (Strep-CP), ChIP promoter arrays, ChIP-Seq, chromatin modification analysis Oncotarget Medium 29069738
2022 miR-200a-3p directly targets the 3'-UTR of PRKACB mRNA, and aluminum exposure increases miR-200a-3p expression, leading to PRKACB downregulation, decreased PKA/CREB pathway activity, and abnormal tau hyperphosphorylation in PC12 nerve cells. Dual-luciferase reporter assay, Western blot, miRNA overexpression/inhibition in PC12 cells Neurotoxicity research Medium 36459375
2019 miR-200a-3p targets the 3'-UTR of PRKACB, reducing its expression, which attenuates PKA-mediated tau hyperphosphorylation at sites including Thr205 and Ser202, 214, 396, 356. Overexpression of PRKACB reversed the neuroprotective effects of miR-200a-3p, increasing tau phosphorylation and cell apoptosis in an AD cell model. Dual-luciferase reporter assay, Western blot, ELISA, flow cytometry, overexpression rescue experiments Frontiers in pharmacology Medium 31379578
2026 PRKACB directly interacts with RhoA and promotes its phosphorylation at S188, thereby inhibiting RhoA signaling and downstream effectors ROCK1 and FAK, suppressing cell migration and invasion in diffuse-type gastric cancer. Common RhoA mutations (V38G and N41K) in DGC weakened interaction with PRKACB, reducing S188 phosphorylation and enhancing metastatic potential. Co-immunoprecipitation, GST pull-down, in situ proximity ligation assay, in vivo mouse peritoneal metastasis model, phosphorylation assay Cell death & disease High 41851075
2026 PRKACB overexpression in IL-1β-treated human CHON-001 chondrocytes activates the PKA/CREB signaling pathway (increasing p-PKA and p-CREB), reduces apoptosis, decreases inflammatory cytokine secretion (TNF-α, IL-6, IL-8), and restores collagen II and aggrecan expression. Inhibition of PKA with H89 reversed these protective effects. Plasmid transfection, MTT assay, flow cytometry, Western blot, ELISA, pharmacological inhibition with H89 Immunity, inflammation and disease Medium 41684158
2024 PRKACB is a novel imprinted gene in marsupials (tammar wallaby, brushtail possum), with parent-of-origin-specific DNA methylation where the maternal allele is methylated and the paternal allele is unmethylated, resulting in paternal expression of a PRKACB mRNA isoform and lncRNA. Whole-genome bisulfite sequencing, allele-specific expression analysis, DMR identification pipeline Epigenetics & chromatin Medium 39342354
1990 PRKACB (Cβ) is one of two mammalian catalytic subunit genes of cAMP-dependent protein kinase, encoding a protein that shows 93% amino acid homology to Cα. Both Cα and Cβ constitute the catalytic core of PKA, which is released from regulatory subunits upon cAMP binding to phosphorylate Ser/Thr substrates. Molecular cloning, cDNA sequence analysis, amino acid homology comparison Molecular endocrinology High 2342480
2000 PKA (including its catalytic subunits, which encompass PRKACB) phosphorylates the ryanodine receptor RyR2, dissociating FKBP12.6 from the channel and increasing its open probability. In failing hearts, RyR2 is PKA hyperphosphorylated, resulting in defective channel function. The macromolecular complex at the SR includes RyR2, FKBP12.6, PKA, PP1, PP2A, and mAKAP. Cosedimentation, co-immunoprecipitation, channel open probability measurements Cell High 10830164
2025 PRKACB knockdown in THP-1 macrophages significantly upregulated TNF-α and IL-1β release and decreased cell viability, establishing PRKACB as a regulator of macrophage inflammatory output, with single-cell analysis confirming predominant expression in myeloid cells. Gene knockdown in macrophages, ELISA for cytokine measurement, viability assay, single-cell RNA analysis Frontiers in immunology Medium 41624837

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 1641 10830164
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1990 cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Annual review of biochemistry 1019 2165385
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2012 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 708 22939624
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). The EMBO journal 648 12628924
2006 Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacology & therapeutics 521 17306374
2002 The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 448 12475787
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2003 TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Current biology : CB 400 12747827
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2011 Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods. The EMBO journal 265 21399614
2001 The effects of aging on gene expression in the hypothalamus and cortex of mice. Proceedings of the National Academy of Sciences of the United States of America 260 11172053
1990 Molecular cloning of a tissue-specific protein kinase (C gamma) from human testis--representing a third isoform for the catalytic subunit of cAMP-dependent protein kinase. Molecular endocrinology (Baltimore, Md.) 223 2342480
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2019 Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct. Gastroenterology 126 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 40 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 31 24916040
2020 MicroRNA-384 Inhibits the Progression of Papillary Thyroid Cancer by Targeting PRKACB. BioMed research international 17 31998791
2020 CircRAD18 Accelerates the Progression of Acute Myeloid Leukemia by Modulation of miR-206/PRKACB Axis. Cancer management and research 16 33154668
2022 Investigation of -PRKACA/-PRKACB fusion genes in oncocytic tumors of the pancreatobiliary and other systems. Virchows Archiv : an international journal of pathology 14 36152045
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 13 37871652
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 10 33055300
2022 miR-200a-3p Regulates PRKACB and Participates in Aluminium-Induced Tau Phosphorylation in PC12 Cells. Neurotoxicity research 8 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