{"gene":"PTGER2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2010,"finding":"DNA hypermethylation of the PTGER2 promoter is responsible for diminished EP2 receptor expression and PGE2 resistance in fibrotic fibroblasts from humans and mice with pulmonary fibrosis. Treatment with DNA methylation inhibitors (5-aza-2'-deoxycytidine, zebularine) and DNMT-specific siRNA decreased PTGER2 methylation, restored EP2 mRNA and protein expression, and recovered PGE2 responsiveness. Increased Akt signaling was identified as the upstream driver of PTGER2 promoter hypermethylation.","method":"Bisulfite sequencing, siRNA knockdown of DNMTs, pharmacological demethylation, western blot, mRNA analysis, functional PGE2 response assays in fibrotic vs. non-fibrotic fibroblasts","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (bisulfite sequencing, siRNA, pharmacological inhibition, functional rescue) in both human and mouse fibrotic fibroblasts, with mechanistic pathway identification (Akt→DNMT→PTGER2 methylation)","pmids":["20889571"],"is_preprint":false},{"year":2007,"finding":"PTGER2 is frequently epigenetically silenced in neuroblastoma cell lines (especially those with MYCN amplification) through DNA methylation of a CpG island in its promoter region, combined with histone H3/H4 deacetylation and histone H3 lysine 9 methylation. Restoration of PTGER2 expression in PTGER2-negative neuroblastoma cells inhibited growth and induced apoptosis. Activation of PTGER2 by the selective agonist butaprost increased intracellular cAMP and inhibited cell growth.","method":"Methylation analysis, chromatin immunoprecipitation (histone modifications), transient and stable transfection of PTGER2, PTGER2-selective agonist (butaprost) treatment, cAMP measurement, cell growth and apoptosis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (methylation analysis, ChIP for histone marks, gain-of-function rescue, pharmacological agonism, cAMP measurement, growth/apoptosis assays) in a single rigorous study","pmids":["17533365"],"is_preprint":false},{"year":2011,"finding":"PGE2 decreases Sclerostin (Sost) expression in osteoblastic cells via PTGER2 (EP2 receptor) signaling through a cyclic AMP/PKA pathway. Selective EP2 agonists mimicked PGE2's suppression of Sost, and siRNA-mediated reduction of Ptger2 prevented PGE2-induced Sost repression. Decreased Sost correlated with increased expression of Wnt/TCF target genes Axin2 and Tcf3, placing PTGER2 upstream of Wnt/β-catenin signaling in bone.","method":"Selective EP receptor agonists, siRNA knockdown of Ptger2, gene expression analysis (Sost, Axin2, Tcf3), cAMP/PKA pathway pharmacological dissection","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus selective agonist pharmacology and pathway analysis in a single lab, two orthogonal approaches confirming PTGER2 mediates PGE2-Sost suppression","pmids":["21436889"],"is_preprint":false},{"year":2013,"finding":"PTGER2 (EP2 receptor) expression increases ~14-fold in porcine trophoblast/conceptus cells during implantation (days 14–25) compared to preimplantation stages. PGE2 stimulated PTGER2 mRNA expression via autocrine PTGER2 signaling. PTGER2 activation by PGE2 or the selective agonist butaprost increased trophoblast adhesion to extracellular matrix via integrin αVβ3, focal adhesion kinase (FAK), and ICAM-1 upregulation, and this adhesion was abolished by the PTGER2 antagonist AH6809. The mechanism operates through estrogen receptor and MEK/MAPK (ERK1/2 phosphorylation) signaling downstream of PTGER2.","method":"Real-time RT-PCR, western blot, selective EP receptor agonists/antagonists, integrin-blocking antibodies and RGD peptides, adhesion assays in human HTR-8/SVneo and primary porcine trophoblast cells, phosphorylation assays for MAPK1/3","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (agonist, antagonist, integrin blockade, siRNA/antibody, MAPK phosphorylation) in two cell systems (porcine primary and human trophoblast), rigorous mechanistic dissection of PTGER2 downstream pathway","pmids":["23861370"],"is_preprint":false},{"year":2010,"finding":"PTGER2 overexpression is positively associated with microsatellite instability-high (MSI-high) status in colorectal cancer, independent of CpG island methylator phenotype (CIMP), in a multivariate analysis of 516 colorectal cancers.","method":"Immunohistochemistry for PTGER2 protein, MSI analysis with 10 microsatellite markers, MethyLight for CIMP, multivariate logistic regression","journal":"Cancer epidemiology, biomarkers & prevention","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — immunohistochemistry and epidemiological association in a large cohort, but no direct functional/mechanistic experiment linking PTGER2 to the MSI phenotype","pmids":["20200425"],"is_preprint":false},{"year":2024,"finding":"PTGER2 (prostaglandin E receptor 2) is identified as a surface marker specifically expressed on mature polymorphonuclear myeloid-derived suppressor cells (mPMN-MDSCs) from cancer patients and G-CSF-treated donors, as part of a distinct gene signature identified by RNA-seq and validated by scRNA-seq, suggesting PTGER2 expression is associated with mPMN-MDSC differentiation and reprogramming.","method":"Bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), flow cytometry/immunophenotyping of PMN-MDSC subsets from cancer patients and G-CSF-treated donors","journal":"Cell reports. Medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptomic identification and surface marker validation by sequencing; no direct functional experiment establishing a mechanistic role for PTGER2 in MDSC biology","pmids":["38242120"],"is_preprint":false}],"current_model":"PTGER2 (EP2 receptor) is a Gs-coupled prostaglandin E2 receptor that signals primarily through cAMP/PKA to regulate diverse cellular processes including osteoblast Wnt/β-catenin signaling (by suppressing Sclerostin expression), trophoblast adhesion during implantation (via MEK/MAPK and integrin αVβ3), and growth inhibition/apoptosis in neuroblastoma; its expression is regulated by epigenetic mechanisms — specifically promoter DNA hypermethylation driven by Akt signaling — which silences PTGER2 in fibrotic fibroblasts and neuroblastoma cells to confer PGE2 resistance and enable tumor progression."},"narrative":{"mechanistic_narrative":"PTGER2 (EP2 receptor) is a prostaglandin E2 (PGE2) receptor that couples to the cAMP second-messenger system to control cell growth, differentiation, and adhesion across multiple tissues [PMID:17533365, PMID:21436889]. Pharmacological activation of PTGER2 by the selective agonist butaprost raises intracellular cAMP, and in neuroblastoma cells this signaling inhibits growth and induces apoptosis [PMID:17533365]. Through a cAMP/PKA pathway, PTGER2 also represses Sclerostin (Sost) in osteoblastic cells, thereby derepressing Wnt/β-catenin target genes (Axin2, Tcf3) and placing the receptor upstream of bone Wnt signaling [PMID:21436889]. In trophoblast cells PTGER2 mediates PGE2-stimulated adhesion to extracellular matrix via integrin αVβ3, FAK, and ICAM-1 upregulation, operating through estrogen receptor and MEK/MAPK (ERK1/2) signaling, with adhesion blocked by the PTGER2 antagonist AH6809 [PMID:23861370]. PTGER2 expression is governed epigenetically: promoter CpG-island DNA hypermethylation — accompanied by histone H3/H4 deacetylation and H3K9 methylation, and driven upstream by Akt signaling — silences the receptor in pulmonary fibrosis fibroblasts and in MYCN-amplified neuroblastoma, conferring PGE2 resistance, and demethylation restores receptor expression and PGE2 responsiveness [PMID:20889571, PMID:17533365].","teleology":[{"year":2007,"claim":"Established that PTGER2 is epigenetically silenced in neuroblastoma and acts as a growth-suppressive, cAMP-elevating receptor, defining a tumor-relevant function.","evidence":"Methylation/ChIP analysis of promoter marks plus gain-of-function rescue, butaprost agonism, cAMP measurement, and growth/apoptosis assays in neuroblastoma cell lines","pmids":["17533365"],"confidence":"High","gaps":["In vivo tumor relevance not tested","Downstream effectors linking cAMP to apoptosis not defined"]},{"year":2010,"claim":"Showed that PTGER2 promoter hypermethylation, driven by Akt signaling, causes PGE2 resistance in fibrotic fibroblasts, generalizing the epigenetic silencing mechanism beyond cancer.","evidence":"Bisulfite sequencing, DNMT siRNA, pharmacological demethylation, and functional PGE2 response assays in human and mouse fibrotic fibroblasts","pmids":["20889571"],"confidence":"High","gaps":["Mechanism linking Akt to DNMT recruitment at the PTGER2 promoter not resolved","In vivo reversal of fibrosis by demethylation not shown"]},{"year":2010,"claim":"Linked PTGER2 protein overexpression to MSI-high colorectal cancer, raising the question of receptor activity in tumors where it is not silenced.","evidence":"Immunohistochemistry and MSI/CIMP analysis with multivariate regression across 516 colorectal cancers","pmids":["20200425"],"confidence":"Low","gaps":["Association only — no functional or mechanistic experiment linking PTGER2 to the MSI phenotype","Causal direction unknown"]},{"year":2011,"claim":"Placed PTGER2 upstream of bone Wnt/β-catenin signaling by showing it represses Sclerostin via cAMP/PKA, defining a signaling output distinct from growth control.","evidence":"Selective EP2 agonists, Ptger2 siRNA, and Sost/Axin2/Tcf3 expression analysis in osteoblastic cells","pmids":["21436889"],"confidence":"Medium","gaps":["Performed in a single lab/cell context","Direct molecular link between PKA and Sost transcription not defined"]},{"year":2013,"claim":"Defined a non-cAMP signaling axis for PTGER2 in trophoblast adhesion during implantation, showing the receptor drives integrin/FAK-mediated ECM attachment via MEK/MAPK.","evidence":"Agonist/antagonist pharmacology, integrin blockade, MAPK phosphorylation, and adhesion assays in porcine primary and human HTR-8/SVneo trophoblast cells","pmids":["23861370"],"confidence":"High","gaps":["Relative contribution of cAMP vs MEK/MAPK branches not dissected","In vivo implantation requirement not tested"]},{"year":2024,"claim":"Identified PTGER2 as a surface marker of mature PMN-MDSCs, raising the question of a functional role in myeloid suppressor cell biology.","evidence":"Bulk and single-cell RNA-seq plus flow cytometry of PMN-MDSC subsets from cancer patients and G-CSF-treated donors","pmids":["38242120"],"confidence":"Low","gaps":["Transcriptomic/marker association only — no functional experiment","Signaling role of PTGER2 in MDSCs unknown"]},{"year":null,"claim":"How PTGER2 signaling output is selected between cAMP/PKA growth control and MEK/MAPK adhesion programs in different cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical determinant of pathway bias identified","In vivo roles across fibrosis, bone, implantation, and tumor immunity not directly compared"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35408","full_name":"Prostaglandin E2 receptor EP4 subtype","aliases":["Prostanoid EP4 receptor"],"length_aa":488,"mass_kda":53.1,"function":"Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. Has a relaxing effect on smooth muscle. May play an important role in regulating renal hemodynamics, intestinal epithelial transport, adrenal aldosterone secretion, and uterine function","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P35408/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTGER2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTGER2","total_profiled":1310},"omim":[{"mim_id":"604186","title":"CHEMOKINE, CXC MOTIF, LIGAND 14; CXCL14","url":"https://www.omim.org/entry/604186"},{"mim_id":"601586","title":"PROSTAGLANDIN E RECEPTOR 4, EP4 SUBTYPE; PTGER4","url":"https://www.omim.org/entry/601586"},{"mim_id":"601313","title":"POLYCYSTIN 1; PKD1","url":"https://www.omim.org/entry/601313"},{"mim_id":"600262","title":"PROSTAGLANDIN-ENDOPEROXIDE SYNTHASE 2; PTGS2","url":"https://www.omim.org/entry/600262"},{"mim_id":"600242","title":"CHEMOKINE, CC MOTIF, RECEPTOR 7; CCR7","url":"https://www.omim.org/entry/600242"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":36.2}],"url":"https://www.proteinatlas.org/search/PTGER2"},"hgnc":{"alias_symbol":["EP2","COX-2"],"prev_symbol":[]},"alphafold":{"accession":"P35408","domains":[{"cath_id":"1.20.1070.10","chopping":"22-232_258-350","consensus_level":"high","plddt":87.515,"start":22,"end":350}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35408","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35408-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35408-F1-predicted_aligned_error_v6.png","plddt_mean":70.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTGER2","jax_strain_url":"https://www.jax.org/strain/search?query=PTGER2"},"sequence":{"accession":"P35408","fasta_url":"https://rest.uniprot.org/uniprotkb/P35408.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35408/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35408"}},"corpus_meta":[{"pmid":"9929039","id":"PMC_9929039","title":"COX-2 inhibitors.","date":"1999","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9929039","citation_count":825,"is_preprint":false},{"pmid":"9249646","id":"PMC_9249646","title":"COX-1 and COX-2 tissue expression: implications and predictions.","date":"1997","source":"The Journal of rheumatology. 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Clinical gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/11566043","citation_count":30,"is_preprint":false},{"pmid":"16012420","id":"PMC_16012420","title":"COX-2 inhibitors: pharmacological data and adverse effects.","date":"2005","source":"Minerva anestesiologica","url":"https://pubmed.ncbi.nlm.nih.gov/16012420","citation_count":30,"is_preprint":false},{"pmid":"24827772","id":"PMC_24827772","title":"Association between length of gestation and cervical DNA methylation of PTGER2 and LINE 1-HS.","date":"2014","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/24827772","citation_count":30,"is_preprint":false},{"pmid":"20333781","id":"PMC_20333781","title":"COX-2 in liver, from regeneration to hepatocarcinogenesis: what we have learned from animal models?","date":"2010","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/20333781","citation_count":30,"is_preprint":false},{"pmid":"24059237","id":"PMC_24059237","title":"Radiotracers for molecular imaging of cyclooxygenase-2 (COX-2) enzyme.","date":"2013","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24059237","citation_count":30,"is_preprint":false},{"pmid":"20200425","id":"PMC_20200425","title":"PTGER2 overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype.","date":"2010","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20200425","citation_count":30,"is_preprint":false},{"pmid":"19203768","id":"PMC_19203768","title":"COX-2 expression in canine normal and neoplastic mammary gland.","date":"2009","source":"Journal of comparative pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19203768","citation_count":30,"is_preprint":false},{"pmid":"23392729","id":"PMC_23392729","title":"Endotoxins potentiate COX-2 and RANKL expression in compressed PDL cells.","date":"2013","source":"Clinical oral investigations","url":"https://pubmed.ncbi.nlm.nih.gov/23392729","citation_count":30,"is_preprint":false},{"pmid":"16226033","id":"PMC_16226033","title":"Roles of LPA3 and COX-2 in implantation.","date":"2005","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/16226033","citation_count":29,"is_preprint":false},{"pmid":"20004565","id":"PMC_20004565","title":"COX-2 expression in chondrosarcoma: a role for celecoxib treatment?","date":"2009","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/20004565","citation_count":29,"is_preprint":false},{"pmid":"16136511","id":"PMC_16136511","title":"COX-2 overexpression in canine tumors: potential therapeutic targets in oncology.","date":"2005","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/16136511","citation_count":29,"is_preprint":false},{"pmid":"38242120","id":"PMC_38242120","title":"Surface CD52, CD84, and PTGER2 mark mature PMN-MDSCs from cancer patients and G-CSF-treated donors.","date":"2024","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38242120","citation_count":28,"is_preprint":false},{"pmid":"33119867","id":"PMC_33119867","title":"COX-2 Signaling in the Tumor Microenvironment.","date":"2020","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/33119867","citation_count":28,"is_preprint":false},{"pmid":"12457568","id":"PMC_12457568","title":"Polyamine-mediated post-transcriptional regulation of COX-2.","date":"2002","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/12457568","citation_count":28,"is_preprint":false},{"pmid":"16507399","id":"PMC_16507399","title":"Taxanes and COX-2 inhibitors: from molecular pathways to clinical practice.","date":"2005","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/16507399","citation_count":26,"is_preprint":false},{"pmid":"37153547","id":"PMC_37153547","title":"Effect of NETs/COX-2 pathway on immune microenvironment and metastasis in gastric cancer.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37153547","citation_count":26,"is_preprint":false},{"pmid":"18650268","id":"PMC_18650268","title":"Corticosteroids induce COX-2 expression in cardiomyocytes: role of glucocorticoid receptor and C/EBP-beta.","date":"2008","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18650268","citation_count":26,"is_preprint":false},{"pmid":"14529401","id":"PMC_14529401","title":"Mucosal repair and COX-2 inhibition.","date":"2003","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/14529401","citation_count":25,"is_preprint":false},{"pmid":"11695255","id":"PMC_11695255","title":"Analgesia and COX-2 inhibition.","date":"2001","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/11695255","citation_count":25,"is_preprint":false},{"pmid":"15120641","id":"PMC_15120641","title":"Fibronectin-induced COX-2 mediates MMP-2 expression and invasiveness of rhabdomyosarcoma.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15120641","citation_count":25,"is_preprint":false},{"pmid":"16797158","id":"PMC_16797158","title":"Cox-2 expression on tissue microarray of breast cancer.","date":"2006","source":"European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16797158","citation_count":25,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46382,"output_tokens":2490,"usd":0.088248,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9120,"output_tokens":2309,"usd":0.051663,"stage2_stop_reason":"end_turn"},"total_usd":0.139911,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at these abstracts, I need to identify papers about PTGER2 (the prostaglandin E receptor 2, EP2 receptor) specifically, not COX-2 (PTGS2). The HGNC aliases note says COX-2 is an alias for PTGER2, but this is almost certainly incorrect — COX-2 is the common name for PTGS2 (prostaglandin-endoperoxide synthase 2), not PTGER2 (prostaglandin E receptor 2). The vast majority of these papers are about COX-2/PTGS2, not PTGER2.\n\nLet me identify papers that are specifically about PTGER2 (the EP2 receptor):\n\n- PMID 20889571: Directly about PTGER2 methylation and EP2 receptor function\n- PMID 21436889: Directly about PTGER2/EP2 signaling in bone\n- PMID 17533365: Directly about PTGER2 epigenetic silencing in neuroblastoma\n- PMID 23861370: Directly about PTGER2 in trophoblast/implantation\n- PMID 24827772: About PTGER2 DNA methylation and gestation\n- PMID 20200425: About PTGER2 overexpression in colorectal cancer\n- PMID 38242120: PTGER2 as marker on PMN-MDSCs\n\nI will exclude the COX-2/PTGS2 papers as they are about a different gene (PTGS2), not PTGER2.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"DNA hypermethylation of the PTGER2 promoter is responsible for diminished EP2 receptor expression and PGE2 resistance in fibrotic fibroblasts from humans and mice with pulmonary fibrosis. Treatment with DNA methylation inhibitors (5-aza-2'-deoxycytidine, zebularine) and DNMT-specific siRNA decreased PTGER2 methylation, restored EP2 mRNA and protein expression, and recovered PGE2 responsiveness. Increased Akt signaling was identified as the upstream driver of PTGER2 promoter hypermethylation.\",\n      \"method\": \"Bisulfite sequencing, siRNA knockdown of DNMTs, pharmacological demethylation, western blot, mRNA analysis, functional PGE2 response assays in fibrotic vs. non-fibrotic fibroblasts\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (bisulfite sequencing, siRNA, pharmacological inhibition, functional rescue) in both human and mouse fibrotic fibroblasts, with mechanistic pathway identification (Akt→DNMT→PTGER2 methylation)\",\n      \"pmids\": [\"20889571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTGER2 is frequently epigenetically silenced in neuroblastoma cell lines (especially those with MYCN amplification) through DNA methylation of a CpG island in its promoter region, combined with histone H3/H4 deacetylation and histone H3 lysine 9 methylation. Restoration of PTGER2 expression in PTGER2-negative neuroblastoma cells inhibited growth and induced apoptosis. Activation of PTGER2 by the selective agonist butaprost increased intracellular cAMP and inhibited cell growth.\",\n      \"method\": \"Methylation analysis, chromatin immunoprecipitation (histone modifications), transient and stable transfection of PTGER2, PTGER2-selective agonist (butaprost) treatment, cAMP measurement, cell growth and apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (methylation analysis, ChIP for histone marks, gain-of-function rescue, pharmacological agonism, cAMP measurement, growth/apoptosis assays) in a single rigorous study\",\n      \"pmids\": [\"17533365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PGE2 decreases Sclerostin (Sost) expression in osteoblastic cells via PTGER2 (EP2 receptor) signaling through a cyclic AMP/PKA pathway. Selective EP2 agonists mimicked PGE2's suppression of Sost, and siRNA-mediated reduction of Ptger2 prevented PGE2-induced Sost repression. Decreased Sost correlated with increased expression of Wnt/TCF target genes Axin2 and Tcf3, placing PTGER2 upstream of Wnt/β-catenin signaling in bone.\",\n      \"method\": \"Selective EP receptor agonists, siRNA knockdown of Ptger2, gene expression analysis (Sost, Axin2, Tcf3), cAMP/PKA pathway pharmacological dissection\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus selective agonist pharmacology and pathway analysis in a single lab, two orthogonal approaches confirming PTGER2 mediates PGE2-Sost suppression\",\n      \"pmids\": [\"21436889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTGER2 (EP2 receptor) expression increases ~14-fold in porcine trophoblast/conceptus cells during implantation (days 14–25) compared to preimplantation stages. PGE2 stimulated PTGER2 mRNA expression via autocrine PTGER2 signaling. PTGER2 activation by PGE2 or the selective agonist butaprost increased trophoblast adhesion to extracellular matrix via integrin αVβ3, focal adhesion kinase (FAK), and ICAM-1 upregulation, and this adhesion was abolished by the PTGER2 antagonist AH6809. The mechanism operates through estrogen receptor and MEK/MAPK (ERK1/2 phosphorylation) signaling downstream of PTGER2.\",\n      \"method\": \"Real-time RT-PCR, western blot, selective EP receptor agonists/antagonists, integrin-blocking antibodies and RGD peptides, adhesion assays in human HTR-8/SVneo and primary porcine trophoblast cells, phosphorylation assays for MAPK1/3\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (agonist, antagonist, integrin blockade, siRNA/antibody, MAPK phosphorylation) in two cell systems (porcine primary and human trophoblast), rigorous mechanistic dissection of PTGER2 downstream pathway\",\n      \"pmids\": [\"23861370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PTGER2 overexpression is positively associated with microsatellite instability-high (MSI-high) status in colorectal cancer, independent of CpG island methylator phenotype (CIMP), in a multivariate analysis of 516 colorectal cancers.\",\n      \"method\": \"Immunohistochemistry for PTGER2 protein, MSI analysis with 10 microsatellite markers, MethyLight for CIMP, multivariate logistic regression\",\n      \"journal\": \"Cancer epidemiology, biomarkers & prevention\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunohistochemistry and epidemiological association in a large cohort, but no direct functional/mechanistic experiment linking PTGER2 to the MSI phenotype\",\n      \"pmids\": [\"20200425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTGER2 (prostaglandin E receptor 2) is identified as a surface marker specifically expressed on mature polymorphonuclear myeloid-derived suppressor cells (mPMN-MDSCs) from cancer patients and G-CSF-treated donors, as part of a distinct gene signature identified by RNA-seq and validated by scRNA-seq, suggesting PTGER2 expression is associated with mPMN-MDSC differentiation and reprogramming.\",\n      \"method\": \"Bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), flow cytometry/immunophenotyping of PMN-MDSC subsets from cancer patients and G-CSF-treated donors\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptomic identification and surface marker validation by sequencing; no direct functional experiment establishing a mechanistic role for PTGER2 in MDSC biology\",\n      \"pmids\": [\"38242120\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTGER2 (EP2 receptor) is a Gs-coupled prostaglandin E2 receptor that signals primarily through cAMP/PKA to regulate diverse cellular processes including osteoblast Wnt/β-catenin signaling (by suppressing Sclerostin expression), trophoblast adhesion during implantation (via MEK/MAPK and integrin αVβ3), and growth inhibition/apoptosis in neuroblastoma; its expression is regulated by epigenetic mechanisms — specifically promoter DNA hypermethylation driven by Akt signaling — which silences PTGER2 in fibrotic fibroblasts and neuroblastoma cells to confer PGE2 resistance and enable tumor progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTGER2 (EP2 receptor) is a prostaglandin E2 (PGE2) receptor that couples to the cAMP second-messenger system to control cell growth, differentiation, and adhesion across multiple tissues [#1, #2]. Pharmacological activation of PTGER2 by the selective agonist butaprost raises intracellular cAMP, and in neuroblastoma cells this signaling inhibits growth and induces apoptosis [#1]. Through a cAMP/PKA pathway, PTGER2 also represses Sclerostin (Sost) in osteoblastic cells, thereby derepressing Wnt/β-catenin target genes (Axin2, Tcf3) and placing the receptor upstream of bone Wnt signaling [#2]. In trophoblast cells PTGER2 mediates PGE2-stimulated adhesion to extracellular matrix via integrin αVβ3, FAK, and ICAM-1 upregulation, operating through estrogen receptor and MEK/MAPK (ERK1/2) signaling, with adhesion blocked by the PTGER2 antagonist AH6809 [#3]. PTGER2 expression is governed epigenetically: promoter CpG-island DNA hypermethylation — accompanied by histone H3/H4 deacetylation and H3K9 methylation, and driven upstream by Akt signaling — silences the receptor in pulmonary fibrosis fibroblasts and in MYCN-amplified neuroblastoma, conferring PGE2 resistance, and demethylation restores receptor expression and PGE2 responsiveness [#0, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that PTGER2 is epigenetically silenced in neuroblastoma and acts as a growth-suppressive, cAMP-elevating receptor, defining a tumor-relevant function.\",\n      \"evidence\": \"Methylation/ChIP analysis of promoter marks plus gain-of-function rescue, butaprost agonism, cAMP measurement, and growth/apoptosis assays in neuroblastoma cell lines\",\n      \"pmids\": [\"17533365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo tumor relevance not tested\", \"Downstream effectors linking cAMP to apoptosis not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that PTGER2 promoter hypermethylation, driven by Akt signaling, causes PGE2 resistance in fibrotic fibroblasts, generalizing the epigenetic silencing mechanism beyond cancer.\",\n      \"evidence\": \"Bisulfite sequencing, DNMT siRNA, pharmacological demethylation, and functional PGE2 response assays in human and mouse fibrotic fibroblasts\",\n      \"pmids\": [\"20889571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking Akt to DNMT recruitment at the PTGER2 promoter not resolved\", \"In vivo reversal of fibrosis by demethylation not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked PTGER2 protein overexpression to MSI-high colorectal cancer, raising the question of receptor activity in tumors where it is not silenced.\",\n      \"evidence\": \"Immunohistochemistry and MSI/CIMP analysis with multivariate regression across 516 colorectal cancers\",\n      \"pmids\": [\"20200425\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Association only — no functional or mechanistic experiment linking PTGER2 to the MSI phenotype\", \"Causal direction unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed PTGER2 upstream of bone Wnt/β-catenin signaling by showing it represses Sclerostin via cAMP/PKA, defining a signaling output distinct from growth control.\",\n      \"evidence\": \"Selective EP2 agonists, Ptger2 siRNA, and Sost/Axin2/Tcf3 expression analysis in osteoblastic cells\",\n      \"pmids\": [\"21436889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed in a single lab/cell context\", \"Direct molecular link between PKA and Sost transcription not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a non-cAMP signaling axis for PTGER2 in trophoblast adhesion during implantation, showing the receptor drives integrin/FAK-mediated ECM attachment via MEK/MAPK.\",\n      \"evidence\": \"Agonist/antagonist pharmacology, integrin blockade, MAPK phosphorylation, and adhesion assays in porcine primary and human HTR-8/SVneo trophoblast cells\",\n      \"pmids\": [\"23861370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of cAMP vs MEK/MAPK branches not dissected\", \"In vivo implantation requirement not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified PTGER2 as a surface marker of mature PMN-MDSCs, raising the question of a functional role in myeloid suppressor cell biology.\",\n      \"evidence\": \"Bulk and single-cell RNA-seq plus flow cytometry of PMN-MDSC subsets from cancer patients and G-CSF-treated donors\",\n      \"pmids\": [\"38242120\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Transcriptomic/marker association only — no functional experiment\", \"Signaling role of PTGER2 in MDSCs unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTGER2 signaling output is selected between cAMP/PKA growth control and MEK/MAPK adhesion programs in different cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical determinant of pathway bias identified\", \"In vivo roles across fibrosis, bone, implantation, and tumor immunity not directly compared\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}