Affinage

PCMT1

Protein-L-isoaspartate(D-aspartate) O-methyltransferase · UniProt P22061

Length
227 aa
Mass
24.6 kDa
Annotated
2026-06-10
28 papers in source corpus 14 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCMT1 is an S-adenosylmethionine-dependent methyltransferase that repairs damaged proteins by acting on spontaneously formed isoaspartyl residues, a function whose physiological importance is evident in Pcmt1-deficient mice, which accumulate isomerized aspartyl proteins, develop constitutively activated brain insulin/PI3K-Akt-mTOR signaling, brain enlargement, and fatal seizures rescued by PI3K inhibition (PMID:23071621). Its substrate repertoire extends to chromatin, where it methylates histone H4 at Asp24 (H4D24me), a mark recognized by the chromodomain protein VprBP and linked to histone homeostasis (PMID:25327473), and to the catalysis of C-terminal cyclic imide modifications on CRBN substrates, co-regulating the metabolic enzymes GLUL and PPA1 (PMID:41461925, PMID:40196534). Beyond its canonical intracellular role, PCMT1 is unconventionally secreted and operates extracellularly: isoaspartate-bearing substrates and PCMT1 interactors are enriched in extracellular and membrane compartments (PMID:40287848). Secreted PCMT1 enzymatically reverses N63 deamidation on the TGFBR2 ectodomain, driving TGFBR2 ubiquitination and degradation to suppress TGF-β1/Smad signaling and kidney fibrosis (PMID:40036072), and in ovarian cancer it interacts with the ECM protein LAMB3 to activate integrin-FAK-Src signaling and promote migration and metastasis (PMID:35033172). PCMT1 abundance is controlled post-translationally by opposing ubiquitin machinery—LITAF promotes its ubiquitin-mediated degradation (PMID:42051267) while USP13 deubiquitinates and stabilizes it (PMID:42056074)—and at the transcript level by miR-195 targeting its 3'UTR (PMID:25119594). PCMT1 additionally suppresses MST1-mediated neuronal apoptosis after subarachnoid hemorrhage (PMID:28534197).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2012 High

    Established the physiological consequence of losing isoaspartyl repair in vivo, connecting accumulated damaged proteins to aberrant insulin/PI3K signaling and a lethal neurological phenotype.

    Evidence Pcmt1 knockout mice with pharmacological PI3K-inhibitor (wortmannin) epistasis and phospho-Akt/PDK1/mTOR immunoblotting

    PMID:23071621

    Open questions at the time
    • Does not identify the specific isoaspartyl substrate(s) driving insulin pathway activation
    • Mechanism linking protein damage to Akt/mTOR signaling not resolved
  2. 2014 High

    Extended PCMT1 substrate scope to chromatin by showing it methylates histone H4 Asp24, tying isoaspartyl repair to histone aging and a reader-based readout.

    Evidence In vitro methyltransferase assay, H4D24me-specific antibodies, and VprBP binding assay in mouse and human cells

    PMID:25327473

    Open questions at the time
    • Functional consequence of H4D24me for histone degradation only implicated, not demonstrated
    • Genome-wide distribution of the mark not mapped
  3. 2014 Medium

    Identified miR-195 as a direct negative regulator of PCMT1 expression, adding a post-transcriptional control layer.

    Evidence Dual luciferase reporter assay with pmirGLO-PCMT1 and pEGP-miR-195 co-transfection

    PMID:25119594

    Open questions at the time
    • Single-method validation without endogenous confirmation
    • Physiological context where miR-195 controls PCMT1 not defined
  4. 2017 Medium

    Placed PCMT1 in a neuroprotective pathway by showing it suppresses MST1-driven neuronal apoptosis, addressing whether the enzyme has signaling-level roles beyond repair.

    Evidence Rat subarachnoid hemorrhage model with pharmacological PCMT1 activation (CGP 3466B) and MST1 modulators, western blot and immunofluorescence

    PMID:28534197

    Open questions at the time
    • Whether PCMT1 acts on MST1 enzymatically or indirectly is unresolved
    • Pharmacological agonist specificity not established
  5. 2020 Medium

    Linked PCMT1 to immune cell fate, positioning it downstream of PKCθ/hnRNPL as a destabilizer of FOXP3 in regulatory T cells.

    Evidence Cell-penetrating peptide/antibody delivery, RNA processing analysis, and T cell differentiation assays

    PMID:32592691

    Open questions at the time
    • FOXP3 promoter methylation mechanism relies on limited methodological detail
    • Direct enzymatic activity of PCMT1 on FOXP3 promoter not biochemically shown
  6. 2022 High

    Revealed an extracellular, signaling function for secreted PCMT1 via LAMB3-integrin-FAK-Src to drive cancer cell metastasis.

    Evidence Genome-wide CRISPR knockout screen, IP-MS identification of LAMB3, live-cell imaging, and in vivo mouse models in ovarian cancer

    PMID:35033172

    Open questions at the time
    • Whether enzymatic isoaspartyl repair is required for the LAMB3 interaction is unclear
    • Mechanism of unconventional secretion not defined
  7. 2023 Low

    Associated PCMT1 with prostate cancer cell behavior through PI3K/AKT/GSK-3β signaling and with broad transcriptome/splicing remodeling in breast cancer.

    Evidence Overexpression/knockdown with xenografts and pathway western blots; shRNA knockdown with RNA-seq

    PMID:37899170 PMID:37953789

    Open questions at the time
    • Pathway placement based on correlative western blot without direct biochemical interaction
    • Transcriptomic changes lack defined mechanistic link to PCMT1 enzymatic activity
  8. 2025 High

    Defined a novel catalytic output—formation of C-terminal cyclic imides on CRBN substrates—connecting PCMT1 to E3-ligase-dependent control of metabolic enzyme levels.

    Evidence In vitro reconstitution, cell-based assays, and in vivo CRBN knockout mouse phenotype analysis (GLUL, PPA1)

    PMID:40196534 PMID:41461925

    Open questions at the time
    • Full substrate range of cyclic imide formation not enumerated
    • Relationship between cyclic imide activity and canonical isoaspartyl repair unclear
  9. 2025 High

    Demonstrated that secreted PCMT1 enzymatically reverses TGFBR2 deamidation to suppress pro-fibrotic TGF-β/Smad signaling, providing a defined extracellular substrate.

    Evidence IP, PTM mass spectrometry, lentiviral overexpression/knockout, and tubule-specific Pcmt1 knockout murine kidney fibrosis models

    PMID:40036072

    Open questions at the time
    • How deamidation reversal triggers TGFBR2 ubiquitination is not detailed
    • Generalizability to other receptor ectodomains untested
  10. 2025 Medium

    Mapped PCMT1 substrate and interactor compartments via multi-omics, supporting an extracellular/membrane repair function beyond the canonical intracellular role.

    Evidence isoD-proteomics, global proteomics, and transcriptomics in Pcmt1 KO vs WT mice plus overexpression cell proteomics

    PMID:40287848

    Open questions at the time
    • No direct enzymatic reconstitution of extracellular activity
    • Specific extracellular substrates not individually validated
  11. 2026 Medium

    Established opposing ubiquitin-system control of PCMT1 stability, with LITAF promoting degradation and USP13 stabilizing the enzyme, each tied to cancer drug sensitivity.

    Evidence Co-IP, ubiquitination/deubiquitination assays, and in vivo xenograft models in breast and prostate cancer

    PMID:42051267 PMID:42056074

    Open questions at the time
    • How PCMT1 mechanistically regulates COX-2 metabolism is not defined
    • Reciprocal validation and direct interaction interfaces not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PCMT1's canonical isoaspartyl repair activity mechanistically connects to its diverse signaling outputs (TGFBR2, LAMB3, MST1, CRBN cyclic imides) and how its secretion is controlled remains unresolved.
  • Unconventional secretion mechanism unknown
  • Whether each signaling role requires methyltransferase catalysis is untested
  • Unifying substrate determinants across compartments not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 2 GO:0042393 histone binding 1
Localization
GO:0005576 extracellular region 3 GO:0000228 nuclear chromosome 1 GO:0031012 extracellular matrix 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 1

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2025 PCMT1 promotes formation of C-terminal cyclic imide modifications on C-terminal asparagine residues of CRBN (cereblon) substrates, co-regulating levels of metabolic enzymes glutamine synthetase (GLUL) and inorganic pyrophosphatase 1 (PPA1) in vitro, in cells, and in vivo; this regulation is associated with the proepileptic phenotype of CRBN knockout mouse models. In vitro biochemical assays, cell-based experiments, in vivo mouse models, CRBN knockout phenotype analysis Nature chemical biology High 40196534 41461925
2025 PCMT1 is unconventionally secreted and enzymatically interacts with the ectodomain of TGF-β receptor 2 (TGFBR2), reversing N63 deamidation (isoaspartate formation) on TGFBR2, which triggers TGFBR2 ubiquitination and degradation, thereby suppressing TGF-β1/Smad signaling and inhibiting kidney fibrosis. Immunoprecipitation, gene lentivirus overexpression/knockout, post-translational modification mass spectrometry, tubule-specific Pcmt1 knockout murine models Journal of the American Society of Nephrology : JASN High 40036072
2022 PCMT1 is released extracellularly from ovarian cancer cells and interacts with the ECM protein LAMB3, which binds to integrin and activates FAK-Src signaling to promote cancer cell migration, adhesion, and metastasis. Immunoprecipitation followed by mass spectrometry (IP-MS), CRISPR/Cas9 knockout screen, western blot, live cell imaging, in vivo mouse models Journal of experimental & clinical cancer research : CR High 35033172
2014 PCMT1 methylates histone H4 at aspartate 24 (H4D24me), acting as a novel histone methyltransferase involved in protein repair of isoaspartate-containing histones; the H4D24me mark is specifically recognized by VprBP (a chromo domain-containing protein), potentially implicating H4D24me in H4 degradation and histone homeostasis. In vitro methyltransferase assay, generation of H4D24me-specific antibodies, in vivo chromatin analysis in mouse and human cells Scientific reports High 25327473
2017 PCMT1 inhibits neuronal apoptosis after subarachnoid hemorrhage by reducing MST1 phosphorylation and levels of cleaved MST1 (cl-MST1); pharmacological activation of PCMT1 with CGP 3466B reduced MST1 activity and apoptosis, while acceleration of MST1 phosphorylation (calyculin A) or increase in cl-MST1 (chelerythrine) reversed these neuroprotective effects. Rat SAH model, pharmacological agonist/antagonist administration, western blotting, immunofluorescence, intracerebroventricular drug delivery Translational stroke research Medium 28534197
2020 Protein kinase C theta (PKCθ) modulates PCMT1 expression through hnRNPL in induced regulatory T cells; PCMT1 acts as an instability factor by methylating the FOXP3 promoter, destabilizing FOXP3 expression. Cell-penetrating peptide mimic delivery of anti-PKCθ, RNA processing analysis, cell-penetrating antibody targeting PCMT1, T cell differentiation assays Molecular therapy : the journal of the American Society of Gene Therapy Medium 32592691
2012 Pcmt1-deficient mice accumulate isomerized aspartyl residues, have constitutively activated insulin signaling in the brain (elevated phospho-Akt, PDK1, mTOR), and show 20-30% brain enlargement leading to fatal seizures; wortmannin (PI3K inhibitor) reduced brain size toward wild-type and nearly doubled lifespan in Pcmt1-/- animals. Pcmt1 knockout mouse model, oral wortmannin administration, immunoblotting for phospho-Akt/PDK1/mTOR, brain size measurement, lifespan analysis PloS one High 23071621
2026 LITAF interacts with PCMT1 and promotes ubiquitination-mediated degradation of PCMT1, thereby inhibiting COX-2-mediated arachidonic acid metabolism and enhancing sensitivity of breast cancer cells to paclitaxel. Co-immunoprecipitation (Co-IP), ubiquitination assay, western blot, in vivo nude mouse model, metabolomics Frontiers in pharmacology Medium 42051267
2026 The deubiquitinating enzyme USP13 directly interacts with PCMT1 and removes polyubiquitination of PCMT1 to maintain its stability, promoting prostate cancer cell proliferation and enzalutamide resistance. Co-immunoprecipitation, ubiquitination assay, USP13 silencing in vitro and in vivo, prostate cancer cell and xenograft models Cell death & disease Medium 42056074
2025 Multi-omics analysis of Pcmt1 knockout mice revealed that PCMT1 substrates (isoaspartate-carrying proteins) accumulate predominantly in extracellular and membrane-related compartments; overexpressed PCMT1 interacts with proteins mainly in extracellular and membrane-related categories, indicating an extracellular repair function beyond its canonical intracellular role. isoD-proteomics, global proteomics, transcriptomics in Pcmt1 KO vs WT mice; proteomic analysis of PCMT1-overexpressing cells Journal of proteome research Medium 40287848
2014 hsa-miR-195 directly targets the PCMT1 3'UTR as validated by co-transfection of pmirGLO-PCMT1 and pEGP-miR-195 in a luciferase reporter assay, significantly decreasing PCMT1 expression. Dual luciferase reporter assay (pmirGLO-PCMT1 + pEGP-miR-195 co-transfection) Tumour biology Medium 25119594
2023 PCMT1 regulates migration, invasion, and apoptosis of prostate cancer cells by modulating the PI3K/AKT/GSK-3β signaling pathway, as demonstrated by PCMT1 overexpression and knockdown experiments in vitro and in vivo. PCMT1 overexpression and knockdown in prostate cancer cell lines, in vivo xenograft model, western blot for PI3K/AKT/GSK-3β pathway components Aging Low 37899170
2023 PCMT1 knockdown in triple-negative breast cancer MDA-MB-231 cells globally altered transcriptome profiles including 1,084 differentially expressed genes enriched in immune/inflammation and cell adhesion pathways, and 2,287 regulated alternative splicing events enriched in cell cycle pathways; 34 RNA binding protein genes were dysregulated. shRNA knockdown, RNA-seq transcriptome analysis, RT-PCR validation PeerJ Low 37953789

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Genome-wide CRISPR/Cas9 library screen identifies PCMT1 as a critical driver of ovarian cancer metastasis. Journal of experimental & clinical cancer research : CR 51 35033172
2014 Hsa-miR-195 targets PCMT1 in hepatocellular carcinoma that increases tumor life span. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 39 25119594
2017 PCMT1 Ameliorates Neuronal Apoptosis by Inhibiting the Activation of MST1 after Subarachnoid Hemorrhage in Rats. Translational stroke research 31 28534197
2018 PCMT1 is an unfavorable predictor and functions as an oncogene in bladder cancer. IUBMB life 29 29517839
1992 The L-isoaspartyl/D-aspartyl protein methyltransferase gene (PCMT1) maps to human chromosome 6q22.3-6q24 and the syntenic region of mouse chromosome 10. Genomics 22 1478665
2014 Methylation of histone H4 at aspartate 24 by protein L-isoaspartate O-methyltransferase (PCMT1) links histone modifications with protein homeostasis. Scientific reports 21 25327473
2025 Circular RNA circCLASP2 promotes nasopharyngeal carcinoma progression through binding to DHX9 to enhance PCMT1 translation. Molecular cancer 17 40050914
2005 A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida. Molecular genetics and metabolism 16 16256389
2021 LINC00511/miRNA-143-3p Modulates Apoptosis and Malignant Phenotype of Bladder Carcinoma Cells via PCMT1. Frontiers in cell and developmental biology 15 33898446
2020 Protein Kinase C Theta Modulates PCMT1 through hnRNPL to Regulate FOXP3 Stability in Regulatory T Cells. Molecular therapy : the journal of the American Society of Gene Therapy 13 32592691
2009 Posttranslational Protein Modifications in Type 1 Diabetes - Genetic Studies with PCMT1, the Repair Enzyme Protein Isoaspartate Methyltransferase (PIMT) Encoding Gene. The review of diabetic studies : RDS 11 19290383
2022 In vitro Anti-malignant Property of PCMT1 Silencing and Identification of the SNHG16/miR-195/PCMT1 Regulatory Axis in Breast Cancer Cells. Clinical breast cancer 9 36639265
2012 Wortmannin reduces insulin signaling and death in seizure-prone Pcmt1-/- mice. PloS one 9 23071621
2025 Repair of Isoaspartyl Residues by PCMT1 and Kidney Fibrosis. Journal of the American Society of Nephrology : JASN 8 40036072
2023 PCMT1 regulates the migration, invasion, and apoptosis of prostate cancer through modulating the PI3K/AKT/GSK-3β pathway. Aging 8 37899170
2013 PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case-control study in a population with relatively low folate intake. Genes & nutrition 8 23918616
2025 PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates. Nature chemical biology 6 41461925
2022 Elevated expression of protein-L-isoaspartate O-methyltransferase-1 (PCMT1) in cervical cancer. Translational cancer research 6 36093534
2012 Maternal PCMT1 gene polymorphisms and the risk of neural tube defects in a Chinese population of Lvliang high-risk area. Gene 6 22647835
2025 PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates. bioRxiv : the preprint server for biology 5 40196534
2023 PCMT1 knockdown attenuates malignant properties by globally regulating transcriptome profiles in triple-negative breast cancer cells. PeerJ 5 37953789
2024 Silencing PCMT1 enhances the sensitivity of breast cancer cells to paclitaxel through the PI3K/Akt/STMN1 pathway. Chemical biology & drug design 3 38853025
2020 Neural stem cell conditioned medium alleviates Aβ25-35 damage to SH-SY5Y cells through the PCMT1/MST1 pathway. European journal of histochemistry : EJH 2 32705859
2025 Multi-omics Analysis Sheds Light on the Extracellular Role of PCMT1. Journal of proteome research 1 40287848
2024 PCMT1 confirmed as a pan-cancer immune biomarker and a contributor to breast cancer metastasis. American journal of cancer research 1 39267673
2020 Retraction: Neural stem cell conditioned medium alleviates Aβ25-35 damage to SH-SY5Y cells through the PCMT1/MST1 pathway. European journal of histochemistry : EJH 1 33334092
2026 LITAF suppresses breast cancer and paclitaxel resistance by ubiquitinating and degrading PCMT1 to inhibit COX-2-dependent arachidonic acid metabolism. Frontiers in pharmacology 0 42051267
2026 USP13 promotes enzalutamide resistance by catalyzing depolyubiquitination of PCMT1 in prostate cancer. Cell death & disease 0 42056074

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