{"gene":"FOLH1","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":1999,"finding":"PSMA (FOLH1) is a type II integral membrane glycoprotein expressed on the surface of prostate cancer cells and in tumor-associated neovasculature of a wide spectrum of malignant neoplasms; antibodies to the extracellular domain (J591, J415) bind viable prostate cancer cells whereas antibodies to the intracellular domain (7E11) do not, establishing domain topology and accessibility.","method":"Immunohistochemistry with five distinct anti-PSMA monoclonal antibodies on viable cell lines and fresh-frozen tissue; CD34 co-staining for endothelial confirmation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple antibodies targeting distinct epitopes, replicated across many tumor types, strong preponderance of evidence","pmids":["10397265"],"is_preprint":false},{"year":2004,"finding":"PSMA has two enzymatic activities—folate hydrolase (gamma-glutamyl carboxypeptidase) and NAALADase (N-acetylated alpha-linked acidic dipeptidase)—and undergoes internalization via clathrin-coated pits, consistent with receptor recycling behavior.","method":"Review consolidating enzymatic activity assays and prior internalization studies","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1 — enzymatic activities established by direct assays cited across multiple independent studies; clathrin-coated pit internalization confirmed experimentally","pmids":["14755683"],"is_preprint":false},{"year":2001,"finding":"The mouse homolog of PSMA (Folh1) encodes a glutamate-preferring carboxypeptidase with both NAALADase and folate hydrolase activities; cells transfected with Folh1 gained both enzymatic activities, confirming the functional equivalence of mouse Folh1 and human PSMA/FOLH1.","method":"cDNA cloning, transfection-based enzymatic activity assays (NAALADase and folate hydrolase), FISH chromosomal mapping, tissue expression analysis","journal":"Mammalian genome","confidence":"High","confidence_rationale":"Tier 1 — direct reconstitution by transfection with enzymatic readout; both activities confirmed","pmids":["11210180"],"is_preprint":false},{"year":1999,"finding":"NAALADase (FOLH1/GCPII) hydrolyzes NAAG to N-acetylaspartate and glutamate; selective inhibition with 2-PMPA reduces extracellular glutamate, increases NAAG, and is neuroprotective in ischemic models, establishing the enzyme's role in glutamate homeostasis in the brain.","method":"In vitro neuronal culture stroke model; in vivo rat transient middle cerebral artery occlusion; microdialysis measurement of extracellular glutamate and NAAG","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic inhibition combined with in vivo pharmacological intervention with defined biochemical readouts; replicated across models","pmids":["10581082"],"is_preprint":false},{"year":1992,"finding":"NAALADase (FOLH1) protein is localized to neuropil (not neuronal cytoplasm) in rat brain regions enriched in NAAG, and to the brush border of proximal convoluted tubules in kidney, consistent with its role in extracellular NAAG catabolism.","method":"Immunocytochemistry with specific anti-NAALADase antiserum in rat brain and kidney sections","journal":"The Journal of comparative neurology","confidence":"High","confidence_rationale":"Tier 2 — direct immunolocalization with specific antiserum; co-localization with NAAG-IR regions supports functional assignment","pmids":["1545010"],"is_preprint":false},{"year":1998,"finding":"Brain NAALADase and prostate PSMA (FOLH1) are the same enzyme: they share identical kinetic profiles, pharmacological sensitivities, common mRNA splice forms (2.8-, 4.0-, and 6.0-kb species), and the anti-PSMA mAb 7E11-C5 immunoprecipitates 82% of cerebellar NAALADase activity.","method":"Kinetic enzyme assays, Northern hybridization, RT-PCR cloning of cerebellar cDNA, immunoprecipitation with anti-PSMA antibody","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (kinetics, Northern, RT-PCR, immunoprecipitation) in single study confirming identity of brain and prostate forms","pmids":["9694964"],"is_preprint":false},{"year":2003,"finding":"Filamin A, an actin cross-linking protein, associates with the cytoplasmic tail of PSMA; this interaction localizes PSMA to the recycling endosomal compartment, reduces its internalization rate, and decreases its NAALADase activity.","method":"Co-immunoprecipitation, ectopic PSMA expression in filamin-negative vs. filamin-positive cell lines, NAALADase activity assays, subcellular fractionation/localization","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional readout (internalization rate and enzymatic activity) in isogenic filamin+/- cell systems","pmids":["12750292"],"is_preprint":false},{"year":2001,"finding":"A tissue-specific enhancer (PSME) located in the third intron (~12 kb downstream of the transcription start) of the FOLH1 gene drives prostate-selective expression; it contains a 72-bp direct repeat, activates transcription >250-fold in LNCaP cells, and its activity is repressed by androgen, mirroring regulation of the endogenous gene.","method":"Enhancer trap assay with overlapping genomic DNA fragments, luciferase reporter assays in prostate and non-prostate cell lines, androgen treatment experiments","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 — enhancer functionally characterized with reporter assays in multiple cell lines plus androgen regulation confirmed","pmids":["11350116"],"is_preprint":false},{"year":2016,"finding":"FOLH1/GCPII enzymatic activity is elevated 2.8- to 41-fold in the affected intestinal mucosa of IBD patients; pharmacological inhibition of this activity with 2-PMPA ameliorates disease in DSS colitis and IL-10−/− mouse models, and FOLH1 knockout mice are resistant to DSS-induced colitis.","method":"Enzymatic activity quantification in surgical specimens, two murine IBD models (DSS colitis and IL-10−/− spontaneous colitis), genetic knockout, pharmacological inhibition with 2-PMPA","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 — human enzymatic activity data corroborated by pharmacological inhibition and genetic knockout in two mouse models; multiple orthogonal approaches","pmids":["27536732"],"is_preprint":false},{"year":2016,"finding":"Cancer cell-conditioned media induces PSMA expression in human umbilical vein endothelial cells (HUVECs) in vitro, and cancer cell co-implantation induces PSMA expression in HUVECs in vivo; PSMA-induced HUVECs can internalize the anti-PSMA mAb J591 and PSMA-binding ligand nanoparticles, demonstrating that tumor cell crosstalk drives neovascular PSMA expression.","method":"Conditioned media experiments, HUVEC-cancer cell co-implantation mouse model, internalization assays with fluorescent-labeled J591 mAb and nanoparticles","journal":"Molecular cancer research","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo induction experiments with functional internalization readout; mechanistic link between tumor cell signals and endothelial PSMA established","pmids":["27458033"],"is_preprint":false},{"year":2018,"finding":"Neuroendocrine differentiation of prostate cancer suppresses FOLH1/PSMA expression; PSMA suppression is associated with loss of p53 and NE induction, and PSMA-suppressed cells show increased colony formation and resistance to enzalutamide.","method":"Transcript analysis across 909 tumors, NE-induced cell line models with hormone depletion and p53 loss, flow cytometry for protein expression, 18 NEPC patient-derived xenograft models","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic link between NE lineage plasticity and FOLH1 suppression supported by cell and PDX models, though causal mechanism not fully dissected","pmids":["30400059"],"is_preprint":false},{"year":2023,"finding":"PSMA (FOLH1) expression heterogeneity in metastatic castration-resistant prostate cancer is mediated by reversible epigenetic mechanisms: PSMA-negative tumors show gain of CpG methylation and loss of H3K27 acetylation at the FOLH1 locus; HDAC inhibitor treatment restores PSMA expression in vitro and in vivo.","method":"ChIP-seq for H3K27ac, DNA methylation analysis, HDAC inhibitor treatment in cell lines and xenograft models, autopsy cohort multi-site sampling","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 — epigenetic marks identified by ChIP, functional rescue by HDAC inhibitors in vitro and in vivo; multiple orthogonal methods","pmids":["36821396"],"is_preprint":false},{"year":2018,"finding":"Sox7 negatively regulates PSMA expression by directly binding to the PSMA enhancer (PSME) through SOX box sites #2 and #4; the nuclear localization sequences (NLS) but not the β-catenin interaction motif of Sox7 are required for this repression.","method":"ChIP assay, EMSA, luciferase reporter assay, stable Sox7 expression in LNCaP/C4-2 and 22Rv1 cells, Sox7 domain mutant analysis","journal":"The Prostate","confidence":"High","confidence_rationale":"Tier 1-2 — direct DNA binding shown by EMSA and ChIP with functional confirmation by reporter assay and gain-of-function; domain requirements mapped by mutagenesis","pmids":["30488457"],"is_preprint":false},{"year":2003,"finding":"Mouse Folh1 (PSMA homolog) is expressed at highest levels in kidney and brain (not in prostate tumor in TRAMP mice); folate hydrolase activity in tissues parallels Folh1 mRNA expression, confirming the enzyme's tissue-specific catalytic activity.","method":"Real-time quantitative PCR, folate hydrolase activity assays in multiple tissues of TRAMP and control mice","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 1 — direct enzymatic activity correlated with mRNA; single lab, moderate evidence","pmids":["12712410"],"is_preprint":false},{"year":2024,"finding":"PSMA expression is regulated by a transcription complex that acts on the FOLH1 promoter via a looping upstream enhancer, intergenic enhancers, and differentially methylated regions; PSMA suppression mechanisms include lineage plasticity, tumor microenvironment, and epigenetic silencing.","method":"Review integrating ChIP, DNA methylation, and enhancer-looping data from prior molecular studies","journal":"Nature reviews. Urology","confidence":"Medium","confidence_rationale":"Tier 2 — review synthesizing multiple mechanistic studies; assigned medium because primary data cited but this paper itself is a review","pmids":["38977769"],"is_preprint":false},{"year":2021,"finding":"Androgen receptor blockade by enzalutamide increases PSMA expression in PSMA-low prostate cancer cell lines (22Rv1) 2.2-fold and in PSMA-high lines (C4-2, LNCaP) ~2.3–2.6-fold; this is confirmed in vivo by 68Ga-PSMA PET in a xenograft model and in an mCRPC patient.","method":"Flow cytometry, immunohistochemistry, 68Ga-PSMA PET/CT in NOD/Scid xenograft mouse model, clinical case","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — AR blockade-PSMA upregulation demonstrated in cell lines, xenograft, and clinical case; mechanism (AR repression of FOLH1) consistent with known enhancer androgen regulation","pmids":["34299051"],"is_preprint":false},{"year":1996,"finding":"PSMA functions as both a neurocarboxypeptidase and a membrane folate hydrolase; an alternatively spliced form, PSM', localizes to the cytoplasm in normal prostate, while PSMA itself is a type II membrane protein.","method":"Biochemical characterization, cloning, localization studies cited in review","journal":"Der Urologe. Ausg. A","confidence":"Medium","confidence_rationale":"Tier 2 — functional enzymatic activities and alternative splice isoform localization established by primary experiments summarized in review","pmids":["8999630"],"is_preprint":false},{"year":2018,"finding":"RNA aptamers (xPSM-A9 and xPSM-A10) that bind to the extracellular domain of PSMA inhibit its glutamate carboxypeptidase enzymatic activity and internalize into PSMA-expressing cancer cells, demonstrating that extracellular domain engagement is sufficient to inhibit catalytic function and trigger endocytosis.","method":"In vitro selection (SELEX) of 2'-fluorpyrimidine RNA aptamers, glutamate carboxypeptidase activity inhibition assay, internalization assays in PSMA-expressing prostate cancer cells","journal":"American journal of clinical and experimental urology","confidence":"Medium","confidence_rationale":"Tier 2 — functional inhibition and internalization confirmed by direct assay; moderate evidence from single lab","pmids":["29666835"],"is_preprint":false},{"year":2016,"finding":"FOLH1/GCPII enzymatic activity is elevated in colorectal tissues of mice with TNBS-induced colitis; 2-PMPA inhibits colonic GCPII activity by >90% and reduces disease activity when administered locally as an enema.","method":"Ex vivo enzymatic activity assays, TNBS-induced colitis mouse model, local enema delivery of 2-PMPA, macroscopic and microscopic disease scoring","journal":"Journal of controlled release","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibition with direct enzymatic readout in disease model; single lab","pmids":["28159515"],"is_preprint":false},{"year":2016,"finding":"MDM2 knockdown reduces PSMA expression and vice versa in metastatic breast cancer cells; siRNA-mediated PSMA knockdown decreases cell growth, adhesion, migration, and invasion, and alters MMP expression (decreasing MMP2, increasing MMP3/10/13), placing PSMA in a pathway regulating matrix metalloproteinase activity.","method":"siRNA knockdown, qPCR, western blotting, proliferation/adhesion/migration/invasion assays in MDA-MB-231 and ZR-75.1 cells","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 3 — loss-of-function with defined cellular phenotype and pathway placement; single lab, moderate methods","pmids":["26977010"],"is_preprint":false}],"current_model":"FOLH1/PSMA is a type II transmembrane glycoprotein with two intrinsic enzymatic activities—NAALADase (hydrolyzing NAAG to N-acetylaspartate and glutamate) and folate hydrolase—whose tissue-specific prostate expression is driven by an intronic enhancer (PSME) repressed by androgen and Sox7, whose surface density is regulated by filamin A-mediated retention in recycling endosomes and by clathrin-dependent internalization, and whose expression can be epigenetically silenced via CpG methylation and H3K27 deacetylation at the FOLH1 locus or suppressed by neuroendocrine lineage transition and androgen receptor activation, while being expressed in tumor-associated neovasculature through paracrine induction by cancer cell-secreted factors."},"narrative":{"teleology":[{"year":1992,"claim":"Establishing where NAALADase protein resides in vivo resolved that this enzyme acts extracellularly in brain neuropil and at the kidney brush border, consistent with a role in catabolism of extracellular substrates.","evidence":"Immunocytochemistry with specific anti-NAALADase antiserum in rat brain and kidney sections","pmids":["1545010"],"confidence":"High","gaps":["Prostate expression not yet linked to the same gene product","Substrate access and regulation of activity in situ unknown"]},{"year":1998,"claim":"Demonstrating that brain NAALADase and prostate PSMA are the same gene product unified two fields and established FOLH1 as a single gene encoding both enzymatic activities in distinct tissues.","evidence":"Kinetic enzyme assays, Northern blots, RT-PCR cloning, and immunoprecipitation with anti-PSMA mAb 7E11-C5 capturing 82% of cerebellar NAALADase activity","pmids":["9694964"],"confidence":"High","gaps":["Tissue-specific transcriptional regulation not yet characterized","Structural basis for dual enzymatic activities unknown"]},{"year":1999,"claim":"Defining PSMA domain topology on viable cells and its expression in tumor-associated neovasculature established the protein as a surface-accessible target in cancer and revealed an unexpected non-prostate expression pattern.","evidence":"Immunohistochemistry with five monoclonal antibodies targeting distinct PSMA epitopes on viable cells and fresh-frozen tumor tissues; CD34 co-staining","pmids":["10397265"],"confidence":"High","gaps":["Mechanism driving neovascular expression unresolved","Functional role of PSMA in endothelial cells unknown"]},{"year":1999,"claim":"Pharmacological inhibition of NAALADase with 2-PMPA established that FOLH1 enzymatic activity directly controls extracellular glutamate levels and that its inhibition is neuroprotective, providing the first functional consequence of FOLH1 catalysis in vivo.","evidence":"In vitro neuronal ischemia model and in vivo rat MCAO with microdialysis measurement of glutamate and NAAG","pmids":["10581082"],"confidence":"High","gaps":["Genetic loss-of-function confirmation in brain not shown","Downstream signaling pathways from glutamate release not dissected"]},{"year":2001,"claim":"Identification of the PSME intronic enhancer and its androgen-mediated repression explained how FOLH1 achieves prostate-selective expression and why androgen deprivation upregulates PSMA, a key clinical observation.","evidence":"Enhancer trap assay, luciferase reporters in prostate/non-prostate lines, androgen treatment experiments","pmids":["11350116"],"confidence":"High","gaps":["Transcription factors binding PSME not identified","Chromatin architecture at enhancer-promoter loop not mapped"]},{"year":2001,"claim":"Reconstitution of mouse Folh1 confirmed functional conservation of both NAALADase and folate hydrolase activities, validating the mouse as a model for FOLH1 biology.","evidence":"Transfection of Folh1 cDNA into cells with enzymatic activity assays for both NAALADase and folate hydrolase","pmids":["11210180"],"confidence":"High","gaps":["Physiological importance of folate hydrolase activity in vivo not tested"]},{"year":2003,"claim":"Discovery that filamin A interacts with the PSMA cytoplasmic tail and retains it in recycling endosomes provided the first mechanism for post-translational regulation of PSMA surface density and enzymatic activity.","evidence":"Co-immunoprecipitation, comparison of filamin-positive vs. filamin-negative isogenic cell lines, NAALADase activity assays, subcellular fractionation","pmids":["12750292"],"confidence":"High","gaps":["Structural basis of filamin A–PSMA interaction not mapped at residue level","In vivo relevance of filamin A regulation not established"]},{"year":2016,"claim":"Genetic knockout and pharmacological inhibition in multiple colitis models established FOLH1 enzymatic activity as a pathogenic driver of intestinal inflammation, extending its functional significance beyond the nervous system.","evidence":"FOLH1-knockout mice resistant to DSS colitis; 2-PMPA ameliorates disease in DSS and IL-10−/− models; elevated GCPII activity in IBD patient specimens","pmids":["27536732","28159515"],"confidence":"High","gaps":["Substrate (NAAG or folate) mediating intestinal pathology not identified","Cell type expressing FOLH1 in gut mucosa not resolved"]},{"year":2016,"claim":"Conditioned media and co-implantation experiments demonstrated that tumor cell-secreted factors are sufficient to induce PSMA expression on endothelial cells, explaining the neovascular PSMA expression seen across solid tumors.","evidence":"Cancer cell-conditioned media treatment of HUVECs in vitro; HUVEC–cancer cell co-implantation in mice with J591 internalization readout","pmids":["27458033"],"confidence":"High","gaps":["Identity of the inducing factor(s) not determined","Signaling pathway in endothelial cells not characterized"]},{"year":2018,"claim":"Identification of Sox7 as a direct transcriptional repressor binding PSME resolved a specific trans-acting factor controlling PSMA expression, with its NLS but not β-catenin interaction required for repression.","evidence":"ChIP, EMSA, luciferase reporters, stable Sox7 expression in prostate cancer lines, domain mutagenesis","pmids":["30488457"],"confidence":"High","gaps":["Other transcription factors binding PSME not systematically identified","Sox7 regulation in prostate cancer progression unknown"]},{"year":2018,"claim":"Neuroendocrine differentiation was shown to suppress FOLH1 expression, linking lineage plasticity to loss of PSMA and resistance to AR-targeted therapy, a clinically important escape mechanism.","evidence":"Transcript analysis of 909 tumors, NE-induced cell models with p53 loss, 18 NEPC PDX models","pmids":["30400059"],"confidence":"Medium","gaps":["Direct transcriptional mechanism of NE-driven FOLH1 suppression not dissected","Whether PSMA loss is cause or consequence of NE phenotype unclear"]},{"year":2023,"claim":"Epigenetic profiling revealed that PSMA-negative prostate tumors acquire CpG methylation and lose H3K27ac at the FOLH1 locus, and that HDAC inhibitors restore PSMA expression, establishing a reversible epigenetic silencing mechanism.","evidence":"ChIP-seq, DNA methylation analysis, HDAC inhibitor treatment in cell lines and xenografts, multi-site autopsy sampling","pmids":["36821396"],"confidence":"High","gaps":["Specific HDAC isoforms responsible not identified","Durability of epigenetic re-expression in patients not tested"]},{"year":null,"claim":"The identity of tumor-secreted factors that induce PSMA on neovasculature, the substrate mediating FOLH1's pathogenic role in colitis, and the complete set of transcription factors governing tissue-specific FOLH1 expression remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Paracrine inducer of neovascular PSMA not identified","NAAG vs. folate substrate relevance in gut inflammation not determined","Full enhancer-promoter looping architecture at FOLH1 locus not mapped in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,2,3,5,8,13,17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,6,16]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2,3,8,13]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,11,12,14,15]}],"complexes":[],"partners":["FLNA","SOX7"],"other_free_text":[]},"mechanistic_narrative":"FOLH1 (also known as PSMA/GCPII) is a type II transmembrane glycoprotein that functions as a dual-specificity metallopeptidase, catalyzing both the hydrolysis of N-acetylaspartylglutamate (NAAG) to N-acetylaspartate and glutamate in the nervous system (NAALADase activity) and the sequential removal of gamma-linked glutamates from folylpolyglutamates (folate hydrolase activity) [PMID:9694964, PMID:11210180]. In the brain, its NAALADase activity regulates extracellular glutamate levels and NAAG signaling, and pharmacological inhibition with 2-PMPA is neuroprotective in ischemia models [PMID:10581082]; in the intestinal mucosa, elevated FOLH1 activity contributes to inflammatory bowel disease pathology, as demonstrated by resistance of Folh1-knockout mice to experimental colitis [PMID:27536732]. Prostate-selective expression is driven by an intronic enhancer (PSME) repressed by androgen receptor signaling and the transcription factor Sox7, while surface density is modulated by filamin A-mediated retention in recycling endosomes and clathrin-dependent internalization [PMID:11350116, PMID:30488457, PMID:12750292]. Expression heterogeneity in prostate cancer is governed by reversible epigenetic silencing through CpG methylation and H3K27 deacetylation at the FOLH1 locus, and by neuroendocrine lineage transitions that suppress FOLH1 transcription [PMID:36821396, PMID:30400059]."},"prefetch_data":{"uniprot":{"accession":"Q04609","full_name":"Glutamate carboxypeptidase 2","aliases":["Cell growth-inhibiting gene 27 protein","Folate hydrolase 1","Folylpoly-gamma-glutamate carboxypeptidase","FGCP","Glutamate carboxypeptidase II","GCPII","Membrane glutamate carboxypeptidase","mGCP","N-acetylated-alpha-linked acidic dipeptidase I","NAALADase I","Prostate-specific membrane antigen","PSM","PSMA","Pteroylpoly-gamma-glutamate carboxypeptidase"],"length_aa":750,"mass_kda":84.3,"function":"Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Has a preference for tri-alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), thereby releasing glutamate. Involved in prostate tumor progression Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q04609/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FOLH1","classification":"Not Classified","n_dependent_lines":56,"n_total_lines":1208,"dependency_fraction":0.046357615894039736},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FOLH1","total_profiled":1310},"omim":[{"mim_id":"618754","title":"CARBOXYPEPTIDASE Q; CPQ","url":"https://www.omim.org/entry/618754"},{"mim_id":"611636","title":"N-ACETYLATED ALPHA-LINKED ACIDIC DIPEPTIDASE 2; NAALAD2","url":"https://www.omim.org/entry/611636"},{"mim_id":"602640","title":"N-ACETYLATED ALPHA-LINKED ACIDIC DIPEPTIDASE-LIKE 1; NAALADL1","url":"https://www.omim.org/entry/602640"},{"mim_id":"600934","title":"FOLATE HYDROLASE 1; FOLH1","url":"https://www.omim.org/entry/600934"},{"mim_id":"260600","title":"LEUKODYSTROPHY, HYPOMYELINATING, 3; HLD3","url":"https://www.omim.org/entry/260600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":250.9},{"tissue":"prostate","ntpm":71.4}],"url":"https://www.proteinatlas.org/search/FOLH1"},"hgnc":{"alias_symbol":["PSM","PSMA","NAALAD1","NAALAdase","GCP2","GCPII"],"prev_symbol":["FOLH"]},"alphafold":{"accession":"Q04609","domains":[{"cath_id":"3.40.630.10","chopping":"55-118_353-468_516-590","consensus_level":"high","plddt":97.497,"start":55,"end":590},{"cath_id":"3.50.30.30","chopping":"127-347","consensus_level":"high","plddt":96.9761,"start":127,"end":347},{"cath_id":"1.20.930.40","chopping":"598-747","consensus_level":"high","plddt":95.862,"start":598,"end":747}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04609","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q04609-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q04609-F1-predicted_aligned_error_v6.png","plddt_mean":93.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FOLH1","jax_strain_url":"https://www.jax.org/strain/search?query=FOLH1"},"sequence":{"accession":"Q04609","fasta_url":"https://rest.uniprot.org/uniprotkb/Q04609.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q04609/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04609"}},"corpus_meta":[{"pmid":"10397265","id":"PMC_10397265","title":"Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10397265","citation_count":723,"is_preprint":false},{"pmid":"14755683","id":"PMC_14755683","title":"Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer.","date":"2004","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14755683","citation_count":662,"is_preprint":false},{"pmid":"26985056","id":"PMC_26985056","title":"PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617.","date":"2016","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26985056","citation_count":486,"is_preprint":false},{"pmid":"26902337","id":"PMC_26902337","title":"Current use of PSMA-PET in prostate cancer management.","date":"2016","source":"Nature reviews. Urology","url":"https://pubmed.ncbi.nlm.nih.gov/26902337","citation_count":475,"is_preprint":false},{"pmid":"26089548","id":"PMC_26089548","title":"68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies.","date":"2015","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26089548","citation_count":422,"is_preprint":false},{"pmid":"10581082","id":"PMC_10581082","title":"Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury.","date":"1999","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10581082","citation_count":261,"is_preprint":false},{"pmid":"24645697","id":"PMC_24645697","title":"Prostate specific membrane antigen (PSMA) expression in primary gliomas and breast cancer brain metastases.","date":"2014","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/24645697","citation_count":166,"is_preprint":false},{"pmid":"11210180","id":"PMC_11210180","title":"Cloning, expression, genomic localization, and enzymatic activities of the mouse homolog of prostate-specific membrane antigen/NAALADase/folate hydrolase.","date":"2001","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/11210180","citation_count":142,"is_preprint":false},{"pmid":"29674422","id":"PMC_29674422","title":"A Perspective on the Evolving Story of PSMA Biology, PSMA-Based Imaging, and Endoradiotherapeutic Strategies.","date":"2018","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29674422","citation_count":141,"is_preprint":false},{"pmid":"30400059","id":"PMC_30400059","title":"Neuroendocrine differentiation of prostate cancer leads to PSMA suppression.","date":"2018","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30400059","citation_count":138,"is_preprint":false},{"pmid":"28775203","id":"PMC_28775203","title":"Immunohistochemical Validation of PSMA Expression Measured by 68Ga-PSMA PET/CT in Primary Prostate Cancer.","date":"2017","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28775203","citation_count":138,"is_preprint":false},{"pmid":"31227053","id":"PMC_31227053","title":"PSMA-Targeted Radiopharmaceuticals for Imaging and Therapy.","date":"2019","source":"Seminars in nuclear medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31227053","citation_count":122,"is_preprint":false},{"pmid":"34050265","id":"PMC_34050265","title":"Advances in PSMA-targeted therapy for prostate cancer.","date":"2021","source":"Prostate cancer and prostatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/34050265","citation_count":113,"is_preprint":false},{"pmid":"23777916","id":"PMC_23777916","title":"PSA-responsive and PSMA-mediated multifunctional liposomes for targeted therapy of prostate cancer.","date":"2013","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/23777916","citation_count":103,"is_preprint":false},{"pmid":"29191856","id":"PMC_29191856","title":"PSMA-11-Derived Dual-Labeled PSMA Inhibitors for Preoperative PET Imaging and Precise Fluorescence-Guided Surgery of Prostate Cancer.","date":"2017","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29191856","citation_count":101,"is_preprint":false},{"pmid":"15168332","id":"PMC_15168332","title":"Expression of prostate specific membrane antigen (PSMA) in prostatic adenocarcinoma and prostatic intraepithelial neoplasia.","date":"2004","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/15168332","citation_count":94,"is_preprint":false},{"pmid":"38977769","id":"PMC_38977769","title":"Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer.","date":"2024","source":"Nature reviews. Urology","url":"https://pubmed.ncbi.nlm.nih.gov/38977769","citation_count":90,"is_preprint":false},{"pmid":"11350116","id":"PMC_11350116","title":"A tissue-specific enhancer of the prostate-specific membrane antigen gene, FOLH1.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11350116","citation_count":89,"is_preprint":false},{"pmid":"23592990","id":"PMC_23592990","title":"Mobile genetic element SCCmec-encoded psm-mec RNA suppresses translation of agrA and attenuates MRSA virulence.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/23592990","citation_count":89,"is_preprint":false},{"pmid":"1545010","id":"PMC_1545010","title":"Immunocytochemical localization of the N-acetyl-aspartyl-glutamate (NAAG) hydrolyzing enzyme N-acetylated alpha-linked acidic dipeptidase (NAALADase).","date":"1992","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/1545010","citation_count":87,"is_preprint":false},{"pmid":"9694964","id":"PMC_9694964","title":"Molecular characterization of human brain N-acetylated alpha-linked acidic dipeptidase (NAALADase).","date":"1998","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/9694964","citation_count":79,"is_preprint":false},{"pmid":"28701709","id":"PMC_28701709","title":"PSMA expression by microvasculature of thyroid tumors - Potential implications for PSMA theranostics.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28701709","citation_count":73,"is_preprint":false},{"pmid":"12750292","id":"PMC_12750292","title":"Prostate-specific membrane antigen association with filamin A modulates its internalization and NAALADase activity.","date":"2003","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12750292","citation_count":73,"is_preprint":false},{"pmid":"21627141","id":"PMC_21627141","title":"Construction of a DOPC/PSM/cholesterol phase diagram based on the fluorescence properties of trans-parinaric acid.","date":"2011","source":"Langmuir : the ACS journal of surfaces and colloids","url":"https://pubmed.ncbi.nlm.nih.gov/21627141","citation_count":71,"is_preprint":false},{"pmid":"36821396","id":"PMC_36821396","title":"Reversible epigenetic alterations mediate PSMA expression heterogeneity in advanced metastatic prostate cancer.","date":"2023","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/36821396","citation_count":67,"is_preprint":false},{"pmid":"29426963","id":"PMC_29426963","title":"Prostate-specific membrane antigen (PSMA) expression in breast cancer and its metastases.","date":"2018","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/29426963","citation_count":67,"is_preprint":false},{"pmid":"28986509","id":"PMC_28986509","title":"Why Targeting PSMA Is a Game Changer in the Management of Prostate Cancer.","date":"2017","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28986509","citation_count":66,"is_preprint":false},{"pmid":"11375762","id":"PMC_11375762","title":"Design of NAALADase inhibitors: a novel neuroprotective strategy.","date":"2001","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11375762","citation_count":64,"is_preprint":false},{"pmid":"11502739","id":"PMC_11502739","title":"Four PSM/SH2-B alternative splice variants and their differential roles in mitogenesis.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11502739","citation_count":63,"is_preprint":false},{"pmid":"29077706","id":"PMC_29077706","title":"Prostate specific membrane antigen (PSMA) expression in non-small cell lung cancer.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29077706","citation_count":62,"is_preprint":false},{"pmid":"17714428","id":"PMC_17714428","title":"Arabidopsis GCP2 and GCP3 are part of a soluble gamma-tubulin complex and have nuclear envelope targeting domains.","date":"2007","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17714428","citation_count":60,"is_preprint":false},{"pmid":"31595044","id":"PMC_31595044","title":"Lutetium-177 prostate-specific membrane antigen (PSMA) theranostics: practical nuances and intricacies.","date":"2019","source":"Prostate cancer and prostatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/31595044","citation_count":55,"is_preprint":false},{"pmid":"26700033","id":"PMC_26700033","title":"(R)-NODAGA-PSMA: A Versatile Precursor for Radiometal Labeling and Nuclear Imaging of PSMA-Positive Tumors.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26700033","citation_count":54,"is_preprint":false},{"pmid":"30617728","id":"PMC_30617728","title":"A Review of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in Renal Cell Carcinoma (RCC).","date":"2019","source":"Molecular imaging and biology","url":"https://pubmed.ncbi.nlm.nih.gov/30617728","citation_count":53,"is_preprint":false},{"pmid":"19895667","id":"PMC_19895667","title":"Inhibition of NAALADase by 2-PMPA attenuates cocaine-induced relapse in rats: a NAAG-mGluR2/3-mediated mechanism.","date":"2009","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19895667","citation_count":53,"is_preprint":false},{"pmid":"28338640","id":"PMC_28338640","title":"Metal-Based PSMA Radioligands.","date":"2017","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/28338640","citation_count":50,"is_preprint":false},{"pmid":"36806966","id":"PMC_36806966","title":"PSMA-Targeted Radiopharmaceuticals in Prostate Cancer: Current Data and New Trials.","date":"2023","source":"The oncologist","url":"https://pubmed.ncbi.nlm.nih.gov/36806966","citation_count":50,"is_preprint":false},{"pmid":"11227049","id":"PMC_11227049","title":"PSMA specific antibodies and their diagnostic and therapeutic use.","date":"2001","source":"Expert opinion on investigational drugs","url":"https://pubmed.ncbi.nlm.nih.gov/11227049","citation_count":49,"is_preprint":false},{"pmid":"31362683","id":"PMC_31362683","title":"Toward the Discovery and Development of PSMA Targeted Inhibitors for Nuclear Medicine Applications.","date":"2020","source":"Current radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/31362683","citation_count":49,"is_preprint":false},{"pmid":"26862945","id":"PMC_26862945","title":"Prostate-specific Membrane Antigen (PSMA) Expression in the Neovasculature of Gynecologic Malignancies: Implications for PSMA-targeted Therapy.","date":"2017","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/26862945","citation_count":43,"is_preprint":false},{"pmid":"34299051","id":"PMC_34299051","title":"Enzalutamide Enhances PSMA Expression of PSMA-Low Prostate Cancer.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34299051","citation_count":42,"is_preprint":false},{"pmid":"12753319","id":"PMC_12753319","title":"Effects of the glutamate carboxypeptidase II (GCP2 1561C>T) and reduced folate carrier (RFC1 80G>A) allelic variants on folate and total homocysteine levels in kidney transplant patients.","date":"2003","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/12753319","citation_count":42,"is_preprint":false},{"pmid":"24410012","id":"PMC_24410012","title":"Heterobivalent agents targeting PSMA and integrin-αvβ3.","date":"2014","source":"Bioconjugate chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24410012","citation_count":41,"is_preprint":false},{"pmid":"27597849","id":"PMC_27597849","title":"PSM-Mec-A Virulence Determinant that Connects Transcriptional Regulation, Virulence, and Antibiotic Resistance in Staphylococci.","date":"2016","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27597849","citation_count":40,"is_preprint":false},{"pmid":"34783177","id":"PMC_34783177","title":"PSMA as a Theranostic Target in Hepatocellular Carcinoma: Immunohistochemistry and 68 Ga-PSMA-11 PET Using Cyclotron-Produced 68 Ga.","date":"2021","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/34783177","citation_count":39,"is_preprint":false},{"pmid":"12629525","id":"PMC_12629525","title":"Morphine tolerance and reward but not expression of morphine dependence are inhibited by the selective glutamate carboxypeptidase II (GCP II, NAALADase) inhibitor, 2-PMPA.","date":"2002","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12629525","citation_count":39,"is_preprint":false},{"pmid":"35965291","id":"PMC_35965291","title":"Hetero-bivalent agents targeting FAP and PSMA.","date":"2022","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/35965291","citation_count":37,"is_preprint":false},{"pmid":"27536732","id":"PMC_27536732","title":"FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities.","date":"2016","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/27536732","citation_count":37,"is_preprint":false},{"pmid":"26887438","id":"PMC_26887438","title":"Small-molecule PSMA ligands. Current state, SAR and perspectives.","date":"2016","source":"Journal of drug targeting","url":"https://pubmed.ncbi.nlm.nih.gov/26887438","citation_count":36,"is_preprint":false},{"pmid":"32503460","id":"PMC_32503460","title":"Prostate-specific membrane antigen (PSMA) expression in adenoid cystic carcinoma of the head and neck.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32503460","citation_count":36,"is_preprint":false},{"pmid":"27458033","id":"PMC_27458033","title":"Induction of PSMA and Internalization of an Anti-PSMA mAb in the Vascular Compartment.","date":"2016","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/27458033","citation_count":35,"is_preprint":false},{"pmid":"29731795","id":"PMC_29731795","title":"Expression of Prostate-Specific Membrane Antigen (PSMA) in Brain Glioma and its Correlation with Tumor Grade.","date":"2018","source":"Iranian journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29731795","citation_count":35,"is_preprint":false},{"pmid":"31605269","id":"PMC_31605269","title":"Renal Cell Carcinoma: the Oncologist Asks, Can PSMA PET/CT Answer?","date":"2019","source":"Current urology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31605269","citation_count":33,"is_preprint":false},{"pmid":"35406467","id":"PMC_35406467","title":"Upregulation of PSMA Expression by Enzalutamide in Patients with Advanced mCRPC.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/35406467","citation_count":31,"is_preprint":false},{"pmid":"32852205","id":"PMC_32852205","title":"Development of PSMA-1007-Related Series of 18F-Labeled Glu-Ureido-Type PSMA Inhibitors.","date":"2020","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32852205","citation_count":30,"is_preprint":false},{"pmid":"25675333","id":"PMC_25675333","title":"Evaluation of a PSMA-targeted BNF nanoparticle construct.","date":"2015","source":"Nanoscale","url":"https://pubmed.ncbi.nlm.nih.gov/25675333","citation_count":30,"is_preprint":false},{"pmid":"28474140","id":"PMC_28474140","title":"Comparison of PSMA-HBED and PSMA-I&T as diagnostic agents in prostate carcinoma.","date":"2017","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/28474140","citation_count":28,"is_preprint":false},{"pmid":"26079448","id":"PMC_26079448","title":"Overexpression and Nucleolar Localization of γ-Tubulin Small Complex Proteins GCP2 and GCP3 in Glioblastoma.","date":"2015","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26079448","citation_count":27,"is_preprint":false},{"pmid":"32998959","id":"PMC_32998959","title":"Acute Statin Treatment Improves Antibody Accumulation in EGFR- and PSMA-Expressing Tumors.","date":"2020","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/32998959","citation_count":27,"is_preprint":false},{"pmid":"30989578","id":"PMC_30989578","title":"68Ga-PSMA PET thyroid incidentalomas.","date":"2019","source":"Hormones (Athens, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/30989578","citation_count":26,"is_preprint":false},{"pmid":"36551776","id":"PMC_36551776","title":"Pharmacological Optimization of PSMA-Based Radioligand Therapy.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/36551776","citation_count":26,"is_preprint":false},{"pmid":"35337180","id":"PMC_35337180","title":"Radiosynthesis and Preclinical Evaluation of Bispecific PSMA/FAP Heterodimers for Tumor Imaging.","date":"2022","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35337180","citation_count":26,"is_preprint":false},{"pmid":"16802724","id":"PMC_16802724","title":"Glutamate carboxypeptidase II (NAALADase) inhibition as a novel therapeutic strategy.","date":"2006","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/16802724","citation_count":25,"is_preprint":false},{"pmid":"34933889","id":"PMC_34933889","title":"The VISION Forward: Recognition and Implication of PSMA-/18F-FDG+ mCRPC.","date":"2021","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34933889","citation_count":25,"is_preprint":false},{"pmid":"37645427","id":"PMC_37645427","title":"PSMA-targeted therapy for non-prostate cancers.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37645427","citation_count":25,"is_preprint":false},{"pmid":"16192687","id":"PMC_16192687","title":"Correlation between PSMA and VEGF expression as markers for LNCaP tumor angiogenesis.","date":"2005","source":"Journal of biomedicine & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/16192687","citation_count":25,"is_preprint":false},{"pmid":"34648046","id":"PMC_34648046","title":"Ga-68 PSMA PET/CT in recurrent high-grade gliomas: evaluating PSMA expression in vivo.","date":"2021","source":"Neuroradiology","url":"https://pubmed.ncbi.nlm.nih.gov/34648046","citation_count":24,"is_preprint":false},{"pmid":"10668445","id":"PMC_10668445","title":"Blockade of NAALADase: a novel neuroprotective strategy based on limiting glutamate and elevating NAAG.","date":"1999","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/10668445","citation_count":24,"is_preprint":false},{"pmid":"14634711","id":"PMC_14634711","title":"Reduced isolation-induced aggressiveness in mice following NAALADase inhibition.","date":"2003","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/14634711","citation_count":24,"is_preprint":false},{"pmid":"31248772","id":"PMC_31248772","title":"Synthesis and biological evaluation of PSMA-targeting paclitaxel conjugates.","date":"2019","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/31248772","citation_count":21,"is_preprint":false},{"pmid":"32703222","id":"PMC_32703222","title":"Peritumoral/vascular expression of PSMA as a diagnostic marker in hepatic lesions.","date":"2020","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32703222","citation_count":21,"is_preprint":false},{"pmid":"18328678","id":"PMC_18328678","title":"Identification of presomitic mesoderm (PSM)-specific Mesp1 enhancer and generation of a PSM-specific Mesp1/Mesp2-null mouse using BAC-based rescue technology.","date":"2008","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/18328678","citation_count":21,"is_preprint":false},{"pmid":"12712410","id":"PMC_12712410","title":"Expression pattern of mouse homolog of prostate-specific membrane antigen (FOLH1) in the transgenic adenocarcinoma of the mouse prostate model.","date":"2003","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/12712410","citation_count":20,"is_preprint":false},{"pmid":"37424944","id":"PMC_37424944","title":"The current status of prostate cancer treatment and PSMA theranostics.","date":"2023","source":"Therapeutic advances in medical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37424944","citation_count":20,"is_preprint":false},{"pmid":"35114745","id":"PMC_35114745","title":"Relative Efficacy of 225Ac-PSMA-617 and 177Lu-PSMA-617 in Prostate Cancer Based on Subcellular Dosimetry.","date":"2022","source":"Molecular imaging and radionuclide therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35114745","citation_count":19,"is_preprint":false},{"pmid":"33273603","id":"PMC_33273603","title":"Intra-individual dynamic comparison of 18F-PSMA-11 and 68Ga-PSMA-11 in LNCaP xenograft bearing mice.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33273603","citation_count":19,"is_preprint":false},{"pmid":"36831218","id":"PMC_36831218","title":"The Potential of PSMA as a Vascular Target in TNBC.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36831218","citation_count":18,"is_preprint":false},{"pmid":"32447644","id":"PMC_32447644","title":"PSMA-PET and micro-ultrasound potential in the diagnostic pathway of prostate cancer.","date":"2020","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/32447644","citation_count":18,"is_preprint":false},{"pmid":"8999630","id":"PMC_8999630","title":"[Significance of prostate-specific membrane antigen (PSMA). A neurocarboxypeptidase and membrane folate hydrolase].","date":"1996","source":"Der Urologe. Ausg. A","url":"https://pubmed.ncbi.nlm.nih.gov/8999630","citation_count":18,"is_preprint":false},{"pmid":"28159515","id":"PMC_28159515","title":"Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease.","date":"2017","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/28159515","citation_count":18,"is_preprint":false},{"pmid":"35220877","id":"PMC_35220877","title":"Lutetium-177-PSMA-617: A Vision of the Future.","date":"2022","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35220877","citation_count":17,"is_preprint":false},{"pmid":"21219587","id":"PMC_21219587","title":"N-substituted glutamyl sulfonamides as inhibitors of glutamate carboxypeptidase II (GCP2).","date":"2011","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/21219587","citation_count":16,"is_preprint":false},{"pmid":"15544947","id":"PMC_15544947","title":"Patterns and clusters within the PSM column in TiBS, 1992-2004.","date":"2004","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/15544947","citation_count":16,"is_preprint":false},{"pmid":"27128184","id":"PMC_27128184","title":"Design, synthesis and biological evaluation of PSMA/hepsin-targeted heterobivalent ligands.","date":"2016","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27128184","citation_count":16,"is_preprint":false},{"pmid":"27070640","id":"PMC_27070640","title":"MADD-FOLH1 Polymorphisms and Their Haplotypes with Serum Lipid Levels and the Risk of Coronary Heart Disease and Ischemic Stroke in a Chinese Han Population.","date":"2016","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/27070640","citation_count":15,"is_preprint":false},{"pmid":"32253231","id":"PMC_32253231","title":"Mechanistic Insights for Optimizing PSMA Radioligand Therapy.","date":"2020","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/32253231","citation_count":15,"is_preprint":false},{"pmid":"35027860","id":"PMC_35027860","title":"Expression of Prostate Specific Membrane Antigen (PSMA) in Breast Cancer.","date":"2022","source":"Geburtshilfe und Frauenheilkunde","url":"https://pubmed.ncbi.nlm.nih.gov/35027860","citation_count":14,"is_preprint":false},{"pmid":"17615553","id":"PMC_17615553","title":"Essential role of PSM/SH2-B variants in insulin receptor catalytic activation and the resulting cellular responses.","date":"2008","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17615553","citation_count":14,"is_preprint":false},{"pmid":"30904185","id":"PMC_30904185","title":"Synthesis and biological evaluation of Doxorubicin-containing conjugate targeting PSMA.","date":"2019","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/30904185","citation_count":14,"is_preprint":false},{"pmid":"29666835","id":"PMC_29666835","title":"Aptamers and apple pies: a mini-review of PSMA aptamers and lessons from Donald S. Coffey.","date":"2018","source":"American journal of clinical and experimental urology","url":"https://pubmed.ncbi.nlm.nih.gov/29666835","citation_count":13,"is_preprint":false},{"pmid":"30488457","id":"PMC_30488457","title":"Sox7 negatively regulates prostate-specific membrane antigen (PSMA) expression through PSMA-enhancer.","date":"2018","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/30488457","citation_count":12,"is_preprint":false},{"pmid":"36728839","id":"PMC_36728839","title":"Prostate-specific membrane antigen (PSMA) as a potential target for molecular imaging and treatment in bone and soft tissue sarcomas.","date":"2023","source":"The British journal of radiology","url":"https://pubmed.ncbi.nlm.nih.gov/36728839","citation_count":12,"is_preprint":false},{"pmid":"31443113","id":"PMC_31443113","title":"68Ga-RM2 PET in PSMA- positive and -negative prostate cancer patients.","date":"2019","source":"Nuklearmedizin. Nuclear medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31443113","citation_count":12,"is_preprint":false},{"pmid":"26977010","id":"PMC_26977010","title":"MDM2 and PSMA Play Inhibitory Roles in Metastatic Breast Cancer Cells Through Regulation of Matrix Metalloproteinases.","date":"2016","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26977010","citation_count":12,"is_preprint":false},{"pmid":"36368471","id":"PMC_36368471","title":"Dose response modelling of secretory cell loss in salivary glands using PSMA PET.","date":"2022","source":"Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36368471","citation_count":11,"is_preprint":false},{"pmid":"30120883","id":"PMC_30120883","title":"Association of FOLH1, DHFR, and MTHFR gene polymorphisms with susceptibility of Neural Tube Defects: A case control study from Eastern India.","date":"2018","source":"Birth defects research","url":"https://pubmed.ncbi.nlm.nih.gov/30120883","citation_count":11,"is_preprint":false},{"pmid":"37190273","id":"PMC_37190273","title":"Theranostics of Primary Prostate Cancer: Beyond PSMA and GRP-R.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37190273","citation_count":11,"is_preprint":false},{"pmid":"18031726","id":"PMC_18031726","title":"Effects of selective inhibition of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) on mice in learning and memory tasks.","date":"2007","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18031726","citation_count":11,"is_preprint":false},{"pmid":"18247337","id":"PMC_18247337","title":"PSM/SH2B1 splice variants: critical role in src catalytic activation and the resulting STAT3s-mediated mitogenic response.","date":"2008","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18247337","citation_count":11,"is_preprint":false},{"pmid":"38473301","id":"PMC_38473301","title":"The Current Landscape of Prostate-Specific Membrane Antigen (PSMA) Imaging Biomarkers for Aggressive Prostate Cancer.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38473301","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52126,"output_tokens":4776,"usd":0.114009},"stage2":{"model":"claude-opus-4-6","input_tokens":8294,"output_tokens":2960,"usd":0.173205},"total_usd":0.287214,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"PSMA (FOLH1) is a type II integral membrane glycoprotein expressed on the surface of prostate cancer cells and in tumor-associated neovasculature of a wide spectrum of malignant neoplasms; antibodies to the extracellular domain (J591, J415) bind viable prostate cancer cells whereas antibodies to the intracellular domain (7E11) do not, establishing domain topology and accessibility.\",\n      \"method\": \"Immunohistochemistry with five distinct anti-PSMA monoclonal antibodies on viable cell lines and fresh-frozen tissue; CD34 co-staining for endothelial confirmation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple antibodies targeting distinct epitopes, replicated across many tumor types, strong preponderance of evidence\",\n      \"pmids\": [\"10397265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PSMA has two enzymatic activities—folate hydrolase (gamma-glutamyl carboxypeptidase) and NAALADase (N-acetylated alpha-linked acidic dipeptidase)—and undergoes internalization via clathrin-coated pits, consistent with receptor recycling behavior.\",\n      \"method\": \"Review consolidating enzymatic activity assays and prior internalization studies\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — enzymatic activities established by direct assays cited across multiple independent studies; clathrin-coated pit internalization confirmed experimentally\",\n      \"pmids\": [\"14755683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The mouse homolog of PSMA (Folh1) encodes a glutamate-preferring carboxypeptidase with both NAALADase and folate hydrolase activities; cells transfected with Folh1 gained both enzymatic activities, confirming the functional equivalence of mouse Folh1 and human PSMA/FOLH1.\",\n      \"method\": \"cDNA cloning, transfection-based enzymatic activity assays (NAALADase and folate hydrolase), FISH chromosomal mapping, tissue expression analysis\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct reconstitution by transfection with enzymatic readout; both activities confirmed\",\n      \"pmids\": [\"11210180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NAALADase (FOLH1/GCPII) hydrolyzes NAAG to N-acetylaspartate and glutamate; selective inhibition with 2-PMPA reduces extracellular glutamate, increases NAAG, and is neuroprotective in ischemic models, establishing the enzyme's role in glutamate homeostasis in the brain.\",\n      \"method\": \"In vitro neuronal culture stroke model; in vivo rat transient middle cerebral artery occlusion; microdialysis measurement of extracellular glutamate and NAAG\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic inhibition combined with in vivo pharmacological intervention with defined biochemical readouts; replicated across models\",\n      \"pmids\": [\"10581082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"NAALADase (FOLH1) protein is localized to neuropil (not neuronal cytoplasm) in rat brain regions enriched in NAAG, and to the brush border of proximal convoluted tubules in kidney, consistent with its role in extracellular NAAG catabolism.\",\n      \"method\": \"Immunocytochemistry with specific anti-NAALADase antiserum in rat brain and kidney sections\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct immunolocalization with specific antiserum; co-localization with NAAG-IR regions supports functional assignment\",\n      \"pmids\": [\"1545010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Brain NAALADase and prostate PSMA (FOLH1) are the same enzyme: they share identical kinetic profiles, pharmacological sensitivities, common mRNA splice forms (2.8-, 4.0-, and 6.0-kb species), and the anti-PSMA mAb 7E11-C5 immunoprecipitates 82% of cerebellar NAALADase activity.\",\n      \"method\": \"Kinetic enzyme assays, Northern hybridization, RT-PCR cloning of cerebellar cDNA, immunoprecipitation with anti-PSMA antibody\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (kinetics, Northern, RT-PCR, immunoprecipitation) in single study confirming identity of brain and prostate forms\",\n      \"pmids\": [\"9694964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Filamin A, an actin cross-linking protein, associates with the cytoplasmic tail of PSMA; this interaction localizes PSMA to the recycling endosomal compartment, reduces its internalization rate, and decreases its NAALADase activity.\",\n      \"method\": \"Co-immunoprecipitation, ectopic PSMA expression in filamin-negative vs. filamin-positive cell lines, NAALADase activity assays, subcellular fractionation/localization\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional readout (internalization rate and enzymatic activity) in isogenic filamin+/- cell systems\",\n      \"pmids\": [\"12750292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"A tissue-specific enhancer (PSME) located in the third intron (~12 kb downstream of the transcription start) of the FOLH1 gene drives prostate-selective expression; it contains a 72-bp direct repeat, activates transcription >250-fold in LNCaP cells, and its activity is repressed by androgen, mirroring regulation of the endogenous gene.\",\n      \"method\": \"Enhancer trap assay with overlapping genomic DNA fragments, luciferase reporter assays in prostate and non-prostate cell lines, androgen treatment experiments\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — enhancer functionally characterized with reporter assays in multiple cell lines plus androgen regulation confirmed\",\n      \"pmids\": [\"11350116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOLH1/GCPII enzymatic activity is elevated 2.8- to 41-fold in the affected intestinal mucosa of IBD patients; pharmacological inhibition of this activity with 2-PMPA ameliorates disease in DSS colitis and IL-10−/− mouse models, and FOLH1 knockout mice are resistant to DSS-induced colitis.\",\n      \"method\": \"Enzymatic activity quantification in surgical specimens, two murine IBD models (DSS colitis and IL-10−/− spontaneous colitis), genetic knockout, pharmacological inhibition with 2-PMPA\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — human enzymatic activity data corroborated by pharmacological inhibition and genetic knockout in two mouse models; multiple orthogonal approaches\",\n      \"pmids\": [\"27536732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cancer cell-conditioned media induces PSMA expression in human umbilical vein endothelial cells (HUVECs) in vitro, and cancer cell co-implantation induces PSMA expression in HUVECs in vivo; PSMA-induced HUVECs can internalize the anti-PSMA mAb J591 and PSMA-binding ligand nanoparticles, demonstrating that tumor cell crosstalk drives neovascular PSMA expression.\",\n      \"method\": \"Conditioned media experiments, HUVEC-cancer cell co-implantation mouse model, internalization assays with fluorescent-labeled J591 mAb and nanoparticles\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo induction experiments with functional internalization readout; mechanistic link between tumor cell signals and endothelial PSMA established\",\n      \"pmids\": [\"27458033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Neuroendocrine differentiation of prostate cancer suppresses FOLH1/PSMA expression; PSMA suppression is associated with loss of p53 and NE induction, and PSMA-suppressed cells show increased colony formation and resistance to enzalutamide.\",\n      \"method\": \"Transcript analysis across 909 tumors, NE-induced cell line models with hormone depletion and p53 loss, flow cytometry for protein expression, 18 NEPC patient-derived xenograft models\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic link between NE lineage plasticity and FOLH1 suppression supported by cell and PDX models, though causal mechanism not fully dissected\",\n      \"pmids\": [\"30400059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSMA (FOLH1) expression heterogeneity in metastatic castration-resistant prostate cancer is mediated by reversible epigenetic mechanisms: PSMA-negative tumors show gain of CpG methylation and loss of H3K27 acetylation at the FOLH1 locus; HDAC inhibitor treatment restores PSMA expression in vitro and in vivo.\",\n      \"method\": \"ChIP-seq for H3K27ac, DNA methylation analysis, HDAC inhibitor treatment in cell lines and xenograft models, autopsy cohort multi-site sampling\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — epigenetic marks identified by ChIP, functional rescue by HDAC inhibitors in vitro and in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"36821396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sox7 negatively regulates PSMA expression by directly binding to the PSMA enhancer (PSME) through SOX box sites #2 and #4; the nuclear localization sequences (NLS) but not the β-catenin interaction motif of Sox7 are required for this repression.\",\n      \"method\": \"ChIP assay, EMSA, luciferase reporter assay, stable Sox7 expression in LNCaP/C4-2 and 22Rv1 cells, Sox7 domain mutant analysis\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct DNA binding shown by EMSA and ChIP with functional confirmation by reporter assay and gain-of-function; domain requirements mapped by mutagenesis\",\n      \"pmids\": [\"30488457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse Folh1 (PSMA homolog) is expressed at highest levels in kidney and brain (not in prostate tumor in TRAMP mice); folate hydrolase activity in tissues parallels Folh1 mRNA expression, confirming the enzyme's tissue-specific catalytic activity.\",\n      \"method\": \"Real-time quantitative PCR, folate hydrolase activity assays in multiple tissues of TRAMP and control mice\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct enzymatic activity correlated with mRNA; single lab, moderate evidence\",\n      \"pmids\": [\"12712410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSMA expression is regulated by a transcription complex that acts on the FOLH1 promoter via a looping upstream enhancer, intergenic enhancers, and differentially methylated regions; PSMA suppression mechanisms include lineage plasticity, tumor microenvironment, and epigenetic silencing.\",\n      \"method\": \"Review integrating ChIP, DNA methylation, and enhancer-looping data from prior molecular studies\",\n      \"journal\": \"Nature reviews. Urology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — review synthesizing multiple mechanistic studies; assigned medium because primary data cited but this paper itself is a review\",\n      \"pmids\": [\"38977769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Androgen receptor blockade by enzalutamide increases PSMA expression in PSMA-low prostate cancer cell lines (22Rv1) 2.2-fold and in PSMA-high lines (C4-2, LNCaP) ~2.3–2.6-fold; this is confirmed in vivo by 68Ga-PSMA PET in a xenograft model and in an mCRPC patient.\",\n      \"method\": \"Flow cytometry, immunohistochemistry, 68Ga-PSMA PET/CT in NOD/Scid xenograft mouse model, clinical case\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — AR blockade-PSMA upregulation demonstrated in cell lines, xenograft, and clinical case; mechanism (AR repression of FOLH1) consistent with known enhancer androgen regulation\",\n      \"pmids\": [\"34299051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"PSMA functions as both a neurocarboxypeptidase and a membrane folate hydrolase; an alternatively spliced form, PSM', localizes to the cytoplasm in normal prostate, while PSMA itself is a type II membrane protein.\",\n      \"method\": \"Biochemical characterization, cloning, localization studies cited in review\",\n      \"journal\": \"Der Urologe. Ausg. A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional enzymatic activities and alternative splice isoform localization established by primary experiments summarized in review\",\n      \"pmids\": [\"8999630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RNA aptamers (xPSM-A9 and xPSM-A10) that bind to the extracellular domain of PSMA inhibit its glutamate carboxypeptidase enzymatic activity and internalize into PSMA-expressing cancer cells, demonstrating that extracellular domain engagement is sufficient to inhibit catalytic function and trigger endocytosis.\",\n      \"method\": \"In vitro selection (SELEX) of 2'-fluorpyrimidine RNA aptamers, glutamate carboxypeptidase activity inhibition assay, internalization assays in PSMA-expressing prostate cancer cells\",\n      \"journal\": \"American journal of clinical and experimental urology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional inhibition and internalization confirmed by direct assay; moderate evidence from single lab\",\n      \"pmids\": [\"29666835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOLH1/GCPII enzymatic activity is elevated in colorectal tissues of mice with TNBS-induced colitis; 2-PMPA inhibits colonic GCPII activity by >90% and reduces disease activity when administered locally as an enema.\",\n      \"method\": \"Ex vivo enzymatic activity assays, TNBS-induced colitis mouse model, local enema delivery of 2-PMPA, macroscopic and microscopic disease scoring\",\n      \"journal\": \"Journal of controlled release\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition with direct enzymatic readout in disease model; single lab\",\n      \"pmids\": [\"28159515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MDM2 knockdown reduces PSMA expression and vice versa in metastatic breast cancer cells; siRNA-mediated PSMA knockdown decreases cell growth, adhesion, migration, and invasion, and alters MMP expression (decreasing MMP2, increasing MMP3/10/13), placing PSMA in a pathway regulating matrix metalloproteinase activity.\",\n      \"method\": \"siRNA knockdown, qPCR, western blotting, proliferation/adhesion/migration/invasion assays in MDA-MB-231 and ZR-75.1 cells\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with defined cellular phenotype and pathway placement; single lab, moderate methods\",\n      \"pmids\": [\"26977010\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOLH1/PSMA is a type II transmembrane glycoprotein with two intrinsic enzymatic activities—NAALADase (hydrolyzing NAAG to N-acetylaspartate and glutamate) and folate hydrolase—whose tissue-specific prostate expression is driven by an intronic enhancer (PSME) repressed by androgen and Sox7, whose surface density is regulated by filamin A-mediated retention in recycling endosomes and by clathrin-dependent internalization, and whose expression can be epigenetically silenced via CpG methylation and H3K27 deacetylation at the FOLH1 locus or suppressed by neuroendocrine lineage transition and androgen receptor activation, while being expressed in tumor-associated neovasculature through paracrine induction by cancer cell-secreted factors.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FOLH1 (also known as PSMA/GCPII) is a type II transmembrane glycoprotein that functions as a dual-specificity metallopeptidase, catalyzing both the hydrolysis of N-acetylaspartylglutamate (NAAG) to N-acetylaspartate and glutamate in the nervous system (NAALADase activity) and the sequential removal of gamma-linked glutamates from folylpolyglutamates (folate hydrolase activity) [PMID:9694964, PMID:11210180]. In the brain, its NAALADase activity regulates extracellular glutamate levels and NAAG signaling, and pharmacological inhibition with 2-PMPA is neuroprotective in ischemia models [PMID:10581082]; in the intestinal mucosa, elevated FOLH1 activity contributes to inflammatory bowel disease pathology, as demonstrated by resistance of Folh1-knockout mice to experimental colitis [PMID:27536732]. Prostate-selective expression is driven by an intronic enhancer (PSME) repressed by androgen receptor signaling and the transcription factor Sox7, while surface density is modulated by filamin A-mediated retention in recycling endosomes and clathrin-dependent internalization [PMID:11350116, PMID:30488457, PMID:12750292]. Expression heterogeneity in prostate cancer is governed by reversible epigenetic silencing through CpG methylation and H3K27 deacetylation at the FOLH1 locus, and by neuroendocrine lineage transitions that suppress FOLH1 transcription [PMID:36821396, PMID:30400059].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing where NAALADase protein resides in vivo resolved that this enzyme acts extracellularly in brain neuropil and at the kidney brush border, consistent with a role in catabolism of extracellular substrates.\",\n      \"evidence\": \"Immunocytochemistry with specific anti-NAALADase antiserum in rat brain and kidney sections\",\n      \"pmids\": [\"1545010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Prostate expression not yet linked to the same gene product\", \"Substrate access and regulation of activity in situ unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that brain NAALADase and prostate PSMA are the same gene product unified two fields and established FOLH1 as a single gene encoding both enzymatic activities in distinct tissues.\",\n      \"evidence\": \"Kinetic enzyme assays, Northern blots, RT-PCR cloning, and immunoprecipitation with anti-PSMA mAb 7E11-C5 capturing 82% of cerebellar NAALADase activity\",\n      \"pmids\": [\"9694964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific transcriptional regulation not yet characterized\", \"Structural basis for dual enzymatic activities unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining PSMA domain topology on viable cells and its expression in tumor-associated neovasculature established the protein as a surface-accessible target in cancer and revealed an unexpected non-prostate expression pattern.\",\n      \"evidence\": \"Immunohistochemistry with five monoclonal antibodies targeting distinct PSMA epitopes on viable cells and fresh-frozen tumor tissues; CD34 co-staining\",\n      \"pmids\": [\"10397265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism driving neovascular expression unresolved\", \"Functional role of PSMA in endothelial cells unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Pharmacological inhibition of NAALADase with 2-PMPA established that FOLH1 enzymatic activity directly controls extracellular glutamate levels and that its inhibition is neuroprotective, providing the first functional consequence of FOLH1 catalysis in vivo.\",\n      \"evidence\": \"In vitro neuronal ischemia model and in vivo rat MCAO with microdialysis measurement of glutamate and NAAG\",\n      \"pmids\": [\"10581082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genetic loss-of-function confirmation in brain not shown\", \"Downstream signaling pathways from glutamate release not dissected\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of the PSME intronic enhancer and its androgen-mediated repression explained how FOLH1 achieves prostate-selective expression and why androgen deprivation upregulates PSMA, a key clinical observation.\",\n      \"evidence\": \"Enhancer trap assay, luciferase reporters in prostate/non-prostate lines, androgen treatment experiments\",\n      \"pmids\": [\"11350116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors binding PSME not identified\", \"Chromatin architecture at enhancer-promoter loop not mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Reconstitution of mouse Folh1 confirmed functional conservation of both NAALADase and folate hydrolase activities, validating the mouse as a model for FOLH1 biology.\",\n      \"evidence\": \"Transfection of Folh1 cDNA into cells with enzymatic activity assays for both NAALADase and folate hydrolase\",\n      \"pmids\": [\"11210180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological importance of folate hydrolase activity in vivo not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that filamin A interacts with the PSMA cytoplasmic tail and retains it in recycling endosomes provided the first mechanism for post-translational regulation of PSMA surface density and enzymatic activity.\",\n      \"evidence\": \"Co-immunoprecipitation, comparison of filamin-positive vs. filamin-negative isogenic cell lines, NAALADase activity assays, subcellular fractionation\",\n      \"pmids\": [\"12750292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of filamin A–PSMA interaction not mapped at residue level\", \"In vivo relevance of filamin A regulation not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic knockout and pharmacological inhibition in multiple colitis models established FOLH1 enzymatic activity as a pathogenic driver of intestinal inflammation, extending its functional significance beyond the nervous system.\",\n      \"evidence\": \"FOLH1-knockout mice resistant to DSS colitis; 2-PMPA ameliorates disease in DSS and IL-10−/− models; elevated GCPII activity in IBD patient specimens\",\n      \"pmids\": [\"27536732\", \"28159515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate (NAAG or folate) mediating intestinal pathology not identified\", \"Cell type expressing FOLH1 in gut mucosa not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Conditioned media and co-implantation experiments demonstrated that tumor cell-secreted factors are sufficient to induce PSMA expression on endothelial cells, explaining the neovascular PSMA expression seen across solid tumors.\",\n      \"evidence\": \"Cancer cell-conditioned media treatment of HUVECs in vitro; HUVEC–cancer cell co-implantation in mice with J591 internalization readout\",\n      \"pmids\": [\"27458033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the inducing factor(s) not determined\", \"Signaling pathway in endothelial cells not characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of Sox7 as a direct transcriptional repressor binding PSME resolved a specific trans-acting factor controlling PSMA expression, with its NLS but not β-catenin interaction required for repression.\",\n      \"evidence\": \"ChIP, EMSA, luciferase reporters, stable Sox7 expression in prostate cancer lines, domain mutagenesis\",\n      \"pmids\": [\"30488457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcription factors binding PSME not systematically identified\", \"Sox7 regulation in prostate cancer progression unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Neuroendocrine differentiation was shown to suppress FOLH1 expression, linking lineage plasticity to loss of PSMA and resistance to AR-targeted therapy, a clinically important escape mechanism.\",\n      \"evidence\": \"Transcript analysis of 909 tumors, NE-induced cell models with p53 loss, 18 NEPC PDX models\",\n      \"pmids\": [\"30400059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional mechanism of NE-driven FOLH1 suppression not dissected\", \"Whether PSMA loss is cause or consequence of NE phenotype unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Epigenetic profiling revealed that PSMA-negative prostate tumors acquire CpG methylation and lose H3K27ac at the FOLH1 locus, and that HDAC inhibitors restore PSMA expression, establishing a reversible epigenetic silencing mechanism.\",\n      \"evidence\": \"ChIP-seq, DNA methylation analysis, HDAC inhibitor treatment in cell lines and xenografts, multi-site autopsy sampling\",\n      \"pmids\": [\"36821396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific HDAC isoforms responsible not identified\", \"Durability of epigenetic re-expression in patients not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of tumor-secreted factors that induce PSMA on neovasculature, the substrate mediating FOLH1's pathogenic role in colitis, and the complete set of transcription factors governing tissue-specific FOLH1 expression remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Paracrine inducer of neovascular PSMA not identified\", \"NAAG vs. folate substrate relevance in gut inflammation not determined\", \"Full enhancer-promoter looping architecture at FOLH1 locus not mapped in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 2, 3, 5, 8, 13, 17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 6, 16]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 3, 8, 13]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 11, 12, 14, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FLNA\",\n      \"SOX7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}