Affinage

PCK1

Phosphoenolpyruvate carboxykinase, cytosolic [GTP] · UniProt P35558

Length
622 aa
Mass
69.2 kDa
Annotated
2026-04-29
100 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCK1 (cytosolic phosphoenolpyruvate carboxykinase) is a GTP-dependent enzyme whose canonical activity—conversion of oxaloacetate to phosphoenolpyruvate—positions it as a master regulator of carbon flux through gluconeogenesis, TCA cataplerosis, glycogenesis, the pentose phosphate pathway, and one-carbon/SAM metabolism, with consequences for NADPH/ROS homeostasis, epigenetic H3K9 trimethylation, O-GlcNAcylation, and cell-cycle control via AMPK/p27 (PMID:29230018, PMID:33690219, PMID:37166978, PMID:30717766). Beyond its metabolic activity, AKT-mediated Ser90 phosphorylation redirects PCK1 to the endoplasmic reticulum where it functions as a protein kinase, phosphorylating INSIG1/2 to release SCAP–SREBP and activate lipogenesis (PMID:32322062). Acetyl-CoA binding at the active site drives PCK1 self-acetylation (K244, K91), which inactivates the gluconeogenic reaction and can reverse catalytic directionality to favor anaplerotic oxaloacetate synthesis (PMID:33334880, PMID:39341205). JNK1/2-mediated S151 phosphorylation promotes PCK1–cGAS interaction and competitive GTP consumption, suppressing cGAS–STING innate immune signaling and enabling tumor immune evasion (PMID:40048154).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 Medium

    Identification of a cis-regulatory element at −232 in the PCK1 promoter established that a single nucleotide variant governs basal transcription and insulin-mediated repression, providing the first functional dissection of how insulin silences PCK1 at the promoter level.

    Evidence Luciferase reporter assays with −232C vs −232G constructs in multiple cell lines with insulin treatment

    PMID:14764811

    Open questions at the time
    • Chromatin context of the −232 element not examined
    • Trans-acting factor binding this element not identified
    • No in vivo confirmation of allele-specific expression
  2. 2015 Medium

    Discovery that insulin-phosphorylated FOXO1 relocates to the nuclear periphery and recruits the histone methyltransferase EHMT2, establishing repressive chromatin at the PCK1 promoter, revealed a spatial–epigenetic mechanism of PCK1 transcriptional silencing beyond simple FOXO1 nuclear exclusion.

    Evidence Live-cell imaging of endogenous phospho-FOXO1, Co-IP of FOXO1–EHMT2, ChIP of histone marks at PCK1 promoter, NUP98 interaction studies

    PMID:25736587

    Open questions at the time
    • Not independently confirmed by a second lab
    • Contribution relative to canonical FOXO1 nuclear export not quantified
    • Whether this mechanism operates genome-wide or is PCK1-specific is unclear
  3. 2017 High

    Demonstration that CD8+ memory T cells upregulate PCK1 to fuel a gluconeogenesis→glycogenesis→PPP axis for NADPH and ROS control established a non-hepatic, immunological role for PCK1 and linked its catalytic activity to adaptive immune memory.

    Evidence T-cell-specific Pck1 KO and overexpression, 13C metabolic flux analysis, NADPH/GSH measurement, mouse tumor immunotherapy models

    PMID:29230018

    Open questions at the time
    • Whether PCK1 is required in all memory T-cell subsets is unknown
    • Upstream signals inducing PCK1 in memory T cells not fully defined
    • Relative contribution of glycogen vs direct PPP flux not dissected
  4. 2018 High

    Showing that forced PCK1 expression in glucose-deprived hepatoma cells causes lethal TCA cataplerosis, energy crisis, and ROS-mediated apoptosis—dependent on catalytic activity—established PCK1 as a context-dependent tumor suppressor whose metabolic drain is cytotoxic.

    Evidence PCK1 overexpression with catalytic-dead mutant controls, TCA metabolite profiling, α-ketoglutarate rescue, xenograft models

    PMID:29335519

    Open questions at the time
    • Threshold of cataplerosis required for apoptosis not quantified
    • Relevance to non-hepatic tumors not tested in this study
    • Downstream ROS sensors mediating apoptosis not identified
  5. 2019 Medium

    Linking PCK1 loss to AMPK inactivation, p27 suppression, and accelerated G1→S transition provided a direct mechanism by which metabolic sensing through PCK1 controls cell-cycle progression in hepatoma cells.

    Evidence PCK1 gain/loss-of-function with AMPK inhibitor/activator, flow cytometry, CDK/Rb/E2F pathway analysis, xenograft models

    PMID:30717766

    Open questions at the time
    • Whether the ATP drop is the sole AMPK-activating signal is unresolved
    • Contribution of other AMPK substrates beyond p27 not tested
    • Single cancer type studied
  6. 2019 Medium

    Identification of PCK1 upregulation in metastatic colorectal cancer cells driving pyrimidine nucleotide biosynthesis under hypoxia revealed that the gluconeogenic reaction can supply carbon for nucleotide synthesis in non-hepatic tumors, expanding PCK1's oncogenic role.

    Evidence PDX in vivo selection, metabolomic profiling of pyrimidine intermediates, DHODH inhibition, PCK1 knockdown in metastasis models

    PMID:31841108

    Open questions at the time
    • Exact carbon routing from PEP to pyrimidines not traced isotopically at single-step resolution
    • Whether this is specific to liver metastases or generalizable is unclear
    • No structural or enzymatic reconstitution
  7. 2020 High

    The landmark finding that AKT phosphorylates PCK1 at Ser90, causing ER translocation and a moonlighting protein kinase activity toward INSIG1/2, fundamentally redefined PCK1 as a signal-regulated enzyme with dual catalytic identities—metabolic and signaling.

    Evidence In vitro kinase assays, site-directed mutagenesis, Co-IP, subcellular fractionation, ER translocation imaging, xenograft and human HCC correlation

    PMID:32322062

    Open questions at the time
    • Full substrate scope of PCK1 kinase activity beyond INSIGs not surveyed
    • Structural basis for GTP-dependent kinase mechanism not resolved
    • Whether kinase activity occurs in non-tumor tissues is unknown
  8. 2021 High

    Crystal-structure-guided discovery that acetyl-CoA binds the PCK1 active site and drives self-acetylation at K244, inactivating the enzyme, established a direct feedback mechanism by which acetyl-CoA availability controls gluconeogenic flux independently of acetyltransferases.

    Evidence X-ray crystallography, mass spectrometry, ITC, STD-NMR, in vitro acetylation assay, site-directed mutagenesis

    PMID:33334880

    Open questions at the time
    • Physiological acetyl-CoA concentrations at which self-acetylation becomes rate-limiting not defined
    • Whether deacetylases counteract this in real time in vivo is unclear
    • Impact on protein kinase activity not tested
  9. 2021 High

    Comprehensive metabolic tracing showed PCK1 loss causes OAA accumulation, increased UDP-GlcNAc, and global O-GlcNAcylation—including CHK2 at T378, which destabilizes CHK2 and drives Rb phosphorylation and proliferation—establishing a PCK1→O-GlcNAc→cell-cycle axis in HCC.

    Evidence PCK1 KO cells, metabolic flux analysis, AMPK–GFAT1 epistasis, O-GlcNAc MS, CHK2 T378 mutagenesis, liver-specific Pck1 KO HCC mice

    PMID:33690219 PMID:34650217

    Open questions at the time
    • Complete O-GlcNAc proteome altered by PCK1 loss not catalogued
    • Whether O-GlcNAcylation changes are reversible upon PCK1 restoration in established tumors is unknown
    • Relative contribution of OAA-driven vs AMPK-driven UDP-GlcNAc increase not quantified
  10. 2023 High

    Discovery that PCK1 fuels serine/SAM biosynthesis and thereby sustains SUV39H1-catalyzed H3K9me3 at the S100A11 promoter linked PCK1 catalytic activity to epigenetic gene silencing and identified a metabolic–epigenetic tumor-suppressive circuit.

    Evidence Metabolomic tracing of serine/SAM, ChIP for H3K9me3, Co-IP of S100A11–AKT1, SAM rescue, S100A11 KO in vivo, PCK1 KO/OE hepatoma models

    PMID:37166978

    Open questions at the time
    • Genome-wide H3K9me3 changes upon PCK1 loss not reported
    • Whether other SAM-consuming methyltransferases are similarly affected is unclear
    • Direct isotope tracing from PEP to SAM not shown at single-step resolution
  11. 2023 Medium

    Kidney-specific PCK1 deletion caused hyperchloremic metabolic acidosis, reduced ammoniagenesis, and impaired tubular ATP production, establishing PCK1 as essential for renal acid-base homeostasis and energy metabolism beyond its hepatic role.

    Evidence Kidney-specific PCK1 KO and knockin mice, metabolic phenotyping, ATP measurement, acid-base challenge

    PMID:37102687 PMID:37199399

    Open questions at the time
    • Whether PCK1 compensates for PCK2 loss in kidney is not tested
    • Mechanism linking PCK1 to ammoniagenesis not fully delineated
    • Long-term renal outcomes of PCK1 overexpression not characterized
  12. 2024 High

    Showing that K91 acetylation reverses PCK1's catalytic direction to favor anaplerotic OAA synthesis from PEP, and that liver-specific K91Q expression ameliorates hyperglycemia in obese mice, revealed a post-translational switch that repurposes PCK1 from catabolic to anabolic function in vivo.

    Evidence In vitro enzyme activity with K91Q mimetic, metabolic flux analysis, liver-specific viral expression in obese mice, SR18292 pharmacology

    PMID:39341205

    Open questions at the time
    • Whether K91 acetylation and K244 acetylation cooperate or are mutually exclusive is unresolved
    • Deacetylase(s) responsible for reversing K91 acetylation in vivo not identified
    • Effect of reverse reaction on non-hepatic tissues not explored
  13. 2025 High

    Identification of JNK1/2-mediated S151 phosphorylation driving PCK1–cGAS association and competitive GTP consumption revealed a non-enzymatic, immune-suppressive function of PCK1 that enables tumor immune evasion via cGAS–STING inhibition.

    Evidence Co-IP, in vitro GTP competition assays, phosphomimetic/phosphodeficient mutants, mouse tumor models with anti-PD-1, human breast cancer specimen correlation

    PMID:40048154

    Open questions at the time
    • Whether PCK1–cGAS interaction occurs in non-tumor immune contexts is unknown
    • Structural basis of the PCK1–cGAS interface not determined
    • Relative contribution of GTP depletion vs direct cGAS inhibition not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the full substrate scope of PCK1's protein kinase activity, the structural basis for its dual catalytic (metabolic and kinase) functions, how the multiple post-translational modifications (Ser90, S151, K91, K244 phosphorylation/acetylation) are hierarchically coordinated in vivo, and whether PCK1's immune-modulatory roles extend beyond the tumor microenvironment.
  • No crystal structure of phospho-Ser90 ER-localized PCK1 in kinase conformation
  • Integrated PTM code governing catalytic direction not mapped
  • Non-cancer immune roles of PCK1 largely unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0016829 lyase activity 2 GO:0016853 isomerase activity 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 3 R-HSA-1640170 Cell Cycle 2 R-HSA-4839726 Chromatin organization 1
Partners
AKT1CGASCHK2INSIG1INSIG2PYGLSCAPUBAP2L

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 AKT phosphorylates PCK1 at Ser90, triggering its translocation from cytosol to the endoplasmic reticulum, where phosphorylated PCK1 acts as a GTP-dependent protein kinase to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces sterol binding to INSIG1/2, disrupts INSIG–SCAP interaction, and releases the SCAP–SREBP complex to translocate to the Golgi, activating lipogenic gene transcription. In vitro kinase assays, site-directed mutagenesis, Co-IP, subcellular fractionation, ER translocation imaging, xenograft tumor models, patient HCC sample correlation Nature High 32322062
2021 PCK1 acetylates itself at its active site (self-acetylation) using acetyl-CoA as a substrate, independently of p300. Site-directed acetylation of K244 inside the active site renders the enzyme inactive, producing a ~3-fold decrease in kcat without changing Km, revealing acetyl-CoA as a regulatory ligand that controls PCK1 gluconeogenic activity. Protein crystallography, mass spectrometry, isothermal titration calorimetry, saturation-transfer difference NMR, molecular docking, in vitro acetylation assay, site-directed mutagenesis The Journal of biological chemistry High 33334880
2024 SR18292 increases PCK1 lysine acetylation (K91 mimicked by K91Q mutant), which reverses PCK1 catalytic direction to favor anaplerotic OAA synthesis from PEP, thereby supplying OAA to the TCA cycle, increasing lactate and glucose oxidation, and suppressing gluconeogenesis. Liver-specific expression of PCK1 K91Q ameliorates hyperglycemia in obese mice. In vitro enzyme activity assays with acetylation-mimetic mutant (K91Q), metabolic flux analysis, liver-specific viral expression in mice, pharmacological treatment with SR18292 Cell chemical biology High 39341205
2025 Hypoxia induces JNK1/2-mediated phosphorylation of PCK1 at S151, which promotes physical interaction between PCK1 and cGAS. PCK1 associated with cGAS competitively consumes GTP (a shared substrate), thereby inhibiting GTP-dependent cGAS activation, suppressing STING-mediated immune cell recruitment, and promoting tumor immune evasion. Co-IP, in vitro GTP competition assays, phosphomimetic/phosphodeficient mutants, mouse tumor models with PCK1 blockade + anti-PD-1 combination, correlation in human breast cancer specimens The Journal of experimental medicine High 40048154
2021 PCK1 deficiency causes oxaloacetate accumulation and increased de novo UTP synthesis, elevating UDP-GlcNAc and global O-GlcNAcylation. Simultaneously, PCK1 loss inactivates the AMPK–GFAT1 axis, further promoting UDP-GlcNAc synthesis. Elevated O-GlcNAcylation of CHK2 at Thr378 counteracts CHK2 stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. PCK1 knockout cells, metabolic flux analysis, AMPK pathway knockdown/rescue, O-GlcNAc mass spectrometry, site-specific mutagenesis of CHK2 T378, liver-specific Pck1 knockout mouse HCC model The Journal of clinical investigation High 33690219
2021 PCK1 depletion increases O-GlcNAcylation of KAT5 (lysine acetyltransferase 5), which suppresses KAT5 ubiquitination and stabilizes it. Stabilized O-GlcNAc-KAT5 epigenetically activates TWIST1 via histone H4 acetylation and upregulates MMP9/MMP14 via c-Myc acetylation, promoting EMT and HCC metastasis. Gain/loss-of-function studies, Co-IP, ubiquitination assays, ChIP, O-GlcNAc site mapping by MS, in vivo lung metastasis in liver-specific Pck1-KO mice Oncogene High 34650217
2023 PCK1 fuels the serine synthesis pathway to generate S-adenosylmethionine (SAM). SAM serves as a methyl donor for SUV39H1-catalyzed H3K9me3 modification at the S100A11 promoter, suppressing this oncogene. PCK1 deficiency reduces SAM, lowers H3K9me3 at S100A11, and induces oncogenic PI3K/AKT signaling via S100A11–AKT1 interaction. Metabolomic tracing of serine/SAM pathway, ChIP for H3K9me3, Co-IP of S100A11–AKT1, SAM supplementation rescue, S100A11 KO in vivo, PCK1 KO/OE hepatoma models The Journal of clinical investigation High 37166978
2017 CD8+ memory T cells upregulate PCK1 to drive gluconeogenesis-dependent glycogenesis. The resulting glycogen is channeled through glycogenolysis → glucose-6-phosphate → pentose phosphate pathway, generating NADPH that maintains reduced glutathione and limits ROS. Abrogation of the Pck1–glycogen–PPP axis impairs memory T-cell formation and maintenance. Pck1 KO and overexpression in T cells, metabolic flux analysis (glycogen, PPP intermediates, NADPH/GSH), mouse tumor immunotherapy models Nature cell biology High 29230018
2018 Forced PCK1 expression in glucose-deprived liver cancer cells induces TCA cataplerosis, leading to energy crisis and oxidative stress that causes apoptosis. This pro-apoptotic effect requires PCK1 catalytic activity, as catalytic-dead mutants fail to recapitulate it. Replenishing α-ketoglutarate or inhibiting ROS blocks the PCK1-induced cell death. PCK1 overexpression with catalytic mutant controls, TCA metabolite profiling, ROS measurement, α-ketoglutarate rescue, xenograft tumor models Oncogene High 29335519
2019 PCK1 upregulation in metastatic colorectal cancer cells drives pyrimidine nucleotide biosynthesis under hypoxia by supplying carbon via the gluconeogenic reaction, thereby supporting liver metastatic colonization and hypoxic growth. In vivo PDX selection for metastatic capacity, metabolomic profiling of pyrimidine intermediates, DHODH inhibition with leflunomide, PCK1 functional knockdown in metastasis models eLife Medium 31841108
2019 PCK1 deficiency inactivates AMPK, suppresses p27Kip1 expression, and stimulates the CDK/Rb/E2F pathway, accelerating G1→S transition and hepatoma cell proliferation under glucose starvation. Conversely, PCK1 overexpression reduces ATP, enhances AMPK phosphorylation, and induces G1 arrest; AMPK knockdown reverses the PCK1-induced arrest. Gain/loss-of-function with AMPK inhibitor/activator, flow cytometry cell-cycle analysis, Western blotting of CDK/Rb/E2F/AMPK/p27, xenograft models Journal of experimental & clinical cancer research Medium 30717766
2023 SHP-1 phosphatase is recruited to the regulatory regions of the PCK1 gene, interacts with RNA polymerase II, and acts as a transcriptional coactivator for PCK1 expression. This recruitment is dependent on SHP-1's association with the transcription factor STAT5. Loss of SHP-1 or STAT5 reduces RNA Pol II at the PCK1 promoter, decreasing PCK1 mRNA and gluconeogenesis. Co-IP, ChIP-seq, luciferase reporter assay, gluconeogenesis assay, siRNA knockdown of SHP-1 and STAT5 The Journal of biological chemistry Medium 37595871
2015 Insulin-induced Ser256 phosphorylation of FOXO1 triggers its translocation from nuclear speckles to the nuclear periphery, where FOXO1 forms a complex with EHMT2 histone methyltransferase. This complex induces repressive histone modifications at the PCK1 promoter and requires NUP98 for nuclear peripheral positioning, leading to transcriptional repression of PCK1. Live-cell imaging of endogenous phospho-FOXO1, Co-IP of FOXO1-EHMT2, ChIP of histone marks at PCK1 promoter, dominant-negative FOXO1 mutants, NUP98 interaction studies Genes to cells Medium 25736587
2016 The oncoprotein HBXIP suppresses PCK1 expression by: (1) upregulating miR-135a, which targets the 3′UTR of FOXO1 mRNA, and (2) activating PI3K/Akt to phosphorylate FOXO1, causing its nuclear export. Both mechanisms reduce FOXO1-driven PCK1 transcription. Overexpression of PCK1 abolishes HBXIP-promoted hepatoma growth in vitro and in vivo. miR-135a reporter assay (3′UTR luciferase), FOXO1 phosphorylation/localization by Western blot and IF, PCK1 rescue overexpression, xenograft models Cancer letters Medium 27609066
2023 METTL3-mediated N6-methyladenosine (m6A) modification of PCK1 mRNA is induced during hepatic ischemia-reperfusion (I/R) injury, promoting PCK1 mRNA export and increased PCK1 expression. Hepatic-specific knockout of METTL3 reduces m6A on PCK1 transcript, decreases PCK1 expression, and worsens I/R injury, while PCK1 overexpression is protective. MeRIP-seq, hepatocyte-specific METTL3 KO mice, I/R mouse models, PCK1 inhibitor and overexpression, mRNA export assays Hepatology Medium 38085830
2023 PCK1 loss in hepatoma cells increases global protein O-GlcNAcylation through two mechanisms: (1) oxaloacetate accumulation drives increased de novo UTP and UDP-GlcNAc synthesis, and (2) AMPK inactivation releases inhibitory GFAT1 phosphorylation. hnRNPA2B1 promotes HCC by binding PCK1 mRNA and reducing its m6A methylation, thereby decreasing PCK1 expression. RNA immunoprecipitation (RIP), MeRIP assay for m6A, CRISPR-Cas9 KO of hnRNPA2B1, RNA-seq, subcutaneous and orthotopic HCC mouse models Journal of translational medicine Medium 38017546
2005 Loss of PCK1 in myeloid cells (macrophage-specific Pck1 deletion) reduces 13C labeling of TCA intermediates (citrate, malate) from [U-13C]glucose, increases 13C-lactate labeling, and elevates ROS, shifting macrophages toward a pro-inflammatory M1 phenotype with increased TNFα, IL-1β, and IL-6 expression. Myeloid-specific Pck1 KO mice, stable isotopomer MS with [U-13C]glucose in BMDM, ROS measurement, cytokine ELISA The Journal of biological chemistry Medium 29317502
2016 A single amino acid substitution Met139Leu (c.A2456C SNP) in pig PCK1 reduces kcat in the glyceroneogenic direction, enhances kcat in the anaplerotic direction, and reduces ability of the enzyme to be acetylated, increasing its susceptibility to ubiquitin-proteasome degradation. The substitution results in ~30% lower glucose and ~9% lower lipid production in cell cultures. Recombinant enzyme kinetic assays (kcat, Km in both directions), acetylation assay, cell culture metabolic flux measurement, pig phenotype association Scientific reports Medium 26792594
2023 Kidney-specific PCK1 deletion in mice causes hyperchloremic metabolic acidosis with reduced ammoniagenesis, glycosuria, lactaturia, and decreased ATP generation. PCK1 is required for proximal tubule energy production and acid-base control; its loss increases tubular injury during acidosis, while overexpression protects against proteinuric renal disease. Kidney-specific PCK1 KO and knockin (PAX8 promoter), metabolic phenotyping (creatinine clearance, albuminuria, glycosuria), ATP measurement, acid-base challenge experiments American journal of physiology. Renal physiology Medium 37102687
2020 PCK1 loss in HCC deficiency activates the RhoA/PI3K/AKT pathway by increasing intracellular GTP levels, stimulates paracrine secretion of PDGF-AA, and promotes hepatic stellate cell activation and liver fibrosis. Treatment with RhoA and AKT inhibitors or silencing of RhoA/AKT1 alleviates MAFLD progression in PCK1-deficient mice. Liver-specific Pck1 KO mice, intracellular GTP measurement, PDGF-AA ELISA, hepatic stellate cell co-culture, RhoA/AKT inhibitor treatment, AAV-mediated PCK1 rescue Nature communications Medium 36918564
2024 PCK1 enhances PYGL phosphorylation in cervical cancer stem cells, promoting glycogen breakdown and channeling glucose-6-phosphate into the pentose phosphate pathway, increasing NADPH production and ROS clearance, thereby promoting chemoresistance. siRNA knockdown of PCK1, PYGL, GYS1 in HCC94/CaSki cells, glycogen measurement, LC-MS of PPP intermediates, NADPH/NADP+ ratio, NSG mouse tumor growth assays Scientific reports Medium 38871968
2024 PRRSV infection activates AKT, which in turn activates PCK1. Activated PCK1 phosphorylates INSIG proteins (INSIGs), causing their degradation and releasing SCAP–SREBP complexes to the nucleus to activate lipid biosynthesis; ROS produced by PRRSV are required for AKT activation in this axis. Pharmacological inhibitors of AKT and PCK1, INSIG protein level monitoring by Western blot, SREBP nuclear translocation assay, ROS scavenger treatment, MARC-145 cell infection model International journal of biological macromolecules Low 39433189
2019 Rev-erbα directly binds a RevRE site at −325 to −320 bp in the PCK1 promoter to trans-repress PCK1 transcription, reducing hepatic Pck1 mRNA and protein levels and lowering fasting plasma glucose in diabetic mice. Luciferase reporter assay with promoter deletions, gel-shift (EMSA) with RevRE site probe, ChIP assay in hepatoma cells, SR9009 (Rev-erbα agonist) treatment in WT and STZ diabetic mice Pharmacological research Medium 30639375
2023 PCK1 antagonizes CRC cell growth by inactivating UBAP2L phosphorylation at serine 454, thereby enhancing autophagy flux and suppressing tumor proliferation in vitro and in vivo. Overexpression and knockdown of PCK1, phosphoproteomic identification of UBAP2L pS454, autophagy flux assay (LC3, p62), xenograft models Cancer cell international Low 37062825
2004 The −232C>G promoter SNP of human PCK1 lies within a cis-acting element required for basal and cAMP-mediated transcription. The −232G allele in luciferase reporter assays shows increased basal expression and loss of insulin-mediated downregulation, establishing that this element is required for insulin suppression of PCK1 transcription. Luciferase reporter gene assay in three cell lines with −232C vs −232G constructs, insulin suppression experiments The Journal of clinical endocrinology and metabolism Medium 14764811
2023 PCK1 overexpression in proximal tubules suppresses HK2 upregulation (rate-limiting enzyme of glycolysis), thereby blocking excess glycolysis. PCK1 overexpression preserves mitoribosomal function and prevents tubular fibrosis in diabetic nephropathy; conversely, PCK1 CKO mice develop mitoribosomal defects and renal fibrosis. PT-specific Pck1 TG and CKO mice, STZ diabetic model, Western blot for mitoribosomes and HK2, type IV collagen deposition, albuminuria measurement Journal of the American Society of Nephrology Medium 37199399

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 290 32322062
2017 A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8+ T cells. Nature cell biology 174 29230018
2018 Metabolic reprogramming by PCK1 promotes TCA cataplerosis, oxidative stress and apoptosis in liver cancer cells and suppresses hepatocellular carcinoma. Oncogene 163 29335519
2007 PCK1 and PCK2 as candidate diabetes and obesity genes. Cell biochemistry and biophysics 162 17709878
2023 Deficiency of gluconeogenic enzyme PCK1 promotes metabolic-associated fatty liver disease through PI3K/AKT/PDGF axis activation in male mice. Nature communications 126 36918564
2008 Pck1 gene silencing in the liver improves glycemia control, insulin sensitivity, and dyslipidemia in db/db mice. Diabetes 111 18443203
2021 Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation. The Journal of clinical investigation 101 33690219
2004 Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene. Trends in endocrinology and metabolism: TEM 99 15046742
2018 Circular RNA circC3P1 suppresses hepatocellular carcinoma growth and metastasis through miR-4641/PCK1 pathway. Biochemical and biophysical research communications 91 29608893
2013 PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis. Journal of hepatology 87 23466304
2010 Phosphoenolpyruvate carboxykinase (Pck1) helps regulate the triglyceride/fatty acid cycle and development of insulin resistance in mice. Journal of lipid research 81 20124556
2019 PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis. eLife 80 31841108
1997 Sequence and promoter regulation of the PCK1 gene encoding phosphoenolpyruvate carboxykinase of the fungal pathogen Candida albicans. Gene 80 9224895
2024 A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1. Cell metabolism 72 38718791
2019 PCK1 negatively regulates cell cycle progression and hepatoma cell proliferation via the AMPK/p27Kip1 axis. Journal of experimental & clinical cancer research : CR 69 30717766
2018 Overexpression of PCK1 Gene Antagonizes Hepatocellular Carcinoma Through the Activation of Gluconeogenesis and Suppression of Glycolysis Pathways. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 65 29768256
2014 Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity. Molecular genetics and metabolism 56 24863970
2007 Candidate gene association study of insulin signaling genes and Alzheimer's disease: evidence for SOS2, PCK1, and PPARgamma as susceptibility loci. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 52 17440948
1992 Regulatory regions in the yeast FBP1 and PCK1 genes. FEBS letters 52 1327878
2021 O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis. Oncogene 49 34650217
2023 Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma progression. The Journal of clinical investigation 48 37166978
2016 The oncoprotein HBXIP suppresses gluconeogenesis through modulating PCK1 to enhance the growth of hepatoma cells. Cancer letters 47 27609066
2018 PCK1 Downregulation Promotes TXNRD1 Expression and Hepatoma Cell Growth via the Nrf2/Keap1 Pathway. Frontiers in oncology 45 30619751
2004 Promoter polymorphism in PCK1 (phosphoenolpyruvate carboxykinase gene) associated with type 2 diabetes mellitus. The Journal of clinical endocrinology and metabolism 45 14764811
2023 PCK1 is a key regulator of metabolic and mitochondrial functions in renal tubular cells. American journal of physiology. Renal physiology 42 37102687
1995 Identification and characterization of regulatory elements in the phosphoenolpyruvate carboxykinase gene PCK1 of Saccharomyces cerevisiae. Molecular & general genetics : MGG 41 7854322
2019 Induction of Inflammatory Responses in Human Bronchial Epithelial Cells by Pb2+-Containing Model PM2.5 Particles via Downregulation of a Novel Long Noncoding RNA lnc-PCK1-2:1. Environmental science & technology 38 30913382
2018 Macrophages with a deletion of the phosphoenolpyruvate carboxykinase 1 (Pck1) gene have a more proinflammatory phenotype. The Journal of biological chemistry 38 29317502
2023 PCK1 Protects against Mitoribosomal Defects in Diabetic Nephropathy in Mouse Models. Journal of the American Society of Nephrology : JASN 37 37199399
2011 Insulin-regulated Srebp-1c and Pck1 mRNA expression in primary hepatocytes from zucker fatty but not lean rats is affected by feeding conditions. PloS one 35 21731709
2020 A newly discovered role of metabolic enzyme PCK1 as a protein kinase to promote cancer lipogenesis. Cancer communications (London, England) 34 32809272
2014 Rho1 GTPase and PKC ortholog Pck1 are upstream activators of the cell integrity MAPK pathway in fission yeast. PloS one 33 24498240
2020 PCK1 Regulates Glycolysis and Tumor Progression in Clear Cell Renal Cell Carcinoma Through LDHA. OncoTargets and therapy 32 32280238
2017 Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal pattern of urine metabolites and liver dysfunction. Molecular genetics and metabolism 28 28216384
2013 Androgen inhibits abdominal fat accumulation and negatively regulates the PCK1 gene in male chickens. PloS one 28 23544081
2020 Comparative transcriptome analysis reveals that PCK1 is a potential gene affecting IMF deposition in buffalo. BMC genomics 27 33045988
2018 The key gluconeogenic gene PCK1 is crucial for virulence of Botrytis cinerea via initiating its conidial germination and host penetration. Environmental microbiology 27 29614212
2017 Genistein represses PEPCK-C expression in an insulin-independent manner in HepG2 cells and in alloxan-induced diabetic mice. Journal of cellular biochemistry 27 28816409
2011 Berberine regulated Gck, G6pc, Pck1 and Srebp-1c expression and activated AMP-activated protein kinase in primary rat hepatocytes. International journal of biological sciences 27 21647250
2000 Differences in regulation of yeast gluconeogenesis revealed by Cat8p-independent activation of PCK1 and FBP1 genes in Kluyveromyces lactis. Molecular & general genetics : MGG 27 11016849
2019 Rev-erbα activation down-regulates hepatic Pck1 enzyme to lower plasma glucose in mice. Pharmacological research 26 30639375
2009 The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population. BMC medical genetics 25 19725958
1993 cDNA sequence and localization of polymorphic human cytosolic phosphoenolpyruvate carboxykinase gene (PCK1) to chromosome 20, band q13.31: PCK1 is not tightly linked to maturity-onset diabetes of the young. Human molecular genetics 25 8490617
2011 Retinoids induced Pck1 expression and attenuated insulin-mediated suppression of its expression via activation of retinoic acid receptor in primary rat hepatocytes. Molecular and cellular biochemistry 24 21519922
2007 Liver lipid molecules induce PEPCK-C gene transcription and attenuate insulin action. Biochemical and biophysical research communications 24 17678617
1993 Phosphoenolpyruvate carboxykinase (GTP): characterization of the human PCK1 gene and localization distal to MODY on chromosome 20. Genomics 24 8325643
2022 PCK1 dysregulation in cancer: Metabolic reprogramming, oncogenic activation, and therapeutic opportunities. Genes & diseases 23 37013052
2015 Translocation of forkhead box O1 to the nuclear periphery induces histone modifications that regulate transcriptional repression of PCK1 in HepG2 cells. Genes to cells : devoted to molecular & cellular mechanisms 21 25736587
2023 hnRNPA2B1 promotes the occurrence and progression of hepatocellular carcinoma by downregulating PCK1 mRNA via a m6A RNA methylation manner. Journal of translational medicine 20 38017546
2020 Hepatocellular carcinoma cell-derived extracellular vesicles encapsulated microRNA-584-5p facilitates angiogenesis through PCK1-mediated nuclear factor E2-related factor 2 signaling pathway. The international journal of biochemistry & cell biology 20 32522621
2014 Involvement of KLF11 in hepatic glucose metabolism in mice via suppressing of PEPCK-C expression. PloS one 20 24586865
1996 Indication for genetic linkage of the phosphoenolpyruvate carboxykinase (PCK1) gene region on chromosome 20q to non-insulin-dependent diabetes mellitus. Diabetes & metabolism 20 8985654
2019 Relationships of SLC2A4, RBP4, PCK1, and PI3K Gene Polymorphisms with Gestational Diabetes Mellitus in a Chinese Population. BioMed research international 19 30805369
2016 c.A2456C-substitution in Pck1 changes the enzyme kinetic and functional properties modifying fat distribution in pigs. Scientific reports 19 26792594
2016 Gentiopicroside and sweroside from Veratrilla baillonii Franch. induce phosphorylation of Akt and suppress Pck1 expression in hepatoma cells. Biochemistry and cell biology = Biochimie et biologie cellulaire 19 27248905
2016 Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep. American journal of physiology. Regulatory, integrative and comparative physiology 18 27170658
2016 PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1 del/del mice, unmasking role in non-gluconeogenic tissues. Journal of physiology and biochemistry 18 27785616
2023 m 6 A-mediated gluconeogenic enzyme PCK1 upregulation protects against hepatic ischemia-reperfusion injury. Hepatology (Baltimore, Md.) 17 38085830
2005 Disparate associations of a functional promoter polymorphism in PCK1 with carotid wall ultrasound traits. Stroke 17 16282543
2023 Hepatic retinaldehyde deficiency is involved in diabetes deterioration by enhancing PCK1- and G6PC-mediated gluconeogenesis. Acta pharmaceutica Sinica. B 16 37719384
2010 A putative Alzheimer's disease risk allele in PCK1 influences brain atrophy in multiple sclerosis. PloS one 16 21152065
1993 Human PCK1 encoding phosphoenolpyruvate carboxykinase is located on chromosome 20q13.2. Genomics 16 8432541
2022 Nintedanib Alleviates Experimental Colitis by Inhibiting CEBPB/PCK1 and CEBPB/EFNA1 Pathways. Frontiers in pharmacology 15 35910380
2024 Porcine reproductive and respiratory syndrome virus activates lipid synthesis through a ROS-dependent AKT/PCK1/INSIG/SREBPs axis. International journal of biological macromolecules 13 39433189
1995 Thirteen genes (Cebpb, E2f1, Tcf4, Cyp24, Pck1, Acra4, Edn3, Kcnb1, Mc3r, Ntsr, Cd40, Plcg1 and Rcad) that probably lie in the distal imprinting region of mouse chromosome 2 are not monoallelically expressed. Genetical research 13 7781998
2020 Novel missense variants in PCK1 gene cause cytosolic PEPCK deficiency with growth failure from inadequate caloric intake. Journal of human genetics 12 32908218
1992 The genes coding for phosphoenolpyruvate carboxykinase-1 (PCK1) and neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) map to human chromosome 20, extending the known region of homology with mouse chromosome 2. Annals of human genetics 12 1492743
2024 Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 11 38651689
2023 Role of phosphoenolpyruvate carboxykinase 1 (pck1) in mediating nutrient metabolism in zebrafish. Functional & integrative genomics 11 36840800
2016 PCK1 is negatively regulated by bta-miR-26a, and a single-nucleotide polymorphism in the 3' untranslated region is involved in semen quality and longevity of Holstein bulls. Molecular reproduction and development 11 26725319
2006 Association of the promoter polymorphism -232C/G of the phosphoenolpyruvate carboxykinase gene (PCK1) with Type 2 diabetes mellitus. Diabetic medicine : a journal of the British Diabetic Association 11 16620271
2024 PCK1-mediated glycogenolysis facilitates ROS clearance and chemotherapy resistance in cervical cancer stem cells. Scientific reports 10 38871968
2021 PCK1 regulates neuroendocrine differentiation in a positive feedback loop of LIF/ZBTB46 signalling in castration-resistant prostate cancer. British journal of cancer 10 34815524
2025 Positively Charged Nanoplastics Destruct the Structure of the PCK1 Enzyme, Promote the Aerobic Gycolysis Pathway, and Induce Hepatic Tumor Risks. Environmental science & technology 9 39907589
2023 PCK1 activates oncogenic autophagy via down-regulation Serine phosphorylation of UBAP2L and antagonizes colorectal cancer growth. Cancer cell international 9 37062825
2022 NFYA promotes the anti-tumor effects of gluconeogenesis in hepatocellular carcinoma through the regulation of PCK1 expression. Frontiers in cell and developmental biology 9 36092708
2022 T3 and glucose increase expression of phosphoenolpyruvate carboxykinase (PCK1) leading to increased β-cell proliferation. Molecular metabolism 9 36455788
2019 Transcriptomic changes associated with PCK1 overexpression in hepatocellular carcinoma cells detected by RNA-seq. Genes & diseases 9 32181286
2008 [Glyceroneogenesis and PEPCK-C: pharmacological targets in type 2 diabetes]. Medecine sciences : M/S 9 18405640
2020 PCK1 Deficiency Shortens the Replicative Lifespan of Saccharomyces cerevisiae through Upregulation of PFK1. BioMed research international 8 32104690
2010 Lack of association between PCK1 polymorphisms and obesity, physical activity, and fitness in European Youth Heart Study (EYHS). Obesity (Silver Spring, Md.) 8 20134411
2008 Identification of conserved regulatory elements in mammalian promoter regions: a case study using the PCK1 promoter. Genomics, proteomics & bioinformatics 8 19329064
2006 Large-scale study of the -232C > G polymorphism of PCK1 in Type 2 diabetes. Diabetic medicine : a journal of the British Diabetic Association 8 16978381
2024 SIRT2 Alleviates Inflammatory Response, Apoptosis, and ECM Degradation in Osteoarthritic Chondrocytes by Stabilizing PCK1. Discovery medicine 7 39463224
2024 PCK1 as a target for cancer therapy: from metabolic reprogramming to immune microenvironment remodeling. Cell death discovery 7 39578429
2023 SHP-1 phosphatase acts as a coactivator of PCK1 transcription to control gluconeogenesis. The Journal of biological chemistry 7 37595871
2021 Self-acetylation at the active site of phosphoenolpyruvate carboxykinase (PCK1) controls enzyme activity. The Journal of biological chemistry 7 33334880
2019 Role of PCK1 gene on oil tea-induced glucose homeostasis and type 2 diabetes: an animal experiment and a case-control study. Nutrition & metabolism 7 30805021
2017 PCK1 expression is correlated with the plasma glucose level in the duck. Animal genetics 7 28198082
2015 Phosphoenolpyruvate carboxykinase 1 gene (Pck1) displays parallel evolution between Old World and New World fruit bats. PloS one 7 25807515
2025 PCK1 inhibits cGAS-STING activation by consumption of GTP to promote tumor immune evasion. The Journal of experimental medicine 6 40048154
2008 A Leu184Val polymorphism in PCK1 gene is associated with type 2 diabetes in Eastern Chinese population with BMI<23 kg/m2. Diabetes research and clinical practice 6 19070910
2024 Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation. Cell chemical biology 5 39341205
2023 Emerging roles of cytosolic phosphoenolpyruvate kinase 1 (PCK1) in cancer. Biochemistry and biophysics reports 5 37637941
2021 Identification of promoter response elements that mediate propionate induction of bovine cytosolic phosphoenolpyruvate carboxykinase (PCK1) gene transcription. Journal of dairy science 5 33741163
2021 Chronic AT1 blockade improves hyperglycemia by decreasing adipocyte inflammation and decreasing hepatic PCK1 and G6PC1 expression in obese rats. American journal of physiology. Endocrinology and metabolism 5 34658252
2019 Knockdown of the Sonic Hedgehog (SHH) Gene Inhibits Proliferation of Hep3B and SMMC-7721 Hepatocellular Carcinoma Cells via the PI3K/Akt/PCK1 Signaling Pathway. Medical science monitor : international medical journal of experimental and clinical research 5 31406102
2019 Recognition of the gluconeogenic enzyme, Pck1, via the Gid4 E3 ligase: An in silico perspective. Journal of molecular recognition : JMR 5 31883179
2015 Association of PCK1 with Body Mass Index and Other Metabolic Features in Patients With Psychotropic Treatments. Journal of clinical psychopharmacology 5 26280835
2013 Novel splice variants of the bovine PCK1 gene. Genetics and molecular research : GMR 5 24089092