Affinage

PKIA

cAMP-dependent protein kinase inhibitor alpha · UniProt P61925

Length
76 aa
Mass
8.0 kDa
Annotated
2026-06-10
36 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PKIA (PKIα) is an endogenous pseudosubstrate inhibitor of cAMP-dependent protein kinase A (PKA) that, by binding and blocking PKA catalytic activity, reroutes GPCR–Gαs–cAMP signaling away from PKA and toward the noncanonical EPAC–Rap1–ERK axis to control cell growth, survival, and migration (PMID:32830375). Because PKIA suppresses PKA-mediated negative feedback on cAMP, its overexpression paradoxically raises intracellular cAMP while lowering PKA activity, an arrangement that drives tumor cell migration, anoikis resistance, and drug efflux—exemplified in prostate cancer (PMID:32830375) and in vincristine-resistant Ewing sarcoma, where PKIA-driven EPAC signaling confers chemoresistance reversible by EPAC inhibition or PKIA knockdown (PMID:41313792). In the heart, PKIA acts as a brake on PKA: its loss permits PKA-dependent DRP1 phosphorylation, mitochondrial fusion, and protection against cardiomyocyte hypertrophy, while its induction attenuates hypertrophy (PMID:32152556, PMID:38654563). PKIA also gates PKA-dependent osteogenic differentiation through β-catenin and CREB phosphorylation (PMID:36222334). Beyond PKA inhibition, PKIA carries a leucine-rich, CRM1-dependent nuclear export signal that is functionally sufficient to direct cytoplasmic localization and, when transplanted, to drive CRM1-dependent nuclear export of heterologous proteins (PMID:20685962, PMID:23487024). PKIA expression is tissue-restricted, with strongest transcripts in heart and skeletal muscle (PMID:10880337), and is controlled transcriptionally by the SIRT1/FOXO3 axis (PMID:38654563) and post-transcriptionally by miRNAs including miR-129/miR-129-5p (PMID:32152556, PMID:36222334) and miR-10a-3p (PMID:36652551).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2000 Medium

    Establishing that human PKIA is a distinct, tissue-restricted family member with conserved functional motifs separated it from its paralogs and defined the structural elements underlying its dual activity.

    Evidence Northern blot across human tissues plus sequence alignment of 11 PKI proteins defining conserved pseudosubstrate and NES motifs

    PMID:10880337

    Open questions at the time
    • Does not test the functional output of either motif
    • No protein-level localization or PKA-binding data
  2. 2007 Low

    Correlating PKIA induction with loss of PKA-responsive transcripts in brain provided the first in vivo link between PKIA levels and suppression of nuclear PKA activity.

    Evidence Microarray and RT-PCR in three brain regions of chronic alcohol-exposed rats

    PMID:17270154

    Open questions at the time
    • Correlative only—no direct manipulation of PKIA
    • Causal link between PKIA and the downregulated transcripts not established
  3. 2010 Medium

    Demonstrating that the PKIA NES alone restores cytoplasmic localization established it as a portable, CRM1-dependent export signal independent of PKA binding.

    Evidence Substitution of the PKIA NES into a Drosophila AMPKα export mutant with leptomycin B sensitivity testing

    PMID:20685962

    Open questions at the time
    • Tested in a heterologous protein, not endogenous PKIA
    • Does not address how NES activity is regulated
  4. 2013 Medium

    Showing the PKIA NES could substitute for oncogenic fusion NES motifs confirmed its export function is strong and transplantable, decoupling the NES from PKIA's kinase-inhibitory role.

    Evidence Retroviral NES-AF10 fusion constructs transforming murine hematopoietic progenitors with leptomycin B confirmation

    PMID:23487024

    Open questions at the time
    • Uses the isolated NES motif, not full-length PKIA
    • Does not implicate endogenous PKIA in leukemogenesis
  5. 2020 Medium

    Direct overexpression and depletion established the central paradox—that PKIA raises cAMP while inhibiting PKA—and placed it as a driver of EPAC-Rap1-ERK signaling and tumor cell migration/survival.

    Evidence PKIA OE/knockdown in prostate cancer cells with cAMP, EPAC-RAP1, ERK, migration, anoikis, and tumor growth readouts

    PMID:32830375

    Open questions at the time
    • Single lab and largely one cancer context
    • Mechanism by which EPAC drives migration not dissected
  6. 2020 Medium

    Identifying miR-129 as a repressor of PKIA connected PKIA suppression to PKA-dependent mitochondrial fusion and anti-hypertrophic protection in cardiomyocytes.

    Evidence RNA-seq, miR-129 gain/loss, PKA activity assays, and mitochondrial morphology/calcium readouts in an angiotensin-(1-9) hypertrophy model

    PMID:32152556

    Open questions at the time
    • Direct miR-129–PKIA binding not luciferase-validated here
    • DRP1 phosphorylation linkage inferred from pathway activity
  7. 2022 Medium

    Direct target validation showed miR-129-5p represses PKIA to de-repress PKA-driven β-catenin/CREB phosphorylation and osteogenic differentiation, extending the PKIA-PKA axis to differentiation control.

    Evidence miR-129-5p mimic/inhibitor, dual-luciferase PKIA target assay, PKA ELISA, H89 rescue, and in vivo heterotopic implantation

    PMID:36222334

    Open questions at the time
    • Does not distinguish nuclear vs cytoplasmic PKA pools
    • Cell-type generality beyond the studied MSC model untested
  8. 2023 Low

    Placing PKIA upstream of RhoA/ROCK via miR-10a-3p extended its regulatory reach to smooth muscle phenotype in a therapeutic extracellular-vesicle context.

    Evidence miR-10a-3p inhibition with PKIA overexpression rescue in a cavernous nerve injury rat model, with RhoA/ROCK readouts

    PMID:36652551

    Open questions at the time
    • Direct miR-10a-3p–PKIA binding not validated by luciferase
    • Mechanistic link from PKIA to RhoA/ROCK not resolved
  9. 2024 Medium

    Defining the SIRT1/FOXO3 axis as a direct transcriptional activator of PKIA established an upstream control circuit for its anti-hypertrophic, PKA-suppressing function.

    Evidence SIRT1/FOXO3 OE/silencing in Ang II-treated H9C2 cells, FOXO3-PKIA promoter luciferase assay, and a TAC rat model

    PMID:38654563

    Open questions at the time
    • Does not reconcile cardioprotective PKIA induction with pro-tumor PKIA roles
    • Other transcriptional regulators not surveyed
  10. 2024 Medium

    Demonstrating PKIA-driven EPAC-Rap1-ERK signaling promotes drug efflux and chemoresistance, reversible pharmacologically, defined a therapeutically actionable mechanism in sarcoma.

    Evidence PKIA OE/knockdown, cAMP/PKA measurements, EPAC inhibitor (ESI-09) treatment, IC50 assays, and xenografts in vincristine-resistant Ewing sarcoma

    PMID:41313792

    Open questions at the time
    • Single cancer type and single lab
    • Drug efflux transporter linkage downstream of EPAC not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PKIA's cytoplasmic NES-driven retention is coordinated with its PKA-inhibitory activity, and what reconciles its opposing roles across cardiac protection versus tumor promotion, remains unresolved.
  • No structural model of full-length PKIA bound to PKA in the corpus
  • No reconciliation of context-dependent pro- vs anti-growth outcomes
  • Regulation linking NES export to PKA inhibition uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0060089 molecular transducer activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-1266738 Developmental Biology 1
Partners
PRKACA

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 PKIA (PKIα) binds PKA with high affinity and blocks its kinase activity, thereby diverting GPCR-Gαs-cAMP signaling away from PKA and toward EPAC-RAP1 and MAPK activation. Overexpression of PKIA increases intracellular cAMP (by relieving PKA-mediated negative feedback on cAMP), enhances EPAC and ERK activation, and promotes tumor cell migration and growth. Depletion of PKIA in prostate cancer cells reduces migration, increases sensitivity to anoikis, and reduces tumor growth. PKI overexpression and depletion (knockdown) in cell lines measuring MAPK pathway activation, cAMP levels, EPAC-RAP1 activation, migration assay, anoikis assay, tumor growth assay FASEB journal Medium 32830375
2020 Angiotensin-(1-9) upregulates miR-129, which decreases PKIA transcript levels, resulting in activation of PKA signaling. PKA activity downstream of PKIA suppression is necessary for angiotensin-(1-9)-mediated mitochondrial fusion (via DRP1 phosphorylation), prevention of mitochondrial fission and calcium dysregulation, and anti-hypertrophic effects on cardiomyocytes. RNA-seq to identify miR-129 upregulation; miR-129 overexpression/inhibition; Western blot for PKIA and PKA targets; PKA activity assays; measurement of mitochondrial morphology and calcium handling; calcineurin/NFAT pathway readouts in cardiomyocyte hypertrophy model Cell death and differentiation Medium 32152556
2024 PKIA overexpression elevates intracellular cAMP but suppresses PKA activity, instead activating the noncanonical EPAC-Rap1-ERK pathway to promote drug efflux and cell survival in vincristine-resistant Ewing sarcoma. Pharmacological inhibition of EPAC reversed resistance, and PKIA knockdown restored vincristine sensitivity in xenografts. Transcriptomic analysis of vincristine-resistant cells; PKIA overexpression and knockdown; cAMP and PKA activity measurements; EPAC inhibitor (ESI-09) treatment; IC50 assays; xenograft models Molecular carcinogenesis Medium 41313792
2024 Dronedarone activates SIRT1, which deacetylates FOXO3, leading to FOXO3 transcriptional upregulation of PKIA. Elevated PKIA in turn suppresses PKA activity and attenuates myocardial hypertrophy. JASPAR/luciferase assays confirmed FOXO3 binding to the PKIA promoter. SIRT1/FOXO3 overexpression and silencing in Ang II-treated H9C2 cells; JASPAR prediction and luciferase reporter assay for FOXO3-PKIA promoter interaction; RT-qPCR and Western blot; TAC rat model; crystal violet and rhodamine phalloidin staining for cell size Korean circulation journal Medium 38654563
2022 miR-129-5p promotes osteogenic differentiation by directly targeting and inhibiting PKIA, thereby activating PKA and increasing phosphorylation of β-catenin and CREB. Dual-luciferase reporter assays confirmed PKIA as a direct miR-129-5p target; PKA inhibitor H89 blocked the osteogenic effects of miR-129-5p overexpression. miR-129-5p mimic/inhibitor transfection; dual-luciferase reporter assay for miR-129-5p–PKIA interaction; PKA activity ELISA; Western blot for β-catenin and CREB phosphorylation; ALP activity assay; alizarin red staining; H89 rescue experiment; in vivo heterotopic implantation Journal of periodontal research Medium 36222334
2000 Human PKIA is specifically expressed as two transcripts (3.3 kb and 1.5 kb) in heart and skeletal muscle, with distinct tissue distribution from paralogs PKIB and PKIG. Both the pseudosubstrate site and leucine-rich nuclear export signal (NES) motifs are conserved across 11 PKI proteins from different species. Northern blot analysis of PKIA, PKIB, and PKIG across multiple human tissues; sequence alignment of 11 PKI proteins to define conserved pseudosubstrate and NES motifs The Biochemical journal Medium 10880337
2010 The PKIA nuclear export signal (NES) is a well-defined CRM1-binding leucine-rich motif. Substituting the PKIA NES into AMPKα restored cytoplasmic localization of an AMPKα mutant lacking its own NES, demonstrating that the PKIA NES is functionally sufficient for CRM1-dependent nuclear export. Substitution of PKIA NES into Drosophila AMPKα; leptomycin B treatment; transgenic Drosophila complementation assay; fluorescence localization imaging Molecular biology of the cell Medium 20685962
2013 The PKIA NES is functionally sufficient for CRM1-dependent nuclear export: fusion of the PKIA NES (or NES motifs from ABL1, Rev, APC) in-frame with AF10 was sufficient to immortalize murine hematopoietic progenitors and drive HOXA gene upregulation and H3K79 hypomethylation, phenocopying the oncogenic CALM-AF10 fusion. Retroviral transduction of NES-AF10 constructs (including PKIA NES) into murine hematopoietic progenitors; colony-forming assay; gene expression analysis; leptomycin B treatment Blood Medium 23487024
2023 miR-10a-3p, enriched in melatonin-primed MSC-derived small extracellular vesicles, directly targets PKIA. Suppression of miR-10a-3p abolished therapeutic effects (erectile function restoration, inhibition of RhoA/ROCK signaling, prevention of smooth muscle phenotypic modulation), which were rescued by PKIA overexpression, placing PKIA upstream of RhoA/ROCK in cavernous nerve injury. miR-10a-3p inhibition and PKIA overexpression in CNI ED rats; measurement of erectile function; Western blot for RhoA/ROCK pathway; sequencing of sEV miRNA content Advanced healthcare materials Low 36652551
2007 PKIA (PKI-alpha) expression is increased in medial prefrontal cortex, nucleus accumbens, and amygdala during chronic intermittent alcohol exposure, coinciding with downregulation of multiple PKA-regulated transcripts (Ania-1, -3, -7, -8, Egr1, Nr4a1, NPY), consistent with PKIA acting as a suppressor of nuclear PKA activity in these brain regions. High-density oligonucleotide microarrays with independent RT-PCR validation in three brain regions of alcohol-exposed rats Brain research Low 17270154

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 A genome-wide association study of bipolar disorder in Norwegian individuals, followed by replication in Icelandic sample. Journal of affective disorders 96 20451256
2010 Identification of a nuclear export signal in the catalytic subunit of AMP-activated protein kinase. Molecular biology of the cell 96 20685962
1988 Isolation and transformation of the pyruvate kinase gene of Aspergillus nidulans. Current genetics 70 2839306
2020 Improved Production of Malic Acid in Aspergillus niger by Abolishing Citric Acid Accumulation and Enhancing Glycolytic Flux. ACS synthetic biology 60 32379964
2001 Combined molecular and biochemical approach identifies Aspergillus japonicus and Aspergillus aculeatus as two species. Applied and environmental microbiology 50 11157212
2020 Angiotensin-(1-9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway. Cell death and differentiation 44 32152556
1993 Phosphorylation is involved in transcriptional activation by the 1,25-dihydroxyvitamin D3 receptor. Biochimica et biophysica acta 40 8384884
1992 Isolation and characterization of the Aspergillus niger pyruvate kinase gene. Current genetics 38 1611667
2020 Protein kinase A inhibitor proteins (PKIs) divert GPCR-Gαs-cAMP signaling toward EPAC and ERK activation and are involved in tumor growth. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 32830375
2013 A CALM-derived nuclear export signal is essential for CALM-AF10-mediated leukemogenesis. Blood 31 23487024
2019 Silencing of lncRNA PKIA-AS1 Attenuates Spinal Nerve Ligation-Induced Neuropathic Pain Through Epigenetic Downregulation of CDK6 Expression. Frontiers in cellular neuroscience 29 30873006
2008 Molecular correlates for maximal oxygen uptake and type 1 fibers. American journal of physiology. Endocrinology and metabolism 26 18445752
2007 Increased expression of protein kinase A inhibitor alpha (PKI-alpha) and decreased PKA-regulated genes in chronic intermittent alcohol exposure. Brain research 25 17270154
2000 Cloning and mapping of human PKIB and PKIG, and comparison of tissue expression patterns of three members of the protein kinase inhibitor family, including PKIA. The Biochemical journal 23 10880337
2009 A novel expression system for intracellular production and purification of recombinant affinity-tagged proteins in Aspergillus niger. Applied microbiology and biotechnology 19 19908039
1992 Steady-state kinetics and isotope effects on the mutant catalytic trimer of aspartate transcarbamoylase containing the replacement of histidine 134 by alanine. Biochemistry 17 1633170
2019 An integrated approach for mining precise RNA-based cervical cancer staging biomarkers. Gene 14 31279709
2023 Melatonin-Primed Mesenchymal Stem Cells-Derived Small Extracellular Vesicles Alleviated Neurogenic Erectile Dysfunction by Reversing Phenotypic Modulation. Advanced healthcare materials 13 36652551
2018 Carbocisteine stimulated an increase in ciliary bend angle via a decrease in [Cl-]i in mouse airway cilia. Pflugers Archiv : European journal of physiology 13 30291431
1993 Characterization of the pyruvate kinase-encoding gene (pki1) of Trichoderma reesei. Gene 13 8359694
2022 The regulatory mechanism of LncRNA-mediated ceRNA network in osteosarcoma. Scientific reports 10 35610231
2021 An Integrative Pharmacology-Based Strategy to Uncover the Mechanism of Xiong-Pi-Fang in Treating Coronary Heart Disease with Depression. Frontiers in pharmacology 10 33867976
2014 Highly expressed protein kinase A inhibitor α and suppression of protein kinase A may potentiate acetaminophen-induced hepatotoxicity. Toxicology letters 8 24910983
2023 Exploring the methylation status of CFTR and PKIA genes as potential biomarkers for lung adenocarcinoma. Orphanet journal of rare diseases 6 37644544
2022 A grooved porous hydroxyapatite scaffold induces osteogenic differentiation via regulation of PKA activity by upregulating miR-129-5p expression. Journal of periodontal research 6 36222334
2021 Molecular characterization of the stress network in individuals at risk for schizophrenia. Neurobiology of stress 6 33644266
2024 Dronedarone Attenuates Ang II-Induced Myocardial Hypertrophy Through Regulating SIRT1/FOXO3/PKIA Axis. Korean circulation journal 4 38654563
2020 Glucose deprivation affects the expression of genes encoding cAMP-activated protein kinase and related proteins in U87 glioma cells in ERN1 dependent manner. Endocrine regulations 4 33885249
2021 An Epigenetic Signature is Associated with Serum 25-Hydroxyvitamin D in Colorectal Cancer Tumors. Molecular nutrition & food research 3 34289228
2024 Transcriptional dynamics and regulatory function of milRNAs in Ascosphaera apis invading Apis mellifera larvae. Frontiers in microbiology 2 38650880
2025 Multiple data sets to explore the key molecules and mechanism of lymph node metastasis in gastric cancer. Discover oncology 1 40272615
2026 Ascosphaeraapis LncRNA6140 promotes the infection of honeybee larvae through the milR5658-x-ATPase axis. Insect biochemistry and molecular biology 0 42177950
2025 PFKP Mediates Breast Cancer Metastasis Through Altered Glycolysis. Cureus 0 40821334
2025 Protein Kinase Inhibitor Alpha Drives Vincristine Resistance in Ewing Sarcoma via cAMP-EPAC Signaling Reprogramming. Molecular carcinogenesis 0 41313792
2022 T-cell Lymphoblastic Lymphoma in a Patient With Chromosome 8q21.11 Microdeletion. Journal of pediatric hematology/oncology 0 34486555
1975 [Different forms of pyruvate kinase from the rabbit adrenal cortex]. Biokhimiia (Moscow, Russia) 0 1212447

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