PADI1

PADI1 is a calcium-dependent peptidylarginine deiminase that reprogrammes substrate protein function through site-specific citrullination, with broad consequences for cell metabolism, migration, and stress signaling (PMID:33741961). Biochemically, PADI1 citrullinates pyruvate kinase M2 (PKM2) at R106, altering allosteric cross-talk among PKM2 ligands — lowering sensitivity to the inhibitors tryptophan, alanine, and phenylalanine while enhancing serine-driven activation — so that PKM2 bypasses normal regulation by low serine and drives excessive glycolysis (PMID:33741961). In keratinocytes, PADI1 transcription is driven by the transcription factors MZF1 and Sp1/Sp3, which bind its promoter, and MZF1 rises in parallel with PADI1 during differentiation (PMID:17851584). Beyond its biochemical activity, PADI1 acts upstream of MAPK cascades in disease contexts: it promotes pancreatic ductal adenocarcinoma migration, invasion, and EMT via ERK1/2-p38 signaling (PMID:34295566), and it drives endoplasmic reticulum stress and apoptosis in trophoblast cells through the FAK/ERK1/2 pathway (PMID:40424721). Apart from the PKM2 R106 site, additional direct substrates underlying these signaling phenotypes have not been identified in the available corpus.

1. 2007 High

   Established how PADI1 expression is controlled, identifying the transcriptional inputs that couple it to keratinocyte differentiation.

   Evidence Promoter deletion/luciferase reporters, binding-site mutagenesis, ChIP, and siRNA knockdown in human keratinocytes

   PMID:17851584

   Open questions at the time

   • Does not address PADI1 enzymatic substrates or catalytic mechanism
   • Regulation outside keratinocyte differentiation not examined
   • No link drawn between transcriptional control and downstream citrullination targets
2. 2021 High

   Defined a direct molecular substrate and catalytic consequence for PADI1, showing that citrullination of PKM2 R106 reprogrammes allosteric ligand cross-talk to drive glycolysis.

   Evidence Mass spectrometry site mapping, biochemical activity assays, and knockdown/overexpression with metabolic readouts in cancer cells under hypoxia

   PMID:33741961

   Open questions at the time

   • Whether PKM2 is the principal substrate driving phenotypes in other cell types is unknown
   • No structural model of the PADI1-PKM2 interaction
   • Calcium-dependence and regulation of PADI1 catalytic activity in vivo not detailed
3. 2021 Medium

   Placed PADI1 upstream of a MAPK cascade in cancer cell motility, linking its activity to migration, invasion, and EMT.

   Evidence siRNA knockdown/cDNA overexpression in PAAD cells with wound-healing, Transwell, western blot, and MEK1/2 inhibitor epistasis

   PMID:34295566

   Open questions at the time

   • No direct citrullination substrate identified to connect PADI1 enzymatic activity to ERK1/2-p38 activation
   • Pathway placement rests on pharmacological epistasis from a single lab
   • Whether catalytic activity is required for the phenotype is untested
4. 2025 Medium

   Extended PADI1's signaling role to trophoblast ER stress, showing it acts upstream of FAK/ERK1/2 to promote stress-induced apoptosis.

   Evidence siRNA knockdown in HTR-8 and Swan-71 cells, thapsigargin-induced ERS model, ERS marker western blots, and FAK/ERK1/2 inhibitor epistasis

   PMID:40424721

   Open questions at the time

   • No biochemical substrate identified linking PADI1 to FAK/ERK1/2
   • Single-lab pharmacological epistasis without catalytic-dead controls
   • Physiological relevance to placental disease not established

• Whether the diverse signaling phenotypes (ERK1/2-p38, FAK/ERK1/2) depend on PADI1's deiminase activity and which citrullinated substrates mediate them remains unresolved.
• No substrate beyond PKM2 R106 identified for the signaling phenotypes
• Catalytic requirement for migration/invasion and ERS phenotypes untested
• No structural data on PADI1 substrate recognition