Affinage

PRKAR2B

cAMP-dependent protein kinase type II-beta regulatory subunit · UniProt P31323

Length
418 aa
Mass
46.3 kDa
Annotated
2026-06-10
13 papers in source corpus 9 papers cited in narrative 9 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

PRKAR2B is the type II-beta regulatory subunit of protein kinase A (PKA) and functions as an inhibitory constraint on PKA catalytic activity, with its loss de-repressing PKA and downstream signaling (PMID:25268545, PMID:36847534, PMID:41704777). In adrenocortical cells, PRKAR2B depletion activates PKA and MEK/ERK, drives NF-κB activation through impaired IκB, promotes Bcl-xL-mediated apoptosis resistance, and specifically accumulates cyclins A and B, cdk1/cdc2, and p21Cip, a profile distinct from that of the type I-alpha subunit PRKAR1A whose loss it can compensate for (PMID:25268545). Paradoxically, in prostate cancer PRKAR2B acts as a driver of malignancy: it activates Wnt/β-catenin signaling to induce epithelial-mesenchymal transition and invasion (PMID:29761841), enhances aerobic glycolysis through a HIF-1α positive-feedback loop (PMID:33025691), and accelerates the cell cycle by modulating CCNB1, MCM2, PLK1, and AURKB (PMID:28008150). PRKAR2B levels are set post-transcriptionally by the miR-200 family (miR-200b-3p/200c-3p) and miR-34c-3p and transcriptionally by XBP1, FOXG1, HHEX, and HIF-1α, integrating these regulators into control of PKA-dependent proliferation, glycolysis, and metastasis (PMID:33025691, PMID:31986411, PMID:30539330, PMID:36847534, PMID:41704777). Beyond cancer, PRKAR2B is required for mouse oocyte maturation, where its knockdown causes metaphase I arrest, abnormal spindle formation, and chromosome aggregation (PMID:29518769).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2014 Medium

    Established that PRKAR2B restrains PKA activity and shapes a specific signaling and cell-cycle output, distinguishing it functionally from the PRKAR1A regulatory subunit.

    Evidence siRNA knockdown in adrenocortical H295R cells with signaling, cyclin, and apoptosis readouts

    PMID:25268545

    Open questions at the time
    • Single cell line and single method type
    • Direct biochemical inhibition of PKA holoenzyme not reconstituted
    • Mechanism of PRKAR1A compensatory upregulation unresolved
  2. 2017 Medium

    Defined PRKAR2B as a pro-proliferative, pro-invasive factor in castration-resistant prostate cancer acting through cell-cycle gene programs.

    Evidence Knockdown with whole-genome transcriptome/GO analysis and proliferation/invasion/apoptosis assays

    PMID:28008150

    Open questions at the time
    • Mechanism is transcriptome-level correlation, not direct regulation of CCNB1/PLK1/AURKB
    • Single lab
    • How a PKA inhibitory subunit promotes proliferation not mechanistically reconciled
  3. 2018 Medium

    Connected PRKAR2B to a defined oncogenic pathway by showing it activates Wnt/β-catenin to drive EMT and metastasis.

    Evidence Reciprocal gain/loss-of-function in CRPC lines, in vivo metastasis assay, EMT marker blotting, and Wnt inhibition rescue

    PMID:29761841

    Open questions at the time
    • Molecular link between PRKAR2B and Wnt/β-catenin not identified
    • Single lab
    • Whether effect requires PKA catalytic activity unknown
  4. 2018 Medium

    Established PRKAR2B as a physiological requirement for meiotic progression and spindle integrity in oocytes, outside any cancer context.

    Evidence RNAi microinjection in mouse oocytes with immunofluorescence, time-lapse imaging, and qRT-PCR

    PMID:29518769

    Open questions at the time
    • Mechanistic link between PRKAR2B and spindle assembly unresolved
    • Effect on PPP gene expression correlative
    • Single lab
  5. 2018 Medium

    Identified an upstream regulatory axis in which FOXG1 controls PRKAR2B both transcriptionally and via miR-200 biogenesis, linking PRKAR2B to postsynaptic PKA tone.

    Evidence Small RNA-seq, proteomics, RNA-seq of Foxg1cre/+ hippocampi, N2a miR-200 overexpression, and FOXG1–DDX5–DROSHA Co-IP

    PMID:30539330

    Open questions at the time
    • Direct miR-200 binding to PRKAR2B in neurons not fully demonstrated
    • Functional consequence of postsynaptic PKA inhibition not measured
    • Single lab
  6. 2020 Medium

    Showed PRKAR2B drives the Warburg effect through a HIF-1α positive-feedback loop, linking it to tumor metabolic reprogramming.

    Evidence Gain/loss-of-function, metabolic assays, luciferase reporter, ChIP, HIF-1α siRNA, and 2-DG treatment in prostate cancer

    PMID:33025691

    Open questions at the time
    • How PRKAR2B raises HIF-1α not defined mechanistically
    • Single lab
    • Relationship to PKA catalytic activity unclear
  7. 2020 Medium

    Placed PRKAR2B downstream of miR-200b/c and XBP1, defining a regulatory hierarchy controlling its oncogenic output.

    Evidence miRNA and XBP1 knockdown/overexpression with PRKAR2B rescue, reporter assays, qPCR and Western blot

    PMID:31986411

    Open questions at the time
    • XBP1 direct binding to PRKAR2B promoter not shown
    • Single lab
    • Interplay between transcriptional and post-transcriptional control not resolved
  8. 2023 Medium

    Demonstrated that pathogen-induced miR-34c-3p represses PRKAR2B to activate PKA independent of cAMP, extending PRKAR2B regulation to infection-driven transformation.

    Evidence miR-34c-3p target validation, miRNA overexpression, PKA activity assays in Theileria- and Plasmodium-infected cells

    PMID:36847534

    Open questions at the time
    • Direct miR-34c-3p:PRKAR2B binding details limited
    • Single lab
    • Generality across infection models unestablished
  9. 2026 Medium

    Defined an HHEX–PRKAR2B–PKA–HK2 axis coupling glucose availability to PKA-driven glycolysis and metastasis in pancreatic cancer.

    Evidence HHEX knockdown, PKA activity and HK2/glycolysis assays, and in vivo high-glucose and glycolysis-inhibition experiments

    PMID:41704777

    Open questions at the time
    • HHEX direct transcriptional control of PRKAR2B not fully mapped
    • Single study
    • Link between PKA activation and HK2 upregulation mechanistically incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a PKA-inhibitory regulatory subunit acts as an oncogenic driver across multiple cancers, and whether its tumor-promoting effects depend on PKA catalytic activity or on PKA-independent functions.
  • No structural or biochemical reconstitution of PRKAR2B-PKA holoenzyme in these contexts
  • Direct molecular link to Wnt/β-catenin and HIF-1α unknown
  • No in vivo genetic model distinguishing catalytic-dependent from independent roles

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-1430728 Metabolism 2
Partners
PRKACAPRKAR1A
Complex memberships
PKA holoenzyme

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 PRKAR2B promotes prostate cancer cell invasion and metastasis by activating Wnt/β-catenin signaling, which in turn induces epithelial-mesenchymal transition (EMT), evidenced by decreased E-cadherin and increased Vimentin, N-cadherin, and Fibronectin; inhibition of Wnt/β-catenin attenuated PRKAR2B-induced EMT and invasion. Loss-of-function (knockdown) and gain-of-function (overexpression) in CRPC cell lines; in vivo metastasis assay; Western blotting for EMT markers; Wnt/β-catenin pathway inhibition rescue experiment Journal of cellular biochemistry Medium 29761841
2020 PRKAR2B enhances aerobic glycolysis (Warburg effect) in prostate cancer by upregulating HIF-1α; conversely, HIF-1α transcriptionally induces PRKAR2B expression, forming a positive feedback loop. Glycolytic inhibition or HIF-1α silencing abolished PRKAR2B-mediated tumor growth. Loss-of-function and gain-of-function studies; glucose consumption, lactate production, and extracellular acidification rate assays; luciferase reporter assay; chromatin immunoprecipitation (ChIP); siRNA silencing of HIF-1α; glycolytic inhibitor 2-DG treatment Cell proliferation Medium 33025691
2020 PRKAR2B expression in prostate cancer is regulated post-transcriptionally by miR-200b-3p and miR-200c-3p (which directly repress it) and transcriptionally by the transcription factor XBP1 (which induces it); knockdown of miR-200b-3p/200c-3p or XBP1 effects on proliferation and apoptosis were rescued by PRKAR2B overexpression, placing PRKAR2B downstream of both regulators. miRNA overexpression and knockdown; XBP1 knockdown; rescue experiments with PRKAR2B overexpression; luciferase reporter assay (implied from context); qPCR and Western blotting Biomedicine & pharmacotherapy Medium 31986411
2018 FOXG1 regulates PRKAR2B expression both transcriptionally and post-transcriptionally via the miR-200 family; FOXG1 affects biogenesis of miR-200b/a/429 by interacting with DDX5/p68, which recruits FOXG1 to the DROSHA microprocessor complex. PRKAR2B was identified as a miR-200 target in neural cells, and elevated PRKAR2B inhibits postsynaptic PKA activity. Genome-wide small RNA sequencing; quantitative proteomics; RNA-Seq of Foxg1cre/+ hippocampi; N2a cells overexpressing miR-200 family; Co-IP/association of FOXG1 with DDX5 and DROSHA Molecular neurobiology Medium 30539330
2014 Depletion of PRKAR2B in adrenocortical H295R cells is compensated by upregulation of PRKAR1A protein (but not vice versa). PRKAR2B depletion activates PKA and MEK/ERK pathways, impairs IκB leading to NF-κB activation, promotes Bcl-xL expression and apoptosis resistance, and specifically drives accumulation of cyclins A, B, cdk1, cdc2, and p21Cip (distinct from PRKAR1A depletion which accumulates cyclin D1 and p27kip). siRNA-mediated knockdown; Western blotting for signaling pathway components, cyclins, and apoptotic markers; cell cycle analysis Hormone and metabolic research Medium 25268545
2017 PRKAR2B promotes CRPC cell proliferation and invasion and inhibits apoptosis; transcriptome analysis following PRKAR2B knockdown revealed that it accelerates the cell cycle by modulating cell cycle genes including CCNB1, MCM2, PLK1, and AURKB. Knockdown (loss-of-function); whole genome transcriptome and GO enrichment analysis; functional assays for proliferation, invasion, apoptosis Oncotarget Medium 28008150
2018 PRKAR2B is required for oocyte maturation: RNAi-mediated knockdown of Prkar2b in mouse oocytes caused arrest at metaphase I, abnormal spindle formation, and chromosome aggregation. Knockdown also reduced expression of other PKA family members (except Prkaca) and the majority of pentose phosphate pathway (PPP) factors. RNAi microinjection into mouse oocytes; immunofluorescence for spindle/chromosome morphology; time-lapse video microscopy; qRT-PCR for PKA family and PPP gene expression Cellular physiology and biochemistry Medium 29518769
2023 In Theileria annulata-infected bovine leukocytes and Plasmodium falciparum-infected red blood cells, infection-induced upregulation of miR-34c-3p represses PRKAR2B expression, leading to increased PKA activity independent of cAMP fluxes; this mechanism enhances the disseminating tumor-like phenotype of T. annulata-transformed macrophages. miR-34c-3p target identification (PRKAR2B as target gene); miRNA overexpression; PRKAR2B mRNA and protein level measurement; PKA activity assay; infection model experiments mSphere Medium 36847534
2026 In pancreatic ductal adenocarcinoma, downregulation of transcription factor HHEX represses PRKAR2B expression, relieving inhibition of PKA catalytic activity; activated PKA then enhances glycolysis via upregulation of hexokinase 2 (HK2). A high-glucose microenvironment promotes cAMP production to further activate PKA, and glycolysis inhibition blocked metastasis in vivo. HHEX knockdown; PRKAR2B expression analysis; PKA activity assay; HK2 expression and glycolysis assays; in vivo high-glucose synergy and glycolysis inhibition experiments iScience Medium 41704777

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 PRKAR2B-HIF-1α loop promotes aerobic glycolysis and tumour growth in prostate cancer. Cell proliferation 47 33025691
2018 PRKAR2B promotes prostate cancer metastasis by activating Wnt/β-catenin and inducing epithelial-mesenchymal transition. Journal of cellular biochemistry 31 29761841
2020 Transcriptional regulation of PRKAR2B by miR-200b-3p/200c-3p and XBP1 in human prostate cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 27 31986411
2018 FOXG1 Regulates PRKAR2B Transcriptionally and Posttranscriptionally via miR200 in the Adult Hippocampus. Molecular neurobiology 21 30539330
2014 Comparison of the effects of PRKAR1A and PRKAR2B depletion on signaling pathways, cell growth, and cell cycle control of adrenocortical cells. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 18 25268545
2017 PRKAR2B plays an oncogenic role in the castration-resistant prostate cancer. Oncotarget 17 28008150
2018 Knockdown of PRKAR2B Results in the Failure of Oocyte Maturation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 16 29518769
2023 miR-34c-3p Regulates Protein Kinase A Activity Independent of cAMP by Dicing prkar2b Transcripts in Theileria annulata-Infected Leukocytes. mSphere 9 36847534
2014 Protein kinase cAMP-dependent regulatory type II beta (PRKAR2B) gene variants in antipsychotic-induced weight gain. Human psychopharmacology 8 24737441
2023 MAPKAPK2-centric transcriptome profiling reveals its major role in governing molecular crosstalk of IGFBP2, MUC4, and PRKAR2B during HNSCC pathogenesis. Computational and structural biotechnology journal 6 36817960
2025 ceRNA Profiling Reveals circSAMD4A Promoted Porcine Adipocytes Differentiation via Targeting miR-127/PRKAR2B. Animal science journal = Nihon chikusan Gakkaiho 1 40589305
2026 HHEX-PRKAR2B axis-mediated PKA activation drives glucose metabolism-dependent progression of pancreatic ductal adenocarcinoma. iScience 0 41704777
2025 Glomerular mesangial derived extracellular vesicles deteriorate diabetic kidney disease via miR-3147/PRKAR2B axis. Renal failure 0 40571682

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