{"gene":"PRKACB","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2018,"finding":"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.","method":"Whole-exome sequencing, BRET, surface plasmon resonance, in vitro kinase assay (recombinant proteins and cell lysates), active-site variant functional analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins, multiple orthogonal biophysical and enzymatic methods in a single study","pmids":["29669941"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Whole-exome sequencing, computational structural analysis, functional cAMP-sensitivity assays, hedgehog signaling reporter assays in NIH 3T3 fibroblasts with PRKACB variant overexpression","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional methods (cAMP sensitivity assay, hedgehog pathway reporter, cell-based expression), single lab but several independent variants studied","pmids":["33058759"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Functional studies with recombinant/expressed variants: protein stability assays and PKA signaling assays in cell-based systems","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — cell-based functional assays, single lab, single study, limited methodological detail in abstract","pmids":["33055300"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Streptavidin/biotin-based chromatin precipitation (Strep-CP), ChIP promoter arrays, ChIP-seq, reporter assays in K562 cells and primary human CD34+ cells","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based binding assays combined with differentiation model and isoform expression analysis, single lab","pmids":["29069738"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Dual-luciferase reporter assay, Western blot, ELISA, flow cytometry, PRKACB overexpression rescue experiments in cell culture","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR luciferase validation plus rescue experiments with multiple readouts, single lab","pmids":["31379578"],"is_preprint":false},{"year":2022,"finding":"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.","method":"miRNA target prediction (TargetScan), Western blot, RT-PCR, miRNA overexpression/inhibition in PC12 cells","journal":"Neurotoxicity research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — target validation inferred from expression changes without direct 3'UTR luciferase confirmation noted in abstract; single lab, single method set","pmids":["36459375"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Co-immunoprecipitation, GST pull-down assay, in situ proximity ligation assay, PRKACB knockdown/overexpression, mouse peritoneal metastasis model, RhoA inhibitor rescue","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal protein interaction assays (Co-IP, GST pull-down, PLA), phosphorylation biochemistry, in vivo model, pathway rescue; multiple orthogonal methods in single study","pmids":["41851075"],"is_preprint":false},{"year":2026,"finding":"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.","method":"PRKACB plasmid transfection, MTT assay, flow cytometry apoptosis, Western blot (p-PKA, p-CREB, caspase-3, collagen II, aggrecan), ELISA (cytokines), H89 pharmacological inhibition","journal":"Immunity, inflammation and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression plus pharmacological inhibitor rescue with multiple readouts; single lab","pmids":["41684158"],"is_preprint":false},{"year":2013,"finding":"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.","method":"PRKACB plasmid transfection, MTT assay, colony formation, flow cytometry, Transwell invasion assay","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple functional cellular assays with gain-of-function, single lab, no pathway placement","pmids":["23833645"],"is_preprint":false},{"year":2025,"finding":"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.","method":"PRKACB knockdown, ELISA (TNF-α, IL-1β), cell viability assay in THP-1 macrophages","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment in one cell line, limited pathway mechanistic detail, single lab","pmids":["41624837"],"is_preprint":false},{"year":2023,"finding":"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.","method":"ChIP-Seq, dual-luciferase reporter assay, RT-qPCR, CCK-8, flow cytometry in rabbit dermal papilla cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct promoter binding confirmed by dual-luciferase assay and ChIP-Seq; functional consequences assessed; single lab","pmids":["38381512"],"is_preprint":false},{"year":2019,"finding":"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.","method":"RNA-based targeted sequencing panel (fusion gene detection), RT-PCR validation, analysis of matched cyst fluid and bile duct brushings","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — replicated across multiple patient samples with matched controls, RNA-based detection of fusion transcripts; mechanistic implication is activation of PKA catalytic activity via fusion","pmids":["31678302"],"is_preprint":false},{"year":2025,"finding":"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.","method":"16S rRNA sequencing, FISH, bioinformatics, in vitro migration/invasion assays, in vivo metastasis model, Western blot, mechanistic pathway analysis","journal":"Journal of nanobiotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement based on expression changes and functional assays; the claim that PRKACB acts as a 'pattern recognition receptor' is mechanistically unusual and not fully validated biochemically in the abstract","pmids":["41419976"],"is_preprint":false}],"current_model":"PRKACB encodes the catalytic subunit beta (Cβ) of cAMP-dependent protein kinase A (PKA); it phosphorylates substrates including CREB (at Ser133), tau, and RhoA (at Ser188), assembles into type I and II PKA holoenzymes whose activation threshold is set by its interaction with regulatory subunits, and is regulated transcriptionally by TAL1/RUNX1/GATA1 complexes and post-transcriptionally by multiple miRNAs; activating mutations (e.g., p.S54L) or gene fusions (e.g., ATP1B1-PRKACB) constitutively elevate PKA activity driving adrenal tumors or pancreatobiliary oncocytic neoplasms, while loss of PRKACB promotes metastasis through RhoA/ROCK1/FAK signaling activation and enhances macrophage inflammatory output."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2013,"claim":"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","pmids":["23833645"],"confidence":"Medium","gaps":["No pathway or substrate placement for the growth-suppressive effect","Gain-of-function only; no loss-of-function comparison"]},{"year":2017,"claim":"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","pmids":["29069738"],"confidence":"Medium","gaps":["Isoform-specific function of Cβ3 not characterized","Mechanism limited to megakaryocytic context"]},{"year":2018,"claim":"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","pmids":["29669941"],"confidence":"High","gaps":["Substrate specificity changes downstream of altered activation not mapped","In vivo tumor causation not directly demonstrated"]},{"year":2019,"claim":"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","pmids":["33058759"],"confidence":"High","gaps":["Direct molecular link between PKA activity and the hedgehog node not detailed","Tissue-specific basis of distinct malformations unresolved"]},{"year":2019,"claim":"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","pmids":["31678302"],"confidence":"Medium","gaps":["Biochemical proof that the fusion elevates PKA activity not shown directly","Mechanism of regulatory-subunit escape unresolved"]},{"year":2019,"claim":"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","pmids":["31379578"],"confidence":"Medium","gaps":["Direct PRKACB phosphorylation of tau not shown biochemically","Relevance beyond cell model not established"]},{"year":2020,"claim":"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","pmids":["33055300"],"confidence":"Medium","gaps":["Pathogenicity of p.T300M unresolved","Limited methodological detail; single study"]},{"year":2023,"claim":"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","pmids":["38381512"],"confidence":"Medium","gaps":["Conservation of HOXC13 regulation in human cells not shown","Link between PRKACB and WNT effectors mechanistically unmapped"]},{"year":2025,"claim":"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","pmids":["41624837"],"confidence":"Low","gaps":["Single knockdown in one cell line; not independently confirmed","No pathway mechanism linking PRKACB to cytokine regulation"]},{"year":2025,"claim":"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","pmids":["41419976"],"confidence":"Low","gaps":["Pattern recognition receptor claim not biochemically validated","Direct PRKACB-JNK linkage not demonstrated"]},{"year":2026,"claim":"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","pmids":["41851075"],"confidence":"High","gaps":["Whether RhoA Ser188 phosphorylation is cAMP-dependent in vivo not established","Generality across cancer types beyond DGC unknown"]},{"year":2026,"claim":"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","pmids":["41684158"],"confidence":"Medium","gaps":["Direct CREB Ser133 phosphorylation by PRKACB not shown in this system","Single cell-based model"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,6]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,11,6]}],"complexes":["PKA holoenzyme"],"partners":["RHOA","PRKAR1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P22694","full_name":"cAMP-dependent protein kinase catalytic subunit beta","aliases":[],"length_aa":351,"mass_kda":40.6,"function":"Mediates cAMP-dependent signaling triggered by receptor binding to GPCRs (PubMed:12420224, PubMed:21423175, PubMed:31112131). PKA activation regulates diverse cellular processes such as cell proliferation, the cell cycle, differentiation and regulation of microtubule dynamics, chromatin condensation and decondensation, nuclear envelope disassembly and reassembly, as well as regulation of intracellular transport mechanisms and ion flux (PubMed:12420224, PubMed:21423175). Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis (PubMed:12420224, PubMed:21423175). Phosphorylates GPKOW which regulates its ability to bind RNA (PubMed:21880142). Acts as a negative regulator of mTORC1 by mediating phosphorylation of RPTOR (PubMed:31112131)","subcellular_location":"Cytoplasm; Cell membrane; Membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/P22694/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRKACB","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRKACA","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/PRKACB","total_profiled":1310},"omim":[{"mim_id":"619143","title":"CARDIOACROFACIAL DYSPLASIA 2; CAFD2","url":"https://www.omim.org/entry/619143"},{"mim_id":"619142","title":"CARDIOACROFACIAL DYSPLASIA 1; CAFD1","url":"https://www.omim.org/entry/619142"},{"mim_id":"601639","title":"PROTEIN KINASE, cAMP-DEPENDENT, CATALYTIC, ALPHA; PRKACA","url":"https://www.omim.org/entry/601639"},{"mim_id":"176893","title":"PROTEIN KINASE, cAMP-DEPENDENT, CATALYTIC, GAMMA; PRKACG","url":"https://www.omim.org/entry/176893"},{"mim_id":"176892","title":"PROTEIN KINASE, cAMP-DEPENDENT, CATALYTIC, BETA; PRKACB","url":"https://www.omim.org/entry/176892"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":178.7}],"url":"https://www.proteinatlas.org/search/PRKACB"},"hgnc":{"alias_symbol":["PKACb"],"prev_symbol":[]},"alphafold":{"accession":"P22694","domains":[{"cath_id":"3.30.200.20","chopping":"35-125_322-351","consensus_level":"medium","plddt":96.135,"start":35,"end":351},{"cath_id":"1.10.510.10","chopping":"128-307","consensus_level":"high","plddt":97.7887,"start":128,"end":307}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22694","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22694-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22694-F1-predicted_aligned_error_v6.png","plddt_mean":95.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRKACB","jax_strain_url":"https://www.jax.org/strain/search?query=PRKACB"},"sequence":{"accession":"P22694","fasta_url":"https://rest.uniprot.org/uniprotkb/P22694.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22694/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22694"}},"corpus_meta":[{"pmid":"31678302","id":"PMC_31678302","title":"Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct.","date":"2019","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/31678302","citation_count":131,"is_preprint":false},{"pmid":"31379578","id":"PMC_31379578","title":"MicroRNA-200a-3p Mediates Neuroprotection in Alzheimer-Related Deficits and Attenuates Amyloid-Beta Overproduction and Tau Hyperphosphorylation via Coregulating BACE1 and PRKACB.","date":"2019","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31379578","citation_count":75,"is_preprint":false},{"pmid":"29669941","id":"PMC_29669941","title":"Activating PRKACB somatic mutation in cortisol-producing adenomas.","date":"2018","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/29669941","citation_count":49,"is_preprint":false},{"pmid":"33058759","id":"PMC_33058759","title":"Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation 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sepsis.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41624837","citation_count":0,"is_preprint":false},{"pmid":"41488747","id":"PMC_41488747","title":"A novel PRKACB variant associated with bilateral postaxial polydactyly and intrauterine growth restriction: A case report and literature review.","date":"2025","source":"Global medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41488747","citation_count":0,"is_preprint":false},{"pmid":"41851075","id":"PMC_41851075","title":"Loss of PRKACB facilitates metastasis of diffuse-type gastric cancer through RhoA signaling activation.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41851075","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16416,"output_tokens":3551,"usd":0.051257,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11131,"output_tokens":3701,"usd":0.07409,"stage2_stop_reason":"end_turn"},"total_usd":0.125347,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing, BRET, surface plasmon resonance, in vitro kinase assay (recombinant proteins and cell lysates), active-site variant functional analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins, multiple orthogonal biophysical and enzymatic methods in a single study\",\n      \"pmids\": [\"29669941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing, computational structural analysis, functional cAMP-sensitivity assays, hedgehog signaling reporter assays in NIH 3T3 fibroblasts with PRKACB variant overexpression\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional methods (cAMP sensitivity assay, hedgehog pathway reporter, cell-based expression), single lab but several independent variants studied\",\n      \"pmids\": [\"33058759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Functional studies with recombinant/expressed variants: protein stability assays and PKA signaling assays in cell-based systems\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — cell-based functional assays, single lab, single study, limited methodological detail in abstract\",\n      \"pmids\": [\"33055300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Streptavidin/biotin-based chromatin precipitation (Strep-CP), ChIP promoter arrays, ChIP-seq, reporter assays in K562 cells and primary human CD34+ cells\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based binding assays combined with differentiation model and isoform expression analysis, single lab\",\n      \"pmids\": [\"29069738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Dual-luciferase reporter assay, Western blot, ELISA, flow cytometry, PRKACB overexpression rescue experiments in cell culture\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR luciferase validation plus rescue experiments with multiple readouts, single lab\",\n      \"pmids\": [\"31379578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"miRNA target prediction (TargetScan), Western blot, RT-PCR, miRNA overexpression/inhibition in PC12 cells\",\n      \"journal\": \"Neurotoxicity research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — target validation inferred from expression changes without direct 3'UTR luciferase confirmation noted in abstract; single lab, single method set\",\n      \"pmids\": [\"36459375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down assay, in situ proximity ligation assay, PRKACB knockdown/overexpression, mouse peritoneal metastasis model, RhoA inhibitor rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal protein interaction assays (Co-IP, GST pull-down, PLA), phosphorylation biochemistry, in vivo model, pathway rescue; multiple orthogonal methods in single study\",\n      \"pmids\": [\"41851075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"PRKACB plasmid transfection, MTT assay, flow cytometry apoptosis, Western blot (p-PKA, p-CREB, caspase-3, collagen II, aggrecan), ELISA (cytokines), H89 pharmacological inhibition\",\n      \"journal\": \"Immunity, inflammation and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression plus pharmacological inhibitor rescue with multiple readouts; single lab\",\n      \"pmids\": [\"41684158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"PRKACB plasmid transfection, MTT assay, colony formation, flow cytometry, Transwell invasion assay\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple functional cellular assays with gain-of-function, single lab, no pathway placement\",\n      \"pmids\": [\"23833645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"PRKACB knockdown, ELISA (TNF-α, IL-1β), cell viability assay in THP-1 macrophages\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment in one cell line, limited pathway mechanistic detail, single lab\",\n      \"pmids\": [\"41624837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-Seq, dual-luciferase reporter assay, RT-qPCR, CCK-8, flow cytometry in rabbit dermal papilla cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct promoter binding confirmed by dual-luciferase assay and ChIP-Seq; functional consequences assessed; single lab\",\n      \"pmids\": [\"38381512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-based targeted sequencing panel (fusion gene detection), RT-PCR validation, analysis of matched cyst fluid and bile duct brushings\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across multiple patient samples with matched controls, RNA-based detection of fusion transcripts; mechanistic implication is activation of PKA catalytic activity via fusion\",\n      \"pmids\": [\"31678302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"16S rRNA sequencing, FISH, bioinformatics, in vitro migration/invasion assays, in vivo metastasis model, Western blot, mechanistic pathway analysis\",\n      \"journal\": \"Journal of nanobiotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement based on expression changes and functional assays; the claim that PRKACB acts as a 'pattern recognition receptor' is mechanistically unusual and not fully validated biochemically in the abstract\",\n      \"pmids\": [\"41419976\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRKACB encodes the catalytic subunit beta (Cβ) of cAMP-dependent protein kinase A (PKA); it phosphorylates substrates including CREB (at Ser133), tau, and RhoA (at Ser188), assembles into type I and II PKA holoenzymes whose activation threshold is set by its interaction with regulatory subunits, and is regulated transcriptionally by TAL1/RUNX1/GATA1 complexes and post-transcriptionally by multiple miRNAs; activating mutations (e.g., p.S54L) or gene fusions (e.g., ATP1B1-PRKACB) constitutively elevate PKA activity driving adrenal tumors or pancreatobiliary oncocytic neoplasms, while loss of PRKACB promotes metastasis through RhoA/ROCK1/FAK signaling activation and enhances macrophage inflammatory output.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #6]. 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 [#0, #2]. Catalytically, PRKACB drives the canonical PKA/CREB axis—phosphorylating CREB at Ser133 to support cell survival, anti-apoptotic, and anti-inflammatory programs in chondrocytes [#7]—and also directly binds and phosphorylates RhoA at Ser188, thereby inhibiting RhoA/ROCK1/FAK signaling and suppressing migration, invasion, and EMT [#6]. 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 [#6, #8]. 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 [#1, #11]. 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 [#3, #4, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a cellular phenotype for PRKACB before its molecular mechanism was placed, showing it restrains rather than drives transformed cell behavior.\",\n      \"evidence\": \"PRKACB overexpression in LTEP-A2 NSCLC cells with proliferation, colony, invasion, and apoptosis assays\",\n      \"pmids\": [\"23833645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No pathway or substrate placement for the growth-suppressive effect\", \"Gain-of-function only; no loss-of-function comparison\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined how PRKACB expression is set during hematopoietic differentiation, addressing transcriptional control of an isoform.\",\n      \"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\",\n      \"pmids\": [\"29069738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform-specific function of Cβ3 not characterized\", \"Mechanism limited to megakaryocytic context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved how a somatic mutation perturbs PKA regulation, identifying a residue critical for holoenzyme assembly and cAMP control.\",\n      \"evidence\": \"Whole-exome sequencing of cortisol-producing adenoma plus BRET, SPR, and in vitro kinase assays on the p.S54L variant with recombinant proteins\",\n      \"pmids\": [\"29669941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate specificity changes downstream of altered activation not mapped\", \"In vivo tumor causation not directly demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected PRKACB to a Mendelian developmental phenotype through a specific signaling output, linking heightened cAMP sensitivity to hedgehog suppression.\",\n      \"evidence\": \"Whole-exome sequencing, cAMP-sensitivity assays, and hedgehog reporter assays in NIH 3T3 fibroblasts expressing PRKACB variants\",\n      \"pmids\": [\"33058759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between PKA activity and the hedgehog node not detailed\", \"Tissue-specific basis of distinct malformations unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established PRKACB rearrangement as a cancer driver, indicating activation of catalytic activity via fusion in a defined neoplasm.\",\n      \"evidence\": \"RNA-based targeted fusion sequencing with RT-PCR validation across pancreatobiliary neoplasms and 126 controls\",\n      \"pmids\": [\"31678302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical proof that the fusion elevates PKA activity not shown directly\", \"Mechanism of regulatory-subunit escape unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated post-transcriptional control of PRKACB and its consequence for tau phosphorylation, defining a miRNA-PKA-tau axis.\",\n      \"evidence\": \"Dual-luciferase 3'UTR validation, Western blot, and PRKACB overexpression rescue in an AD cell model\",\n      \"pmids\": [\"31379578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PRKACB phosphorylation of tau not shown biochemically\", \"Relevance beyond cell model not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Distinguished mechanisms of pathogenic variants, showing protein destabilization as an alternative route to increased PKA signaling.\",\n      \"evidence\": \"Protein stability and PKA signaling assays on p.K286del and p.T300M variants in cell-based systems\",\n      \"pmids\": [\"33055300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathogenicity of p.T300M unresolved\", \"Limited methodological detail; single study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an additional transcriptional repressor of PRKACB and a developmental phenotype, extending promoter-level control beyond hematopoiesis.\",\n      \"evidence\": \"ChIP-Seq, dual-luciferase reporter, and functional assays in rabbit dermal papilla cells with HOXC13\",\n      \"pmids\": [\"38381512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of HOXC13 regulation in human cells not shown\", \"Link between PRKACB and WNT effectors mechanistically unmapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Probed PRKACB's role in myeloid inflammation, indicating it suppresses cytokine output.\",\n      \"evidence\": \"PRKACB knockdown in THP-1 macrophages with cytokine ELISA and viability assays\",\n      \"pmids\": [\"41624837\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown in one cell line; not independently confirmed\", \"No pathway mechanism linking PRKACB to cytokine regulation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed PRKACB in a microbe-induced pro-metastatic pathway, an unusual assignment as a pattern recognition receptor.\",\n      \"evidence\": \"P. gingivalis EV stimulation, JNK/NFATC2 pathway analysis, and migration/invasion plus in vivo metastasis assays in ESCC\",\n      \"pmids\": [\"41419976\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pattern recognition receptor claim not biochemically validated\", \"Direct PRKACB-JNK linkage not demonstrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a direct substrate-level mechanism by which PRKACB restrains metastasis, the strongest mechanistic placement in the corpus.\",\n      \"evidence\": \"Co-IP, GST pull-down, PLA, Ser188 phosphorylation biochemistry, and peritoneal metastasis model with RhoA mutants in diffuse-type gastric cancer\",\n      \"pmids\": [\"41851075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RhoA Ser188 phosphorylation is cAMP-dependent in vivo not established\", \"Generality across cancer types beyond DGC unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed the PKA/CREB axis as the effector route for PRKACB's anti-apoptotic and anti-inflammatory function via pharmacological dependency.\",\n      \"evidence\": \"PRKACB overexpression plus H89 inhibitor rescue with apoptosis, matrix protein, and cytokine readouts in IL-1β-treated chondrocytes\",\n      \"pmids\": [\"41684158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CREB Ser133 phosphorylation by PRKACB not shown in this system\", \"Single cell-based model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 11, 6]}\n    ],\n    \"complexes\": [\"PKA holoenzyme\"],\n    \"partners\": [\"RhoA\", \"PRKAR1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}