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Showing PTGER2 — COX-2 is a alias.

PTGER2

Prostaglandin E2 receptor EP4 subtype · UniProt P35408

Length
488 aa
Mass
53.1 kDa
Annotated
2026-06-10
100 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2007 High

    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

    PMID:17533365

    Open questions at the time
    • In vivo tumor relevance not tested
    • Downstream effectors linking cAMP to apoptosis not defined
  2. 2010 High

    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

    PMID:20889571

    Open questions at the time
    • Mechanism linking Akt to DNMT recruitment at the PTGER2 promoter not resolved
    • In vivo reversal of fibrosis by demethylation not shown
  3. 2010 Low

    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

    PMID:20200425

    Open questions at the time
    • Association only — no functional or mechanistic experiment linking PTGER2 to the MSI phenotype
    • Causal direction unknown
  4. 2011 Medium

    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

    PMID:21436889

    Open questions at the time
    • Performed in a single lab/cell context
    • Direct molecular link between PKA and Sost transcription not defined
  5. 2013 High

    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

    PMID:23861370

    Open questions at the time
    • Relative contribution of cAMP vs MEK/MAPK branches not dissected
    • In vivo implantation requirement not tested
  6. 2024 Low

    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

    PMID:38242120

    Open questions at the time
    • Transcriptomic/marker association only — no functional experiment
    • Signaling role of PTGER2 in MDSCs unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PTGER2 signaling output is selected between cAMP/PKA growth control and MEK/MAPK adhesion programs in different cell types remains unresolved.
  • No structural or biochemical determinant of pathway bias identified
  • In vivo roles across fibrosis, bone, implantation, and tumor immunity not directly compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. Bisulfite sequencing, siRNA knockdown of DNMTs, pharmacological demethylation, western blot, mRNA analysis, functional PGE2 response assays in fibrotic vs. non-fibrotic fibroblasts The American journal of pathology High 20889571
2007 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. Methylation analysis, chromatin immunoprecipitation (histone modifications), transient and stable transfection of PTGER2, PTGER2-selective agonist (butaprost) treatment, cAMP measurement, cell growth and apoptosis assays Oncogene High 17533365
2011 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. Selective EP receptor agonists, siRNA knockdown of Ptger2, gene expression analysis (Sost, Axin2, Tcf3), cAMP/PKA pathway pharmacological dissection PloS one Medium 21436889
2013 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. 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 Endocrinology High 23861370
2010 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. Immunohistochemistry for PTGER2 protein, MSI analysis with 10 microsatellite markers, MethyLight for CIMP, multivariate logistic regression Cancer epidemiology, biomarkers & prevention Low 20200425
2024 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. Bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), flow cytometry/immunophenotyping of PMN-MDSC subsets from cancer patients and G-CSF-treated donors Cell reports. Medicine Low 38242120

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 COX-2 inhibitors. Lancet (London, England) 825 9929039
1997 COX-1 and COX-2 tissue expression: implications and predictions. The Journal of rheumatology. Supplement 504 9249646
2005 COX-2: a molecular target for colorectal cancer prevention. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 437 15837998
2010 COX-2 as a target for cancer chemotherapy. Pharmacological reports : PR 260 20508278
2007 NSAIDs and cancer prevention: targets downstream of COX-2. Annual review of medicine 245 17100552
2014 COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends in pharmacological sciences 207 24684963
2012 Vascular COX-2 modulates blood pressure and thrombosis in mice. Science translational medicine 188 22553252
2001 COX-1 and COX-2 inhibitors. Best practice & research. Clinical gastroenterology 173 11566042
2007 Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. Sub-cellular biochemistry 146 17612047
2003 COX-2 and neurodegeneration in Parkinson's disease. Annals of the New York Academy of Sciences 131 12846993
2014 Over-expression of COX-2 mRNA in colorectal cancer. BMC gastroenterology 125 24383454
2011 Biology of Cox-2: an application in cancer therapeutics. Current drug targets 122 21443470
2010 Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice. The American journal of pathology 120 20889571
2001 Aromatase and COX-2 expression in human breast cancers. The Journal of steroid biochemistry and molecular biology 120 11850206
2022 COX-2/PGE2 Pathway Inhibits the Ferroptosis Induced by Cerebral Ischemia Reperfusion. Molecular neurobiology 114 35013936
2003 The role and regulation of COX-2 during viral infection. Viral immunology 111 14733733
2004 COX-2 inhibition and lung cancer. Seminars in oncology 105 15179623
2010 COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Current opinion in investigational drugs (London, England : 2000) 100 20047157
2007 Function of COX-2 and prostaglandins in neurological disease. Journal of molecular neuroscience : MN 99 17901552
2005 New insights into COX-2 biology and inhibition. Brain research. Brain research reviews 96 15850674
2005 COX-2-derived prostacyclin modulates vascular remodeling. Circulation research 95 15905461
2008 COX-2 inhibition in schizophrenia and major depression. Current pharmaceutical design 93 18537668
2008 Complexity of COX-2 gene regulation. Biochemical Society transactions 89 18482003
2011 COX-2 and PGE2-dependent immunomodulation in breast cancer. Prostaglandins & other lipid mediators 82 21907301
1999 The role of COX-2 in intestinal cancer. Annals of the New York Academy of Sciences 80 10668484
2007 Role of COX-2 in inflammatory and degenerative brain diseases. Sub-cellular biochemistry 79 17612048
2013 Mechanistic aspects of COX-2 expression in colorectal neoplasia. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 76 22893198
2000 COX-2 and iNOS, good targets for chemoprevention of colon cancer. BioFactors (Oxford, England) 75 11216473
2012 Cell intrinsic role of COX-2 in pancreatic cancer development. Molecular cancer therapeutics 74 22784710
2020 COX-2 in liver fibrosis. Clinica chimica acta; international journal of clinical chemistry 72 32184095
2018 COX-2 in Radiotherapy: A Potential Target for Radioprotection and Radiosensitization. Current molecular pharmacology 68 29468988
2014 COX-2 signaling and cancer: new players in old arena. Current drug targets 68 24467618
2012 COX-2 in the neurodegenerative process of Parkinson's disease. BioFactors (Oxford, England) 68 22826171
2006 The potential and rationale for COX-2 inhibitors in lung cancer. Anti-cancer agents in medicinal chemistry 68 16712449
2014 Regulation of COX-2 expression by miR-146a in lung cancer cells. RNA (New York, N.Y.) 64 25047043
2020 COX-2-PGE2-EPs in gynecological cancers. Archives of gynecology and obstetrics 63 32363546
2005 Transcriptional Control of COX-2 via C/EBPbeta. Arteriosclerosis, thrombosis, and vascular biology 62 15681294
2022 The COX-2-PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas. Cancer prevention research (Philadelphia, Pa.) 61 35121582
1998 COX-2 and colon cancer. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 61 9831333
2006 COX-2 and atherosclerosis. Journal of cardiovascular pharmacology 60 16785826
2002 COX-2 inhibitors and their role in gynecology. Obstetrical & gynecological survey 60 12447099
2018 The COX-2/prostanoid signaling cascades in seizure disorders. Expert opinion on therapeutic targets 59 30484341
2000 Cyclooxygenase isoenzymes and newer therapeutic potential for selective COX-2 inhibitors. Methods and findings in experimental and clinical pharmacology 59 11031730
2021 Progress in PET Imaging of Neuroinflammation Targeting COX-2 Enzyme. Molecules (Basel, Switzerland) 58 34071951
2004 Cancer and cyclooxygenase-2 (COX-2) inhibition. Current pharmaceutical design 56 14965325
2018 COX-2 induces oncogenic micro RNA miR655 in human breast cancer. Scientific reports 55 29321644
2007 COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARdelta activation. The Journal of experimental medicine 54 17724132
2018 COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer. Oncogene 52 29765153
2011 Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression. PloS one 52 21436889
2000 COX-2 and colon cancer: potential targets for chemoprevention. Journal of cellular biochemistry. Supplement 52 10762021
2008 Current status of COX-2 inhibitors. Mini reviews in medicinal chemistry 50 18220987
2000 COX-2 and the kidneys. Current pharmaceutical design 50 11102561
1998 Roles of COX-1 and COX-2 in gastrointestinal pathophysiology. Journal of gastroenterology 50 9773924
2016 Role of COX-2-derived PGE2 on vascular stiffness and function in hypertension. British journal of pharmacology 49 26856544
2003 COX-2 and colorectal cancer. Current pharmaceutical design 49 14529404
2005 Positive feedback regulation of COX-2 expression by prostaglandin metabolites. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 48 15883739
2009 Probiotics regulate the expression of COX-2 in intestinal epithelial cells. Nutrition and cancer 45 19116880
2004 COX-2 inhibition as a tool to treat and prevent colorectal cancer. Critical reviews in oncology/hematology 45 15501074
2019 COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 44 30819896
2007 Epigenetic silencing of prostaglandin E receptor 2 (PTGER2) is associated with progression of neuroblastomas. Oncogene 44 17533365
1999 COX-2 in synovial tissues. Osteoarthritis and cartilage 44 10419782
2017 HNE as an inducer of COX-2. Free radical biology & medicine 41 28192229
2006 Ca2+ stimulates COX-2 expression through calcium-sensing receptor in fibroblasts. Biochemical and biophysical research communications 41 17097611
2004 Expression of Cox-2 protein in radioresistant laryngeal cancer. Annals of oncology : official journal of the European Society for Medical Oncology 41 15111350
2015 Exercise suppresses COX-2 pro-inflammatory pathway in vestibular migraine. Brain research bulletin 40 26151770
2008 Expression of 15-PGDH is downregulated by COX-2 in gastric cancer. Carcinogenesis 40 18174234
2015 Differential expression of COX-2 in osteoarthritis and rheumatoid arthritis. Genetics and molecular research : GMR 38 26505439
2013 Autocrine and paracrine mechanisms of prostaglandin E₂ action on trophoblast/conceptus cells through the prostaglandin E₂ receptor (PTGER2) during implantation. Endocrinology 37 23861370
2002 Cyclooxygenase-2 (COX-2) expression by immunohistochemistry in glioblastoma multiforme. Annals of diagnostic pathology 37 12089724
2017 Combination therapy of PKCζ and COX-2 inhibitors synergistically suppress melanoma metastasis. Journal of experimental & clinical cancer research : CR 36 28865485
2005 COX-2 inhibitors and metabolism of essential fatty acids. Medical science monitor : international medical journal of experimental and clinical research 36 15990700
2004 Cyclooxygenase-2 (Cox-2) expression in lymphomas. Leukemia & lymphoma 36 15359639
2007 COX-2 expression in atherosclerosis: the good, the bad or the ugly? Current medicinal chemistry 34 17584067
2007 COX-2: friend or foe? Current pharmaceutical design 34 17584101
2005 COX-2: a protein with an active role in gynecological cancers. Current opinion in obstetrics & gynecology 33 15711411
2004 Significance of COX-2 expression in human renal cell carcinoma. Urology 33 15596182
2014 COX-2 Inhibitors and Gastric Cancer. Gastroenterology research and practice 32 25371669
2008 EGFR, HER-2 and COX-2 levels in colorectal cancer. Histopathology 32 19102009
2024 COX 2-inhibitors; a thorough and updated survey into combinational therapies in cancers. Medical oncology (Northwood, London, England) 30 38165473
2014 Association between length of gestation and cervical DNA methylation of PTGER2 and LINE 1-HS. Epigenetics 30 24827772
2013 Endotoxins potentiate COX-2 and RANKL expression in compressed PDL cells. Clinical oral investigations 30 23392729
2013 Radiotracers for molecular imaging of cyclooxygenase-2 (COX-2) enzyme. Current medicinal chemistry 30 24059237
2010 PTGER2 overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 30 20200425
2010 COX-2 in liver, from regeneration to hepatocarcinogenesis: what we have learned from animal models? World journal of gastroenterology 30 20333781
2009 COX-2 expression in canine normal and neoplastic mammary gland. Journal of comparative pathology 30 19203768
2005 COX-2 inhibitors: pharmacological data and adverse effects. Minerva anestesiologica 30 16012420
2001 COX-2 inhibition and prevention of cancer. Best practice & research. Clinical gastroenterology 30 11566043
2009 COX-2 expression in chondrosarcoma: a role for celecoxib treatment? European journal of cancer (Oxford, England : 1990) 29 20004565
2005 COX-2 overexpression in canine tumors: potential therapeutic targets in oncology. Histology and histopathology 29 16136511
2005 Roles of LPA3 and COX-2 in implantation. Trends in endocrinology and metabolism: TEM 29 16226033
2024 Surface CD52, CD84, and PTGER2 mark mature PMN-MDSCs from cancer patients and G-CSF-treated donors. Cell reports. Medicine 28 38242120
2020 COX-2 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology 28 33119867
2002 Polyamine-mediated post-transcriptional regulation of COX-2. Biochimie 28 12457568
2023 Effect of NETs/COX-2 pathway on immune microenvironment and metastasis in gastric cancer. Frontiers in immunology 26 37153547
2008 Corticosteroids induce COX-2 expression in cardiomyocytes: role of glucocorticoid receptor and C/EBP-beta. American journal of physiology. Cell physiology 26 18650268
2005 Taxanes and COX-2 inhibitors: from molecular pathways to clinical practice. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 16507399
2006 Cox-2 expression on tissue microarray of breast cancer. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 25 16797158
2004 Fibronectin-induced COX-2 mediates MMP-2 expression and invasiveness of rhabdomyosarcoma. Biochemical and biophysical research communications 25 15120641
2003 Mucosal repair and COX-2 inhibition. Current pharmaceutical design 25 14529401
2001 Analgesia and COX-2 inhibition. Clinical and experimental rheumatology 25 11695255

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