Pck1 (mouse, Q9Z2V4) curation notes

Deep research status

• 2026-10-16: just deep-research mouse Pck1 --provider falcon was run twice and failed both
  times with Exception: Failed to authenticate / Provider falcon exited with code 1 / All providers failed. No deep-research file was produced, and none has been written by hand.
  These notes are built from the cached publications (publications/PMID_*.md), the UniProt
  record and the GOA/GO-CAM files.

Identity and family

• Pck1 encodes the cytosolic GTP-dependent phosphoenolpyruvate carboxykinase (PEPCK-C,
  EC 4.1.1.32), 622 aa, PANTHER PTHR11561:SF18, Pfam PEPCK_N + PEPCK_GTP. Mitochondrial
  paralog is Pck2. UniProt: "Belongs to the phosphoenolpyruvate carboxykinase [GTP] family."
• Reaction: oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 (RHEA:10388); physiologically
  both directions annotated in UniProt from PMID:30193097.
• Mn2+ cofactor (by similarity to human P35558).

Core function: PEPCK-C catalysis in gluconeogenesis, cataplerosis, glyceroneogenesis

• Whole-body / hepatic knockouts (Magnuson lab).
  PMID:10938127
  PMID:10938127
• Liver flux with 2H/13C: cataplerosis and gluconeogenesis from TCA intermediates require PEPCK-C.
  PMID:15347677 PMID:15347677
• Kidney compensates for hepatic loss. PMID:34156032
• Kidney-specific (Pax8) KO and knock-in: ammoniagenesis, acid-base, glucose/lactate.
  PMID:37102687 PMID:37102687
• Renal expression rises with acidosis and K+ restriction (expression readout).
  PMID:19458124
• Adipose glyceroneogenesis: PPARE promoter mutation abolishes adipose Pck1 expression.
  PMID:11792850 PMID:11792850
• Adipose overexpression increases glyceroneogenesis and FFA re-esterification.
  PMID:11872659
• Skeletal muscle overexpression (PEPCK-Cmus mice). PMID:17716967
  PMID:17716967 This is a gain-of-function phenotype in a tissue with little native
  PEPCK-C; it supports cataplerotic capacity but is not a normal physiological role of muscle Pck1.
• Hanson-lab review framing PEPCK-C as a cataplerotic enzyme: PMID:19636077 (abstract not
  cached; title only).
• Acetylation toggles direction (mouse and human enzymes studied). PMID:30193097 PMID:30193097
• Memory CD8+ T cells. PMID:29230018 PMID:29230018 Pck1 provides metabolic flux; it is not a
  differentiation regulator per se.
• Transcriptional control (Pck1 as target): ATF3 represses the promoter. PMID:11916968 HIF-1alpha liver KO lowers PEPCK. PMID:19643083

The PCK1 "protein kinase" / INSIG / SREBP claim (key issue)

• Single primary study, human HCC cells: PMID:32322062 PMID:32322062
• Only independent follow-up found by PubMed search ("PCK1 INSIG SREBP protein kinase" returns
  only these two): PRRSV infection in monkey MARC-145 cells. PMID:39433189 No mouse
  biochemical or genetic experiment on Pck1 kinase activity or Ser90 was found.
• UniProt mouse record carries the kinase activity only "By similarity" to human P35558
  (RHEA:64020, ECO:0000250).
• GO-CAM gomodel:6205c24300000880 (human SREBP model): PCK1 activity GO:0106264 (part_of
  GO:0046889, occurs_in ER) has RO:0002630 (directly negatively regulates) edges to INSIG2 and
  INSIG1 sterol-binding activities (GO:0008142), which are part_of GO:0036316 SREBP-SCAP complex
  retention in ER. Downstream: SCAP -> MBTPS1/MBTPS2 (GO:0051604 protein maturation) -> KPNB1
  (GO:0006607 NLS-bearing protein import into nucleus) -> SREBF1/2 (GO:0045542 positive regulation
  of cholesterol biosynthetic process). The GO-CAM-to-GAF conversion emitted
  acts_upstream_of_or_within rows for PCK1 to each of these downstream processes, which were then
  projected to mouse Pck1 by ISO (GO_REF:0000119, with UniProtKB:P35558). The current human PCK1
  GOA file in this repo has no GO:0036316 / GO:0051604 / GO:0006607 / GO:0045542 rows, so the
  mouse rows are stale relative to the source.
• Assessment: PCK1 is not part of the retention machinery; the model says it inhibits retention
  (opposite sign); evidence is one human cancer-cell study plus a monkey-cell virus study.
  -> MARK_AS_OVER_ANNOTATED for GO:0036316, GO:0051604, GO:0006607, GO:0045542; same for the
  GO:0106264 kinase rows, peptidyl-serine phosphorylation rows and (positive) regulation of lipid
  biosynthetic process rows, all of which trace to PMID:32322062. Do not propose SREBP terms as NEW.

Localization

• Cytosol is the principal compartment (IBA, IDA PMID:19458124, ISO). ER association is the
  AKT-phosphorylated pool in the human study; there is also a mouse IDA (PMID:19458124; abstract
  does not describe the localization data). Kept as non-core.
• Mitochondrion IBA (PTN000169230) is inherited from the node that also covers Pck2; mouse Pck1 is
  the cytosolic isozyme and has no transit peptide -> REMOVE.

GO term notes

• GO:0046327 "glycerol biosynthetic process from pyruvate" (synonym glyceroneogenesis) is obsolete
  and points to GO:0006114 glycerol biosynthetic process, so GO:0006114 is GO's intended term for
  glyceroneogenesis, even though the pathway product is glycerol 3-phosphate.