Pck1

Summary: Magnesium ion binding by Pck1, transferred from human PCK1.

Reason: PEPCK-C uses a divalent metal-nucleotide complex (Mg-GTP) as substrate in addition to the active-site Mn2+ (by similarity to human P35558, which has a direct IDA for Mg2+ binding, PMID:11851336). The binding is real but serves the catalytic activity; it is not a separate function. Kept as non-core.

Summary: Magnesium ion binding by Pck1, transferred from human PCK1.

Reason: PEPCK-C uses a divalent metal-nucleotide complex (Mg-GTP) as substrate in addition to the active-site Mn2+ (by similarity to human P35558, which has a direct IDA for Mg2+ binding, PMID:11851336). The binding is real but serves the catalytic activity; it is not a separate function. Kept as non-core.

Summary: Nucleoside diphosphate kinase activity, projected from rat Pck1 (RGD:3267).

Reason: GO:0004550 is ATP + NDP = ADP + NTP. PEPCK-C transfers the gamma-phosphoryl of GTP to the enolate formed by decarboxylating oxaloacetate. A nucleotide phosphoryl exchange measured for the rat enzyme in vitro would at most be a partial or side reaction of the carboxykinase mechanism. No mouse data, UniProt curated text or Rhea reaction supports an NDP kinase function. The physiological activity is fully captured by GO:0004613.

Summary: Generic phosphoenolpyruvate carboxykinase activity.

Reason: This is correct, but GO:0004611 does not specify the phosphoryl donor. Pck1 is the GTP-dependent enzyme (EC 4.1.1.32; RHEA:10388), and the gene already carries the precise child term GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity from EXP/IMP/IBA rows. PMID:11792850 (adipose PPARE mutant) supports PEPCK-C activity in vivo.

Proposed replacements: phosphoenolpyruvate carboxykinase (GTP) activity

Summary: Generic phosphoenolpyruvate carboxykinase activity.

Reason: This is correct, but GO:0004611 does not specify the phosphoryl donor. Pck1 is the GTP-dependent enzyme (EC 4.1.1.32; RHEA:10388), and the gene already carries the precise child term GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity from EXP/IMP/IBA rows. PMID:11792850 (adipose PPARE mutant) supports PEPCK-C activity in vivo.

Proposed replacements: phosphoenolpyruvate carboxykinase (GTP) activity

Summary: Generic phosphoenolpyruvate carboxykinase activity.

Reason: This is correct, but GO:0004611 does not specify the phosphoryl donor. Pck1 is the GTP-dependent enzyme (EC 4.1.1.32; RHEA:10388), and the gene already carries the precise child term GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity from EXP/IMP/IBA rows. PMID:11792850 (adipose PPARE mutant) supports PEPCK-C activity in vivo.

Proposed replacements: phosphoenolpyruvate carboxykinase (GTP) activity

Summary: GTP-dependent phosphoenolpyruvate carboxykinase activity, the defining catalytic activity of Pck1.

Reason: This is the core molecular function. UniProt records experimentally supported catalysis of oxaloacetate + GTP = PEP + GDP + CO2 for the mouse enzyme (PMID:11792850, PMID:29230018, PMID:30193097). PMID:30193097 shows the reaction runs in both directions depending on Lys91 acetylation. Mouse knockouts (PMID:10938127, PMID:15347677) abolish the PEPCK-dependent fluxes, and the IBA places the activity at the PEPCK-GTP family root. Rows from every evidence source agree.

Summary: GTP-dependent phosphoenolpyruvate carboxykinase activity, the defining catalytic activity of Pck1.

Reason: This is the core molecular function. UniProt records experimentally supported catalysis of oxaloacetate + GTP = PEP + GDP + CO2 for the mouse enzyme (PMID:11792850, PMID:29230018, PMID:30193097). PMID:30193097 shows the reaction runs in both directions depending on Lys91 acetylation. Mouse knockouts (PMID:10938127, PMID:15347677) abolish the PEPCK-dependent fluxes, and the IBA places the activity at the PEPCK-GTP family root. Rows from every evidence source agree.

Summary: GTP-dependent phosphoenolpyruvate carboxykinase activity, the defining catalytic activity of Pck1.

Reason: This is the core molecular function. UniProt records experimentally supported catalysis of oxaloacetate + GTP = PEP + GDP + CO2 for the mouse enzyme (PMID:11792850, PMID:29230018, PMID:30193097). PMID:30193097 shows the reaction runs in both directions depending on Lys91 acetylation. Mouse knockouts (PMID:10938127, PMID:15347677) abolish the PEPCK-dependent fluxes, and the IBA places the activity at the PEPCK-GTP family root. Rows from every evidence source agree.

Summary: GTP-dependent phosphoenolpyruvate carboxykinase activity, the defining catalytic activity of Pck1.

Reason: This is the core molecular function. UniProt records experimentally supported catalysis of oxaloacetate + GTP = PEP + GDP + CO2 for the mouse enzyme (PMID:11792850, PMID:29230018, PMID:30193097). PMID:30193097 shows the reaction runs in both directions depending on Lys91 acetylation. Mouse knockouts (PMID:10938127, PMID:15347677) abolish the PEPCK-dependent fluxes, and the IBA places the activity at the PEPCK-GTP family root. Rows from every evidence source agree.

Summary: GTP-dependent phosphoenolpyruvate carboxykinase activity, the defining catalytic activity of Pck1.

Reason: This is the core molecular function. UniProt records experimentally supported catalysis of oxaloacetate + GTP = PEP + GDP + CO2 for the mouse enzyme (PMID:11792850, PMID:29230018, PMID:30193097). PMID:30193097 shows the reaction runs in both directions depending on Lys91 acetylation. Mouse knockouts (PMID:10938127, PMID:15347677) abolish the PEPCK-dependent fluxes, and the IBA places the activity at the PEPCK-GTP family root. Rows from every evidence source agree.

Summary: GTP-dependent phosphoenolpyruvate carboxykinase activity, the defining catalytic activity of Pck1.

Reason: This is the core molecular function. UniProt records experimentally supported catalysis of oxaloacetate + GTP = PEP + GDP + CO2 for the mouse enzyme (PMID:11792850, PMID:29230018, PMID:30193097). PMID:30193097 shows the reaction runs in both directions depending on Lys91 acetylation. Mouse knockouts (PMID:10938127, PMID:15347677) abolish the PEPCK-dependent fluxes, and the IBA places the activity at the PEPCK-GTP family root. Rows from every evidence source agree.

Summary: GTP-dependent phosphoenolpyruvate carboxykinase activity, the defining catalytic activity of Pck1.

Reason: This is the core molecular function. UniProt records experimentally supported catalysis of oxaloacetate + GTP = PEP + GDP + CO2 for the mouse enzyme (PMID:11792850, PMID:29230018, PMID:30193097). PMID:30193097 shows the reaction runs in both directions depending on Lys91 acetylation. Mouse knockouts (PMID:10938127, PMID:15347677) abolish the PEPCK-dependent fluxes, and the IBA places the activity at the PEPCK-GTP family root. Rows from every evidence source agree.

Summary: GTP-dependent phosphoenolpyruvate carboxykinase activity, the defining catalytic activity of Pck1.

Reason: This is the core molecular function. UniProt records experimentally supported catalysis of oxaloacetate + GTP = PEP + GDP + CO2 for the mouse enzyme (PMID:11792850, PMID:29230018, PMID:30193097). PMID:30193097 shows the reaction runs in both directions depending on Lys91 acetylation. Mouse knockouts (PMID:10938127, PMID:15347677) abolish the PEPCK-dependent fluxes, and the IBA places the activity at the PEPCK-GTP family root. Rows from every evidence source agree.

Summary: GTP-dependent phosphoenolpyruvate carboxykinase activity, the defining catalytic activity of Pck1.

Reason: This is the core molecular function. UniProt records experimentally supported catalysis of oxaloacetate + GTP = PEP + GDP + CO2 for the mouse enzyme (PMID:11792850, PMID:29230018, PMID:30193097). PMID:30193097 shows the reaction runs in both directions depending on Lys91 acetylation. Mouse knockouts (PMID:10938127, PMID:15347677) abolish the PEPCK-dependent fluxes, and the IBA places the activity at the PEPCK-GTP family root. Rows from every evidence source agree.

Summary: GTP binding (GTP is the phosphoryl donor substrate).

Reason: GTP is the co-substrate of the PEPCK-C reaction, so GTP binding is real but is entailed by GO:0004613. It is kept as non-core substrate binding rather than an independent function.

Summary: GTP binding (GTP is the phosphoryl donor substrate).

Reason: GTP is the co-substrate of the PEPCK-C reaction, so GTP binding is real but is entailed by GO:0004613. It is kept as non-core substrate binding rather than an independent function.

Summary: GTP binding (GTP is the phosphoryl donor substrate).

Reason: GTP is the co-substrate of the PEPCK-C reaction, so GTP binding is real but is entailed by GO:0004613. It is kept as non-core substrate binding rather than an independent function.

Summary: Cytoplasm localization.

Reason: This is correct but general. Pck1 is the cytosolic PEPCK isozyme (PEPCK-C), and the gene already carries GO:0005829 cytosol from IBA, IDA and ISO rows. The more precise term should be used.

Proposed replacements: cytosol

Summary: Cytoplasm localization.

Reason: This is correct but general. Pck1 is the cytosolic PEPCK isozyme (PEPCK-C), and the gene already carries GO:0005829 cytosol from IBA, IDA and ISO rows. The more precise term should be used.

Proposed replacements: cytosol

Summary: Mitochondrion, inherited by IBA from PANTHER node PTN000169230.

Reason: Vertebrates have two PEPCK-GTP isozymes: the cytosolic Pck1 and the mitochondrial Pck2. The IBA donors (MGI:1860456 = Pck2, UniProtKB:Q16822 = human PCK2) are both the mitochondrial paralog. Mouse Pck1 is the cytosolic form. It has no mitochondrial transit peptide, and every experimental localization (IDA cytosol, PMID:19458124) and the UniProt curated location place it in the cytosol. The mitochondrial localization of the ancestral node was lost on the PCK1 branch after the duplication, so the inheritance does not apply to this gene.

Summary: Endoplasmic reticulum localization.

Reason: Pck1 is predominantly cytosolic. The ER association comes from the human HCC study (PMID:32322062), where the AKT Ser90-phosphorylated pool moves to the ER. UniProt transfers this to mouse 'By similarity'. There is also a mouse IDA from PMID:19458124, whose full text we could not read (the abstract describes only mRNA and transporter data). We defer to that curator rather than remove the row. Because the ER pool is minor and conditional, all ER rows are kept as non-core. They do not imply the kinase function, which is reviewed separately.

Summary: Endoplasmic reticulum localization.

Reason: Pck1 is predominantly cytosolic. The ER association comes from the human HCC study (PMID:32322062), where the AKT Ser90-phosphorylated pool moves to the ER. UniProt transfers this to mouse 'By similarity'. There is also a mouse IDA from PMID:19458124, whose full text we could not read (the abstract describes only mRNA and transporter data). We defer to that curator rather than remove the row. Because the ER pool is minor and conditional, all ER rows are kept as non-core. They do not imply the kinase function, which is reviewed separately.

Summary: Endoplasmic reticulum localization.

Reason: Pck1 is predominantly cytosolic. The ER association comes from the human HCC study (PMID:32322062), where the AKT Ser90-phosphorylated pool moves to the ER. UniProt transfers this to mouse 'By similarity'. There is also a mouse IDA from PMID:19458124, whose full text we could not read (the abstract describes only mRNA and transporter data). We defer to that curator rather than remove the row. Because the ER pool is minor and conditional, all ER rows are kept as non-core. They do not imply the kinase function, which is reviewed separately.

Summary: Endoplasmic reticulum localization.

Reason: Pck1 is predominantly cytosolic. The ER association comes from the human HCC study (PMID:32322062), where the AKT Ser90-phosphorylated pool moves to the ER. UniProt transfers this to mouse 'By similarity'. There is also a mouse IDA from PMID:19458124, whose full text we could not read (the abstract describes only mRNA and transporter data). We defer to that curator rather than remove the row. Because the ER pool is minor and conditional, all ER rows are kept as non-core. They do not imply the kinase function, which is reviewed separately.

Summary: Endoplasmic reticulum localization.

Reason: Pck1 is predominantly cytosolic. The ER association comes from the human HCC study (PMID:32322062), where the AKT Ser90-phosphorylated pool moves to the ER. UniProt transfers this to mouse 'By similarity'. There is also a mouse IDA from PMID:19458124, whose full text we could not read (the abstract describes only mRNA and transporter data). We defer to that curator rather than remove the row. Because the ER pool is minor and conditional, all ER rows are kept as non-core. They do not imply the kinase function, which is reviewed separately.

Summary: Cytosol, the principal compartment of PEPCK-C.

Reason: Pck1 encodes the cytosolic isozyme (PEPCK-C). The cytosol is where it converts oxaloacetate exported from mitochondria (as malate/aspartate) into PEP for gluconeogenesis and glyceroneogenesis. This is supported by mouse IDA (PMID:19458124), IBA, UniProt and the Reactome placement.

Summary: Cytosol, the principal compartment of PEPCK-C.

Reason: Pck1 encodes the cytosolic isozyme (PEPCK-C). The cytosol is where it converts oxaloacetate exported from mitochondria (as malate/aspartate) into PEP for gluconeogenesis and glyceroneogenesis. This is supported by mouse IDA (PMID:19458124), IBA, UniProt and the Reactome placement.

Summary: Cytosol, the principal compartment of PEPCK-C.

Reason: Pck1 encodes the cytosolic isozyme (PEPCK-C). The cytosol is where it converts oxaloacetate exported from mitochondria (as malate/aspartate) into PEP for gluconeogenesis and glyceroneogenesis. This is supported by mouse IDA (PMID:19458124), IBA, UniProt and the Reactome placement.

Summary: Cytosol, the principal compartment of PEPCK-C.

Reason: Pck1 encodes the cytosolic isozyme (PEPCK-C). The cytosol is where it converts oxaloacetate exported from mitochondria (as malate/aspartate) into PEP for gluconeogenesis and glyceroneogenesis. This is supported by mouse IDA (PMID:19458124), IBA, UniProt and the Reactome placement.

Summary: Cytosol, the principal compartment of PEPCK-C.

Reason: Pck1 encodes the cytosolic isozyme (PEPCK-C). The cytosol is where it converts oxaloacetate exported from mitochondria (as malate/aspartate) into PEP for gluconeogenesis and glyceroneogenesis. This is supported by mouse IDA (PMID:19458124), IBA, UniProt and the Reactome placement.

Summary: Cytosol, the principal compartment of PEPCK-C.

Reason: Pck1 encodes the cytosolic isozyme (PEPCK-C). The cytosol is where it converts oxaloacetate exported from mitochondria (as malate/aspartate) into PEP for gluconeogenesis and glyceroneogenesis. This is supported by mouse IDA (PMID:19458124), IBA, UniProt and the Reactome placement.

Summary: Cytosol, the principal compartment of PEPCK-C.

Reason: Pck1 encodes the cytosolic isozyme (PEPCK-C). The cytosol is where it converts oxaloacetate exported from mitochondria (as malate/aspartate) into PEP for gluconeogenesis and glyceroneogenesis. This is supported by mouse IDA (PMID:19458124), IBA, UniProt and the Reactome placement.

Summary: Glucose metabolic process.

Reason: This is correct but general. Pck1's role in glucose metabolism is gluconeogenesis, for which the gene already carries GO:0006094 (an is_a descendant via glucose biosynthesis) from IMP, IDA and IBA rows.

Proposed replacements: gluconeogenesis

Summary: Glucose metabolic process.

Reason: This is correct but general. Pck1's role in glucose metabolism is gluconeogenesis, for which the gene already carries GO:0006094 (an is_a descendant via glucose biosynthesis) from IMP, IDA and IBA rows.

Proposed replacements: gluconeogenesis

Summary: Glucose metabolic process.

Reason: This is correct but general. Pck1's role in glucose metabolism is gluconeogenesis, for which the gene already carries GO:0006094 (an is_a descendant via glucose biosynthesis) from IMP, IDA and IBA rows.

Proposed replacements: gluconeogenesis

Summary: Gluconeogenesis; Pck1 catalyses the committed conversion of oxaloacetate to PEP.

Reason: This is the core process. Liver-specific Pck1 knockout nearly abolishes gluconeogenesis from TCA-cycle intermediates, amino acids and lactate (PMID:15347677). Renal gluconeogenesis rises to compensate (PMID:34156032), and kidney-specific deletion disturbs glucose/lactate handling (PMID:37102687). The IDA rows (ATF3 transgenic, PMID:11916968; HIF-1alpha liver KO, PMID:19643083) report reduced gluconeogenesis that follows reduced PEPCK expression. They are weaker, but the curators' call is consistent with the rest of the evidence.

Summary: Gluconeogenesis; Pck1 catalyses the committed conversion of oxaloacetate to PEP.

Reason: This is the core process. Liver-specific Pck1 knockout nearly abolishes gluconeogenesis from TCA-cycle intermediates, amino acids and lactate (PMID:15347677). Renal gluconeogenesis rises to compensate (PMID:34156032), and kidney-specific deletion disturbs glucose/lactate handling (PMID:37102687). The IDA rows (ATF3 transgenic, PMID:11916968; HIF-1alpha liver KO, PMID:19643083) report reduced gluconeogenesis that follows reduced PEPCK expression. They are weaker, but the curators' call is consistent with the rest of the evidence.

Summary: Gluconeogenesis; Pck1 catalyses the committed conversion of oxaloacetate to PEP.

Reason: This is the core process. Liver-specific Pck1 knockout nearly abolishes gluconeogenesis from TCA-cycle intermediates, amino acids and lactate (PMID:15347677). Renal gluconeogenesis rises to compensate (PMID:34156032), and kidney-specific deletion disturbs glucose/lactate handling (PMID:37102687). The IDA rows (ATF3 transgenic, PMID:11916968; HIF-1alpha liver KO, PMID:19643083) report reduced gluconeogenesis that follows reduced PEPCK expression. They are weaker, but the curators' call is consistent with the rest of the evidence.

Summary: Gluconeogenesis; Pck1 catalyses the committed conversion of oxaloacetate to PEP.

Reason: This is the core process. Liver-specific Pck1 knockout nearly abolishes gluconeogenesis from TCA-cycle intermediates, amino acids and lactate (PMID:15347677). Renal gluconeogenesis rises to compensate (PMID:34156032), and kidney-specific deletion disturbs glucose/lactate handling (PMID:37102687). The IDA rows (ATF3 transgenic, PMID:11916968; HIF-1alpha liver KO, PMID:19643083) report reduced gluconeogenesis that follows reduced PEPCK expression. They are weaker, but the curators' call is consistent with the rest of the evidence.

Summary: Gluconeogenesis; Pck1 catalyses the committed conversion of oxaloacetate to PEP.

Reason: This is the core process. Liver-specific Pck1 knockout nearly abolishes gluconeogenesis from TCA-cycle intermediates, amino acids and lactate (PMID:15347677). Renal gluconeogenesis rises to compensate (PMID:34156032), and kidney-specific deletion disturbs glucose/lactate handling (PMID:37102687). The IDA rows (ATF3 transgenic, PMID:11916968; HIF-1alpha liver KO, PMID:19643083) report reduced gluconeogenesis that follows reduced PEPCK expression. They are weaker, but the curators' call is consistent with the rest of the evidence.

Summary: Gluconeogenesis; Pck1 catalyses the committed conversion of oxaloacetate to PEP.

Reason: This is the core process. Liver-specific Pck1 knockout nearly abolishes gluconeogenesis from TCA-cycle intermediates, amino acids and lactate (PMID:15347677). Renal gluconeogenesis rises to compensate (PMID:34156032), and kidney-specific deletion disturbs glucose/lactate handling (PMID:37102687). The IDA rows (ATF3 transgenic, PMID:11916968; HIF-1alpha liver KO, PMID:19643083) report reduced gluconeogenesis that follows reduced PEPCK expression. They are weaker, but the curators' call is consistent with the rest of the evidence.

Summary: Gluconeogenesis; Pck1 catalyses the committed conversion of oxaloacetate to PEP.

Reason: This is the core process. Liver-specific Pck1 knockout nearly abolishes gluconeogenesis from TCA-cycle intermediates, amino acids and lactate (PMID:15347677). Renal gluconeogenesis rises to compensate (PMID:34156032), and kidney-specific deletion disturbs glucose/lactate handling (PMID:37102687). The IDA rows (ATF3 transgenic, PMID:11916968; HIF-1alpha liver KO, PMID:19643083) report reduced gluconeogenesis that follows reduced PEPCK expression. They are weaker, but the curators' call is consistent with the rest of the evidence.

Summary: Gluconeogenesis; Pck1 catalyses the committed conversion of oxaloacetate to PEP.

Reason: This is the core process. Liver-specific Pck1 knockout nearly abolishes gluconeogenesis from TCA-cycle intermediates, amino acids and lactate (PMID:15347677). Renal gluconeogenesis rises to compensate (PMID:34156032), and kidney-specific deletion disturbs glucose/lactate handling (PMID:37102687). The IDA rows (ATF3 transgenic, PMID:11916968; HIF-1alpha liver KO, PMID:19643083) report reduced gluconeogenesis that follows reduced PEPCK expression. They are weaker, but the curators' call is consistent with the rest of the evidence.

Summary: Gluconeogenesis; Pck1 catalyses the committed conversion of oxaloacetate to PEP.

Reason: This is the core process. Liver-specific Pck1 knockout nearly abolishes gluconeogenesis from TCA-cycle intermediates, amino acids and lactate (PMID:15347677). Renal gluconeogenesis rises to compensate (PMID:34156032), and kidney-specific deletion disturbs glucose/lactate handling (PMID:37102687). The IDA rows (ATF3 transgenic, PMID:11916968; HIF-1alpha liver KO, PMID:19643083) report reduced gluconeogenesis that follows reduced PEPCK expression. They are weaker, but the curators' call is consistent with the rest of the evidence.

Summary: Gluconeogenesis; Pck1 catalyses the committed conversion of oxaloacetate to PEP.

Reason: This is the core process. Liver-specific Pck1 knockout nearly abolishes gluconeogenesis from TCA-cycle intermediates, amino acids and lactate (PMID:15347677). Renal gluconeogenesis rises to compensate (PMID:34156032), and kidney-specific deletion disturbs glucose/lactate handling (PMID:37102687). The IDA rows (ATF3 transgenic, PMID:11916968; HIF-1alpha liver KO, PMID:19643083) report reduced gluconeogenesis that follows reduced PEPCK expression. They are weaker, but the curators' call is consistent with the rest of the evidence.

Summary: Oxaloacetate metabolic process.

Reason: Oxaloacetate is the PEPCK-C substrate (gluconeogenic direction) and product (anaplerotic direction, PMID:30193097). Pck1 directly converts it, so the term is an accurate process description of the catalysed step and is supported across IMP, IBA and ISO rows.

Summary: Oxaloacetate metabolic process.

Reason: Oxaloacetate is the PEPCK-C substrate (gluconeogenic direction) and product (anaplerotic direction, PMID:30193097). Pck1 directly converts it, so the term is an accurate process description of the catalysed step and is supported across IMP, IBA and ISO rows.

Summary: Oxaloacetate metabolic process.

Reason: Oxaloacetate is the PEPCK-C substrate (gluconeogenic direction) and product (anaplerotic direction, PMID:30193097). Pck1 directly converts it, so the term is an accurate process description of the catalysed step and is supported across IMP, IBA and ISO rows.

Summary: Oxaloacetate metabolic process.

Reason: Oxaloacetate is the PEPCK-C substrate (gluconeogenic direction) and product (anaplerotic direction, PMID:30193097). Pck1 directly converts it, so the term is an accurate process description of the catalysed step and is supported across IMP, IBA and ISO rows.

Summary: Oxaloacetate metabolic process.

Reason: Oxaloacetate is the PEPCK-C substrate (gluconeogenic direction) and product (anaplerotic direction, PMID:30193097). Pck1 directly converts it, so the term is an accurate process description of the catalysed step and is supported across IMP, IBA and ISO rows.

Summary: Glycerol biosynthetic process (glyceroneogenesis).

Reason: GO folded glyceroneogenesis into this term when it obsoleted GO:0046327 'glycerol biosynthetic process from pyruvate' (exact synonym 'glyceroneogenesis', replaced_by GO:0006114). Mouse genetics show that PEPCK-C drives adipose glyceroneogenesis. Ablating adipose expression via the PPARE promoter mutation reduces triglyceride deposition (PMID:11792850), and adipose overexpression increases glyceroneogenesis and fatty-acid re-esterification (PMID:11872659).

Summary: Glycerol biosynthetic process (glyceroneogenesis).

Reason: GO folded glyceroneogenesis into this term when it obsoleted GO:0046327 'glycerol biosynthetic process from pyruvate' (exact synonym 'glyceroneogenesis', replaced_by GO:0006114). Mouse genetics show that PEPCK-C drives adipose glyceroneogenesis. Ablating adipose expression via the PPARE promoter mutation reduces triglyceride deposition (PMID:11792850), and adipose overexpression increases glyceroneogenesis and fatty-acid re-esterification (PMID:11872659).

Summary: Glycerol biosynthetic process (glyceroneogenesis).

Reason: GO folded glyceroneogenesis into this term when it obsoleted GO:0046327 'glycerol biosynthetic process from pyruvate' (exact synonym 'glyceroneogenesis', replaced_by GO:0006114). Mouse genetics show that PEPCK-C drives adipose glyceroneogenesis. Ablating adipose expression via the PPARE promoter mutation reduces triglyceride deposition (PMID:11792850), and adipose overexpression increases glyceroneogenesis and fatty-acid re-esterification (PMID:11872659).

Summary: NLS-bearing protein import into nucleus, from the human SREBP GO-CAM.

Reason: Provenance chain: the human GO-CAM gomodel:6205c24300000880 (SREBP regulation) models PCK1 GO:0106264 activity as directly NEGATIVELY regulating (RO:0002630) the sterol-binding activities of INSIG1 and INSIG2. Those INSIG activities are part_of GO:0036316 SREBP-SCAP complex retention in ER, and further downstream the model has SCAP, MBTPS1/2 (GO:0051604 protein maturation), KPNB1 (GO:0006607 NLS-bearing protein import into nucleus) and SREBF1/2 (GO:0045542 positive regulation of cholesterol biosynthetic process). The GO-CAM-to-GAF conversion gave PCK1 an 'acts upstream of or within' annotation to each downstream process, and these were projected to mouse Pck1 by ISO (GO_REF:0000119, with UniProtKB:P35558). The current human PCK1 GOA file has no row for GO:0006607, so the mouse row is also stale with respect to its source. This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. In the model this process is carried out by KPNB1 importing processed SREBP, several causal steps away from PCK1. Pck1 does not do any of the work of nuclear import. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Lipid metabolic process, from the adipose PPARE-mutant mice.

Reason: Loss of adipose Pck1 expression reduces triglyceride deposition (PMID:11792850), and the IMP is as precise as that lipid phenotype allows. Pck1's direct contribution is the glycerol backbone (glyceroneogenesis, GO:0006114 and GO:0046166, accepted separately), not a lipid-modifying step. This lipid-level consequence is kept as non-core.

Summary: Response to bacterium, from intestinal transcriptomics during Listeria infection.

Reason: The IEP comes from a whole-genome intestinal expression profile in gnotobiotic mice infected with L. monocytogenes (PMID:23012479). A change in transcript level does not show that Pck1 does any of the work of an antibacterial response, and nothing links PEPCK-C activity to host defence.

Summary: Response to activity (rat-derived IEA).

Reason: This is projected by Ensembl Compara from a rat expression-response annotation. Exercise induction of Pck1 expression does not make the enzyme a participant in a response to activity. The PEPCK-Cmus overexpression mice (PMID:17716967) show that excess muscle PEPCK-C changes exercise capacity, but that is a gain-of-function phenotype, not a native role.

Summary: Purine nucleotide binding (InterPro2GO).

Reason: This is true but uninformative. The specific nucleotide interactions (GTP binding GO:0005525, GDP binding GO:0019003) are kept elsewhere in this review and entail this term.

Summary: Peptidyl-serine phosphorylation, transferred from human PCK1 (INSIG phosphorylation).

Reason: This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. The human source is an IDA from PMID:32322062 for PCK1 phosphorylating INSIG1 Ser207 and INSIG2 Ser151. This row is judged the same way as the GO:0106264 kinase rows: a single-study, cancer-context activity that has not been reproduced in mouse or in a physiological gluconeogenic tissue. It should not stand as a mouse Pck1 process. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Peptidyl-serine phosphorylation, transferred from human PCK1 (INSIG phosphorylation).

Reason: This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. The human source is an IDA from PMID:32322062 for PCK1 phosphorylating INSIG1 Ser207 and INSIG2 Ser151. This row is judged the same way as the GO:0106264 kinase rows: a single-study, cancer-context activity that has not been reproduced in mouse or in a physiological gluconeogenic tissue. It should not stand as a mouse Pck1 process. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: GDP binding (GDP is a reaction product/substrate in reverse).

Reason: GDP is the nucleotide product of the gluconeogenic direction and the substrate of the anaplerotic direction (PMID:30193097). The binding is entailed by GO:0004613 and kept as non-core.

Summary: GDP binding (GDP is a reaction product/substrate in reverse).

Reason: GDP is the nucleotide product of the gluconeogenic direction and the substrate of the anaplerotic direction (PMID:30193097). The binding is entailed by GO:0004613 and kept as non-core.

Summary: Manganese ion binding; Mn2+ is the active-site catalytic metal.

Reason: PEPCK-GTP enzymes need Mn2+ bound at the active site for catalysis. UniProt records one Mn2+ per subunit (by similarity to human, with structures for the rat enzyme), and the IBA places this at the family root. Correct, but cofactor binding is a component of the core PEPCK activity rather than a function in its own right, so it is kept as non-core, like the Mg2+ and GTP binding rows here and the same IBA in the human PCK1 review.

Summary: Manganese ion binding; Mn2+ is the active-site catalytic metal.

Reason: PEPCK-GTP enzymes need Mn2+ bound at the active site for catalysis. UniProt records one Mn2+ per subunit (by similarity to human, with structures for the rat enzyme), and the IBA places this at the family root. Correct, but cofactor binding is a component of the core PEPCK activity rather than a function in its own right, so it is kept as non-core, like the Mg2+ and GTP binding rows here and the same IBA in the human PCK1 review.

Summary: Manganese ion binding; Mn2+ is the active-site catalytic metal.

Reason: PEPCK-GTP enzymes need Mn2+ bound at the active site for catalysis. UniProt records one Mn2+ per subunit (by similarity to human, with structures for the rat enzyme), and the IBA places this at the family root. Correct, but cofactor binding is a component of the core PEPCK activity rather than a function in its own right, so it is kept as non-core, like the Mg2+ and GTP binding rows here and the same IBA in the human PCK1 review.

Summary: Manganese ion binding; Mn2+ is the active-site catalytic metal.

Reason: PEPCK-GTP enzymes need Mn2+ bound at the active site for catalysis. UniProt records one Mn2+ per subunit (by similarity to human, with structures for the rat enzyme), and the IBA places this at the family root. Correct, but cofactor binding is a component of the core PEPCK activity rather than a function in its own right, so it is kept as non-core, like the Mg2+ and GTP binding rows here and the same IBA in the human PCK1 review.

Summary: Carboxylic acid binding (oxaloacetate/PEP).

Reason: Pck1 binds the carboxylic acids oxaloacetate and phosphoenolpyruvate as substrates, so the term is accurate (human IDA PMID:11851336). It is substrate binding entailed by GO:0004613 and is kept as non-core.

Summary: Carboxylic acid binding (oxaloacetate/PEP).

Reason: Pck1 binds the carboxylic acids oxaloacetate and phosphoenolpyruvate as substrates, so the term is accurate (human IDA PMID:11851336). It is substrate binding entailed by GO:0004613 and is kept as non-core.

Summary: Carboxylic acid binding (oxaloacetate/PEP).

Reason: Pck1 binds the carboxylic acids oxaloacetate and phosphoenolpyruvate as substrates, so the term is accurate (human IDA PMID:11851336). It is substrate binding entailed by GO:0004613 and is kept as non-core.

Summary: Response to nutrient levels (rat-derived IEA).

Reason: Pck1 expression and activity track nutritional state. Fasting induces it, and high glucose shifts the enzyme to the anaplerotic direction by acetylation (PMID:30193097). The enzyme's output (glucose production during fasting) is part of the organismal response. This is non-core, consistent with the response to starvation row.

Summary: Response to lipopolysaccharide (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Response to insulin; Pck1 expression is a canonical hormonal target.

Reason: Pck1 is a classic hormone-responsive gene. Its transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin (UniProt induction, PMID:16100117). The enzyme does not transduce these signals, but its induction is a physiologically central part of the fasting response of liver and kidney. These response terms are kept as non-core: they describe how Pck1 is regulated, not what it does.

Summary: Response to insulin; Pck1 expression is a canonical hormonal target.

Reason: Pck1 is a classic hormone-responsive gene. Its transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin (UniProt induction, PMID:16100117). The enzyme does not transduce these signals, but its induction is a physiologically central part of the fasting response of liver and kidney. These response terms are kept as non-core: they describe how Pck1 is regulated, not what it does.

Summary: Cellular response to insulin stimulus; Pck1 expression is a canonical hormonal target.

Reason: Pck1 is a classic hormone-responsive gene. Its transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin (UniProt induction, PMID:16100117). The enzyme does not transduce these signals, but its induction is a physiologically central part of the fasting response of liver and kidney. These response terms are kept as non-core: they describe how Pck1 is regulated, not what it does.

Summary: Cellular response to insulin stimulus; Pck1 expression is a canonical hormonal target.

Reason: Pck1 is a classic hormone-responsive gene. Its transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin (UniProt induction, PMID:16100117). The enzyme does not transduce these signals, but its induction is a physiologically central part of the fasting response of liver and kidney. These response terms are kept as non-core: they describe how Pck1 is regulated, not what it does.

Summary: Cellular response to insulin stimulus; Pck1 expression is a canonical hormonal target.

Reason: Pck1 is a classic hormone-responsive gene. Its transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin (UniProt induction, PMID:16100117). The enzyme does not transduce these signals, but its induction is a physiologically central part of the fasting response of liver and kidney. These response terms are kept as non-core: they describe how Pck1 is regulated, not what it does.

Summary: Cellular response to insulin stimulus; Pck1 expression is a canonical hormonal target.

Reason: Pck1 is a classic hormone-responsive gene. Its transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin (UniProt induction, PMID:16100117). The enzyme does not transduce these signals, but its induction is a physiologically central part of the fasting response of liver and kidney. These response terms are kept as non-core: they describe how Pck1 is regulated, not what it does.

Summary: Response to lipid (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: SREBP-SCAP complex retention in ER, projected from human PCK1 through a GO-CAM-derived causal-upstream annotation.

Reason: Provenance chain: the human GO-CAM gomodel:6205c24300000880 (SREBP regulation) models PCK1 GO:0106264 activity as directly NEGATIVELY regulating (RO:0002630) the sterol-binding activities of INSIG1 and INSIG2. Those INSIG activities are part_of GO:0036316 SREBP-SCAP complex retention in ER, and further downstream the model has SCAP, MBTPS1/2 (GO:0051604 protein maturation), KPNB1 (GO:0006607 NLS-bearing protein import into nucleus) and SREBF1/2 (GO:0045542 positive regulation of cholesterol biosynthetic process). The GO-CAM-to-GAF conversion gave PCK1 an 'acts upstream of or within' annotation to each downstream process, and these were projected to mouse Pck1 by ISO (GO_REF:0000119, with UniProtKB:P35558). The current human PCK1 GOA file has no row for GO:0036316, so the mouse row is also stale with respect to its source. This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. Three problems follow. (1) Role: GO:0036316 is carried out by INSIG binding sterol-loaded SCAP. PCK1 is not part of the retention machinery, and its only connection is as an upstream modifier of INSIG. (2) Sign: the reported effect is the opposite of retention. INSIG phosphorylation reduces sterol binding and releases SCAP-SREBP to the Golgi, so PCK1 would, if anything, antagonise retention. An 'acts upstream of or within' annotation hides that sign. (3) Context: the evidence is one human cancer-cell study plus a monkey-cell virus-infection study, with nothing in mouse. Pck1's established role is GTP-dependent PEP carboxykinase activity in gluconeogenesis, glyceroneogenesis and cataplerosis. No replacement SREBP-pathway term is proposed for mouse Pck1. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Glucose homeostasis.

Reason: Hepatic and renal PEPCK-C-dependent gluconeogenesis contributes to blood glucose homeostasis. When liver Pck1 is lost, the kidney raises gluconeogenesis to hold glucose constant (PMID:34156032), and kidney deletion alters systemic glucose/lactate handling (PMID:37102687). This organism-level outcome of the core gluconeogenic activity is kept as non-core.

Summary: Glucose homeostasis.

Reason: Hepatic and renal PEPCK-C-dependent gluconeogenesis contributes to blood glucose homeostasis. When liver Pck1 is lost, the kidney raises gluconeogenesis to hold glucose constant (PMID:34156032), and kidney deletion alters systemic glucose/lactate handling (PMID:37102687). This organism-level outcome of the core gluconeogenic activity is kept as non-core.

Summary: Response to starvation (IBA).

Reason: During fasting, PEPCK-C-dependent hepatic and renal gluconeogenesis maintains blood glucose (PMID:34156032, PMID:15347677), so Pck1 contributes to the starvation response. The core description is gluconeogenesis, so this is kept as non-core.

Summary: Positive regulation of memory T cell differentiation (IMP).

Reason: In CD8+ memory T cells, Pck1 is upregulated and supplies gluconeogenic carbon to glycogen and the pentose phosphate pathway. Abrogating this pathway impairs Tm formation and maintenance (PMID:29230018). Pck1 acts as a metabolic enzyme whose output the cells need, not as a signalling regulator of differentiation. This is a context-specific experimental finding, so it is retained as non-core.

Summary: Positive regulation of cholesterol biosynthetic process, from the human SREBP GO-CAM.

Reason: Provenance chain: the human GO-CAM gomodel:6205c24300000880 (SREBP regulation) models PCK1 GO:0106264 activity as directly NEGATIVELY regulating (RO:0002630) the sterol-binding activities of INSIG1 and INSIG2. Those INSIG activities are part_of GO:0036316 SREBP-SCAP complex retention in ER, and further downstream the model has SCAP, MBTPS1/2 (GO:0051604 protein maturation), KPNB1 (GO:0006607 NLS-bearing protein import into nucleus) and SREBF1/2 (GO:0045542 positive regulation of cholesterol biosynthetic process). The GO-CAM-to-GAF conversion gave PCK1 an 'acts upstream of or within' annotation to each downstream process, and these were projected to mouse Pck1 by ISO (GO_REF:0000119, with UniProtKB:P35558). The current human PCK1 GOA file has no row for GO:0045542, so the mouse row is also stale with respect to its source. This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. In the model, GO:0045542 is the process of the SREBF1/SREBF2 transcription factors. PCK1 reaches it only through INSIG, SCAP, the site-1/site-2 proteases and nuclear import. Mouse sterol synthesis is not known to depend on Pck1. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Positive regulation of transcription by RNA polymerase II (IDA, kidney potassium restriction study).

Reason: Nothing in Pck1 biology suggests it regulates RNA polymerase II transcription. The cited study (PMID:19458124) measures PEPCK as a readout. Its mRNA rises with metabolic acidosis and K+ restriction, and the abstract reports no experiment in which Pck1 controls another gene's transcription. This looks like an expression readout coded as a regulatory function. We could not read the full text (abstract only, no PMC copy), so we flag the row for curator re-examination rather than remove an experimental annotation.

Summary: Glyceraldehyde-3-phosphate biosynthetic process (glyceroneogenesis/gluconeogenesis route).

Reason: PEP made by PEPCK-C is converted through the lower gluconeogenic reactions to glyceraldehyde-3-phosphate/DHAP. In adipose tissue this supplies glycerol-3-phosphate for triglyceride synthesis (glyceroneogenesis), and the PPARE mutant mice show the pathway depends on Pck1 (PMID:11792850). The mouse GO-CAM 'Glyceraldehyde-3-phosphate biosynthetic process 1' models Pck1 GO:0004613 in this process. Pck1 catalyses the committed step, so it is accepted.

Summary: Positive regulation of lipid biosynthetic process, transferred from human PCK1 (INSIG/SREBP mechanism).

Reason: This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. The human source rows are IDA from PMID:32322062 and describe SREBP-driven lipogenesis in HCC cells. In mouse, Pck1 affects lipid accumulation as a metabolic supplier: glyceroneogenesis provides the glycerol backbone for triglyceride re-esterification (PMID:11792850, PMID:11872659), and liver Pck1 loss causes steatosis through disrupted cataplerosis (PMID:15347677). Those effects are covered by the glycerol biosynthetic and TCA/oxaloacetate process terms. They are not regulation of lipid biosynthesis. This row is marked over-annotated, consistent with the kinase rows. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Positive regulation of lipid biosynthetic process, transferred from human PCK1 (INSIG/SREBP mechanism).

Reason: This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. The human source rows are IDA from PMID:32322062 and describe SREBP-driven lipogenesis in HCC cells. In mouse, Pck1 affects lipid accumulation as a metabolic supplier: glyceroneogenesis provides the glycerol backbone for triglyceride re-esterification (PMID:11792850, PMID:11872659), and liver Pck1 loss causes steatosis through disrupted cataplerosis (PMID:15347677). Those effects are covered by the glycerol biosynthetic and TCA/oxaloacetate process terms. They are not regulation of lipid biosynthesis. This row is marked over-annotated, consistent with the kinase rows. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Regulation of lipid biosynthetic process, transferred from human PCK1 (INSIG/SREBP mechanism).

Reason: This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. The human source rows are IDA from PMID:32322062 and describe SREBP-driven lipogenesis in HCC cells. In mouse, Pck1 affects lipid accumulation as a metabolic supplier: glyceroneogenesis provides the glycerol backbone for triglyceride re-esterification (PMID:11792850, PMID:11872659), and liver Pck1 loss causes steatosis through disrupted cataplerosis (PMID:15347677). Those effects are covered by the glycerol biosynthetic and TCA/oxaloacetate process terms. They are not regulation of lipid biosynthesis. This row is marked over-annotated, consistent with the kinase rows. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Regulation of lipid biosynthetic process, transferred from human PCK1 (INSIG/SREBP mechanism).

Reason: This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. The human source rows are IDA from PMID:32322062 and describe SREBP-driven lipogenesis in HCC cells. In mouse, Pck1 affects lipid accumulation as a metabolic supplier: glyceroneogenesis provides the glycerol backbone for triglyceride re-esterification (PMID:11792850, PMID:11872659), and liver Pck1 loss causes steatosis through disrupted cataplerosis (PMID:15347677). Those effects are covered by the glycerol biosynthetic and TCA/oxaloacetate process terms. They are not regulation of lipid biosynthesis. This row is marked over-annotated, consistent with the kinase rows. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Regulation of lipid biosynthetic process, transferred from human PCK1 (INSIG/SREBP mechanism).

Reason: This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. The human source rows are IDA from PMID:32322062 and describe SREBP-driven lipogenesis in HCC cells. In mouse, Pck1 affects lipid accumulation as a metabolic supplier: glyceroneogenesis provides the glycerol backbone for triglyceride re-esterification (PMID:11792850, PMID:11872659), and liver Pck1 loss causes steatosis through disrupted cataplerosis (PMID:15347677). Those effects are covered by the glycerol biosynthetic and TCA/oxaloacetate process terms. They are not regulation of lipid biosynthesis. This row is marked over-annotated, consistent with the kinase rows. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Cellular response to potassium ion starvation (IDA, mouse kidney).

Reason: Renal PEPCK mRNA rises after 14 days of dietary K+ restriction, together with increased ammoniagenesis (PMID:19458124). Renal PEPCK-C supports ammoniagenesis and acid-base control (PMID:37102687), so the induction is physiologically meaningful. It is an expression response, though, and is kept as non-core.

Summary: Protein maturation, from the human SREBP GO-CAM.

Reason: Provenance chain: the human GO-CAM gomodel:6205c24300000880 (SREBP regulation) models PCK1 GO:0106264 activity as directly NEGATIVELY regulating (RO:0002630) the sterol-binding activities of INSIG1 and INSIG2. Those INSIG activities are part_of GO:0036316 SREBP-SCAP complex retention in ER, and further downstream the model has SCAP, MBTPS1/2 (GO:0051604 protein maturation), KPNB1 (GO:0006607 NLS-bearing protein import into nucleus) and SREBF1/2 (GO:0045542 positive regulation of cholesterol biosynthetic process). The GO-CAM-to-GAF conversion gave PCK1 an 'acts upstream of or within' annotation to each downstream process, and these were projected to mouse Pck1 by ISO (GO_REF:0000119, with UniProtKB:P35558). The current human PCK1 GOA file has no row for GO:0051604, so the mouse row is also stale with respect to its source. This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. In the model, GO:0051604 is carried out by the Golgi proteases MBTPS1/MBTPS2 cleaving SREBP. PCK1 does no proteolytic or maturation work on SREBP. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Hepatocyte differentiation (IBA from PTN000169232).

Reason: Pck1 is a marker of mature, gluconeogenic hepatocytes, but nothing shows that the enzyme drives hepatocyte differentiation. Liver-specific Pck1 knockout mice are viable with functioning livers (PMID:10938127). The donors are rat/human expression-based annotations (P05153, P21642), so the node reflects marker expression, not participation.

Summary: Response to interleukin-6 (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Cellular response to retinoic acid (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Cellular response to camp; Pck1 expression is a canonical hormonal target.

Reason: Pck1 is a classic hormone-responsive gene. Its transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin (UniProt induction, PMID:16100117). The enzyme does not transduce these signals, but its induction is a physiologically central part of the fasting response of liver and kidney. These response terms are kept as non-core: they describe how Pck1 is regulated, not what it does.

Summary: Cellular response to fructose stimulus (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Cellular response to glucose stimulus.

Reason: High glucose triggers p300-dependent acetylation of Pck1 Lys91, which switches the enzyme toward the anaplerotic PEP-to-oxaloacetate direction. SIRT1 deacetylation at low glucose restores gluconeogenic activity (PMID:30193097). So Pck1 activity does respond to glucose, but this regulation of the core enzyme is kept as non-core.

Summary: Cellular response to glucose stimulus.

Reason: High glucose triggers p300-dependent acetylation of Pck1 Lys91, which switches the enzyme toward the anaplerotic PEP-to-oxaloacetate direction. SIRT1 deacetylation at low glucose restores gluconeogenic activity (PMID:30193097). So Pck1 activity does respond to glucose, but this regulation of the core enzyme is kept as non-core.

Summary: Cellular response to glucose stimulus.

Reason: High glucose triggers p300-dependent acetylation of Pck1 Lys91, which switches the enzyme toward the anaplerotic PEP-to-oxaloacetate direction. SIRT1 deacetylation at low glucose restores gluconeogenic activity (PMID:30193097). So Pck1 activity does respond to glucose, but this regulation of the core enzyme is kept as non-core.

Summary: Cellular response to glucose stimulus.

Reason: High glucose triggers p300-dependent acetylation of Pck1 Lys91, which switches the enzyme toward the anaplerotic PEP-to-oxaloacetate direction. SIRT1 deacetylation at low glucose restores gluconeogenic activity (PMID:30193097). So Pck1 activity does respond to glucose, but this regulation of the core enzyme is kept as non-core.

Summary: Cellular response to glucose stimulus.

Reason: High glucose triggers p300-dependent acetylation of Pck1 Lys91, which switches the enzyme toward the anaplerotic PEP-to-oxaloacetate direction. SIRT1 deacetylation at low glucose restores gluconeogenic activity (PMID:30193097). So Pck1 activity does respond to glucose, but this regulation of the core enzyme is kept as non-core.

Summary: Cellular response to interleukin-1 (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Cellular response to tumor necrosis factor (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Cellular response to glucagon stimulus; Pck1 expression is a canonical hormonal target.

Reason: Pck1 is a classic hormone-responsive gene. Its transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin (UniProt induction, PMID:16100117). The enzyme does not transduce these signals, but its induction is a physiologically central part of the fasting response of liver and kidney. These response terms are kept as non-core: they describe how Pck1 is regulated, not what it does.

Summary: Cellular response to hypoxia (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Cellular hyperosmotic response (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Cellular hyperosmotic salinity response (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Cellular hypotonic response (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Cellular hypotonic salinity response (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Cellular response to dexamethasone stimulus; Pck1 expression is a canonical hormonal target.

Reason: Pck1 is a classic hormone-responsive gene. Its transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin (UniProt induction, PMID:16100117). The enzyme does not transduce these signals, but its induction is a physiologically central part of the fasting response of liver and kidney. These response terms are kept as non-core: they describe how Pck1 is regulated, not what it does.

Summary: Tricarboxylic acid metabolic process (cataplerosis/anaplerosis).

Reason: The biology is sound: PEPCK-C is the main cataplerotic enzyme of liver and kidney, removing TCA-cycle carbon as oxaloacetate/PEP. Without hepatic Pck1, TCA-cycle intermediates accumulate and TCA flux falls (PMID:15347677), and acetylation reverses it to an anaplerotic role (PMID:30193097). The term is wrong, though: GO:0072350 is defined as metabolism of acids with three carboxyl groups, and its only children are citrate and isocitrate metabolic process. Pck1 acts on oxaloacetate (a dicarboxylic acid) and PEP. GO:0006107 oxaloacetate metabolic process, which Pck1 already carries, states the cataplerotic role correctly. Same verdict as the human PCK1 donor row.

Proposed replacements: oxaloacetate metabolic process

Summary: Tricarboxylic acid metabolic process (cataplerosis/anaplerosis).

Reason: The biology is sound: PEPCK-C is the main cataplerotic enzyme of liver and kidney, removing TCA-cycle carbon as oxaloacetate/PEP. Without hepatic Pck1, TCA-cycle intermediates accumulate and TCA flux falls (PMID:15347677), and acetylation reverses it to an anaplerotic role (PMID:30193097). The term is wrong, though: GO:0072350 is defined as metabolism of acids with three carboxyl groups, and its only children are citrate and isocitrate metabolic process. Pck1 acts on oxaloacetate (a dicarboxylic acid) and PEP. GO:0006107 oxaloacetate metabolic process, which Pck1 already carries, states the cataplerotic role correctly. Same verdict as the human PCK1 donor row.

Proposed replacements: oxaloacetate metabolic process

Summary: Cellular response to raffinose (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Protein serine kinase activity using GTP as donor, transferred from the single human PCK1/INSIG study.

Reason: This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. All three mouse rows are transfers of that one human finding: ISO (GO_REF:0000119) and ISS (GO_REF:0000024) from P35558, and the IEA (GO_REF:0000120) from the UniProt 'By similarity' catalytic-activity line (RHEA:64020). They are not independent evidence. A protein kinase activity for a metabolic enzyme, shown in one cancer-cell context and reproduced only in a virus-infected monkey cell line, does not establish a function of mouse Pck1. PEPCK-C has no protein kinase fold. The proposed mechanism, an AKT-induced switch of the active site to protein substrates, has not been tested in mouse tissue. MARK_AS_OVER_ANNOTATED is preferred over KEEP_AS_NON_CORE because keeping it would assert an activity for which there is no mouse evidence. It is not REMOVE because we cannot refute the human finding. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Protein serine kinase activity using GTP as donor, transferred from the single human PCK1/INSIG study.

Reason: This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. All three mouse rows are transfers of that one human finding: ISO (GO_REF:0000119) and ISS (GO_REF:0000024) from P35558, and the IEA (GO_REF:0000120) from the UniProt 'By similarity' catalytic-activity line (RHEA:64020). They are not independent evidence. A protein kinase activity for a metabolic enzyme, shown in one cancer-cell context and reproduced only in a virus-infected monkey cell line, does not establish a function of mouse Pck1. PEPCK-C has no protein kinase fold. The proposed mechanism, an AKT-induced switch of the active site to protein substrates, has not been tested in mouse tissue. MARK_AS_OVER_ANNOTATED is preferred over KEEP_AS_NON_CORE because keeping it would assert an activity for which there is no mouse evidence. It is not REMOVE because we cannot refute the human finding. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Protein serine kinase activity using GTP as donor, transferred from the single human PCK1/INSIG study.

Reason: This row traces to a single human study, PMID:32322062 (Xu et al. 2020): in human hepatocellular carcinoma cells, AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151. The only independent follow-up we found is PMID:39433189, a study of PRRSV infection in monkey MARC-145 cells. We found no mouse experiment on Pck1 protein kinase activity, Ser90 phosphorylation or INSIG phosphorylation. UniProt carries the mouse kinase activity only 'By similarity' to human P35558. All three mouse rows are transfers of that one human finding: ISO (GO_REF:0000119) and ISS (GO_REF:0000024) from P35558, and the IEA (GO_REF:0000120) from the UniProt 'By similarity' catalytic-activity line (RHEA:64020). They are not independent evidence. A protein kinase activity for a metabolic enzyme, shown in one cancer-cell context and reproduced only in a virus-infected monkey cell line, does not establish a function of mouse Pck1. PEPCK-C has no protein kinase fold. The proposed mechanism, an AKT-induced switch of the active site to protein substrates, has not been tested in mouse tissue. MARK_AS_OVER_ANNOTATED is preferred over KEEP_AS_NON_CORE because keeping it would assert an activity for which there is no mouse evidence. It is not REMOVE because we cannot refute the human finding. (The abstract's 'tumorigenesis in mice' appears to be human HCC xenograft work, not mouse Pck1 data; the full text is not cached.)

Summary: Cellular response to phorbol 13-acetate 12-myristate (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.

Summary: Response to methionine (rat-derived IEA, expression response).

Reason: This is projected by Ensembl Compara from a rat annotation that records altered Pck1/PEPCK expression after the stimulus. A change in expression level shows that Pck1 is a downstream target, not that the enzyme does any of the work of a response to this stimulus. No mouse data link PEPCK-C activity to this response.