Affinage

PRKCA

Protein kinase C alpha type · UniProt P17252

Length
672 aa
Mass
76.8 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 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

PKCα (PRKCA) is a Ca2+- and lipid-responsive serine/threonine kinase that functions as a membrane-recruited signaling integrator, converting Ca2+ and diacylglycerol cues into phosphorylation of structural, transcriptional, and channel substrates across many tissues (PMID:14966518, PMID:32179476). Its activity is gated by membrane recruitment, which is directed by dedicated scaffolds and cytoskeletal partners: AnxA6 brings PKCα to the plasma membrane to phosphorylate EGFR-T654 and dampen EGFR signaling (PMID:22797061), RACK1 couples β1-integrin mechanotransduction to PKCα translocation (PMID:12435334), and keratin isotypes either sequester PKCα (K5/K14) or license its translocation to drive desmosome disassembly (K6/K17) (PMID:26763440). Once active, PKCα phosphorylates a broad substrate set with tissue-specific consequences: inhibitor-1 to control PP-1/phospholamban and cardiac contractility (PMID:14966518), the Golgi stacking protein GRASP55 to fragment the Golgi upon Ca2+ rise (PMID:32179476), filamin C hinge-2 serines to block calpain cleavage at Z-discs (PMID:28028127), CK1δ C-terminal residues to tune its kinase activity (PMID:26803658), TRPC1 to promote insulin secretion (PMID:31094294), and the transcription factor ZFP64-S226 to activate CSF1 and macrophage-driven immune evasion (PMID:35219791). PKCα also operates as an upstream pathway activator—initiating an early Ca2+-dependent phase of IKK/NF-κB activation in T cells (PMID:12972622), driving ERK1/2-dependent keratinocyte differentiation and NFAT5 activation (PMID:15365248, PMID:25391900), and promoting Rac1 activation in dendritic-spine structural plasticity (PMID:32019972). A recurrent gain-of-function kinase-domain mutation, D463H, found in chordoid gliomas, constitutively activates MAPK/ERK signaling while displacing the mutant protein from the membrane (PMID:29476136, PMID:29915258). In ischemic myocardium, calpain-generated catalytic fragments of PKCα act constitutively in the nucleus to drive HDAC5 export and pathological gene expression (PMID:21642422), and pharmacological PKCα/β inhibition improves contractility in a large-animal heart-failure model (PMID:21998327).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 High

    Established that PKCα acts as the Ca2+-dependent initiator of NF-κB signaling upstream of PKCθ, resolving how early TCR/CD28 signals reach IKK.

    Evidence Constitutively active/dominant-negative constructs, RNAi, pharmacology, and Ca2+-binding-residue mutagenesis in T lymphocytes with kinetic IKK assays

    PMID:12972622

    Open questions at the time
    • Direct IKK substrate of PKCα not defined
    • Physical PKCα–PKCθ ordering inferred from kinetics, not co-complex
  2. 2004 High

    Defined PKCα as a direct regulator of cardiac contractility via I-1/PP-1/phospholamban, establishing a substrate-level mechanism with whole-organ consequences.

    Evidence Prkca KO and cardiac transgenic mice, adenoviral gene transfer in cardiomyocytes, biochemical phosphorylation assays

    PMID:14966518

    Open questions at the time
    • Upstream activator of cardiac PKCα in vivo not isolated
    • Relative contribution of other PKCα cardiac substrates unaddressed
  3. 2007 High

    Placed PKCα in a posttranslational photic input pathway by linking it to PER2 stability and circadian resetting.

    Evidence Prkca KO mice, behavioral circadian assays, PRKCA–PER2 Co-IP and PER2 fractionation in SCN

    PMID:17553429

    Open questions at the time
    • Whether PER2 is a direct PKCα phospho-substrate not shown
    • Phospho-site on PER2 unmapped
  4. 2009 High

    Showed PKCα is required for platelet dense-granule secretion and thrombus formation, with ADP rescue ordering it upstream of granule release.

    Evidence Prkca KO mice, in vivo thrombosis and in vitro aggregation/secretion assays with ADP rescue

    PMID:19147982

    Open questions at the time
    • Granule-secretion substrate of PKCα not identified
  5. 2012 High

    Identified scaffold-directed membrane recruitment as the control point for PKCα substrate selection, exemplified by AnxA6-mediated EGFR-T654 phosphorylation and EGFR inactivation.

    Evidence AnxA6 gain/loss constructs, cytosolic and membrane-anchored AnxA6 mutants, T654A EGFR mutant, PKCα siRNA, ternary Co-IP

    PMID:22797061

    Open questions at the time
    • Generality of AnxA6 scaffolding to other PKCα substrates untested
  6. 2016 High

    Expanded the PKCα substrate map to structural and regulatory targets—filamin C, CK1δ—demonstrating direct phosphorylation events with defined functional consequences.

    Evidence In vitro kinase assays, phosphoproteomics, site-directed mutagenesis, FRAP, kinetic analysis, cellular PKCα inhibition

    PMID:26803658 PMID:28028127

    Open questions at the time
    • In vivo relevance of CK1δ phosphorylation by PKCα not established
    • Trigger for PKCα activation at the Z-disc not defined
  7. 2018 High

    Identified the recurrent D463H kinase-domain mutation as a gain-of-function oncogenic driver acting through MAPK/ERK in chordoid glioma.

    Evidence Genomic sequencing of chordoid gliomas, expression of D463H in astrocytes, phospho-ERK and soft-agar assays with MEK inhibition, replicated in two studies

    PMID:29476136 PMID:29915258

    Open questions at the time
    • How a membrane-depleted mutant achieves MAPK activation mechanistically unclear
    • Direct ERK-activating substrate of mutant PKCα not defined
  8. 2022 High

    Connected PKCα to tumor immune evasion by direct phosphorylation of ZFP64-S226, driving CSF1 transcription and M2 macrophage polarization.

    Evidence MS phospho-site mapping, phospho-mutagenesis, nuclear translocation, ChIP, co-culture, orthotopic HCC xenograft

    PMID:35219791

    Open questions at the time
    • Upstream signal activating PKCα in HCC not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Open question: how the diverse PKCα substrate repertoire and scaffold-directed localizations are selected and integrated within a single cell, and whether a unifying logic governs which substrate is engaged under a given Ca2+/DAG stimulus.
  • No integrated model of substrate-selection logic across tissues
  • Most substrate phosphorylations validated in single labs/contexts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-1643685 Disease 2 R-HSA-397014 Muscle contraction 1
Partners
ANXA6CK1ΔEGFRG3BP2GRASP55RACK1TRPC1ZFP64

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 PKCα directly phosphorylates protein phosphatase inhibitor-1 (I-1), thereby altering the activity of protein phosphatase-1 (PP-1), which in turn affects dephosphorylation of the SERCA-2 inhibitory protein phospholamban (PLB), modulating sarcoplasmic reticulum Ca2+ loading and the Ca2+ transient in cardiac myocytes. Loss of Prkca in mice produces hypercontractile hearts; overexpression produces hypocontractile hearts. Prkca knockout mice, cardiac-specific transgenic overexpression, adenoviral dominant-negative/wild-type gene transfer into cardiomyocytes, biochemical phosphorylation assays Nature medicine High 14966518
2009 PKCα is required for dense-granule biogenesis and secretion in platelets; Prkca−/− mice show attenuated thrombus formation in vivo and defective platelet aggregation in vitro that can be rescued by exogenous ADP, placing PKCα upstream of dense-granule secretion and thrombus formation. Prkca knockout mice, in vivo thrombosis model, in vitro platelet aggregation and secretion assays, ADP rescue experiment The Journal of clinical investigation High 19147982
2003 PKCα acts upstream of PKCθ to activate the IKK complex and NF-κB–dependent transcription following TCR/CD28 co-stimulation. An early phase (1–5 min) of IKK activation is PKCα-dependent and requires Ca2+-binding residues D246/D248 for membrane recruitment; a later phase (5–25 min) is PKCθ-dependent. Catalytically active PKCαA25E drives NF-κB transcription, and this is abrogated by kinase-inactive PKCθ. Genetic analysis (dominant-negative/constitutively active constructs), pharmacological inhibition, RNA interference, kinetic IKK activation assays in T lymphocytes Molecular and cellular biology High 12972622
2007 Light exposure in the SCN evokes a transient interaction between PRKCA and PERIOD 2 (PER2) protein that affects PER2 stability and nucleocytoplasmic distribution; Prkca-deficient mice show impaired light-mediated circadian clock resetting, identifying PKCα as a component of a posttranslational photic input pathway. Prkca knockout mice, behavioral circadian assays, co-immunoprecipitation of PRKCA–PER2 interaction in SCN, subcellular fractionation of PER2 Neuron High 17553429
2011 Calpain-mediated proteolytic processing of PKCα in ischemic myocardium releases a constitutively active free catalytic fragment (PKCα-CT) that localizes to nuclei, directly promotes HDAC5 nucleo-cytoplasmic shuttling independently of PKD, and induces MEF2-dependent pathological cardiac gene expression. Expression of PKCα-CT in cardiomyocytes, nuclear fractionation, HDAC5 localization assays, comparison with phorbol ester-activated full-length PKCα requiring PKD The Journal of biological chemistry Medium 21642422
2012 PKCα directly binds and phosphorylates G3BP2 via its regulatory domain interacting with the C-terminal RNA-binding domain of G3BP2; both proteins co-localize in stress granules (but not P-bodies) upon stress, and PKCα knockdown suppresses heat-shock-induced stress granule assembly and eIF2α phosphorylation. Co-immunoprecipitation, RNase-resistance assay, in vitro kinase assay with recombinant proteins, siRNA knockdown, live-cell imaging of stress granule formation PloS one High 22536444
2012 Annexin A6 (AnxA6) acts as a scaffold that recruits PKCα to the plasma membrane, facilitating PKCα-mediated phosphorylation of EGFR at T654, inhibiting EGFR tyrosine phosphorylation and downstream activation. AnxA6 N-terminal mutant unable to recruit PKCα to the membrane fails to increase T654-EGFR phosphorylation; the T654A EGFR mutant is not inhibited by AnxA6 overexpression. Ectopic AnxA6 expression, PKCα siRNA knockdown, AnxA6(1-175) cytosolic mutant and plasma-membrane-anchored AnxA6, T654A EGFR mutant, Co-IP of AnxA6–EGFR–PKCα complex Oncogene High 22797061
2013 PKCα physically interacts and functionally cooperates with TGFβRI to promote robust SMAD2/3 activation, selectively upregulating IL-17A (but not IL-17F) in Th17 cells. Prkca−/− cells show defective SMAD-dependent IL-2 suppression and decreased STAT3 DNA binding at the Il17a promoter, and are resistant to Th17-cell-dependent EAE. Prkca knockout mice, Co-IP of PKCα–TGFβRI interaction, SMAD2/3 phosphorylation assays, STAT3 ChIP, in vivo EAE model Immunity High 23290522
2015 PKCα interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase complex. Elevated TRM6/61 increases translation of tumorigenic mRNAs via tRNAiMet stabilization, and PKCα overexpression in TRM6/61-overexpressing cells decreases tRNAiMet expression and tumorigenic colony/sphere formation, indicating PKCα controls TRM6/61 activity to prevent translational deregulation. Co-immunoprecipitation of PKCα–TRM61, tRNAiMet expression assays, colony and sphere formation assays with PKCα overexpression vs. TRM6/61 overexpression Oncogene Medium 26234676
2008 PKCα knockdown in endothelial cells increases VEGFR2 tyrosine phosphorylation, protein and mRNA expression, and enhances VEGF-stimulated Akt/eNOS phosphorylation, demonstrating that PKCα negatively regulates VEGFR2 expression and VEGF signaling (opposite to PKCε which positively regulates VEGFR2). siRNA knockdown of PKCα (and PKCε/δ for comparison), VEGFR2 phosphorylation and expression assays, Akt/eNOS phosphorylation, DNA synthesis assay Arteriosclerosis, thrombosis, and vascular biology Medium 18323518
2002 Mechanical stimulation of human articular chondrocytes induces rapid β1 integrin–dependent translocation of PKCα to the cell membrane and increased association of the scaffolding protein RACK1 with both PKCα and β1 integrin, placing RACK1 as a mechanotransduction intermediary for PKCα membrane recruitment. Mechanical stimulation of chondrocytes, anti-integrin antibody blocking, subcellular fractionation, Co-IP of RACK1–PKCα–β1 integrin Osteoarthritis and cartilage Medium 12435334
2016 K5/K14 keratins sequester PKCα in the cytoplasm, whereas wound-healing keratins K6/K17 enable PKCα translocation to the plasma membrane, promoting PKCα-mediated desmosome disassembly. Gain- and loss-of-function of K5 modulates desmosome stability via PKCα. Stable re-expression of keratin isotypes in keratin-null keratinocytes, live-cell imaging of PKCα localization, desmosome stability/adhesion assays, PKCα gain/loss-of-function The Journal of investigative dermatology Medium 26763440
2020 Elevated cytosolic Ca2+ activates PKCα, which phosphorylates the Golgi stacking protein GRASP55, causing Golgi fragmentation. PKCα activation by PMA or histamine also modulates Golgi structure in the same manner; this pathway operates independently of ER stress. Thapsigargin/PMA/histamine treatment of HeLa cells, PKCα activity inhibition, GRASP55 phosphorylation assays, Golgi morphology imaging iScience Medium 32179476
2004 PKCα overexpression in undifferentiated mouse keratinocytes induces differentiation markers (loricrin, filaggrin, K1, K10) and ERK1/2 phosphorylation without affecting p38 or JNK; dominant-negative PKCα blocks Ca2+-mediated differentiation markers; MEK inhibition blocks PKCα-mediated differentiation, placing PKCα→ERK1/2 as the specific pathway for PKCα-driven keratinocyte differentiation. Adenoviral overexpression and dominant-negative PKCα in keratinocytes, differentiation marker assays, MEK/p38/JNK inhibitors, ERK1/2 dominant-negative constructs Experimental & molecular medicine Medium 15365248
2015 PKCα regulates TMEM16A-mediated Cl− secretion in biliary epithelial cells: extracellular ATP induces PKCα translocation from cytosol to plasma membrane; intracellular dialysis with recombinant PKCα activates Cl− currents indistinguishable from TMEM16A; these currents are absent after TMEM16A siRNA, demonstrating direct functional coupling of PKCα to TMEM16A. Whole-cell patch-clamp, intracellular dialysis with recombinant PKCα, PKCα siRNA, TMEM16A siRNA, subcellular fractionation American journal of physiology. Gastrointestinal and liver physiology High 26542395
2022 PKCα directly phosphorylates ZFP64 at S226, leading to its nuclear translocation and transcriptional activation of CSF1, which transforms macrophages toward M2 polarization to drive immune evasion and anti-PD1 resistance in hepatocellular carcinoma. Mass spectrometry, phospho-site mutagenesis, nuclear translocation assays, chromatin immunoprecipitation, in vitro co-culture, orthotopic HCC xenograft model Journal of hepatology High 35219791
2016 PKCα phosphorylates CK1δ at C-terminal residues S328, T329, and S370 in vitro; mutation of these sites dramatically alters CK1δ kinetic parameters; pharmacological PKCα inhibition in cells reduces CK1δ activity, demonstrating that PKCα is a regulator of CK1δ kinase activity. In vitro kinase assay (PKCα phosphorylating CK1δ), site-directed mutagenesis of CK1δ phospho-sites, Go-6983 PKCα inhibitor in cell culture, kinetic analysis Amino acids High 26803658
2018 PKCα interacts with ULK1 through the ULK1 serine/threonine-rich (S/T) domain; phospho-PKCα phosphorylates ULK1 at Ser317/555/777 and Raptor, promoting mitophagy and replacing AMPK-dependent mitophagy during PEDF-induced cardioprotection in OGD cardiomyocytes. A ULK1 deletion mutant lacking the S/T domain fails to mediate PEDF-induced mitophagy. Co-IP of PKCα–ULK1 interaction, deletion mutagenesis of ULK1, phosphorylation assays, mitophagy markers, OGD cardiomyocyte model Journal of cellular and molecular medicine Medium 30230261
2016 PKCα phosphorylates filamin C (FLNc) at distinct serine residues in its hinge 2 region, preventing calpain 1 cleavage at an adjacent tyrosine. FRAP analysis shows this phosphorylation modulates FLNc dynamics at Z-discs in contracting skeletal myotubes. Quantitative phosphoproteomics of Z-disc in electrically stimulated myotubes, in vitro PKCα phosphorylation assay, FRAP, FLNc cleavage assays Molecular & cellular proteomics : MCP High 28028127
2020 PKCα positively regulates Rac1 activation during single-spine structural plasticity in dendritic spines; removal of PKCα expression attenuates Rac1 (but not Ras or Cdc42) activation. Disruption of a PDZ binding domain within PKCα impairs Rac1 activation and structural spine remodeling, positioning PKCα upstream of Rac1 in actin-dependent synaptic plasticity. PKCα knockdown/knockout in postsynaptic spines, FRET-based biosensors for Rac1/Cdc42/Ras activity during single-spine structural plasticity, PDZ domain mutant of PKCα Scientific reports Medium 32019972
2011 Pharmacological inhibition of PKCα/β with ruboxistaurin in a pig model of myocardial infarction-induced heart failure improves contractility, ejection fraction, and cardiac output, extending the mouse/rat cardiac contractility findings to a large-animal model. Left anterior descending artery occlusion in pigs, ruboxistaurin oral administration, echocardiographic measurements over 3 months Circulation research Medium 21998327
2018 The recurrent PRKCA D463H kinase-domain mutation found in all chordoid gliomas is a gain-of-function mutation; expression of mutant PRKCA in immortalized astrocytes increases phospho-ERK and anchorage-independent growth that is blocked by MEK inhibition, implicating the MAPK pathway downstream of mutant PKCα. Genomic sequencing of 13 chordoid gliomas, expression of PRKCA D463H in immortalized astrocytes, phospho-ERK assays, MEK inhibitor treatment, soft-agar colony formation Nature communications High 29476136 29915258
2018 The PKCα D463H mutant protein is depleted from the cell membrane compared to wild-type PKCα, is less stable, and its mRNA is more abundant than wild-type, with enriched activation of the EIF2 translation-initiation pathway. The mutant enhances proliferation of astrocytes and tanycytes. Whole-exome and RNA-sequencing of ChG, subcellular fractionation of PKCαD463H vs WT, protein stability assays, pathway activation analysis, proliferation assays Nature communications Medium 29915258
2015 PKCα promotes ROS production in hepatocellular carcinoma cells by upregulating DUOX2 at the post-transcriptional level; depletion of DUOX2 abrogates PKCα-induced AKT/MAPK pathway activation and cell proliferation, migration, and invasion. PKCα overexpression/knockdown in HCC cells, DUOX2 knockdown, ROS measurement, AKT/MAPK phosphorylation assays, proliferation/migration/invasion assays Biochemical and biophysical research communications Medium 26056003
2021 ECM stiffness activates PKCα which promotes nuclear transport of DNMT3L; stiff ECM leads to global hypermethylation (particularly at pluripotent gene promoters) in a PKCα-dependent manner. DNMT3L binds the Nanog promoter during cell–ECM interactions. Polyacrylamide gel substrates of varying stiffness, PKCα inhibition/knockdown, DNMT3L nuclear fractionation, methylation assays, ChIP of DNMT3L at Nanog promoter Advanced healthcare materials Medium 34174172
2014 PKCα and PKCδ phosphorylate the progesterone receptor (PR) at Ser400 within minutes of PKC activation, inducing PR transcriptional activity and subsequent proteasomal degradation. PR directly associates with PKCα (maximally at 5 min post-TPA), and PR Ser400Ala mutant blocks PKC-mediated PR phosphorylation and degradation. TPA treatment, siRNA silencing and pharmacological inhibition of PKCα/PKCδ, Co-IP of PR–PKCα, immunofluorescence nuclear colocalization, PR S400A mutant, luciferase reporter, proteasome inhibitor Endocrinology Medium 25514083
2016 H2O2-induced poly-ADP-ribose (PAR) formation is mediated by the PLC/IP3R/Ca2+/PKCα signaling axis; PKCα knockdown completely abolishes PAR formation despite persistent DNA damage. Co-depletion of HMGB1 with PKCα restores PAR formation, indicating PKCα activation releases HMGB1-mediated inhibition of PAR synthesis. RPPA signaling analysis, PKCα siRNA, HMGB1 siRNA, Ca2+ chelation, PAR quantification, DNA damage markers Nucleic acids research Medium 27198223
2017 PKCα-mediated phosphorylation of T. gondii GRA7 at Ser52 regulates interaction of GRA7 with the PYD domain of ASC to promote inflammasome activation; PKCα-mediated phosphorylation of GRA7 at Ser135 facilitates interaction with the PX domain of PLD1, enhancing its enzyme activity and phago-lysosomal maturation for antimycobacterial defense. Phospho-site mutagenesis of GRA7 Ser52/Ser135, Co-IP of GRA7–ASC and GRA7–PLD1, PLD1 enzyme activity assay, phagolysosomal fusion assays, mycobacterial killing assays PLoS pathogens Medium 28125719
2019 PKCα promotes insulin secretion in INS-1E cells by phosphorylating TRPC1; inhibition of PKCα reduces TRPC1 phosphorylation and intracellular Ca2+ levels, reducing insulin secretion; TRPC1 overexpression reverses the decrease in Ca2+ and insulin secretion caused by PKCα inhibition. PKCα activation/inhibition in INS-1E cells, TRPC1 phosphorylation assays, intracellular Ca2+ measurement, insulin secretion assay, TRPC1 overexpression rescue Bioscience, biotechnology, and biochemistry Medium 31094294
2014 PKCα contributes to high NaCl-induced NFAT5 activation through ERK1/2 but not through SHP-1-S591 phosphorylation; Prkca knockout reduces ERK1/2 phosphorylation and NFAT5 target gene expression in the renal inner medulla; combined knockdown of PKCα and ERK2 has no greater effect than either alone, placing them in the same pathway. Prkca knockout mice (renal medulla analysis), siRNA knockdown in HEK293 cells, NFAT5 transcriptional activity assay, ERK1/2 phosphorylation, SHP-1 phosphorylation assays American journal of physiology. Renal physiology Medium 25391900
2006 Polycystin-1 (PC1) cytoplasmic tail upregulates NF-κB nuclear levels and transcriptional activity in kidney cells through a PKCα-mediated mechanism; this anti-apoptotic pathway is blocked by the PKCα-specific inhibitor Ro-320432, and PC1-dependent antiapoptotic effects are reduced by PKC and NF-κB inhibitors. Stable expression of PC1 CTT in HEK293 cells, PKCα inhibitor Ro-320432, NF-κB luciferase reporter, apoptosis assays, RNA interference of endogenous PC1 Biochemical and biophysical research communications Medium 17007817
2023 Gi/o GPCR activation drives tunneling nanotube (TNT) formation through a Gβγ→PLCβ3→PKCα signaling axis; PKCα-dependent phosphorylation of cofilin stabilizes actin in TNT structures. PKCα inhibition blocks TNT formation downstream of OXER1 and LPA receptors. Pertussis toxin treatment, PLCβ3 siRNA, PKCα inhibition/siRNA, cofilin phosphorylation assays, TNT quantification by microscopy The Journal of biological chemistry Medium 37390986
2021 LDB3 mutation (Ala165Val) impairs PKCα signaling at the Z-disc in skeletal muscle by disrupting LDB3 interactions with filamin C, HSPA8, and PKCα, leading to protein aggregation and Z-disc disruption; this is linked to TSC2-mTOR downregulation as a parallel pathway. Ldb3Ala165Val/+ knock-in mice, Co-IP of LDB3–filamin C–HSPA8–PKCα complex, PKCα activity assays, mTOR pathway analysis, histology of Z-disc Communications biology Medium 33742095
2016 PHF8 histone demethylase regulates PRKCA transcription by interacting with c-Jun on the PRKCA promoter; PKCα in turn activates Src, which destabilizes PTEN via the PKCα-Src axis in gastric cancer cells. ChIP of PHF8/c-Jun at PRKCA promoter, PHF8/PKCα knockdown and ectopic expression, Src activity and PTEN expression assays, zebrafish migration model Proceedings of the National Academy of Sciences of the United States of America Medium 32958674
2014 In female Prkca−/− mice, PKCα normally suppresses endosteal bone formation by inhibiting osteoblast differentiation and Wnt target gene expression; within osteoblastic cells PKCα enhances proliferation and suppresses differentiation via the Wnt pathway. Estradiol and mechanical strain stimulate WT but not Prkca−/− osteoblastic cell proliferation. Prkca knockout mice (bone phenotype), osteoblast differentiation markers, Wnt target gene expression, estradiol/mechanical strain stimulation assays The Journal of biological chemistry Medium 25070889
2022 TRPM7 channel activity elevates intracellular Ca2+ and drives chondrocyte ferroptosis via the PKCα–NOX4 axis; PKCα was shown to directly bind NOX4, and TRPM7 inhibition reduces this interaction. AAV9-mediated TRPM7 silencing and pharmacological TRPM7 blockade attenuate cartilage destruction in adjuvant arthritis rats. TRPM7 knockdown/pharmacological inhibition, Co-IP of PKCα–NOX4, intracellular Ca2+ measurement, ferroptosis markers, in vivo AA rat model with AAV9 Redox biology Medium 35917680
2014 Absence of PKCα (Prkca KO) prevents lithium-induced downregulation of aquaporin-2 (AQP2) and urea transporter UT-A1 in renal inner medullary collecting duct cells, and attenuates lithium-induced nephrogenic diabetes insipidus (polyuria), indicating PKCα mediates lithium-induced dysregulation of these water/urea channels. Prkca knockout mice, lithium treatment (acute and chronic), Western blot for AQP2/UT-A1 in medullary tissue, urine output and osmolality measurements PloS one Medium 25006961
2019 Inhibition of ezrin disrupts the HER2–PMCA2–NHERF1–HSP90 membrane complex and causes PKCα-mediated internalization and degradation of HER2; inhibition of ezrin synergizes with lapatinib in a PKCα-dependent fashion to reduce proliferation and promote apoptosis in HER2-positive breast cancer cells. Ezrin knockdown/pharmacological inhibition, Co-IP of HER2–PMCA2–NHERF1–HSP90–ezrin complex, HER2 membrane retention assays, PKCα inhibition rescue, proliferation/apoptosis assays The Journal of biological chemistry Medium 30463939
2010 PKCα suppresses osteoblastic differentiation (ALP activity, ALP/osteocalcin gene expression) but promotes osteoblastic cell proliferation; siRNA knockdown of PKCα increases differentiation markers, while wild-type PKCα overexpression decreases them in MC3T3-E1 cells. Gö6976 inhibitor, PKCα siRNA knockdown, wild-type PKCα overexpression, ALP activity assay, gene expression analysis Bone Medium 20951242
2012 Integrin αv upregulates PKCα expression in a 3D collagen microenvironment; PKCα promotes cytoplasmic relocalization of p53 from the nucleus, suppressing p53 activity and promoting melanoma cell survival; stable knockdown of PKCα inhibits integrin αv-mediated p53 relocalization and promotes apoptosis in 3D collagen and in vivo. Microarray (integrin αv KD), stable PKCα knockdown, p53 subcellular fractionation in 3D collagen and in vivo, apoptosis assays, tumor xenograft The Journal of biological chemistry Medium 22773839

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nature medicine 491 14966518
2022 PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma. Journal of hepatology 139 35219791
2009 PKCalpha regulates platelet granule secretion and thrombus formation in mice. The Journal of clinical investigation 130 19147982
2013 Hydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKCα and PKCβ1 inhibition. Atherosclerosis 112 24401212
2003 Protein kinase Calpha (PKCalpha) acts upstream of PKCtheta to activate IkappaB kinase and NF-kappaB in T lymphocytes. Molecular and cellular biology 105 12972622
2010 PKCalpha expression is a marker for breast cancer aggressiveness. Molecular cancer 93 20398285
2022 TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis. Redox biology 88 35917680
2017 miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/β-catenin Complex in Lung Adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 86 28751441
2013 miR-203 inhibits cell proliferation and migration of lung cancer cells by targeting PKCα. PloS one 82 24040137
2021 Metabolomics and integrated network pharmacology analysis reveal Tricin as the active anti-cancer component of Weijing decoction by suppression of PRKCA and sphingolipid signaling. Pharmacological research 81 34419228
2017 Genomic Analysis of Pigmented Epithelioid Melanocytomas Reveals Recurrent Alterations in PRKAR1A, and PRKCA Genes. The American journal of surgical pathology 79 28796000
2015 TRM6/61 connects PKCα with translational control through tRNAi(Met) stabilization: impact on tumorigenesis. Oncogene 77 26234676
2008 Differential regulation of VEGF signaling by PKC-alpha and PKC-epsilon in endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 69 18323518
2012 Annexin A6 is a scaffold for PKCα to promote EGFR inactivation. Oncogene 68 22797061
2007 Light entrainment of the mammalian circadian clock by a PRKCA-dependent posttranslational mechanism. Neuron 67 17553429
2022 ATF4/CEMIP/PKCα promotes anoikis resistance by enhancing protective autophagy in prostate cancer cells. Cell death & disease 66 35013120
2018 A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nature communications 59 29476136
2012 Identification of a novel, recurrent SLC44A1-PRKCA fusion in papillary glioneuronal tumor. Brain pathology (Zurich, Switzerland) 59 22725730
2009 PRKCA: a positional candidate gene for body mass index and asthma. American journal of human genetics 56 19576566
2005 The link between PKCalpha regulation and cellular transformation. Immunology letters 56 15585319
1997 PKC--a pivotal regulator of early development. BioEssays : news and reviews in molecular, cellular and developmental biology 55 9008415
2021 EGCG promotes PRKCA expression to alleviate LPS-induced acute lung injury and inflammatory response. Scientific reports 53 34040072
2021 Curcumin suppresses the malignancy of non-small cell lung cancer by modulating the circ-PRKCA/miR-384/ITGB1 pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 51 33684690
2006 Ceramides and cell signaling molecules in psoriatic epidermis: reduced levels of ceramides, PKC-alpha, and JNK. Journal of Korean medical science 51 16479073
2018 A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas. Nature communications 49 29915258
2015 The Aspergillus fumigatus pkcA G579R Mutant Is Defective in the Activation of the Cell Wall Integrity Pathway but Is Dispensable for Virulence in a Neutropenic Mouse Infection Model. PloS one 49 26295576
2005 PKCalpha expression regulated by Elk-1 and MZF-1 in human HCC cells. Biochemical and biophysical research communications 48 16297876
2011 Inhibition of PKCα/β with ruboxistaurin antagonizes heart failure in pigs after myocardial infarction injury. Circulation research 47 21998327
2010 PKCalpha mediated induction of miR-101 in human hepatoma HepG2 cells. Journal of biomedical science 47 20444294
2006 The protein kinase C orthologue PkcA plays a role in cell wall integrity and polarized growth in Aspergillus nidulans. Fungal genetics and biology : FG & B 47 17118679
2012 PKCα binds G3BP2 and regulates stress granule formation following cellular stress. PloS one 46 22536444
2016 Keratin Isotypes Control Desmosome Stability and Dynamics through PKCα. The Journal of investigative dermatology 45 26763440
2019 Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA. Acta neuropathologica 44 30759284
2015 Papillary glioneuronal tumors: histological and molecular characteristics and diagnostic value of SLC44A1-PRKCA fusion. Acta neuropathologica communications 44 26671581
2002 Activation of Integrin-RACK1/PKCalpha signalling in human articular chondrocyte mechanotransduction. Osteoarthritis and cartilage 43 12435334
2019 Klotho inhibits PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy. Molecular and cellular endocrinology 42 31207271
2006 Protein kinase C (PkcA) of Aspergillus nidulans is involved in penicillin production. Applied and environmental microbiology 41 16598003
2007 A protein kinase C-encoding gene, pkcA, is essential to the viability of the filamentous fungus Aspergillus nidulans. Bioscience, biotechnology, and biochemistry 39 17986778
2006 PRKCA and multiple sclerosis: association in two independent populations. PLoS genetics 39 16596167
2020 The complexities of PKCα signaling in cancer. Advances in biological regulation 38 33307285
2017 Protein kinase C-α (PKCα) modulates cell apoptosis by stimulating nuclear translocation of NF-kappa-B p65 in urothelial cell carcinoma of the bladder. BMC cancer 37 28629334
2013 The kinase PKCα selectively upregulates interleukin-17A during Th17 cell immune responses. Immunity 36 23290522
2014 Functional variations modulating PRKCA expression and alternative splicing predispose to multiple sclerosis. Human molecular genetics 35 25080502
2007 The Aspergillus nidulans pkcA gene is involved in polarized growth, morphogenesis and maintenance of cell wall integrity. Current genetics 35 17406869
2020 Cytosolic Ca2+ Modulates Golgi Structure Through PKCα-Mediated GRASP55 Phosphorylation. iScience 34 32179476
2013 Pharmacologic inhibition of PKCα and PKCθ prevents GVHD while preserving GVL activity in mice. Blood 34 23908466
2010 PKCα suppresses osteoblastic differentiation. Bone 34 20951242
2004 Association of protein kinase C alpha (PRKCA) gene with multiple sclerosis in a UK population. Brain : a journal of neurology 34 15155525
2016 Pigment-Synthesizing Melanocytic Neoplasm With Protein Kinase C Alpha (PRKCA) Fusion. JAMA dermatology 33 26676968
2011 Receptor-independent protein kinase C alpha (PKCalpha) signaling by calpain-generated free catalytic domains induces HDAC5 nuclear export and regulates cardiac transcription. The Journal of biological chemistry 33 21642422
2011 Low molecular weight heparin inhibits melanoma cell adhesion and migration through a PKCa/JNK signaling pathway inducing actin cytoskeleton changes. Cancer letters 33 21906873
2004 PKCalpha induces differentiation through ERK1/2 phosphorylation in mouse keratinocytes. Experimental & molecular medicine 33 15365248
2004 The role of protein kinase C-alpha (PKC-alpha) in melanoma. Melanoma research 32 15057036
1996 Cloning and characterisation of genes (pkc1 and pkcA) encoding protein kinase C homologues from Trichoderma reesei and Aspergillus niger. Molecular & general genetics : MGG 32 8569684
2016 Myofibrillar Z-discs Are a Protein Phosphorylation Hot Spot with Protein Kinase C (PKCα) Modulating Protein Dynamics. Molecular & cellular proteomics : MCP 31 28028127
2022 PRKCA Promotes Mitophagy through the miR-15a-5p/PDK4 Axis to Relieve Sepsis-Induced Acute Lung Injury. Infection and immunity 30 36448837
2016 miR-706 inhibits the oxidative stress-induced activation of PKCα/TAOK1 in liver fibrogenesis. Scientific reports 30 27876854
2021 Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKCα and TSC2-mTOR downregulation. Communications biology 29 33742095
2020 Rac1 is a downstream effector of PKCα in structural synaptic plasticity. Scientific reports 29 32019972
2018 Glucose enhances aggrecan expression in chondrocytes via the PKCα/p38-miR141-3p signaling pathway. Journal of cellular physiology 28 29319178
2021 Extracellular Matrix Stiffness Regulates DNA Methylation by PKCα-Dependent Nuclear Transport of DNMT3L. Advanced healthcare materials 27 34174172
2020 Targeting the histone demethylase PHF8-mediated PKCα-Src-PTEN axis in HER2-negative gastric cancer. Proceedings of the National Academy of Sciences of the United States of America 27 32958674
2017 Toxoplasma gondii GRA7-Targeted ASC and PLD1 Promote Antibacterial Host Defense via PKCα. PLoS pathogens 27 28125719
2015 PKCα regulates TMEM16A-mediated Cl⁻ secretion in human biliary cells. American journal of physiology. Gastrointestinal and liver physiology 27 26542395
2018 Inhibition of ezrin causes PKCα-mediated internalization of erbb2/HER2 tyrosine kinase in breast cancer cells. The Journal of biological chemistry 26 30463939
2014 Protein kinase Cα (PKCα) regulates bone architecture and osteoblast activity. The Journal of biological chemistry 26 25070889
2019 miR-216a promotes breast cancer cell apoptosis by targeting PKCα. Fundamental & clinical pharmacology 25 31119784
2016 Gene-Gene Interactions Among PRKCA, NOS3 and BDKRB2 Polymorphisms Affect the Antihypertensive Effects of Enalapril. Basic & clinical pharmacology & toxicology 25 27696692
2013 K562 cell proliferation is modulated by PLCβ1 through a PKCα-mediated pathway. Cell cycle (Georgetown, Tex.) 25 23656785
2017 Clinical significance of the correlation between PLCE 1 and PRKCA in esophageal inflammation and esophageal carcinoma. Oncotarget 24 28402280
2014 PKC-α contributes to high NaCl-induced activation of NFAT5 (TonEBP/OREBP) through MAPK ERK1/2. American journal of physiology. Renal physiology 24 25391900
2010 Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition through heme oxygenase-1 blockage in cholangiocarcinoma cells. Experimental & molecular medicine 24 20938215
2020 Glucose fluctuations promote vascular BK channels dysfunction via PKCα/NF-κB/MuRF1 signaling. Journal of molecular and cellular cardiology 22 32511969
2018 Role of FGFR2b expression and signaling in keratinocyte differentiation: sequential involvement of PKCδ and PKCα. Cell death & disease 22 29752438
2018 Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα-dependent manner. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 30423260
2014 PKCα and PKCδ activation regulates transcriptional activity and degradation of progesterone receptor in human astrocytoma cells. Endocrinology 22 25514083
2022 PKCα and PKCδ: Friends and Rivals. The Journal of biological chemistry 21 35760100
2020 The P2Y6 receptor signals through Gαq /Ca2+ /PKCα and Gα13 /ROCK pathways to drive the formation of membrane protrusions and dictate cell migration. Journal of cellular physiology 21 32420639
2009 Protein kinase C alpha (PKCalpha) regulates growth and invasion of endometrial cancer cells. Journal of cellular physiology 21 19235902
2020 The specific PKC-α inhibitor chelerythrine blunts costunolide-induced eryptosis. Apoptosis : an international journal on programmed cell death 20 32638182
2016 Distinctive and selective route of PI3K/PKCα-PKCδ/RhoA-Rac1 signaling in osteoclastic cell migration. Molecular and cellular endocrinology 19 27576187
2015 SLC44A1-PRKCA fusion in papillary and rosette-forming glioneuronal tumors. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 19 26260115
2018 PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection. Journal of cellular and molecular medicine 18 30230261
2016 CK1δ kinase activity is modulated by protein kinase C α (PKCα)-mediated site-specific phosphorylation. Amino acids 18 26803658
2016 PKCα and HMGB1 antagonistically control hydrogen peroxide-induced poly-ADP-ribose formation. Nucleic acids research 18 27198223
2019 Cooperative Blockade of PKCα and JAK2 Drives Apoptosis in Glioblastoma. Cancer research 17 31806641
2020 PKCα mediated by the PI3K/Akt-FOXA1 cascade facilitates cypermethrin-induced hyperthyroidism. The Science of the total environment 16 33250241
2019 LPA1 receptor activation induces PKCα nuclear translocation in glioblastoma cells. The international journal of biochemistry & cell biology 16 30849522
2015 PKCα promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma. Biochemical and biophysical research communications 16 26056003
2012 Protein kinase Cα (PKCα) regulates p53 localization and melanoma cell survival downstream of integrin αv in three-dimensional collagen and in vivo. The Journal of biological chemistry 16 22773839
2021 The AXL-PYK2-PKCα axis as a nexus of stemness circuits in TNBC. Life science alliance 15 33785524
2020 miR-709 inhibits GHRP6 induced GH synthesis by targeting PRKCA in pituitary. Molecular and cellular endocrinology 15 32084499
2019 Differential expression of PKCα and -β in the zebrafish retina. Histochemistry and cell biology 15 30604284
2019 PKCα promotes insulin secretion via TRPC1 phosphorylation in INS-1E cells. Bioscience, biotechnology, and biochemistry 15 31094294
2018 Let-7g-5p regulates mouse mammary cells differentiation and function by targeting PRKCA. Journal of cellular physiology 15 30422318
2006 Polycystin-1 promotes PKCalpha-mediated NF-kappaB activation in kidney cells. Biochemical and biophysical research communications 15 17007817
2023 Gi/o GPCRs drive the formation of actin-rich tunneling nanotubes in cancer cells via a Gβγ/PKCα/FARP1/Cdc42 axis. The Journal of biological chemistry 14 37390986
2023 SUMOylation of AnxA6 facilitates EGFR-PKCα complex formation to suppress epithelial cancer growth. Cell communication and signaling : CCS 14 37528485
2021 LPA1 Receptor Promotes Progesterone Receptor Phosphorylation through PKCα in Human Glioblastoma Cells. Cells 14 33916643
2014 Absence of PKC-alpha attenuates lithium-induced nephrogenic diabetes insipidus. PloS one 14 25006961

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