{"gene":"FOLH1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2003,"finding":"Filamin A, an actin cross-linking protein, associates with the cytoplasmic tail of PSMA (FOLH1). This association localizes PSMA to the recycling endosomal compartment, reduces its internalization rate, and decreases its NAALADase enzymatic activity.","method":"Ectopic expression of PSMA in filamin-negative and filamin-positive cell lines; co-immunoprecipitation; functional internalization and enzymatic activity assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal functional rescue using filamin-negative vs positive cell lines plus Co-IP and enzymatic assay, multiple orthogonal methods in one study","pmids":["12750292"],"is_preprint":false},{"year":2001,"finding":"The PSMA gene (FOLH1) contains a tissue-specific enhancer (PSME) located in the third intron (~12 kb downstream from the transcription start site). PSME drives prostate-specific transcription (>250-fold activation in LNCaP cells) and is repressed by androgen, recapitulating androgen regulation of the endogenous FOLH1 gene. Both cell-type specificity and androgen regulation are intrinsic to the enhancer.","method":"Enhancer trap assay with overlapping DNA fragments; luciferase reporter assays in prostate and non-prostate cell lines; androgen treatment experiments","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional reporter assays with multiple cell lines and androgen treatment, multiple orthogonal methods in one study","pmids":["11350116"],"is_preprint":false},{"year":2001,"finding":"Mouse Folh1 (homolog of human PSMA/FOLH1) encodes a glutamate-preferring carboxypeptidase with two enzymatic activities: NAALADase (cleaves NAAG to release glutamate) and gamma-glutamyl carboxypeptidase (folate hydrolase). Cells transfected with Folh1 gained both NAALADase and folate hydrolase activities. Unlike human PSMA, mouse Folh1 is not expressed in the prostate but is expressed primarily in brain and kidney.","method":"cDNA cloning and transfection; NAALADase and folate hydrolase enzymatic activity assays; RT-PCR tissue expression profiling; FISH chromosomal mapping","journal":"Mammalian genome","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic reconstitution by transfection, two orthogonal enzymatic assays in one study","pmids":["11210180"],"is_preprint":false},{"year":1998,"finding":"Human brain NAALADase and prostate PSMA (FOLH1) are products of the same gene and express a common mRNA splice form. Brain NAALADase shares the same kinetic profile, pharmacological sensitivities, and immunoreactivity (82% immunoprecipitation by anti-PSMA mAb 7E11-C5) as PSMA from LNCaP prostate tumor cells.","method":"Kinetic and pharmacological comparison; Northern blot hybridization; immunoprecipitation with monoclonal antibody; RT-PCR cloning of cerebellar cDNA","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (kinetics, Northern blot, immunoprecipitation, RT-PCR) demonstrating identity of brain and prostate enzyme","pmids":["9694964"],"is_preprint":false},{"year":1992,"finding":"NAALADase (FOLH1/GCPII) is a membrane-bound enzyme that cleaves glutamate from the neuropeptide NAAG. Immunocytochemical localization in rat brain showed NAALADase-IR co-localizing with NAAG-IR in neuropil (absent from neuronal cytoplasm), supporting its role in NAAG catabolism in vivo. It was also detected in the brush border of proximal convoluted tubules in the kidney cortex.","method":"Immunocytochemistry with specific anti-NAALADase antiserum in rat brain and kidney; co-localization with NAAG-IR","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunolocalization with specific antiserum across multiple brain regions; indirect mechanistic inference from co-localization, single method","pmids":["1545010"],"is_preprint":false},{"year":2016,"finding":"FOLH1/GCPII enzymatic activity is robustly elevated (2.8–41-fold) in affected intestinal mucosa of IBD patients versus uninvolved areas or healthy controls. Genetic knockout of FOLH1 in mice conferred resistance to DSS-induced colitis, and pharmacological inhibition with 2-PMPA (IC50=300 pM) reduced GCPII activity in colonic mucosa by >90% and substantially ameliorated disease in both DSS and IL-10-/- colitis models.","method":"Enzymatic activity quantification in 31 surgical specimens; FOLH1 knockout mouse model (DSS colitis); pharmacological inhibition with 2-PMPA in two murine IBD models; macroscopic and microscopic disease assessment","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and pharmacological inhibition with defined phenotypic readout, replicated across two independent IBD mouse models plus human tissue data","pmids":["27536732"],"is_preprint":false},{"year":2018,"finding":"Sox7 negatively regulates PSMA (FOLH1) expression by directly binding to SOX box sites #2 and #4 within the PSMA enhancer (PSME). The nuclear localization signal (NLS) regions of Sox7, but not its β-catenin interacting motif, are essential for this suppressive activity. Stable expression of canonical Sox7 in LNCaP/C4-2 and 22Rv1 cells suppressed PSMA protein expression.","method":"ChIP assay; EMSA; luciferase reporter assay; stable Sox7 overexpression in prostate cancer cell lines; Sox7 domain mutant analysis","journal":"The Prostate","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, reporter assay, stable OE with defined mutants) establishing direct transcriptional mechanism","pmids":["30488457"],"is_preprint":false},{"year":2023,"finding":"PSMA (FOLH1) expression loss in metastatic castration-resistant prostate cancer is associated with gain of CpG methylation and loss of H3K27 acetylation at the FOLH1 locus. Treatment with HDAC inhibitors reversed this epigenetic repression and restored PSMA expression both in vitro and in vivo.","method":"Rapid autopsy cohort PSMA expression profiling; ChIP for H3K27ac; bisulfite methylation analysis; HDAC inhibitor treatment in vitro and in vivo xenograft models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epigenetic writer/eraser mechanism identified by ChIP and methylation analysis with functional rescue by HDAC inhibitors in vitro and in vivo","pmids":["36821396"],"is_preprint":false},{"year":2016,"finding":"Cancer cell-conditioned media induces PSMA expression in otherwise PSMA-negative HUVECs both in vitro and in vivo (HUVEC co-implantation mouse model). HUVECs with induced PSMA expression were able to internalize J591 anti-PSMA mAb and PSMA-binding ligand-bearing nanoparticles, demonstrating functional PSMA on induced neovascular endothelium.","method":"Conditioned media experiments; in vitro HUVEC PSMA induction assay; in vivo HUVEC co-implantation mouse model; internalization assays with anti-PSMA mAb and nanoparticles","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo induction experiments with functional internalization readout, single lab","pmids":["27458033"],"is_preprint":false},{"year":2001,"finding":"PSMA undergoes internalization via clathrin-coated pits and is recycled like other membrane-bound receptors. Filamin A binding to PSMA reduces the rate of this internalization.","method":"Previously described clathrin-coated pit internalization (cited in PMID 12750292); filamin association and internalization rate assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — internalization mechanism referenced from prior work; filamin-dependent regulation confirmed by functional cell-based assay in PMID 12750292","pmids":["12750292"],"is_preprint":false},{"year":2001,"finding":"NAALADase inhibition (by 2-PMPA) reduces extracellular glutamate accumulation and produces a reciprocal rise in extracellular NAAG during cerebral ischemia reperfusion in rats, consistent with FOLH1/GCPII controlling glutamate supply from NAAG hydrolysis in vivo.","method":"Suture model of transient middle cerebral artery occlusion in rats; in vivo microdialysis measuring extracellular glutamate and NAAG; pharmacological inhibition with 2-PMPA","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological inhibition with direct metabolite measurement by microdialysis, single lab","pmids":["10668445"],"is_preprint":false},{"year":2001,"finding":"Neuroprotection by NAAG and NAALADase inhibitor 2-PMPA requires the presence of glial cells and group II metabotropic glutamate receptor (mGluR) activation. Selective group II mGlu receptor antagonists reduced protection afforded by both NAAG and 2-PMPA in neuronal/glial co-cultures, while groups I and III mGlu receptor antagonists had no effect.","method":"In vitro metabolic inhibition model using neuronal/glial co-cultures vs. neuron-only cultures; pharmacological dissection with selective mGlu receptor agonists and antagonists","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with selective receptor antagonists in defined cell co-culture system, single lab","pmids":["11525768"],"is_preprint":false},{"year":2020,"finding":"A missense mutation in FOLH1 (rs202676 G allele) is associated with increased FOLH1 mRNA in the dorsolateral prefrontal cortex and decreased NAAG levels (measured by 7-T MRS) in humans. Lower NAAG levels correlated with lower IQ scores and less efficient cortical activity during working memory (fMRI), establishing that FOLH1 genotype influences synaptic NAAG concentration and cognitive function.","method":"Human brain mRNA expression analysis; 7-T magnetic resonance spectroscopy (MRS) of NAAG in vivo; cognitive testing; functional MRI during working memory tasks; genetic association with rs202676","journal":"The American journal of psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vivo human methods (MRS, fMRI, mRNA, cognition) linking FOLH1 variant to NAAG levels and cognitive outcomes, single study","pmids":["33256444"],"is_preprint":false},{"year":2017,"finding":"Mouse GCPII (Folh1) possesses lower catalytic efficiency but similar substrate specificity and inhibitor sensitivity compared to human GCPII, validating mouse models for inhibitor development. Mouse GCPII is highest expressed in kidney, brain, and salivary glands, but is absent from mouse prostate — a key difference from the human enzyme.","method":"Recombinant mouse GCPII preparation; enzymatic kinetic assays; inhibitor panel testing; tissue protein expression profiling","journal":"FEBS open bio","confidence":"High","confidence_rationale":"Tier 1 / Moderate — recombinant enzyme reconstitution with kinetic characterization and inhibitor panel, multiple orthogonal methods in one study","pmids":["28904865"],"is_preprint":false},{"year":2023,"finding":"Genetic deletion of GCPII (FOLH1), but not GCPIII, in mice reduced glutamate production, excitotoxicity, and neuronal damage after traumatic brain injury (TBI) and improved cognitive function. Combined GCPII/GCPIII knockout showed no additional benefit over GCPII deletion alone, indicating GCPIII does not compensate for GCPII in TBI.","method":"CRISPR/Cas9 knockout of GCPII, GCPIII, and GCPII/III in mice; controlled cortical impact TBI model; hippocampal and cortical injury signaling analysis; cognitive function assessment","journal":"CNS neuroscience & therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with clean phenotypic readout; epistatic comparison of single and double KO models provides mechanistic specificity","pmids":["37349952"],"is_preprint":false},{"year":2021,"finding":"Androgen receptor blockade with enzalutamide increases PSMA protein and mRNA expression in prostate cancer cell lines (22Rv1, C4-2, LNCaP) and in vivo in xenograft tumors, demonstrating that androgen receptor signaling negatively regulates FOLH1/PSMA expression.","method":"Flow cytometry; immunohistochemistry; 68Ga-PSMA PET/CT in xenograft-bearing mice; in vitro enzalutamide treatment of cell lines","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional experiments with quantitative imaging, single lab with multiple cell lines","pmids":["34299051"],"is_preprint":false},{"year":2024,"finding":"Exosomal PSM-E (a PSMA splice variant) inhibits macrophage M2 polarization by recruiting RACK1 and suppressing FAK and ERK signaling pathways, thereby suppressing prostate cancer invasion and metastasis. The protease-associated domain of PSM-E and the fourth WD repeat of RACK1 are required for their interaction.","method":"Co-immunoprecipitation; IHC staining; in vitro and in vivo PCa tumorigenesis models; domain deletion/interaction mapping; Western blotting","journal":"Biomarker research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and in vivo functional validation, single lab","pmids":["39538297"],"is_preprint":false}],"current_model":"FOLH1/PSMA/GCPII is a type II transmembrane zinc metallopeptidase (di-zinc carboxypeptidase) with two established enzymatic activities — NAALADase (hydrolysis of NAAG to NAA and glutamate, regulating glutamatergic neurotransmission) and folate hydrolase (intestinal polyglutamate folate processing) — whose prostate-specific expression is driven by an intronic enhancer (PSME) subject to androgen repression and Sox7-mediated transcriptional silencing, epigenetically regulated via H3K27 acetylation and CpG methylation at the FOLH1 locus; PSMA protein function is modulated post-translationally by filamin A association at its cytoplasmic tail (reducing internalization via clathrin-coated pits and NAALADase activity), and a splice isoform (PSM-E) suppresses tumor metastasis by recruiting RACK1 to inhibit macrophage M2 polarization via FAK/ERK signaling."},"narrative":{"mechanistic_narrative":"FOLH1 (PSMA/GCPII/NAALADase) is a membrane-bound glutamate-preferring carboxypeptidase with two reconstituted enzymatic activities: NAALADase, which hydrolyzes the neuropeptide NAAG to release glutamate, and gamma-glutamyl carboxypeptidase (folate hydrolase) activity [PMID:11210180]. The brain NAALADase and prostate PSMA are products of the same gene, sharing a common splice form, kinetic profile, and immunoreactivity [PMID:9694964]. In the central nervous system the enzyme localizes to neuropil where it co-localizes with its NAAG substrate, and it is also present in the brush border of renal proximal tubules [PMID:1545010]; in vivo it controls the balance between extracellular glutamate and NAAG, as pharmacological inhibition lowers glutamate and raises NAAG during ischemia [PMID:10668445], and genetic deletion reduces excitotoxic glutamate and neuronal damage after traumatic brain injury, an effect not compensated by the paralog GCPIII [PMID:37349952]. FOLH1 genotype tunes synaptic NAAG concentration and cognitive performance in humans [PMID:33256444], and its enzymatic activity is elevated in inflamed intestinal mucosa, where genetic or pharmacological abrogation ameliorates colitis [PMID:27536732]. Prostate-restricted expression of the human gene is driven by an intronic enhancer (PSME) that is intrinsically prostate-specific and repressed by androgen [PMID:11350116, PMID:34299051], directly silenced by Sox7 binding [PMID:30488457], and epigenetically controlled via CpG methylation and H3K27 acetylation at the locus [PMID:36821396]. At the protein level, filamin A binds the cytoplasmic tail to slow clathrin-mediated internalization and dampen NAALADase activity [PMID:12750292], and a splice variant, PSM-E, suppresses prostate cancer metastasis by recruiting RACK1 to inhibit macrophage M2 polarization through FAK/ERK signaling [PMID:39538297].","teleology":[{"year":1992,"claim":"Established that NAALADase is a membrane enzyme acting on NAAG in situ, placing it within glutamatergic neurotransmission rather than as a bystander activity.","evidence":"Immunocytochemistry co-localizing NAALADase-IR with NAAG-IR in rat brain neuropil and kidney brush border","pmids":["1545010"],"confidence":"Medium","gaps":["Single immunolocalization method","Did not establish molecular identity with prostate PSMA"]},{"year":1998,"claim":"Resolved whether brain NAALADase and prostate PSMA are distinct proteins by showing they are products of the same gene sharing a common mRNA splice form.","evidence":"Kinetic/pharmacological comparison, Northern blot, immunoprecipitation with anti-PSMA mAb, and RT-PCR cloning","pmids":["9694964"],"confidence":"High","gaps":["Did not address tissue-specific transcriptional control","Functional consequences in each tissue not separated"]},{"year":2001,"claim":"Reconstituted the dual enzymatic identity of FOLH1 by direct transfection, confirming both NAALADase and folate hydrolase activities reside in one gene product.","evidence":"cDNA cloning, transfection, NAALADase and folate hydrolase assays, RT-PCR tissue profiling in mouse Folh1","pmids":["11210180"],"confidence":"High","gaps":["Mouse lacks prostate expression, limiting model fidelity for human prostate biology","Substrate hierarchy in vivo not defined"]},{"year":2001,"claim":"Mapped the cis-regulatory basis of prostate-specific expression to an intronic enhancer (PSME) carrying both tissue specificity and androgen repression.","evidence":"Enhancer trap and luciferase reporter assays in prostate vs non-prostate cell lines with androgen treatment","pmids":["11350116"],"confidence":"High","gaps":["Trans-acting factors binding PSME not yet identified","Mechanism of androgen repression unresolved"]},{"year":2001,"claim":"Demonstrated in vivo that FOLH1 activity governs the extracellular glutamate/NAAG balance and that inhibition is neuroprotective via a glia- and mGluR-dependent route.","evidence":"Rat MCAO microdialysis with 2-PMPA; neuronal/glial co-culture pharmacology with selective mGlu receptor antagonists","pmids":["10668445","11525768"],"confidence":"Medium","gaps":["Single-lab pharmacology","Direct enzymatic measurement of GCPII not coupled to receptor epistasis in same system"]},{"year":2003,"claim":"Identified post-translational regulation of PSMA trafficking and activity through cytoplasmic-tail binding of filamin A.","evidence":"Co-IP and reciprocal functional rescue in filamin-negative vs positive cell lines with internalization and enzymatic assays","pmids":["12750292"],"confidence":"High","gaps":["Structural basis of tail-filamin interaction not defined","Physiological context of internalization control unclear"]},{"year":2016,"claim":"Extended FOLH1 pathophysiology beyond brain and prostate by linking its enzymatic activity to intestinal inflammation with genetic and pharmacological causal evidence.","evidence":"Human IBD specimen activity assays; FOLH1 KO and 2-PMPA inhibition in DSS and IL-10-/- colitis models","pmids":["27536732"],"confidence":"High","gaps":["Substrate/metabolite driving colitis effect not pinpointed","Cell type responsible for elevated activity not defined"]},{"year":2016,"claim":"Showed PSMA expression can be induced de novo on tumor-associated neovascular endothelium, broadening its relevance as a targetable antigen.","evidence":"Cancer-conditioned media induction of PSMA in HUVECs in vitro and in co-implantation model with functional internalization of anti-PSMA mAb and nanoparticles","pmids":["27458033"],"confidence":"Medium","gaps":["Inducing factor in conditioned media unidentified","Single-lab finding"]},{"year":2018,"claim":"Identified Sox7 as a direct transcriptional repressor of PSMA acting through defined SOX sites in the PSME enhancer.","evidence":"ChIP, EMSA, reporter assays, and stable Sox7 overexpression with domain mutants in prostate cancer cells","pmids":["30488457"],"confidence":"High","gaps":["Upstream control of Sox7 in prostate cancer unclear","Interplay with androgen repression not integrated"]},{"year":2020,"claim":"Connected FOLH1 genetic variation to synaptic NAAG levels and human cognition, establishing functional consequence of the locus in vivo.","evidence":"rs202676 genotyping with DLPFC mRNA, 7-T MRS NAAG measurement, cognitive testing, and working-memory fMRI","pmids":["33256444"],"confidence":"Medium","gaps":["Association rather than direct causal manipulation in humans","Mechanism linking mRNA increase to NAAG decrease inferred"]},{"year":2021,"claim":"Confirmed androgen receptor signaling negatively regulates PSMA, defining a therapeutically actionable axis (enzalutamide-induced PSMA upregulation).","evidence":"Enzalutamide treatment of multiple cell lines and xenografts with flow cytometry, IHC, and 68Ga-PSMA PET/CT","pmids":["34299051"],"confidence":"Medium","gaps":["Single-lab study","Direct link to PSME enhancer occupancy not shown"]},{"year":2023,"claim":"Defined the epigenetic basis of PSMA loss in metastatic castration-resistant prostate cancer and showed it is pharmacologically reversible.","evidence":"Autopsy cohort profiling, H3K27ac ChIP, bisulfite methylation analysis, and HDAC inhibitor rescue in vitro and in vivo","pmids":["36821396"],"confidence":"High","gaps":["Writer/eraser enzymes specific to the locus not identified","Durability of HDACi-restored expression unknown"]},{"year":2023,"claim":"Demonstrated GCPII-specific, GCPIII-independent control of excitotoxic glutamate and neuronal injury after traumatic brain injury via clean genetic epistasis.","evidence":"CRISPR/Cas9 single and double GCPII/GCPIII knockout mice in controlled cortical impact TBI with injury signaling and cognitive readouts","pmids":["37349952"],"confidence":"High","gaps":["Cellular source of pathogenic glutamate not localized","Translation to pharmacological timing windows unaddressed"]},{"year":2024,"claim":"Assigned a tumor-suppressive signaling function to the PSM-E splice variant through RACK1 recruitment and macrophage repolarization.","evidence":"Co-IP with domain-mapping, IHC, and in vitro/in vivo PCa tumorigenesis models","pmids":["39538297"],"confidence":"Medium","gaps":["Single-lab finding","Reciprocal validation and structural detail of RACK1 interaction limited"]},{"year":null,"claim":"How the enzyme's catalytic activity is mechanistically coupled to its non-catalytic signaling roles (filamin trafficking, PSM-E/RACK1 immune modulation) and whether they operate independently of NAAG/folate hydrolysis remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking ectodomain catalysis to cytoplasmic-tail signaling","Relative in vivo contribution of NAALADase vs folate hydrolase activities across tissues undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,3,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,9]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,10,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,7,16]}],"complexes":[],"partners":["FLNA","SOX7","RACK1"],"other_free_text":[]}},"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. 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Population.","date":"2016","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/27070640","citation_count":15,"is_preprint":false},{"pmid":"33760944","id":"PMC_33760944","title":"Antihormone treatment differentially regulates PSA secretion, PSMA expression and 68Ga-PSMA uptake in LNCaP cells.","date":"2021","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33760944","citation_count":15,"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":"24291031","id":"PMC_24291031","title":"Association of APOE, GCPII and MMP9 polymorphisms with common diseases and lipid levels in an older adult/elderly cohort.","date":"2013","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24291031","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":"29389139","id":"PMC_29389139","title":"Inhibitor-GCPII Interaction: Selective and Robust System for Targeting Cancer Cells with Structurally Diverse Nanoparticles.","date":"2018","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/29389139","citation_count":13,"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":"23979608","id":"PMC_23979608","title":"GCPII modulates oxidative stress and prostate cancer susceptibility through changes in methylation of RASSF1, BNIP3, GSTP1 and Ec-SOD.","date":"2013","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23979608","citation_count":13,"is_preprint":false},{"pmid":"35399715","id":"PMC_35399715","title":"Expression of Prostate-specific Membrane Antigen (PSMA) in Papillary Renal Cell Carcinoma - Overview and Report on a Large Multicenter Cohort.","date":"2022","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35399715","citation_count":13,"is_preprint":false},{"pmid":"22304710","id":"PMC_22304710","title":"GCPII variants, paralogs and orthologs.","date":"2012","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22304710","citation_count":12,"is_preprint":false},{"pmid":"30844704","id":"PMC_30844704","title":"GCPII and its close homolog GCPIII: from a neuropeptidase to a cancer marker and beyond.","date":"2019","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/30844704","citation_count":12,"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":"38593226","id":"PMC_38593226","title":"CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.","date":"2024","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/38593226","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":"37349952","id":"PMC_37349952","title":"Deletion of glutamate carboxypeptidase II (GCPII), but not GCPIII, provided long-term benefits in mice with traumatic brain injury.","date":"2023","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37349952","citation_count":11,"is_preprint":false},{"pmid":"39538297","id":"PMC_39538297","title":"Exosomal PSM-E inhibits macrophage M2 polarization to suppress prostate cancer metastasis through the RACK1 signaling axis.","date":"2024","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/39538297","citation_count":11,"is_preprint":false},{"pmid":"37573199","id":"PMC_37573199","title":"Standardized PSMA-PET Imaging of Advanced Prostate Cancer.","date":"2023","source":"Seminars in nuclear medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37573199","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":"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53517,"output_tokens":4537,"usd":0.114303,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12615,"output_tokens":4167,"usd":0.083625,"stage2_stop_reason":"end_turn"},"total_usd":0.197928,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Filamin A, an actin cross-linking protein, associates with the cytoplasmic tail of PSMA (FOLH1). This association localizes PSMA to the recycling endosomal compartment, reduces its internalization rate, and decreases its NAALADase enzymatic activity.\",\n      \"method\": \"Ectopic expression of PSMA in filamin-negative and filamin-positive cell lines; co-immunoprecipitation; functional internalization and enzymatic activity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional rescue using filamin-negative vs positive cell lines plus Co-IP and enzymatic assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12750292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The PSMA gene (FOLH1) contains a tissue-specific enhancer (PSME) located in the third intron (~12 kb downstream from the transcription start site). PSME drives prostate-specific transcription (>250-fold activation in LNCaP cells) and is repressed by androgen, recapitulating androgen regulation of the endogenous FOLH1 gene. Both cell-type specificity and androgen regulation are intrinsic to the enhancer.\",\n      \"method\": \"Enhancer trap assay with overlapping 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 / Moderate — functional reporter assays with multiple cell lines and androgen treatment, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11350116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Mouse Folh1 (homolog of human PSMA/FOLH1) encodes a glutamate-preferring carboxypeptidase with two enzymatic activities: NAALADase (cleaves NAAG to release glutamate) and gamma-glutamyl carboxypeptidase (folate hydrolase). Cells transfected with Folh1 gained both NAALADase and folate hydrolase activities. Unlike human PSMA, mouse Folh1 is not expressed in the prostate but is expressed primarily in brain and kidney.\",\n      \"method\": \"cDNA cloning and transfection; NAALADase and folate hydrolase enzymatic activity assays; RT-PCR tissue expression profiling; FISH chromosomal mapping\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic reconstitution by transfection, two orthogonal enzymatic assays in one study\",\n      \"pmids\": [\"11210180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human brain NAALADase and prostate PSMA (FOLH1) are products of the same gene and express a common mRNA splice form. Brain NAALADase shares the same kinetic profile, pharmacological sensitivities, and immunoreactivity (82% immunoprecipitation by anti-PSMA mAb 7E11-C5) as PSMA from LNCaP prostate tumor cells.\",\n      \"method\": \"Kinetic and pharmacological comparison; Northern blot hybridization; immunoprecipitation with monoclonal antibody; RT-PCR cloning of cerebellar cDNA\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (kinetics, Northern blot, immunoprecipitation, RT-PCR) demonstrating identity of brain and prostate enzyme\",\n      \"pmids\": [\"9694964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"NAALADase (FOLH1/GCPII) is a membrane-bound enzyme that cleaves glutamate from the neuropeptide NAAG. Immunocytochemical localization in rat brain showed NAALADase-IR co-localizing with NAAG-IR in neuropil (absent from neuronal cytoplasm), supporting its role in NAAG catabolism in vivo. It was also detected in the brush border of proximal convoluted tubules in the kidney cortex.\",\n      \"method\": \"Immunocytochemistry with specific anti-NAALADase antiserum in rat brain and kidney; co-localization with NAAG-IR\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunolocalization with specific antiserum across multiple brain regions; indirect mechanistic inference from co-localization, single method\",\n      \"pmids\": [\"1545010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOLH1/GCPII enzymatic activity is robustly elevated (2.8–41-fold) in affected intestinal mucosa of IBD patients versus uninvolved areas or healthy controls. Genetic knockout of FOLH1 in mice conferred resistance to DSS-induced colitis, and pharmacological inhibition with 2-PMPA (IC50=300 pM) reduced GCPII activity in colonic mucosa by >90% and substantially ameliorated disease in both DSS and IL-10-/- colitis models.\",\n      \"method\": \"Enzymatic activity quantification in 31 surgical specimens; FOLH1 knockout mouse model (DSS colitis); pharmacological inhibition with 2-PMPA in two murine IBD models; macroscopic and microscopic disease assessment\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and pharmacological inhibition with defined phenotypic readout, replicated across two independent IBD mouse models plus human tissue data\",\n      \"pmids\": [\"27536732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sox7 negatively regulates PSMA (FOLH1) expression by directly binding to SOX box sites #2 and #4 within the PSMA enhancer (PSME). The nuclear localization signal (NLS) regions of Sox7, but not its β-catenin interacting motif, are essential for this suppressive activity. Stable expression of canonical Sox7 in LNCaP/C4-2 and 22Rv1 cells suppressed PSMA protein expression.\",\n      \"method\": \"ChIP assay; EMSA; luciferase reporter assay; stable Sox7 overexpression in prostate cancer cell lines; Sox7 domain mutant analysis\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, reporter assay, stable OE with defined mutants) establishing direct transcriptional mechanism\",\n      \"pmids\": [\"30488457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSMA (FOLH1) expression loss in metastatic castration-resistant prostate cancer is associated with gain of CpG methylation and loss of H3K27 acetylation at the FOLH1 locus. Treatment with HDAC inhibitors reversed this epigenetic repression and restored PSMA expression both in vitro and in vivo.\",\n      \"method\": \"Rapid autopsy cohort PSMA expression profiling; ChIP for H3K27ac; bisulfite methylation analysis; HDAC inhibitor treatment in vitro and in vivo xenograft models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic writer/eraser mechanism identified by ChIP and methylation analysis with functional rescue by HDAC inhibitors in vitro and in vivo\",\n      \"pmids\": [\"36821396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cancer cell-conditioned media induces PSMA expression in otherwise PSMA-negative HUVECs both in vitro and in vivo (HUVEC co-implantation mouse model). HUVECs with induced PSMA expression were able to internalize J591 anti-PSMA mAb and PSMA-binding ligand-bearing nanoparticles, demonstrating functional PSMA on induced neovascular endothelium.\",\n      \"method\": \"Conditioned media experiments; in vitro HUVEC PSMA induction assay; in vivo HUVEC co-implantation mouse model; internalization assays with anti-PSMA mAb and nanoparticles\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo induction experiments with functional internalization readout, single lab\",\n      \"pmids\": [\"27458033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PSMA undergoes internalization via clathrin-coated pits and is recycled like other membrane-bound receptors. Filamin A binding to PSMA reduces the rate of this internalization.\",\n      \"method\": \"Previously described clathrin-coated pit internalization (cited in PMID 12750292); filamin association and internalization rate assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — internalization mechanism referenced from prior work; filamin-dependent regulation confirmed by functional cell-based assay in PMID 12750292\",\n      \"pmids\": [\"12750292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NAALADase inhibition (by 2-PMPA) reduces extracellular glutamate accumulation and produces a reciprocal rise in extracellular NAAG during cerebral ischemia reperfusion in rats, consistent with FOLH1/GCPII controlling glutamate supply from NAAG hydrolysis in vivo.\",\n      \"method\": \"Suture model of transient middle cerebral artery occlusion in rats; in vivo microdialysis measuring extracellular glutamate and NAAG; pharmacological inhibition with 2-PMPA\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological inhibition with direct metabolite measurement by microdialysis, single lab\",\n      \"pmids\": [\"10668445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Neuroprotection by NAAG and NAALADase inhibitor 2-PMPA requires the presence of glial cells and group II metabotropic glutamate receptor (mGluR) activation. Selective group II mGlu receptor antagonists reduced protection afforded by both NAAG and 2-PMPA in neuronal/glial co-cultures, while groups I and III mGlu receptor antagonists had no effect.\",\n      \"method\": \"In vitro metabolic inhibition model using neuronal/glial co-cultures vs. neuron-only cultures; pharmacological dissection with selective mGlu receptor agonists and antagonists\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with selective receptor antagonists in defined cell co-culture system, single lab\",\n      \"pmids\": [\"11525768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A missense mutation in FOLH1 (rs202676 G allele) is associated with increased FOLH1 mRNA in the dorsolateral prefrontal cortex and decreased NAAG levels (measured by 7-T MRS) in humans. Lower NAAG levels correlated with lower IQ scores and less efficient cortical activity during working memory (fMRI), establishing that FOLH1 genotype influences synaptic NAAG concentration and cognitive function.\",\n      \"method\": \"Human brain mRNA expression analysis; 7-T magnetic resonance spectroscopy (MRS) of NAAG in vivo; cognitive testing; functional MRI during working memory tasks; genetic association with rs202676\",\n      \"journal\": \"The American journal of psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vivo human methods (MRS, fMRI, mRNA, cognition) linking FOLH1 variant to NAAG levels and cognitive outcomes, single study\",\n      \"pmids\": [\"33256444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mouse GCPII (Folh1) possesses lower catalytic efficiency but similar substrate specificity and inhibitor sensitivity compared to human GCPII, validating mouse models for inhibitor development. Mouse GCPII is highest expressed in kidney, brain, and salivary glands, but is absent from mouse prostate — a key difference from the human enzyme.\",\n      \"method\": \"Recombinant mouse GCPII preparation; enzymatic kinetic assays; inhibitor panel testing; tissue protein expression profiling\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — recombinant enzyme reconstitution with kinetic characterization and inhibitor panel, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28904865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Genetic deletion of GCPII (FOLH1), but not GCPIII, in mice reduced glutamate production, excitotoxicity, and neuronal damage after traumatic brain injury (TBI) and improved cognitive function. Combined GCPII/GCPIII knockout showed no additional benefit over GCPII deletion alone, indicating GCPIII does not compensate for GCPII in TBI.\",\n      \"method\": \"CRISPR/Cas9 knockout of GCPII, GCPIII, and GCPII/III in mice; controlled cortical impact TBI model; hippocampal and cortical injury signaling analysis; cognitive function assessment\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with clean phenotypic readout; epistatic comparison of single and double KO models provides mechanistic specificity\",\n      \"pmids\": [\"37349952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Androgen receptor blockade with enzalutamide increases PSMA protein and mRNA expression in prostate cancer cell lines (22Rv1, C4-2, LNCaP) and in vivo in xenograft tumors, demonstrating that androgen receptor signaling negatively regulates FOLH1/PSMA expression.\",\n      \"method\": \"Flow cytometry; immunohistochemistry; 68Ga-PSMA PET/CT in xenograft-bearing mice; in vitro enzalutamide treatment of cell lines\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional experiments with quantitative imaging, single lab with multiple cell lines\",\n      \"pmids\": [\"34299051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Exosomal PSM-E (a PSMA splice variant) inhibits macrophage M2 polarization by recruiting RACK1 and suppressing FAK and ERK signaling pathways, thereby suppressing prostate cancer invasion and metastasis. The protease-associated domain of PSM-E and the fourth WD repeat of RACK1 are required for their interaction.\",\n      \"method\": \"Co-immunoprecipitation; IHC staining; in vitro and in vivo PCa tumorigenesis models; domain deletion/interaction mapping; Western blotting\",\n      \"journal\": \"Biomarker research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and in vivo functional validation, single lab\",\n      \"pmids\": [\"39538297\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOLH1/PSMA/GCPII is a type II transmembrane zinc metallopeptidase (di-zinc carboxypeptidase) with two established enzymatic activities — NAALADase (hydrolysis of NAAG to NAA and glutamate, regulating glutamatergic neurotransmission) and folate hydrolase (intestinal polyglutamate folate processing) — whose prostate-specific expression is driven by an intronic enhancer (PSME) subject to androgen repression and Sox7-mediated transcriptional silencing, epigenetically regulated via H3K27 acetylation and CpG methylation at the FOLH1 locus; PSMA protein function is modulated post-translationally by filamin A association at its cytoplasmic tail (reducing internalization via clathrin-coated pits and NAALADase activity), and a splice isoform (PSM-E) suppresses tumor metastasis by recruiting RACK1 to inhibit macrophage M2 polarization via FAK/ERK signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FOLH1 (PSMA/GCPII/NAALADase) is a membrane-bound glutamate-preferring carboxypeptidase with two reconstituted enzymatic activities: NAALADase, which hydrolyzes the neuropeptide NAAG to release glutamate, and gamma-glutamyl carboxypeptidase (folate hydrolase) activity [#2]. The brain NAALADase and prostate PSMA are products of the same gene, sharing a common splice form, kinetic profile, and immunoreactivity [#3]. In the central nervous system the enzyme localizes to neuropil where it co-localizes with its NAAG substrate, and it is also present in the brush border of renal proximal tubules [#4]; in vivo it controls the balance between extracellular glutamate and NAAG, as pharmacological inhibition lowers glutamate and raises NAAG during ischemia [#10], and genetic deletion reduces excitotoxic glutamate and neuronal damage after traumatic brain injury, an effect not compensated by the paralog GCPIII [#14]. FOLH1 genotype tunes synaptic NAAG concentration and cognitive performance in humans [#12], and its enzymatic activity is elevated in inflamed intestinal mucosa, where genetic or pharmacological abrogation ameliorates colitis [#5]. Prostate-restricted expression of the human gene is driven by an intronic enhancer (PSME) that is intrinsically prostate-specific and repressed by androgen [#1, #15], directly silenced by Sox7 binding [#6], and epigenetically controlled via CpG methylation and H3K27 acetylation at the locus [#7]. At the protein level, filamin A binds the cytoplasmic tail to slow clathrin-mediated internalization and dampen NAALADase activity [#0, #9], and a splice variant, PSM-E, suppresses prostate cancer metastasis by recruiting RACK1 to inhibit macrophage M2 polarization through FAK/ERK signaling [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that NAALADase is a membrane enzyme acting on NAAG in situ, placing it within glutamatergic neurotransmission rather than as a bystander activity.\",\n      \"evidence\": \"Immunocytochemistry co-localizing NAALADase-IR with NAAG-IR in rat brain neuropil and kidney brush border\",\n      \"pmids\": [\"1545010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single immunolocalization method\", \"Did not establish molecular identity with prostate PSMA\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved whether brain NAALADase and prostate PSMA are distinct proteins by showing they are products of the same gene sharing a common mRNA splice form.\",\n      \"evidence\": \"Kinetic/pharmacological comparison, Northern blot, immunoprecipitation with anti-PSMA mAb, and RT-PCR cloning\",\n      \"pmids\": [\"9694964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address tissue-specific transcriptional control\", \"Functional consequences in each tissue not separated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Reconstituted the dual enzymatic identity of FOLH1 by direct transfection, confirming both NAALADase and folate hydrolase activities reside in one gene product.\",\n      \"evidence\": \"cDNA cloning, transfection, NAALADase and folate hydrolase assays, RT-PCR tissue profiling in mouse Folh1\",\n      \"pmids\": [\"11210180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mouse lacks prostate expression, limiting model fidelity for human prostate biology\", \"Substrate hierarchy in vivo not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapped the cis-regulatory basis of prostate-specific expression to an intronic enhancer (PSME) carrying both tissue specificity and androgen repression.\",\n      \"evidence\": \"Enhancer trap and luciferase reporter assays in prostate vs non-prostate cell lines with androgen treatment\",\n      \"pmids\": [\"11350116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-acting factors binding PSME not yet identified\", \"Mechanism of androgen repression unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated in vivo that FOLH1 activity governs the extracellular glutamate/NAAG balance and that inhibition is neuroprotective via a glia- and mGluR-dependent route.\",\n      \"evidence\": \"Rat MCAO microdialysis with 2-PMPA; neuronal/glial co-culture pharmacology with selective mGlu receptor antagonists\",\n      \"pmids\": [\"10668445\", \"11525768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pharmacology\", \"Direct enzymatic measurement of GCPII not coupled to receptor epistasis in same system\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified post-translational regulation of PSMA trafficking and activity through cytoplasmic-tail binding of filamin A.\",\n      \"evidence\": \"Co-IP and reciprocal functional rescue in filamin-negative vs positive cell lines with internalization and enzymatic assays\",\n      \"pmids\": [\"12750292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of tail-filamin interaction not defined\", \"Physiological context of internalization control unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended FOLH1 pathophysiology beyond brain and prostate by linking its enzymatic activity to intestinal inflammation with genetic and pharmacological causal evidence.\",\n      \"evidence\": \"Human IBD specimen activity assays; FOLH1 KO and 2-PMPA inhibition in DSS and IL-10-/- colitis models\",\n      \"pmids\": [\"27536732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate/metabolite driving colitis effect not pinpointed\", \"Cell type responsible for elevated activity not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed PSMA expression can be induced de novo on tumor-associated neovascular endothelium, broadening its relevance as a targetable antigen.\",\n      \"evidence\": \"Cancer-conditioned media induction of PSMA in HUVECs in vitro and in co-implantation model with functional internalization of anti-PSMA mAb and nanoparticles\",\n      \"pmids\": [\"27458033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inducing factor in conditioned media unidentified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified Sox7 as a direct transcriptional repressor of PSMA acting through defined SOX sites in the PSME enhancer.\",\n      \"evidence\": \"ChIP, EMSA, reporter assays, and stable Sox7 overexpression with domain mutants in prostate cancer cells\",\n      \"pmids\": [\"30488457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream control of Sox7 in prostate cancer unclear\", \"Interplay with androgen repression not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected FOLH1 genetic variation to synaptic NAAG levels and human cognition, establishing functional consequence of the locus in vivo.\",\n      \"evidence\": \"rs202676 genotyping with DLPFC mRNA, 7-T MRS NAAG measurement, cognitive testing, and working-memory fMRI\",\n      \"pmids\": [\"33256444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Association rather than direct causal manipulation in humans\", \"Mechanism linking mRNA increase to NAAG decrease inferred\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed androgen receptor signaling negatively regulates PSMA, defining a therapeutically actionable axis (enzalutamide-induced PSMA upregulation).\",\n      \"evidence\": \"Enzalutamide treatment of multiple cell lines and xenografts with flow cytometry, IHC, and 68Ga-PSMA PET/CT\",\n      \"pmids\": [\"34299051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct link to PSME enhancer occupancy not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the epigenetic basis of PSMA loss in metastatic castration-resistant prostate cancer and showed it is pharmacologically reversible.\",\n      \"evidence\": \"Autopsy cohort profiling, H3K27ac ChIP, bisulfite methylation analysis, and HDAC inhibitor rescue in vitro and in vivo\",\n      \"pmids\": [\"36821396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Writer/eraser enzymes specific to the locus not identified\", \"Durability of HDACi-restored expression unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated GCPII-specific, GCPIII-independent control of excitotoxic glutamate and neuronal injury after traumatic brain injury via clean genetic epistasis.\",\n      \"evidence\": \"CRISPR/Cas9 single and double GCPII/GCPIII knockout mice in controlled cortical impact TBI with injury signaling and cognitive readouts\",\n      \"pmids\": [\"37349952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source of pathogenic glutamate not localized\", \"Translation to pharmacological timing windows unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Assigned a tumor-suppressive signaling function to the PSM-E splice variant through RACK1 recruitment and macrophage repolarization.\",\n      \"evidence\": \"Co-IP with domain-mapping, IHC, and in vitro/in vivo PCa tumorigenesis models\",\n      \"pmids\": [\"39538297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Reciprocal validation and structural detail of RACK1 interaction limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the enzyme's catalytic activity is mechanistically coupled to its non-catalytic signaling roles (filamin trafficking, PSM-E/RACK1 immune modulation) and whether they operate independently of NAAG/folate hydrolysis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model linking ectodomain catalysis to cytoplasmic-tail signaling\", \"Relative in vivo contribution of NAALADase vs folate hydrolase activities across tissues undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 3, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 10, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 7, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FLNA\", \"SOX7\", \"RACK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}