{"gene":"PCK1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2020,"finding":"AKT phosphorylates PCK1 at Ser90 in hepatocellular carcinoma cells, causing PCK1 to translocate from the cytosol to the endoplasmic reticulum. At the ER, phosphorylated PCK1 acts as a protein kinase using GTP (not ATP) as phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces sterol binding to INSIG1/2, disrupts INSIG-SCAP interaction, and allows SCAP-SREBP to translocate to the Golgi for SREBP activation and downstream lipogenesis gene transcription.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, subcellular fractionation, mass spectrometry, xenograft mouse models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution with mutagenesis, multiple orthogonal methods (Co-IP, fractionation, MS), validated in vivo, published in peer-reviewed journal","pmids":["32322062"],"is_preprint":false},{"year":2021,"finding":"Self-acetylation of PCK1 at the active site using acetyl-CoA as substrate (independently of p300) inhibits enzymatic activity, producing a ~3-fold decrease in kcat without changes in Km. Acetylation of K244 inside the active site renders the enzyme inactive. Acetyl-CoA binding to the active site is specific and metal-dependent.","method":"Protein crystallization, mass spectrometry, isothermal titration calorimetry, saturation-transfer difference NMR, molecular docking, site-directed mutagenesis, in vitro kinetic assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in vitro, structure (crystal), multiple orthogonal biophysical methods, mutagenesis validation in single rigorous study","pmids":["33334880"],"is_preprint":false},{"year":2021,"finding":"PCK1 deficiency causes oxaloacetate accumulation, which increases de novo UTP synthesis contributing to UDP-GlcNAc biosynthesis, and also inactivates the AMPK-GFAT1 axis, together promoting global O-GlcNAcylation. Elevated O-GlcNAcylation results in CHK2 threonine 378 O-GlcNAcylation, which counteracts CHK2 stability and dimer formation, increases CHK2-dependent Rb phosphorylation, and promotes HCC cell proliferation.","method":"PCK1 knockout cells, metabolic flux analysis, Co-immunoprecipitation, O-GlcNAc immunoprecipitation, mass spectrometry, mouse liver-specific Pck1 knockout models, pharmacological inhibition of HBP","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mass spectrometry, genetic KO models, pharmacological rescue, multiple orthogonal approaches","pmids":["33690219"],"is_preprint":false},{"year":2021,"finding":"PCK1 depletion increases O-GlcNAcylation of lysine acetyltransferase KAT5 (TIP60), suppressing KAT5 ubiquitination and thereby stabilizing KAT5. Stabilized O-GlcNAcylated KAT5 epigenetically activates TWIST1 expression via histone H4 acetylation and enhances MMP9 and MMP14 expression via c-Myc acetylation, promoting epithelial-mesenchymal transition and HCC metastasis.","method":"Gain- and loss-of-function experiments, Co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation, hepatospecific Pck1-deletion mouse models, lung metastasis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, genetic KO mouse model, multiple downstream readouts, in vivo validation","pmids":["34650217"],"is_preprint":false},{"year":2023,"finding":"PCK1 fuels S-adenosylmethionine (SAM) generation through the serine synthesis pathway. SAM serves as methyl donor for SUV39H1-catalyzed H3K9me3 modification on the S100A11 oncogene promoter, suppressing S100A11 expression. PCK1 deficiency reduces SAM/H3K9me3, de-represses S100A11, which then interacts with AKT1 to upregulate PI3K/AKT signaling and promote HCC progression.","method":"Metabolomics, Co-immunoprecipitation, chromatin immunoprecipitation, SAM supplementation rescue experiments, S100A11 knockout in vivo, gain- and loss-of-function studies","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (metabolomics, ChIP, Co-IP, genetic rescue), in vivo validation, single lab with rigorous controls","pmids":["37166978"],"is_preprint":false},{"year":2019,"finding":"PCK1 negatively regulates hepatoma cell cycle progression via the AMPK/p27Kip1 axis: PCK1 overexpression reduces cellular ATP, enhances AMPK phosphorylation and p27Kip1 expression, and decreases Rb phosphorylation, causing G1 cell cycle arrest. AMPK knockdown reverses the G1 arrest caused by PCK1 overexpression.","method":"Gain- and loss-of-function experiments, flow cytometry, MTS assay, western blotting, AMPK knockdown epistasis, xenograft mouse models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (AMPK knockdown reversal), clean KO/OE with defined phenotype, single lab with multiple readouts","pmids":["30717766"],"is_preprint":false},{"year":2018,"finding":"Forced PCK1 expression in glucose-starved 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 mutants fail to induce apoptosis. Replenishing TCA intermediate α-ketoglutarate or inhibiting ROS production blocks the cell death caused by PCK1 expression.","method":"Catalytic mutant expression, metabolite supplementation rescue, ROS inhibition rescue, cell death assays, xenograft mouse models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — catalytic mutant mutagenesis establishing mechanism-dependence, metabolite rescue, in vivo validation, single lab with multiple orthogonal approaches","pmids":["29335519"],"is_preprint":false},{"year":2017,"finding":"CD8+ memory T cells upregulate PCK1 to drive gluconeogenesis, producing glycogen. This glycogen is channeled through glycogenolysis to generate glucose-6-phosphate and fuel the pentose phosphate pathway, generating NADPH and maintaining high reduced glutathione levels. Abrogation of the Pck1-glycogen-PPP axis decreases GSH/GSSG ratios, increases ROS, and impairs CD8+ memory T cell formation and maintenance.","method":"Pck1 knockout/knockdown in T cells, metabolic flux analysis, GSH/GSSG measurement, ROS measurement, adoptive transfer experiments, mouse tumor models","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined metabolic and cellular phenotype, metabolic flux tracing, in vivo validation, multiple orthogonal readouts","pmids":["29230018"],"is_preprint":false},{"year":2019,"finding":"PCK1 upregulation in colorectal cancer drives pyrimidine nucleotide biosynthesis under hypoxia, promoting liver metastatic colonization and growth. This function is distinct from its canonical gluconeogenic role and is suppressed by DHODH inhibitor leflunomide.","method":"In vivo PDX selection for metastatic colonization, metabolomics (pyrimidine intermediates), pharmacological inhibition, xenograft models","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo PDX model, metabolomics, pharmacological intervention, single lab","pmids":["31841108"],"is_preprint":false},{"year":2023,"finding":"PCK1 deficiency in the liver activates the RhoA/PI3K/AKT pathway by increasing intracellular GTP levels, increases secretion of PDGF-AA, and promotes hepatic stellate cell activation to drive fibrosis. RhoA and AKT inhibition or gene silencing alleviated MAFLD in vivo.","method":"Liver-specific Pck1 knockout mice, adeno-associated virus PCK1 rescue, RhoA/AKT inhibitors and gene silencing, GTP measurement, PDGF-AA ELISA, in vivo models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse, AAV rescue, pharmacological epistasis (inhibitors + gene silencing), in vivo validation, multiple orthogonal methods","pmids":["36918564"],"is_preprint":false},{"year":2023,"finding":"SHP-1 phosphatase acts as a transcriptional coactivator of PCK1 by being recruited to the PCK1 promoter regulatory regions via interaction with STAT5 and RNA polymerase II. Loss of SHP-1 or STAT5 decreases RNA polymerase II recruitment to the PCK1 promoter, reducing PCK1 mRNA levels and gluconeogenesis.","method":"Co-immunoprecipitation, chromatin immunoprecipitation sequencing (ChIP-seq), gluconeogenesis assays, SHP-1 and STAT5 loss-of-function","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, loss-of-function with functional readout, single lab","pmids":["37595871"],"is_preprint":false},{"year":2025,"finding":"Hypoxic stimulation induces JNK1/2-mediated S151 phosphorylation of PCK1, triggering interaction between PCK1 and cGAS. PCK1 associated with cGAS competitively consumes GTP (a shared substrate), inhibiting GTP-dependent cGAS activation and subsequent STING-mediated immune cell infiltration, thereby promoting tumor immune evasion.","method":"Co-immunoprecipitation, GTP competition assays, phosphorylation site mutagenesis, STING pathway reporters, mouse tumor models, combination with anti-PD-1 therapy, human breast cancer specimens","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, GTP substrate competition, site mutagenesis, in vivo tumor models, human specimen correlation, multiple orthogonal methods","pmids":["40048154"],"is_preprint":false},{"year":2024,"finding":"SR18292 increases PCK1 acetylation at K91, which reverses the gluconeogenic reaction direction of PCK1 to favor OAA synthesis from phosphoenolpyruvate (anaplerotic direction). This PCK1 reverse catalytic reaction supplies OAA to the TCA cycle, increases glucose and lactate oxidation, and suppresses gluconeogenesis. Acetylation-mimetic PCK1 K91Q mutant expressed in mouse liver ameliorates hyperglycemia.","method":"Acetylation mimetic mutant (K91Q), metabolic flux analysis, hepatocyte gluconeogenesis assays, liver-specific K91Q Cre-Lox expression in obese mice, Seahorse metabolic analysis","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — acetylation mimetic mutagenesis (K91Q) with direct functional consequence, metabolic flux analysis, in vivo rescue, single lab with multiple methods","pmids":["39341205"],"is_preprint":false},{"year":2016,"finding":"A single amino acid substitution Met139Leu in pig PCK1 reduces kcat in the glyceroneogenic direction and enhances kcat in the anaplerotic direction, resulting in ~30% lower glucose and ~9% lower lipid production in cell cultures. The p.139L isoform also has compromised ability to be acetylated, increasing its susceptibility to ubiquitin-proteasome degradation.","method":"In vitro kinase/enzyme assays with purified recombinant proteins, cell culture glucose/lipid measurements, acetylation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzyme kinetics with natural variant, cell culture functional assay, acetylation experiment, single lab","pmids":["26792594"],"is_preprint":false},{"year":2015,"finding":"Insulin-induced phosphorylation of FOXO1 at Ser256 (by Akt) causes translocation of FOXO1 from nuclear speckles to the nuclear periphery. This translocation is associated with formation of a FOXO1-EHMT2 complex and histone modifications at the PCK1 promoter region, leading to transcriptional repression of PCK1. FOXO1 uses nucleoporin NUP98 in this regulation.","method":"Live-cell imaging of FOXO1 localization, Co-immunoprecipitation (FOXO1-EHMT2), chromatin immunoprecipitation of PCK1 promoter histone marks, site-directed mutants, luciferase reporter assays","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging, Co-IP, ChIP, multiple methods, single lab","pmids":["25736587"],"is_preprint":false},{"year":2023,"finding":"hnRNPA2B1 (an m6A reader) binds PCK1 mRNA and reduces its m6A methylation, leading to decreased PCK1 mRNA stability and expression. PCK1 knockout partially counteracted tumor inhibition by hnRNPA2B1 knockout, placing PCK1 downstream of hnRNPA2B1-mediated m6A regulation.","method":"RNA binding protein immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), CRISPR-Cas9 KO, RNA-seq, in vivo HCC mouse models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirming direct mRNA binding, MeRIP for m6A status, genetic epistasis in vivo, single lab","pmids":["38017546"],"is_preprint":false},{"year":2023,"finding":"Methyltransferase 3 (METTL3)-mediated N6-methyladenosine (m6A) modification of PCK1 mRNA transcript contributes to PCK1 upregulation during hepatic ischemia-reperfusion injury by increasing PCK1 mRNA export and expression. Hepatic-specific knockout of METTL3 reduces m6A deposition on PCK1 transcript and decreases PCK1 expression, worsening hepatic I/R injury.","method":"Human liver specimens, mouse I/R models, hepatocyte hypoxia/reoxygenation, METTL3 conditional KO, m6A sequencing, PCK1 overexpression rescue","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO of writer enzyme with specific mRNA target validation, m6A sequencing, functional rescue, single lab","pmids":["38085830"],"is_preprint":false},{"year":2024,"finding":"In cervical cancer stem cells, PCK1 enhances phosphorylation of PYGL (glycogen phosphorylase), increasing glycogen breakdown and shifting glucose metabolism towards the pentose phosphate pathway, generating NADPH. This facilitates ROS clearance and contributes to chemoresistance.","method":"siRNA knockdown of PCK1/PYGL/GYS1, glycogen measurement, PPP intermediate quantification by LC-MS, NADPH/NADP+ ratio, NSG mouse tumor growth assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with metabolic flux measurement (LC-MS), functional tumor assay, single lab with multiple readouts","pmids":["38871968"],"is_preprint":false},{"year":2019,"finding":"REV-ERBα (NR1D1) directly binds to a RevRE site at -325 to -320 bp in the PCK1 promoter to transcriptionally repress PCK1 expression, reducing hepatic gluconeogenesis and lowering plasma glucose in mice.","method":"Luciferase reporter assay, electromobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), SR9009 pharmacological activation, streptozotocin diabetic mouse model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA binding (EMSA + ChIP), reporter assay, in vivo validation, single lab","pmids":["30639375"],"is_preprint":false},{"year":2016,"finding":"HBXIP oncoprotein inhibits PCK1 expression by downregulating transcription factor FOXO1 through two mechanisms: upregulating miR-135a targeting the 3'UTR of FOXO1 mRNA, and activating PI3K/Akt to phosphorylate FOXO1 and export it from the nucleus. Overexpression of PCK1 abolished HBXIP-promoted hepatoma cell growth in vitro and in vivo.","method":"miRNA target assays (3'UTR luciferase), western blotting of p-FOXO1, nuclear fractionation, PCK1 overexpression rescue, xenograft models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR luciferase, nuclear fractionation, functional epistasis via PCK1 rescue, single lab","pmids":["27609066"],"is_preprint":false},{"year":2023,"finding":"Kidney-specific PCK1 knockout in mice leads to hyperchloremic metabolic acidosis with reduced ammoniagenesis, glycosuria, lactaturia, altered systemic glucose and lactate metabolism, decreased ATP generation in proximal tubule cells, and increased tubular injury during metabolic acidosis. PCK1 overexpression in proteinuric chronic kidney disease preserves renal function.","method":"Kidney-specific KO and knockin mice (PAX8 promoter), acid-base and metabolic phenotyping, creatinine clearance, metabolomics, ATP measurements","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO and knockin mouse models, multiple physiological readouts, both loss- and gain-of-function, published in peer-reviewed journal","pmids":["37102687"],"is_preprint":false},{"year":2023,"finding":"In proximal tubule-specific Pck1 transgenic mice, PCK1 overexpression preserves mitoribosomal function and suppresses renal fibrosis in diabetic nephropathy. PCK1 overexpression also blocks upregulation of HK2 (the rate-limiting glycolysis enzyme), suppressing excess glycolysis. Proximal tubule-specific Pck1 CKO mice exhibit mitoribosomal defects and tubular apoptosis similar to diabetic mice.","method":"Proximal tubule-specific transgenic and conditional KO mice, STZ-induced diabetic model, mitoribosome integrity assays, fibrosis markers (collagen IV), albuminuria measurements","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO and TG mice with specific molecular readout (mitoribosomes), both loss and gain-of-function, in vivo models","pmids":["37199399"],"is_preprint":false},{"year":2018,"finding":"Myeloid cell-specific Pck1 deletion increases the proinflammatory M1 phenotype in macrophages. In LPS-stimulated bone marrow-derived macrophages, Pck1 deletion reduces 13C labeling of citrate and malate, increases 13C labeling of lactate, increases ROS, and elevates M1 cytokines TNFα, IL-1β, and IL-6.","method":"Myeloid-specific Pck1 knockout mouse, stable isotopomer MS analysis with [U-13C]glucose, cytokine ELISA, ROS measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO mouse, stable isotope metabolic flux tracing (MS), multiple orthogonal readouts, single lab","pmids":["29317502"],"is_preprint":false},{"year":2024,"finding":"Retinoids induce PCK1 expression through retinoic acid receptor (RAR) activation via the proximal (not distal) RA-responsive element in the PCK1 promoter, and attenuate insulin-mediated suppression of PCK1 expression in primary rat hepatocytes. An RARα antagonist abolished retinal-mediated induction of PCK1.","method":"Promoter reporter assays, RAR/RXR selective agonists/antagonists, primary hepatocyte cultures, real-time PCR","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with promoter element deletion, pharmacological receptor specificity, primary hepatocytes, single lab","pmids":["21519922"],"is_preprint":false},{"year":2023,"finding":"PCK1 antagonizes CRC growth via inactivating UBAP2L phosphorylation at serine 454, which enhances autophagy. PCK1 overexpression or knockdown experiments in CRC cells in vitro and in vivo showed that PCK1 inhibits CRC growth through this mechanism.","method":"PCK1 overexpression and knockdown in CRC cells, phosphorylation site analysis, autophagy assays, xenograft mouse models, immunohistochemistry","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with specific phosphorylation site readout, in vivo validation, single lab","pmids":["37062825"],"is_preprint":false},{"year":2013,"finding":"In a liver-specific PEPCK-C (PCK1) knockout mouse, expressing the mitochondrial isoform PEPCK-M partially rescued defects in lipid metabolism, gluconeogenesis, and TCA cycle function, whereas ~10% re-expression of PEPCK-C normalized most parameters. This demonstrates that PEPCK-M has independent gluconeogenic potential and cooperates with PEPCK-C in adjusting gluconeogenic/TCA flux.","method":"NMR tracer studies (2H and 13C) in isolated livers, liver-specific KO mice, adenoviral PEPCK-M expression, primary hepatocyte metabolic profiling","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — isotope tracer/NMR metabolic flux analysis in genetic KO model, partial rescue with both isoforms tested, single lab with rigorous methods","pmids":["23466304"],"is_preprint":false},{"year":2024,"finding":"PCK1 inhibition by 3-MPA in intestinal epithelial cells (IECs) alleviates acute pancreatitis by improving intestinal permeability, reducing epithelial apoptosis, increasing tight junction protein expression, restoring Paneth cell lysozyme and goblet cell MUC2 secretion, and improving intestinal immune response (elevated M2/M1 macrophage ratio, elevated sIgA).","method":"L-arginine-induced AP mouse model, Pck1 inhibitor 3-MPA, intestinal permeability assays (FITC-Dextran, DAO, D-lactate), in vitro LPS-treated enteroids, histopathology","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with specific mechanistic readouts in vivo and in vitro, multiple functional readouts, single lab","pmids":["38651689"],"is_preprint":false},{"year":2010,"finding":"Deletion of the PPARγ binding site (PPARE) in the Pck1 promoter reduces fasting Pck1 mRNA in white and brown adipose tissue, causing profound insulin resistance (measured by hyperinsulinemic-euglycemic clamp) with increased FFA and glycerol release, and a 2-fold increase in insulin secretion. This establishes that Pck1 in adipose tissue is required for normal lipid metabolism and glucose homeostasis via glyceroneogenesis.","method":"PPARE(-/-) mice, hyperinsulinemic-euglycemic clamp, isolated islet insulin secretion assay, gene expression analysis","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model (promoter deletion), gold-standard hyperinsulinemic clamp, functional islet assay, defined molecular mechanism (promoter element for adipose expression)","pmids":["20124556"],"is_preprint":false},{"year":2024,"finding":"T3 (thyroid hormone) and glucose coordinately regulate PCK1 expression in β-cells via ChREBPβ. The thyroid hormone receptor (THR) and ChREBP interact (confirmed by proximity ligation assay and ChIP), and their response elements are co-located on target genes. Overexpression of Pck1 together with a substrate precursor (dimethyl malate) significantly increased β-cell proliferation in human islets, and ChREBPβ contributes to Pck1-dependent β-cell proliferation.","method":"RNA-seq of human islets, ChIP, proximity ligation assay (THR-ChREBP), PCK1 overexpression with substrate, Cre-Lox ChREBPβ deletion, ki67 proliferation staining","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + PLA for physical interaction, genetic Cre-Lox model, functional proliferation readout, single lab with multiple methods","pmids":["36455788"],"is_preprint":false},{"year":2004,"finding":"The -232C→G promoter SNP in PCK1 falls within a cis-acting element required for basal and cAMP-mediated PCK1 gene transcription. A luciferase reporter construct containing -232G showed significantly increased basal expression and no down-regulation by insulin compared to -232C, establishing that this element mediates insulin-dependent repression of PCK1.","method":"Luciferase reporter assay in three cell lines, promoter sequencing, association study","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct reporter assay establishing functional consequence of specific promoter variant, replicated across three cell lines, single lab","pmids":["14764811"],"is_preprint":false},{"year":2016,"finding":"Neonatal re-expression of PCK1 in the liver of whole-body PEPCK-C knockout mice by adenoviral delivery was sufficient to partially rescue hypoglycemia and allow pups to survive, establishing that liver PCK1 is the critical determinant of the lethal hypoglycemic phenotype in whole-body knockouts.","method":"Adenoviral liver-specific PCK1 re-expression in whole-body KO pups, blood glucose measurements, survival analysis","journal":"Journal of physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment in KO mice with defined phenotypic readout, single lab","pmids":["27785616"],"is_preprint":false},{"year":2024,"finding":"SIRT2 prevents PCK1 degradation (via deacetylation, stabilizing the protein) in chondrocytes. PCK1 overexpression inhibits Wnt/β-catenin signaling, reduces inflammatory factor levels, ECM degradation (MMP-13), and apoptosis in IL-1β-treated chondrocytes. SIRT2 overexpression rescued the pro-inflammatory effects of PCK1 silencing, establishing SIRT2 as an upstream stabilizer of PCK1.","method":"Overexpression and knockdown of SIRT2 and PCK1 in chondrocytes, ELISA for cytokines, western blotting for Wnt/β-catenin pathway, apoptosis assays","journal":"Discovery medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/functional assay in cell model only, no direct deacetylation assay shown in abstract, single lab","pmids":["39463224"],"is_preprint":false},{"year":2024,"finding":"PRRSV infection activates AKT, which then activates PCK1. Activated PCK1 phosphorylates INSIG proteins, causing their degradation, which allows SCAP-SREBP translocation from the ER to the nucleus and activation of lipid biosynthesis. ROS produced by PRRSV activates AKT upstream of PCK1.","method":"MARC-145 cell infection, metabolic analysis, AKT/PCK1/INSIG western blotting, SREBPs nuclear translocation assay, ROS measurement","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway validation using infection model, consistent with the established AKT-PCK1-INSIG axis (PMID 32322062), single lab","pmids":["39433189"],"is_preprint":false}],"current_model":"PCK1 (PEPCK-C) is a multifunctional cytosolic enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in gluconeogenesis; it is regulated by AKT-mediated S90 phosphorylation (causing ER translocation and a GTP-dependent protein kinase activity toward INSIG1/2 to activate SREBP-driven lipogenesis), by acetylation at the active site (including self-acetylation using acetyl-CoA at K244/K91 that reverses its catalytic direction), by SIRT2-dependent stabilization, and by transcriptional control through FOXO1-EHMT2, SHP-1/STAT5, REV-ERBα, RAR, and METTL3-m6A mRNA modification; beyond gluconeogenesis, PCK1 supports glyceroneogenesis in adipose tissue, glycogen-PPP-NADPH generation in memory T cells, cataplerosis for TCA cycle maintenance, SAM-H3K9me3 epigenetic regulation, pyrimidine biosynthesis under hypoxia, and immune evasion by competitively consuming GTP to inhibit cGAS-STING activation, while its deficiency drives HCC progression through hyper-O-GlcNAcylation of CHK2 and KAT5, and MAFLD through GTP-dependent RhoA/PI3K/AKT and PDGF-AA paracrine signaling."},"narrative":{"mechanistic_narrative":"PCK1 (PEPCK-C) is a cytosolic enzyme whose canonical conversion between oxaloacetate and phosphoenolpyruvate places it at the control point of gluconeogenesis, glyceroneogenesis, and TCA cataplerosis, but which moonlights as a signaling kinase and metabolic node that shapes cancer, metabolic, and immune phenotypes [PMID:23466304, PMID:29335519, PMID:20124556]. Liver PCK1 is the critical determinant of systemic glucose homeostasis, as neonatal liver-specific re-expression rescues the lethal hypoglycemia of whole-body knockouts, while the mitochondrial isoform PEPCK-M can partially substitute for its gluconeogenic and TCA functions [PMID:27785616, PMID:23466304]. In adipose tissue PPARgamma-driven PCK1 sustains glyceroneogenesis required for normal lipid and glucose homeostasis, and in kidney proximal tubule PCK1 supports ammoniagenesis, ATP production, and mitoribosomal integrity against acidosis and diabetic fibrosis [PMID:20124556, PMID:37102687, PMID:37199399]. Beyond catalysis, AKT phosphorylation at Ser90 relocates PCK1 to the ER where it functions as a GTP-dependent protein kinase that phosphorylates INSIG1/INSIG2, releasing SCAP-SREBP to drive lipogenesis—an axis co-opted in HCC and by viral infection [PMID:32322062, PMID:39433189]. PCK1 activity is gated by acetylation: active-site self-acetylation at K244 using acetyl-CoA inhibits the enzyme, while K91 acetylation reverses its directional preference toward anaplerotic OAA synthesis to suppress gluconeogenesis [PMID:33334880, PMID:39341205]. As a tumor suppressor in liver, PCK1 loss elevates oxaloacetate and GTP to drive global O-GlcNAcylation of CHK2 and KAT5 promoting proliferation and metastasis, reduces SAM-dependent H3K9me3 to de-repress S100A11/AKT signaling, and activates GTP-dependent RhoA/PI3K/AKT and PDGF-AA signaling that promotes hepatic fibrosis [PMID:33690219, PMID:34650217, PMID:37166978, PMID:36918564]. PCK1 also competitively consumes GTP to suppress cGAS-STING upon JNK-mediated Ser151 phosphorylation, enabling tumor immune evasion [PMID:40048154], and supports redox homeostasis by feeding glycogen-derived flux into the pentose phosphate pathway for NADPH generation in memory CD8+ T cells and chemoresistant cancer stem cells [PMID:29230018, PMID:38871968]. Its expression is controlled by an interlocking transcriptional network including FOXO1-EHMT2, SHP-1/STAT5, REV-ERBalpha, RAR, ChREBP, and m6A mRNA modification [PMID:25736587, PMID:37595871, PMID:30639375, PMID:21519922, PMID:36455788, PMID:38085830].","teleology":[{"year":2004,"claim":"Identifying the cis-element where the -232C/G promoter variant lies established a discrete DNA module mediating insulin-dependent repression of PCK1 transcription, explaining how hormonal signals tune gluconeogenic gene output.","evidence":"Luciferase reporter assays across three cell lines with promoter variant constructs","pmids":["14764811"],"confidence":"Medium","gaps":["Does not identify the transcription factor binding the element","Population-level metabolic consequences not directly shown"]},{"year":2010,"claim":"Deleting the adipose PPARE answered whether adipose PCK1 contributes to whole-body metabolism, showing it is required for glyceroneogenesis and glucose homeostasis independent of liver gluconeogenesis.","evidence":"PPARE(-/-) mice with hyperinsulinemic-euglycemic clamp and islet secretion assays","pmids":["20124556"],"confidence":"High","gaps":["Tissue-autonomous versus systemic contributions not fully separated","Molecular link between glyceroneogenesis and insulin resistance not detailed"]},{"year":2013,"claim":"Re-expressing each PEPCK isoform in liver-specific knockout mice resolved the relative gluconeogenic capacity of cytosolic versus mitochondrial PEPCK, showing PEPCK-M has independent gluconeogenic potential and cooperates with PCK1 in flux control.","evidence":"NMR (2H/13C) tracer studies in isolated KO livers with adenoviral isoform expression","pmids":["23466304"],"confidence":"High","gaps":["Quantitative in vivo contribution of PEPCK-M in intact animals unresolved","Regulation distinguishing the two isoforms not addressed"]},{"year":2015,"claim":"Linking insulin-driven FOXO1 Ser256 phosphorylation to FOXO1-EHMT2 complex formation at the PCK1 promoter explained the chromatin mechanism by which insulin represses PCK1 transcription.","evidence":"Live-cell imaging, Co-IP, ChIP of promoter histone marks in cell models","pmids":["25736587"],"confidence":"Medium","gaps":["NUP98 role mechanistically incomplete","In vivo relevance to hepatic gluconeogenesis not tested"]},{"year":2016,"claim":"A natural pig Met139Leu variant demonstrated that single residue changes shift PCK1 between glyceroneogenic and anaplerotic directions and alter its acetylation/degradation, connecting catalytic directionality to protein stability.","evidence":"In vitro kinetics of recombinant variant proteins plus cell culture glucose/lipid and acetylation assays","pmids":["26792594"],"confidence":"Medium","gaps":["Human relevance of the variant not established","Structural basis of directional shift not resolved"]},{"year":2016,"claim":"Neonatal liver-specific re-expression in whole-body KO pups established that hepatic PCK1 is the critical determinant of survival-limiting hypoglycemia, isolating the liver's role from other tissues.","evidence":"Adenoviral liver re-expression in KO pups with glucose and survival readouts","pmids":["27785616"],"confidence":"Medium","gaps":["Partial rescue only; non-hepatic contributions to phenotype remain","Long-term metabolic outcomes not assessed"]},{"year":2016,"claim":"Showing HBXIP suppresses PCK1 via miR-135a and PI3K/Akt-driven FOXO1 export, and that PCK1 overexpression abolishes HBXIP-driven growth, positioned PCK1 as a tumor suppressor downstream of an oncoprotein.","evidence":"3'UTR luciferase, nuclear fractionation, PCK1 rescue in xenografts","pmids":["27609066"],"confidence":"Medium","gaps":["Direct enzymatic mechanism of growth suppression not defined here","Relative weight of the two repression arms unquantified"]},{"year":2017,"claim":"Discovering that memory CD8+ T cells route PCK1-driven gluconeogenesis into glycogen and the PPP redefined PCK1 as a redox-supporting enzyme controlling immune memory rather than purely a glucose-producing one.","evidence":"Pck1 KO/KD in T cells with flux analysis, GSH/GSSG, ROS, and adoptive transfer","pmids":["29230018"],"confidence":"High","gaps":["Upstream signals inducing PCK1 in T cells unclear","Generalizability to other immune subsets untested"]},{"year":2018,"claim":"Forced PCK1 expression in glucose-starved liver cancer cells driving catalysis-dependent TCA cataplerosis and apoptosis demonstrated that PCK1's enzymatic flux itself can be cytotoxic, providing a tumor-suppressive mechanism.","evidence":"Catalytic mutants, alpha-KG and ROS rescue, xenograft models","pmids":["29335519"],"confidence":"High","gaps":["Context dependence on nutrient state not generalized","Does not address chronic low-level expression effects"]},{"year":2018,"claim":"Myeloid Pck1 deletion shifting macrophages toward M1 inflammatory phenotype with altered TCA labeling established a role for PCK1 in immunometabolic polarization.","evidence":"Myeloid-specific KO mouse with [U-13C]glucose flux tracing and cytokine assays","pmids":["29317502"],"confidence":"High","gaps":["Molecular link between flux change and cytokine induction not defined","In vivo disease relevance not addressed"]},{"year":2019,"claim":"Demonstrating PCK1 overexpression triggers AMPK/p27Kip1-mediated G1 arrest, reversible by AMPK knockdown, provided an energy-sensing mechanism for PCK1's anti-proliferative effect in hepatoma.","evidence":"Gain/loss-of-function, flow cytometry, AMPK knockdown epistasis, xenografts","pmids":["30717766"],"confidence":"Medium","gaps":["Whether ATP depletion is catalysis-dependent not fully shown","Relationship to cataplerosis-driven apoptosis unclear"]},{"year":2019,"claim":"Finding PCK1 drives hypoxic pyrimidine biosynthesis to enable colorectal liver metastasis revealed an oncogenic, gluconeogenesis-independent function opposite to its hepatic tumor-suppressor role.","evidence":"PDX metastatic selection, pyrimidine metabolomics, DHODH inhibition","pmids":["31841108"],"confidence":"Medium","gaps":["Direct enzymatic link to pyrimidine pool not mechanistically resolved","Why context determines oncogenic vs suppressive role unexplained"]},{"year":2019,"claim":"Mapping REV-ERBalpha binding to a RevRE in the PCK1 promoter placed gluconeogenesis under direct circadian transcriptional control.","evidence":"Luciferase, EMSA, ChIP, SR9009 activation in diabetic mice","pmids":["30639375"],"confidence":"Medium","gaps":["Integration with other promoter regulators not addressed","Diurnal dynamics in vivo not fully characterized"]},{"year":2020,"claim":"Discovering that AKT-phosphorylated PCK1 translocates to the ER and acts as a GTP-dependent protein kinase on INSIG1/2 to activate SREBP fundamentally reclassified PCK1 as a moonlighting kinase coupling metabolism to lipogenic gene transcription.","evidence":"Co-IP, in vitro kinase reconstitution, mutagenesis, fractionation, MS, xenografts","pmids":["32322062"],"confidence":"High","gaps":["Structural basis of the kinase activity not defined","Balance between cytosolic enzyme and ER kinase pools unquantified"]},{"year":2021,"claim":"Structural and biophysical analysis showed active-site self-acetylation at K244 using acetyl-CoA inhibits PCK1 catalysis independently of p300, establishing a metabolite-driven autoregulatory switch.","evidence":"Crystallography, ITC, STD-NMR, docking, kinetics, mutagenesis","pmids":["33334880"],"confidence":"High","gaps":["In vivo prevalence of self-acetylation not quantified","Deacetylase counteracting K244 not identified here"]},{"year":2021,"claim":"Linking PCK1 loss to oxaloacetate-driven O-GlcNAcylation of CHK2 explained how PCK1 deficiency destabilizes CHK2 and promotes HCC proliferation through hexosamine pathway flux.","evidence":"KO cells, flux analysis, O-GlcNAc IP/MS, liver KO mice, HBP inhibition","pmids":["33690219"],"confidence":"High","gaps":["Site-specific reversibility of CHK2 O-GlcNAcylation in vivo not detailed","Contribution of AMPK-GFAT1 versus UDP-GlcNAc arm not separated"]},{"year":2021,"claim":"Showing PCK1 depletion stabilizes O-GlcNAcylated KAT5 to drive EMT-promoting transcription extended the O-GlcNAcylation mechanism to metastasis.","evidence":"Gain/loss-of-function, Co-IP, ubiquitination, ChIP, Pck1-deletion mice, metastasis assays","pmids":["34650217"],"confidence":"High","gaps":["Whether CHK2 and KAT5 effects are independent or coupled unclear","Therapeutic targeting of the O-GlcNAc node not tested"]},{"year":2023,"claim":"Connecting PCK1 to SAM-dependent H3K9me3 at the S100A11 promoter revealed an epigenetic mechanism by which PCK1 loss de-represses an AKT-activating oncogene.","evidence":"Metabolomics, Co-IP, ChIP, SAM rescue, S100A11 KO in vivo","pmids":["37166978"],"confidence":"High","gaps":["Direct flux from PCK1 to SAM not fully traced","Generality across other H3K9me3 loci unknown"]},{"year":2023,"claim":"Showing PCK1 deficiency raises intracellular GTP to activate RhoA/PI3K/AKT and PDGF-AA secretion driving stellate cell activation defined a mechanism for PCK1 loss in MAFLD fibrosis.","evidence":"Liver-specific KO mice, AAV rescue, RhoA/AKT inhibition and silencing, GTP and PDGF-AA measurements","pmids":["36918564"],"confidence":"High","gaps":["How GTP accumulation specifically activates RhoA not detailed","Reversibility of established fibrosis not tested"]},{"year":2023,"claim":"Identifying SHP-1/STAT5 recruitment of RNA polymerase II to the PCK1 promoter added a transcriptional coactivation route controlling gluconeogenic output.","evidence":"Co-IP, ChIP-seq, loss-of-function with gluconeogenesis readout","pmids":["37595871"],"confidence":"Medium","gaps":["Phosphatase activity versus scaffold role of SHP-1 not separated","Physiological trigger for this axis unclear"]},{"year":2023,"claim":"m6A-reader and writer studies (hnRNPA2B1 destabilizing, METTL3 stabilizing PCK1 mRNA) established post-transcriptional m6A control of PCK1 levels in HCC and ischemia-reperfusion injury.","evidence":"RIP, MeRIP, m6A-seq, CRISPR KO, conditional METTL3 KO, in vivo models","pmids":["38017546","38085830"],"confidence":"Medium","gaps":["Reconciliation of opposing m6A effects on stability versus export incomplete","Site-specific m6A residues on PCK1 transcript not mapped"]},{"year":2023,"claim":"Kidney- and proximal-tubule-specific KO/transgenic models established PCK1 as essential for renal ammoniagenesis, acid-base balance, ATP supply, and mitoribosomal integrity against diabetic injury.","evidence":"Conditional KO and knockin/transgenic mice, metabolic and fibrosis phenotyping","pmids":["37102687","37199399"],"confidence":"High","gaps":["Mechanism linking PCK1 to mitoribosome maintenance unresolved","Whether HK2 suppression is direct or metabolic not defined"]},{"year":2024,"claim":"Demonstrating that K91 acetylation reverses PCK1's directional preference toward anaplerotic OAA synthesis and that the K91Q mimetic ameliorates hyperglycemia established acetylation as a directional switch with therapeutic relevance.","evidence":"K91Q mimetic, flux analysis, hepatocyte assays, liver K91Q expression in obese mice, Seahorse","pmids":["39341205"],"confidence":"High","gaps":["Endogenous regulation of K91 acetylation stoichiometry unclear","Long-term consequences of directional reversal untested"]},{"year":2024,"claim":"Showing PCK1 phosphorylates PYGL to enhance glycogenolysis and PPP-derived NADPH in cervical cancer stem cells extended the redox-support role to chemoresistance.","evidence":"siRNA knockdown, glycogen and PPP LC-MS, NADPH ratio, NSG tumor assays","pmids":["38871968"],"confidence":"Medium","gaps":["Whether PCK1 directly phosphorylates PYGL not biochemically reconstituted","Relationship to ER kinase activity unclear"]},{"year":2024,"claim":"Several studies extended PCK1 regulation and function across tissues: RAR-mediated induction in hepatocytes, ChREBP/THR-coupled control driving beta-cell proliferation, UBAP2L dephosphorylation-driven autophagy suppressing CRC, intestinal epithelial effects in pancreatitis, and SIRT2-dependent stabilization in chondrocytes.","evidence":"Reporter/PLA/ChIP, Cre-Lox models, phospho-site analysis, pharmacological inhibition, and cell models","pmids":["21519922","36455788","37062825","38651689","39463224"],"confidence":"Medium","gaps":["Several of these mechanisms rest on single-lab cell models","Direct enzymatic versus signaling contributions often not separated"]},{"year":2025,"claim":"Discovering that JNK-driven Ser151 phosphorylation lets PCK1 bind cGAS and competitively consume shared GTP to suppress cGAS-STING signaling defined a metabolite-competition mechanism for tumor immune evasion.","evidence":"Co-IP, GTP competition assays, site mutagenesis, STING reporters, tumor models with anti-PD-1, human specimens","pmids":["40048154"],"confidence":"High","gaps":["Whether catalytic activity is required for GTP sequestration not fully separated","Relationship of Ser151 to other phospho-sites (Ser90) unresolved"]},{"year":null,"claim":"How the multiple post-translational switches (Ser90/Ser151 phosphorylation, K91/K244 acetylation, SIRT2 stabilization) are integrated to partition PCK1 between cytosolic gluconeogenic enzyme, ER/cGAS-bound GTP-consuming protein, and directional anaplerotic states in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified structural or quantitative model of how modifications compete or cooperate","Tissue- and context-specific determinants of oncogenic versus tumor-suppressor behavior undefined","Stoichiometry of the moonlighting kinase pool versus catalytic pool in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[25,6,1,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,32,11]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,32]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[25,27,6,7,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,4,9,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,22,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,10,18,23,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,9,11,32]}],"complexes":[],"partners":["INSIG1","INSIG2","CGAS","CHK2","KAT5","PYGL","UBAP2L","SIRT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35558","full_name":"Phosphoenolpyruvate carboxykinase, cytosolic [GTP]","aliases":["Serine-protein kinase PCK1"],"length_aa":622,"mass_kda":69.2,"function":"Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis (PubMed:24863970, PubMed:26971250, PubMed:28216384, PubMed:30193097). Regulates cataplerosis and anaplerosis, the processes that control the levels of metabolic intermediates in the citric acid cycle (PubMed:24863970, PubMed:26971250, PubMed:28216384, PubMed:30193097). At low glucose levels, it catalyzes the cataplerotic conversion of oxaloacetate to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle (PubMed:30193097). At high glucose levels, it catalyzes the anaplerotic conversion of phosphoenolpyruvate to oxaloacetate (PubMed:30193097). Acts as a regulator of formation and maintenance of memory CD8(+) T-cells: up-regulated in these cells, where it generates phosphoenolpyruvate, via gluconeogenesis (By similarity). The resultant phosphoenolpyruvate flows to glycogen and pentose phosphate pathway, which is essential for memory CD8(+) T-cells homeostasis (By similarity). In addition to the phosphoenolpyruvate carboxykinase activity, also acts as a protein kinase when phosphorylated at Ser-90: phosphorylation at Ser-90 by AKT1 reduces the binding affinity to oxaloacetate and promotes an atypical serine protein kinase activity using GTP as donor (PubMed:32322062). The protein kinase activity regulates lipogenesis: upon phosphorylation at Ser-90, translocates to the endoplasmic reticulum and catalyzes phosphorylation of INSIG proteins (INSIG1 and INSIG2), thereby disrupting the interaction between INSIG proteins and SCAP and promoting nuclear translocation of SREBP proteins (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-related genes (PubMed:32322062)","subcellular_location":"Cytoplasm, cytosol; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/P35558/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PCK1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PCK1","total_profiled":1310},"omim":[{"mim_id":"618964","title":"REQUIRED FOR MEIOTIC NUCLEAR DIVISION 5 HOMOLOG A; RMND5A","url":"https://www.omim.org/entry/618964"},{"mim_id":"617758","title":"ZINC FINGER PROTEIN 692; ZNF692","url":"https://www.omim.org/entry/617758"},{"mim_id":"617699","title":"GID COMPLEX, SUBUNIT 4; GID4","url":"https://www.omim.org/entry/617699"},{"mim_id":"614168","title":"PHOSPHOENOLPYRUVATE CARBOXYKINASE 1, SOLUBLE; PCK1","url":"https://www.omim.org/entry/614168"},{"mim_id":"614095","title":"PHOSPHOENOLPYRUVATE CARBOXYKINASE 2, MITOCHONDRIAL; PCK2","url":"https://www.omim.org/entry/614095"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":403.6},{"tissue":"liver","ntpm":643.7}],"url":"https://www.proteinatlas.org/search/PCK1"},"hgnc":{"alias_symbol":["PEPCK-C"],"prev_symbol":[]},"alphafold":{"accession":"P35558","domains":[{"cath_id":"3.40.449.10","chopping":"12-65_92-247","consensus_level":"high","plddt":97.5506,"start":12,"end":247},{"cath_id":"3.90.228.20","chopping":"262-331_418-622","consensus_level":"high","plddt":97.0031,"start":262,"end":622},{"cath_id":"2.170.8.10","chopping":"334-413","consensus_level":"medium","plddt":96.8014,"start":334,"end":413}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35558","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35558-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35558-F1-predicted_aligned_error_v6.png","plddt_mean":96.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PCK1","jax_strain_url":"https://www.jax.org/strain/search?query=PCK1"},"sequence":{"accession":"P35558","fasta_url":"https://rest.uniprot.org/uniprotkb/P35558.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35558/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35558"}},"corpus_meta":[{"pmid":"32322062","id":"PMC_32322062","title":"The 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Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17440948","citation_count":52,"is_preprint":false},{"pmid":"37166978","id":"PMC_37166978","title":"Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma progression.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37166978","citation_count":51,"is_preprint":false},{"pmid":"34650217","id":"PMC_34650217","title":"O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34650217","citation_count":51,"is_preprint":false},{"pmid":"27609066","id":"PMC_27609066","title":"The oncoprotein HBXIP suppresses gluconeogenesis through modulating PCK1 to enhance the growth of hepatoma cells.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27609066","citation_count":47,"is_preprint":false},{"pmid":"30619751","id":"PMC_30619751","title":"PCK1 Downregulation Promotes TXNRD1 Expression and Hepatoma Cell Growth via the Nrf2/Keap1 Pathway.","date":"2018","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30619751","citation_count":46,"is_preprint":false},{"pmid":"14764811","id":"PMC_14764811","title":"Promoter polymorphism in PCK1 (phosphoenolpyruvate carboxykinase gene) associated with type 2 diabetes mellitus.","date":"2004","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/14764811","citation_count":45,"is_preprint":false},{"pmid":"37102687","id":"PMC_37102687","title":"PCK1 is a key regulator of metabolic and mitochondrial functions in renal tubular cells.","date":"2023","source":"American journal of physiology. 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At the ER, phosphorylated PCK1 acts as a protein kinase using GTP (not ATP) as phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces sterol binding to INSIG1/2, disrupts INSIG-SCAP interaction, and allows SCAP-SREBP to translocate to the Golgi for SREBP activation and downstream lipogenesis gene transcription.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, subcellular fractionation, mass spectrometry, xenograft mouse models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution with mutagenesis, multiple orthogonal methods (Co-IP, fractionation, MS), validated in vivo, published in peer-reviewed journal\",\n      \"pmids\": [\"32322062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Self-acetylation of PCK1 at the active site using acetyl-CoA as substrate (independently of p300) inhibits enzymatic activity, producing a ~3-fold decrease in kcat without changes in Km. Acetylation of K244 inside the active site renders the enzyme inactive. Acetyl-CoA binding to the active site is specific and metal-dependent.\",\n      \"method\": \"Protein crystallization, mass spectrometry, isothermal titration calorimetry, saturation-transfer difference NMR, molecular docking, site-directed mutagenesis, in vitro kinetic assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in vitro, structure (crystal), multiple orthogonal biophysical methods, mutagenesis validation in single rigorous study\",\n      \"pmids\": [\"33334880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PCK1 deficiency causes oxaloacetate accumulation, which increases de novo UTP synthesis contributing to UDP-GlcNAc biosynthesis, and also inactivates the AMPK-GFAT1 axis, together promoting global O-GlcNAcylation. Elevated O-GlcNAcylation results in CHK2 threonine 378 O-GlcNAcylation, which counteracts CHK2 stability and dimer formation, increases CHK2-dependent Rb phosphorylation, and promotes HCC cell proliferation.\",\n      \"method\": \"PCK1 knockout cells, metabolic flux analysis, Co-immunoprecipitation, O-GlcNAc immunoprecipitation, mass spectrometry, mouse liver-specific Pck1 knockout models, pharmacological inhibition of HBP\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mass spectrometry, genetic KO models, pharmacological rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"33690219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PCK1 depletion increases O-GlcNAcylation of lysine acetyltransferase KAT5 (TIP60), suppressing KAT5 ubiquitination and thereby stabilizing KAT5. Stabilized O-GlcNAcylated KAT5 epigenetically activates TWIST1 expression via histone H4 acetylation and enhances MMP9 and MMP14 expression via c-Myc acetylation, promoting epithelial-mesenchymal transition and HCC metastasis.\",\n      \"method\": \"Gain- and loss-of-function experiments, Co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation, hepatospecific Pck1-deletion mouse models, lung metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, genetic KO mouse model, multiple downstream readouts, in vivo validation\",\n      \"pmids\": [\"34650217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCK1 fuels S-adenosylmethionine (SAM) generation through the serine synthesis pathway. SAM serves as methyl donor for SUV39H1-catalyzed H3K9me3 modification on the S100A11 oncogene promoter, suppressing S100A11 expression. PCK1 deficiency reduces SAM/H3K9me3, de-represses S100A11, which then interacts with AKT1 to upregulate PI3K/AKT signaling and promote HCC progression.\",\n      \"method\": \"Metabolomics, Co-immunoprecipitation, chromatin immunoprecipitation, SAM supplementation rescue experiments, S100A11 knockout in vivo, gain- and loss-of-function studies\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (metabolomics, ChIP, Co-IP, genetic rescue), in vivo validation, single lab with rigorous controls\",\n      \"pmids\": [\"37166978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PCK1 negatively regulates hepatoma cell cycle progression via the AMPK/p27Kip1 axis: PCK1 overexpression reduces cellular ATP, enhances AMPK phosphorylation and p27Kip1 expression, and decreases Rb phosphorylation, causing G1 cell cycle arrest. AMPK knockdown reverses the G1 arrest caused by PCK1 overexpression.\",\n      \"method\": \"Gain- and loss-of-function experiments, flow cytometry, MTS assay, western blotting, AMPK knockdown epistasis, xenograft mouse models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (AMPK knockdown reversal), clean KO/OE with defined phenotype, single lab with multiple readouts\",\n      \"pmids\": [\"30717766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Forced PCK1 expression in glucose-starved 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 mutants fail to induce apoptosis. Replenishing TCA intermediate α-ketoglutarate or inhibiting ROS production blocks the cell death caused by PCK1 expression.\",\n      \"method\": \"Catalytic mutant expression, metabolite supplementation rescue, ROS inhibition rescue, cell death assays, xenograft mouse models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — catalytic mutant mutagenesis establishing mechanism-dependence, metabolite rescue, in vivo validation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"29335519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD8+ memory T cells upregulate PCK1 to drive gluconeogenesis, producing glycogen. This glycogen is channeled through glycogenolysis to generate glucose-6-phosphate and fuel the pentose phosphate pathway, generating NADPH and maintaining high reduced glutathione levels. Abrogation of the Pck1-glycogen-PPP axis decreases GSH/GSSG ratios, increases ROS, and impairs CD8+ memory T cell formation and maintenance.\",\n      \"method\": \"Pck1 knockout/knockdown in T cells, metabolic flux analysis, GSH/GSSG measurement, ROS measurement, adoptive transfer experiments, mouse tumor models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined metabolic and cellular phenotype, metabolic flux tracing, in vivo validation, multiple orthogonal readouts\",\n      \"pmids\": [\"29230018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PCK1 upregulation in colorectal cancer drives pyrimidine nucleotide biosynthesis under hypoxia, promoting liver metastatic colonization and growth. This function is distinct from its canonical gluconeogenic role and is suppressed by DHODH inhibitor leflunomide.\",\n      \"method\": \"In vivo PDX selection for metastatic colonization, metabolomics (pyrimidine intermediates), pharmacological inhibition, xenograft models\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo PDX model, metabolomics, pharmacological intervention, single lab\",\n      \"pmids\": [\"31841108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCK1 deficiency in the liver activates the RhoA/PI3K/AKT pathway by increasing intracellular GTP levels, increases secretion of PDGF-AA, and promotes hepatic stellate cell activation to drive fibrosis. RhoA and AKT inhibition or gene silencing alleviated MAFLD in vivo.\",\n      \"method\": \"Liver-specific Pck1 knockout mice, adeno-associated virus PCK1 rescue, RhoA/AKT inhibitors and gene silencing, GTP measurement, PDGF-AA ELISA, in vivo models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse, AAV rescue, pharmacological epistasis (inhibitors + gene silencing), in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"36918564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SHP-1 phosphatase acts as a transcriptional coactivator of PCK1 by being recruited to the PCK1 promoter regulatory regions via interaction with STAT5 and RNA polymerase II. Loss of SHP-1 or STAT5 decreases RNA polymerase II recruitment to the PCK1 promoter, reducing PCK1 mRNA levels and gluconeogenesis.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation sequencing (ChIP-seq), gluconeogenesis assays, SHP-1 and STAT5 loss-of-function\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, loss-of-function with functional readout, single lab\",\n      \"pmids\": [\"37595871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hypoxic stimulation induces JNK1/2-mediated S151 phosphorylation of PCK1, triggering interaction between PCK1 and cGAS. PCK1 associated with cGAS competitively consumes GTP (a shared substrate), inhibiting GTP-dependent cGAS activation and subsequent STING-mediated immune cell infiltration, thereby promoting tumor immune evasion.\",\n      \"method\": \"Co-immunoprecipitation, GTP competition assays, phosphorylation site mutagenesis, STING pathway reporters, mouse tumor models, combination with anti-PD-1 therapy, human breast cancer specimens\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, GTP substrate competition, site mutagenesis, in vivo tumor models, human specimen correlation, multiple orthogonal methods\",\n      \"pmids\": [\"40048154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SR18292 increases PCK1 acetylation at K91, which reverses the gluconeogenic reaction direction of PCK1 to favor OAA synthesis from phosphoenolpyruvate (anaplerotic direction). This PCK1 reverse catalytic reaction supplies OAA to the TCA cycle, increases glucose and lactate oxidation, and suppresses gluconeogenesis. Acetylation-mimetic PCK1 K91Q mutant expressed in mouse liver ameliorates hyperglycemia.\",\n      \"method\": \"Acetylation mimetic mutant (K91Q), metabolic flux analysis, hepatocyte gluconeogenesis assays, liver-specific K91Q Cre-Lox expression in obese mice, Seahorse metabolic analysis\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — acetylation mimetic mutagenesis (K91Q) with direct functional consequence, metabolic flux analysis, in vivo rescue, single lab with multiple methods\",\n      \"pmids\": [\"39341205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A single amino acid substitution Met139Leu in pig PCK1 reduces kcat in the glyceroneogenic direction and enhances kcat in the anaplerotic direction, resulting in ~30% lower glucose and ~9% lower lipid production in cell cultures. The p.139L isoform also has compromised ability to be acetylated, increasing its susceptibility to ubiquitin-proteasome degradation.\",\n      \"method\": \"In vitro kinase/enzyme assays with purified recombinant proteins, cell culture glucose/lipid measurements, acetylation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzyme kinetics with natural variant, cell culture functional assay, acetylation experiment, single lab\",\n      \"pmids\": [\"26792594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Insulin-induced phosphorylation of FOXO1 at Ser256 (by Akt) causes translocation of FOXO1 from nuclear speckles to the nuclear periphery. This translocation is associated with formation of a FOXO1-EHMT2 complex and histone modifications at the PCK1 promoter region, leading to transcriptional repression of PCK1. FOXO1 uses nucleoporin NUP98 in this regulation.\",\n      \"method\": \"Live-cell imaging of FOXO1 localization, Co-immunoprecipitation (FOXO1-EHMT2), chromatin immunoprecipitation of PCK1 promoter histone marks, site-directed mutants, luciferase reporter assays\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging, Co-IP, ChIP, multiple methods, single lab\",\n      \"pmids\": [\"25736587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"hnRNPA2B1 (an m6A reader) binds PCK1 mRNA and reduces its m6A methylation, leading to decreased PCK1 mRNA stability and expression. PCK1 knockout partially counteracted tumor inhibition by hnRNPA2B1 knockout, placing PCK1 downstream of hnRNPA2B1-mediated m6A regulation.\",\n      \"method\": \"RNA binding protein immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), CRISPR-Cas9 KO, RNA-seq, in vivo HCC mouse models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirming direct mRNA binding, MeRIP for m6A status, genetic epistasis in vivo, single lab\",\n      \"pmids\": [\"38017546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Methyltransferase 3 (METTL3)-mediated N6-methyladenosine (m6A) modification of PCK1 mRNA transcript contributes to PCK1 upregulation during hepatic ischemia-reperfusion injury by increasing PCK1 mRNA export and expression. Hepatic-specific knockout of METTL3 reduces m6A deposition on PCK1 transcript and decreases PCK1 expression, worsening hepatic I/R injury.\",\n      \"method\": \"Human liver specimens, mouse I/R models, hepatocyte hypoxia/reoxygenation, METTL3 conditional KO, m6A sequencing, PCK1 overexpression rescue\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO of writer enzyme with specific mRNA target validation, m6A sequencing, functional rescue, single lab\",\n      \"pmids\": [\"38085830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In cervical cancer stem cells, PCK1 enhances phosphorylation of PYGL (glycogen phosphorylase), increasing glycogen breakdown and shifting glucose metabolism towards the pentose phosphate pathway, generating NADPH. This facilitates ROS clearance and contributes to chemoresistance.\",\n      \"method\": \"siRNA knockdown of PCK1/PYGL/GYS1, glycogen measurement, PPP intermediate quantification by LC-MS, NADPH/NADP+ ratio, NSG mouse tumor growth assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with metabolic flux measurement (LC-MS), functional tumor assay, single lab with multiple readouts\",\n      \"pmids\": [\"38871968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"REV-ERBα (NR1D1) directly binds to a RevRE site at -325 to -320 bp in the PCK1 promoter to transcriptionally repress PCK1 expression, reducing hepatic gluconeogenesis and lowering plasma glucose in mice.\",\n      \"method\": \"Luciferase reporter assay, electromobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), SR9009 pharmacological activation, streptozotocin diabetic mouse model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA binding (EMSA + ChIP), reporter assay, in vivo validation, single lab\",\n      \"pmids\": [\"30639375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HBXIP oncoprotein inhibits PCK1 expression by downregulating transcription factor FOXO1 through two mechanisms: upregulating miR-135a targeting the 3'UTR of FOXO1 mRNA, and activating PI3K/Akt to phosphorylate FOXO1 and export it from the nucleus. Overexpression of PCK1 abolished HBXIP-promoted hepatoma cell growth in vitro and in vivo.\",\n      \"method\": \"miRNA target assays (3'UTR luciferase), western blotting of p-FOXO1, nuclear fractionation, PCK1 overexpression rescue, xenograft models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR luciferase, nuclear fractionation, functional epistasis via PCK1 rescue, single lab\",\n      \"pmids\": [\"27609066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Kidney-specific PCK1 knockout in mice leads to hyperchloremic metabolic acidosis with reduced ammoniagenesis, glycosuria, lactaturia, altered systemic glucose and lactate metabolism, decreased ATP generation in proximal tubule cells, and increased tubular injury during metabolic acidosis. PCK1 overexpression in proteinuric chronic kidney disease preserves renal function.\",\n      \"method\": \"Kidney-specific KO and knockin mice (PAX8 promoter), acid-base and metabolic phenotyping, creatinine clearance, metabolomics, ATP measurements\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO and knockin mouse models, multiple physiological readouts, both loss- and gain-of-function, published in peer-reviewed journal\",\n      \"pmids\": [\"37102687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In proximal tubule-specific Pck1 transgenic mice, PCK1 overexpression preserves mitoribosomal function and suppresses renal fibrosis in diabetic nephropathy. PCK1 overexpression also blocks upregulation of HK2 (the rate-limiting glycolysis enzyme), suppressing excess glycolysis. Proximal tubule-specific Pck1 CKO mice exhibit mitoribosomal defects and tubular apoptosis similar to diabetic mice.\",\n      \"method\": \"Proximal tubule-specific transgenic and conditional KO mice, STZ-induced diabetic model, mitoribosome integrity assays, fibrosis markers (collagen IV), albuminuria measurements\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO and TG mice with specific molecular readout (mitoribosomes), both loss and gain-of-function, in vivo models\",\n      \"pmids\": [\"37199399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Myeloid cell-specific Pck1 deletion increases the proinflammatory M1 phenotype in macrophages. In LPS-stimulated bone marrow-derived macrophages, Pck1 deletion reduces 13C labeling of citrate and malate, increases 13C labeling of lactate, increases ROS, and elevates M1 cytokines TNFα, IL-1β, and IL-6.\",\n      \"method\": \"Myeloid-specific Pck1 knockout mouse, stable isotopomer MS analysis with [U-13C]glucose, cytokine ELISA, ROS measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO mouse, stable isotope metabolic flux tracing (MS), multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"29317502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Retinoids induce PCK1 expression through retinoic acid receptor (RAR) activation via the proximal (not distal) RA-responsive element in the PCK1 promoter, and attenuate insulin-mediated suppression of PCK1 expression in primary rat hepatocytes. An RARα antagonist abolished retinal-mediated induction of PCK1.\",\n      \"method\": \"Promoter reporter assays, RAR/RXR selective agonists/antagonists, primary hepatocyte cultures, real-time PCR\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with promoter element deletion, pharmacological receptor specificity, primary hepatocytes, single lab\",\n      \"pmids\": [\"21519922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCK1 antagonizes CRC growth via inactivating UBAP2L phosphorylation at serine 454, which enhances autophagy. PCK1 overexpression or knockdown experiments in CRC cells in vitro and in vivo showed that PCK1 inhibits CRC growth through this mechanism.\",\n      \"method\": \"PCK1 overexpression and knockdown in CRC cells, phosphorylation site analysis, autophagy assays, xenograft mouse models, immunohistochemistry\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with specific phosphorylation site readout, in vivo validation, single lab\",\n      \"pmids\": [\"37062825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In a liver-specific PEPCK-C (PCK1) knockout mouse, expressing the mitochondrial isoform PEPCK-M partially rescued defects in lipid metabolism, gluconeogenesis, and TCA cycle function, whereas ~10% re-expression of PEPCK-C normalized most parameters. This demonstrates that PEPCK-M has independent gluconeogenic potential and cooperates with PEPCK-C in adjusting gluconeogenic/TCA flux.\",\n      \"method\": \"NMR tracer studies (2H and 13C) in isolated livers, liver-specific KO mice, adenoviral PEPCK-M expression, primary hepatocyte metabolic profiling\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — isotope tracer/NMR metabolic flux analysis in genetic KO model, partial rescue with both isoforms tested, single lab with rigorous methods\",\n      \"pmids\": [\"23466304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PCK1 inhibition by 3-MPA in intestinal epithelial cells (IECs) alleviates acute pancreatitis by improving intestinal permeability, reducing epithelial apoptosis, increasing tight junction protein expression, restoring Paneth cell lysozyme and goblet cell MUC2 secretion, and improving intestinal immune response (elevated M2/M1 macrophage ratio, elevated sIgA).\",\n      \"method\": \"L-arginine-induced AP mouse model, Pck1 inhibitor 3-MPA, intestinal permeability assays (FITC-Dextran, DAO, D-lactate), in vitro LPS-treated enteroids, histopathology\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with specific mechanistic readouts in vivo and in vitro, multiple functional readouts, single lab\",\n      \"pmids\": [\"38651689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Deletion of the PPARγ binding site (PPARE) in the Pck1 promoter reduces fasting Pck1 mRNA in white and brown adipose tissue, causing profound insulin resistance (measured by hyperinsulinemic-euglycemic clamp) with increased FFA and glycerol release, and a 2-fold increase in insulin secretion. This establishes that Pck1 in adipose tissue is required for normal lipid metabolism and glucose homeostasis via glyceroneogenesis.\",\n      \"method\": \"PPARE(-/-) mice, hyperinsulinemic-euglycemic clamp, isolated islet insulin secretion assay, gene expression analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model (promoter deletion), gold-standard hyperinsulinemic clamp, functional islet assay, defined molecular mechanism (promoter element for adipose expression)\",\n      \"pmids\": [\"20124556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"T3 (thyroid hormone) and glucose coordinately regulate PCK1 expression in β-cells via ChREBPβ. The thyroid hormone receptor (THR) and ChREBP interact (confirmed by proximity ligation assay and ChIP), and their response elements are co-located on target genes. Overexpression of Pck1 together with a substrate precursor (dimethyl malate) significantly increased β-cell proliferation in human islets, and ChREBPβ contributes to Pck1-dependent β-cell proliferation.\",\n      \"method\": \"RNA-seq of human islets, ChIP, proximity ligation assay (THR-ChREBP), PCK1 overexpression with substrate, Cre-Lox ChREBPβ deletion, ki67 proliferation staining\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + PLA for physical interaction, genetic Cre-Lox model, functional proliferation readout, single lab with multiple methods\",\n      \"pmids\": [\"36455788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The -232C→G promoter SNP in PCK1 falls within a cis-acting element required for basal and cAMP-mediated PCK1 gene transcription. A luciferase reporter construct containing -232G showed significantly increased basal expression and no down-regulation by insulin compared to -232C, establishing that this element mediates insulin-dependent repression of PCK1.\",\n      \"method\": \"Luciferase reporter assay in three cell lines, promoter sequencing, association study\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct reporter assay establishing functional consequence of specific promoter variant, replicated across three cell lines, single lab\",\n      \"pmids\": [\"14764811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Neonatal re-expression of PCK1 in the liver of whole-body PEPCK-C knockout mice by adenoviral delivery was sufficient to partially rescue hypoglycemia and allow pups to survive, establishing that liver PCK1 is the critical determinant of the lethal hypoglycemic phenotype in whole-body knockouts.\",\n      \"method\": \"Adenoviral liver-specific PCK1 re-expression in whole-body KO pups, blood glucose measurements, survival analysis\",\n      \"journal\": \"Journal of physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment in KO mice with defined phenotypic readout, single lab\",\n      \"pmids\": [\"27785616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT2 prevents PCK1 degradation (via deacetylation, stabilizing the protein) in chondrocytes. PCK1 overexpression inhibits Wnt/β-catenin signaling, reduces inflammatory factor levels, ECM degradation (MMP-13), and apoptosis in IL-1β-treated chondrocytes. SIRT2 overexpression rescued the pro-inflammatory effects of PCK1 silencing, establishing SIRT2 as an upstream stabilizer of PCK1.\",\n      \"method\": \"Overexpression and knockdown of SIRT2 and PCK1 in chondrocytes, ELISA for cytokines, western blotting for Wnt/β-catenin pathway, apoptosis assays\",\n      \"journal\": \"Discovery medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/functional assay in cell model only, no direct deacetylation assay shown in abstract, single lab\",\n      \"pmids\": [\"39463224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRRSV infection activates AKT, which then activates PCK1. Activated PCK1 phosphorylates INSIG proteins, causing their degradation, which allows SCAP-SREBP translocation from the ER to the nucleus and activation of lipid biosynthesis. ROS produced by PRRSV activates AKT upstream of PCK1.\",\n      \"method\": \"MARC-145 cell infection, metabolic analysis, AKT/PCK1/INSIG western blotting, SREBPs nuclear translocation assay, ROS measurement\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway validation using infection model, consistent with the established AKT-PCK1-INSIG axis (PMID 32322062), single lab\",\n      \"pmids\": [\"39433189\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PCK1 (PEPCK-C) is a multifunctional cytosolic enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in gluconeogenesis; it is regulated by AKT-mediated S90 phosphorylation (causing ER translocation and a GTP-dependent protein kinase activity toward INSIG1/2 to activate SREBP-driven lipogenesis), by acetylation at the active site (including self-acetylation using acetyl-CoA at K244/K91 that reverses its catalytic direction), by SIRT2-dependent stabilization, and by transcriptional control through FOXO1-EHMT2, SHP-1/STAT5, REV-ERBα, RAR, and METTL3-m6A mRNA modification; beyond gluconeogenesis, PCK1 supports glyceroneogenesis in adipose tissue, glycogen-PPP-NADPH generation in memory T cells, cataplerosis for TCA cycle maintenance, SAM-H3K9me3 epigenetic regulation, pyrimidine biosynthesis under hypoxia, and immune evasion by competitively consuming GTP to inhibit cGAS-STING activation, while its deficiency drives HCC progression through hyper-O-GlcNAcylation of CHK2 and KAT5, and MAFLD through GTP-dependent RhoA/PI3K/AKT and PDGF-AA paracrine signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PCK1 (PEPCK-C) is a cytosolic enzyme whose canonical conversion between oxaloacetate and phosphoenolpyruvate places it at the control point of gluconeogenesis, glyceroneogenesis, and TCA cataplerosis, but which moonlights as a signaling kinase and metabolic node that shapes cancer, metabolic, and immune phenotypes [#25, #6, #27]. Liver PCK1 is the critical determinant of systemic glucose homeostasis, as neonatal liver-specific re-expression rescues the lethal hypoglycemia of whole-body knockouts, while the mitochondrial isoform PEPCK-M can partially substitute for its gluconeogenic and TCA functions [#30, #25]. In adipose tissue PPARgamma-driven PCK1 sustains glyceroneogenesis required for normal lipid and glucose homeostasis, and in kidney proximal tubule PCK1 supports ammoniagenesis, ATP production, and mitoribosomal integrity against acidosis and diabetic fibrosis [#27, #20, #21]. Beyond catalysis, AKT phosphorylation at Ser90 relocates PCK1 to the ER where it functions as a GTP-dependent protein kinase that phosphorylates INSIG1/INSIG2, releasing SCAP-SREBP to drive lipogenesis—an axis co-opted in HCC and by viral infection [#0, #32]. PCK1 activity is gated by acetylation: active-site self-acetylation at K244 using acetyl-CoA inhibits the enzyme, while K91 acetylation reverses its directional preference toward anaplerotic OAA synthesis to suppress gluconeogenesis [#1, #12]. As a tumor suppressor in liver, PCK1 loss elevates oxaloacetate and GTP to drive global O-GlcNAcylation of CHK2 and KAT5 promoting proliferation and metastasis, reduces SAM-dependent H3K9me3 to de-repress S100A11/AKT signaling, and activates GTP-dependent RhoA/PI3K/AKT and PDGF-AA signaling that promotes hepatic fibrosis [#2, #3, #4, #9]. PCK1 also competitively consumes GTP to suppress cGAS-STING upon JNK-mediated Ser151 phosphorylation, enabling tumor immune evasion [#11], and supports redox homeostasis by feeding glycogen-derived flux into the pentose phosphate pathway for NADPH generation in memory CD8+ T cells and chemoresistant cancer stem cells [#7, #17]. Its expression is controlled by an interlocking transcriptional network including FOXO1-EHMT2, SHP-1/STAT5, REV-ERBalpha, RAR, ChREBP, and m6A mRNA modification [#14, #10, #18, #23, #28, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying the cis-element where the -232C/G promoter variant lies established a discrete DNA module mediating insulin-dependent repression of PCK1 transcription, explaining how hormonal signals tune gluconeogenic gene output.\",\n      \"evidence\": \"Luciferase reporter assays across three cell lines with promoter variant constructs\",\n      \"pmids\": [\"14764811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the transcription factor binding the element\", \"Population-level metabolic consequences not directly shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Deleting the adipose PPARE answered whether adipose PCK1 contributes to whole-body metabolism, showing it is required for glyceroneogenesis and glucose homeostasis independent of liver gluconeogenesis.\",\n      \"evidence\": \"PPARE(-/-) mice with hyperinsulinemic-euglycemic clamp and islet secretion assays\",\n      \"pmids\": [\"20124556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-autonomous versus systemic contributions not fully separated\", \"Molecular link between glyceroneogenesis and insulin resistance not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Re-expressing each PEPCK isoform in liver-specific knockout mice resolved the relative gluconeogenic capacity of cytosolic versus mitochondrial PEPCK, showing PEPCK-M has independent gluconeogenic potential and cooperates with PCK1 in flux control.\",\n      \"evidence\": \"NMR (2H/13C) tracer studies in isolated KO livers with adenoviral isoform expression\",\n      \"pmids\": [\"23466304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative in vivo contribution of PEPCK-M in intact animals unresolved\", \"Regulation distinguishing the two isoforms not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linking insulin-driven FOXO1 Ser256 phosphorylation to FOXO1-EHMT2 complex formation at the PCK1 promoter explained the chromatin mechanism by which insulin represses PCK1 transcription.\",\n      \"evidence\": \"Live-cell imaging, Co-IP, ChIP of promoter histone marks in cell models\",\n      \"pmids\": [\"25736587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NUP98 role mechanistically incomplete\", \"In vivo relevance to hepatic gluconeogenesis not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A natural pig Met139Leu variant demonstrated that single residue changes shift PCK1 between glyceroneogenic and anaplerotic directions and alter its acetylation/degradation, connecting catalytic directionality to protein stability.\",\n      \"evidence\": \"In vitro kinetics of recombinant variant proteins plus cell culture glucose/lipid and acetylation assays\",\n      \"pmids\": [\"26792594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human relevance of the variant not established\", \"Structural basis of directional shift not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Neonatal liver-specific re-expression in whole-body KO pups established that hepatic PCK1 is the critical determinant of survival-limiting hypoglycemia, isolating the liver's role from other tissues.\",\n      \"evidence\": \"Adenoviral liver re-expression in KO pups with glucose and survival readouts\",\n      \"pmids\": [\"27785616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Partial rescue only; non-hepatic contributions to phenotype remain\", \"Long-term metabolic outcomes not assessed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing HBXIP suppresses PCK1 via miR-135a and PI3K/Akt-driven FOXO1 export, and that PCK1 overexpression abolishes HBXIP-driven growth, positioned PCK1 as a tumor suppressor downstream of an oncoprotein.\",\n      \"evidence\": \"3'UTR luciferase, nuclear fractionation, PCK1 rescue in xenografts\",\n      \"pmids\": [\"27609066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic mechanism of growth suppression not defined here\", \"Relative weight of the two repression arms unquantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovering that memory CD8+ T cells route PCK1-driven gluconeogenesis into glycogen and the PPP redefined PCK1 as a redox-supporting enzyme controlling immune memory rather than purely a glucose-producing one.\",\n      \"evidence\": \"Pck1 KO/KD in T cells with flux analysis, GSH/GSSG, ROS, and adoptive transfer\",\n      \"pmids\": [\"29230018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals inducing PCK1 in T cells unclear\", \"Generalizability to other immune subsets untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Forced PCK1 expression in glucose-starved liver cancer cells driving catalysis-dependent TCA cataplerosis and apoptosis demonstrated that PCK1's enzymatic flux itself can be cytotoxic, providing a tumor-suppressive mechanism.\",\n      \"evidence\": \"Catalytic mutants, alpha-KG and ROS rescue, xenograft models\",\n      \"pmids\": [\"29335519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context dependence on nutrient state not generalized\", \"Does not address chronic low-level expression effects\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Myeloid Pck1 deletion shifting macrophages toward M1 inflammatory phenotype with altered TCA labeling established a role for PCK1 in immunometabolic polarization.\",\n      \"evidence\": \"Myeloid-specific KO mouse with [U-13C]glucose flux tracing and cytokine assays\",\n      \"pmids\": [\"29317502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between flux change and cytokine induction not defined\", \"In vivo disease relevance not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating PCK1 overexpression triggers AMPK/p27Kip1-mediated G1 arrest, reversible by AMPK knockdown, provided an energy-sensing mechanism for PCK1's anti-proliferative effect in hepatoma.\",\n      \"evidence\": \"Gain/loss-of-function, flow cytometry, AMPK knockdown epistasis, xenografts\",\n      \"pmids\": [\"30717766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATP depletion is catalysis-dependent not fully shown\", \"Relationship to cataplerosis-driven apoptosis unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Finding PCK1 drives hypoxic pyrimidine biosynthesis to enable colorectal liver metastasis revealed an oncogenic, gluconeogenesis-independent function opposite to its hepatic tumor-suppressor role.\",\n      \"evidence\": \"PDX metastatic selection, pyrimidine metabolomics, DHODH inhibition\",\n      \"pmids\": [\"31841108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic link to pyrimidine pool not mechanistically resolved\", \"Why context determines oncogenic vs suppressive role unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapping REV-ERBalpha binding to a RevRE in the PCK1 promoter placed gluconeogenesis under direct circadian transcriptional control.\",\n      \"evidence\": \"Luciferase, EMSA, ChIP, SR9009 activation in diabetic mice\",\n      \"pmids\": [\"30639375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration with other promoter regulators not addressed\", \"Diurnal dynamics in vivo not fully characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovering that AKT-phosphorylated PCK1 translocates to the ER and acts as a GTP-dependent protein kinase on INSIG1/2 to activate SREBP fundamentally reclassified PCK1 as a moonlighting kinase coupling metabolism to lipogenic gene transcription.\",\n      \"evidence\": \"Co-IP, in vitro kinase reconstitution, mutagenesis, fractionation, MS, xenografts\",\n      \"pmids\": [\"32322062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the kinase activity not defined\", \"Balance between cytosolic enzyme and ER kinase pools unquantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural and biophysical analysis showed active-site self-acetylation at K244 using acetyl-CoA inhibits PCK1 catalysis independently of p300, establishing a metabolite-driven autoregulatory switch.\",\n      \"evidence\": \"Crystallography, ITC, STD-NMR, docking, kinetics, mutagenesis\",\n      \"pmids\": [\"33334880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo prevalence of self-acetylation not quantified\", \"Deacetylase counteracting K244 not identified here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking PCK1 loss to oxaloacetate-driven O-GlcNAcylation of CHK2 explained how PCK1 deficiency destabilizes CHK2 and promotes HCC proliferation through hexosamine pathway flux.\",\n      \"evidence\": \"KO cells, flux analysis, O-GlcNAc IP/MS, liver KO mice, HBP inhibition\",\n      \"pmids\": [\"33690219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site-specific reversibility of CHK2 O-GlcNAcylation in vivo not detailed\", \"Contribution of AMPK-GFAT1 versus UDP-GlcNAc arm not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing PCK1 depletion stabilizes O-GlcNAcylated KAT5 to drive EMT-promoting transcription extended the O-GlcNAcylation mechanism to metastasis.\",\n      \"evidence\": \"Gain/loss-of-function, Co-IP, ubiquitination, ChIP, Pck1-deletion mice, metastasis assays\",\n      \"pmids\": [\"34650217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CHK2 and KAT5 effects are independent or coupled unclear\", \"Therapeutic targeting of the O-GlcNAc node not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connecting PCK1 to SAM-dependent H3K9me3 at the S100A11 promoter revealed an epigenetic mechanism by which PCK1 loss de-represses an AKT-activating oncogene.\",\n      \"evidence\": \"Metabolomics, Co-IP, ChIP, SAM rescue, S100A11 KO in vivo\",\n      \"pmids\": [\"37166978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct flux from PCK1 to SAM not fully traced\", \"Generality across other H3K9me3 loci unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing PCK1 deficiency raises intracellular GTP to activate RhoA/PI3K/AKT and PDGF-AA secretion driving stellate cell activation defined a mechanism for PCK1 loss in MAFLD fibrosis.\",\n      \"evidence\": \"Liver-specific KO mice, AAV rescue, RhoA/AKT inhibition and silencing, GTP and PDGF-AA measurements\",\n      \"pmids\": [\"36918564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GTP accumulation specifically activates RhoA not detailed\", \"Reversibility of established fibrosis not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying SHP-1/STAT5 recruitment of RNA polymerase II to the PCK1 promoter added a transcriptional coactivation route controlling gluconeogenic output.\",\n      \"evidence\": \"Co-IP, ChIP-seq, loss-of-function with gluconeogenesis readout\",\n      \"pmids\": [\"37595871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphatase activity versus scaffold role of SHP-1 not separated\", \"Physiological trigger for this axis unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"m6A-reader and writer studies (hnRNPA2B1 destabilizing, METTL3 stabilizing PCK1 mRNA) established post-transcriptional m6A control of PCK1 levels in HCC and ischemia-reperfusion injury.\",\n      \"evidence\": \"RIP, MeRIP, m6A-seq, CRISPR KO, conditional METTL3 KO, in vivo models\",\n      \"pmids\": [\"38017546\", \"38085830\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of opposing m6A effects on stability versus export incomplete\", \"Site-specific m6A residues on PCK1 transcript not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Kidney- and proximal-tubule-specific KO/transgenic models established PCK1 as essential for renal ammoniagenesis, acid-base balance, ATP supply, and mitoribosomal integrity against diabetic injury.\",\n      \"evidence\": \"Conditional KO and knockin/transgenic mice, metabolic and fibrosis phenotyping\",\n      \"pmids\": [\"37102687\", \"37199399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking PCK1 to mitoribosome maintenance unresolved\", \"Whether HK2 suppression is direct or metabolic not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that K91 acetylation reverses PCK1's directional preference toward anaplerotic OAA synthesis and that the K91Q mimetic ameliorates hyperglycemia established acetylation as a directional switch with therapeutic relevance.\",\n      \"evidence\": \"K91Q mimetic, flux analysis, hepatocyte assays, liver K91Q expression in obese mice, Seahorse\",\n      \"pmids\": [\"39341205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulation of K91 acetylation stoichiometry unclear\", \"Long-term consequences of directional reversal untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing PCK1 phosphorylates PYGL to enhance glycogenolysis and PPP-derived NADPH in cervical cancer stem cells extended the redox-support role to chemoresistance.\",\n      \"evidence\": \"siRNA knockdown, glycogen and PPP LC-MS, NADPH ratio, NSG tumor assays\",\n      \"pmids\": [\"38871968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PCK1 directly phosphorylates PYGL not biochemically reconstituted\", \"Relationship to ER kinase activity unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Several studies extended PCK1 regulation and function across tissues: RAR-mediated induction in hepatocytes, ChREBP/THR-coupled control driving beta-cell proliferation, UBAP2L dephosphorylation-driven autophagy suppressing CRC, intestinal epithelial effects in pancreatitis, and SIRT2-dependent stabilization in chondrocytes.\",\n      \"evidence\": \"Reporter/PLA/ChIP, Cre-Lox models, phospho-site analysis, pharmacological inhibition, and cell models\",\n      \"pmids\": [\"21519922\", \"36455788\", \"37062825\", \"38651689\", \"39463224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several of these mechanisms rest on single-lab cell models\", \"Direct enzymatic versus signaling contributions often not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovering that JNK-driven Ser151 phosphorylation lets PCK1 bind cGAS and competitively consume shared GTP to suppress cGAS-STING signaling defined a metabolite-competition mechanism for tumor immune evasion.\",\n      \"evidence\": \"Co-IP, GTP competition assays, site mutagenesis, STING reporters, tumor models with anti-PD-1, human specimens\",\n      \"pmids\": [\"40048154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether catalytic activity is required for GTP sequestration not fully separated\", \"Relationship of Ser151 to other phospho-sites (Ser90) unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple post-translational switches (Ser90/Ser151 phosphorylation, K91/K244 acetylation, SIRT2 stabilization) are integrated to partition PCK1 between cytosolic gluconeogenic enzyme, ER/cGAS-bound GTP-consuming protein, and directional anaplerotic states in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural or quantitative model of how modifications compete or cooperate\", \"Tissue- and context-specific determinants of oncogenic versus tumor-suppressor behavior undefined\", \"Stoichiometry of the moonlighting kinase pool versus catalytic pool in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [25, 6, 1, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 32, 11]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [25, 27, 6, 7, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4, 9, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 22, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 10, 18, 23, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 9, 11, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"INSIG1\", \"INSIG2\", \"cGAS\", \"CHK2\", \"KAT5\", \"PYGL\", \"UBAP2L\", \"SIRT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}