Affinage

PTGER4

Prostaglandin E2 receptor EP4 subtype · UniProt P35408

Length
488 aa
Mass
53.1 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTGER4 encodes the prostaglandin E2 receptor EP4, a class A GPCR that serves as a central transducer of PGE2 signaling across cardiovascular, immune, skeletal, neural, and epithelial systems. EP4 primarily couples to Gαs to elevate cAMP but also engages Gαi, β-arrestin, PI3K/AKT, Rap1/ERK, and EGFR transactivation pathways in a ligand- and cell-type-dependent manner, as demonstrated by BRET-based functional selectivity assays and cryo-EM structural determination of the EP4–Gs complex revealing a distinctive TM6 displacement and Gs C-terminal hook engagement (PMID:19584306, PMID:33264604). Cell-type-specific conditional knockouts have established essential roles for EP4 in neonatal ductus arteriosus closure, macula densa–mediated renin secretion, endothelial eNOS/AMPK-dependent blood pressure regulation, macrophage-driven mucosal healing via CXCL1/MAPK, microglial phagocytic tone affecting both neuroinflammation and hypothalamic energy balance, fibroblast RANKL-driven osteoclastogenesis, and NLRP3 inflammasome suppression in macrophages (PMID:9600059, PMID:21835766, PMID:32641583, PMID:33558271, PMID:36318114, PMID:19419302, PMID:25917098). In cancer, EP4 promotes tumor cell migration and stemness through β-arrestin1–c-Src, PI3K–Orai1–ERK, and PI3K/AKT–NOTCH/WNT signalomes, while in myeloid cells it drives a pro-tumorigenic M2 polarization via mTOR/ERK signaling (PMID:20353998, PMID:31755615, PMID:27301070, PMID:26378024).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 High

    The first loss-of-function study established that EP4 is non-redundant in vivo by showing it is required for neonatal ductus arteriosus closure, answering whether individual EP receptors have essential physiological roles.

    Evidence EP4 knockout mice exhibiting patent ductus arteriosus and neonatal lethality, confirmed by in situ hybridization

    PMID:9600059

    Open questions at the time
    • Downstream signaling pathway mediating ductus closure not identified
    • Whether EP4 acts on smooth muscle or endothelium of the ductus not resolved
  2. 2001 Medium

    Cloning and reconstitution of canine EP4 confirmed canonical Gαs/cAMP coupling and revealed that short-term desensitization does not require the intracellular C-terminal tail, raising questions about species-specific desensitization mechanisms.

    Evidence CHO-K1 transfection of full-length and C-terminally truncated EP4, cAMP accumulation and Scatchard binding

    PMID:11444589

    Open questions at the time
    • Contradiction with human EP4 C-tail desensitization reports not resolved
    • GRK/β-arrestin involvement not tested
  3. 2003 Medium

    Demonstration that EP4 activates PI3K and ERK1/2 independently of its canonical cAMP/PKA pathway established the principle of EP4 signaling bifurcation, distinguishing it from EP2.

    Evidence Pharmacological EP-subtype selective ligands and signaling assays in transfected cells measuring cAMP, PI3K, ERK, and EGR-1

    PMID:14607241

    Open questions at the time
    • Adaptor proteins linking EP4 to PI3K not identified
    • Cell-type generalizability not established
  4. 2004 High

    Multiple groups showed EP4 drives pathologically significant outcomes—colon cancer proliferation via PI3K/ERK, cardiac hypertrophy via EGFR transactivation, and bone resorption via RANKL induction—establishing EP4 as a pleiotropic effector across tissues.

    Evidence EP4-selective agonists/antagonists in colon adenocarcinoma proliferation assays, neonatal myocyte EGFR phosphorylation/MAPK assays, and osteoblast RANKL mRNA quantification

    PMID:11792579 PMID:15123663 PMID:15626689

    Open questions at the time
    • Direct structural basis for EP4 coupling to distinct G proteins unknown
    • Whether EGFR transactivation requires β-arrestin scaffold not tested
  5. 2006 High

    EP4 was placed in both the pain sensitization circuit (DRG neurons) and the metastatic cascade (breast cancer), broadening its pathological relevance to sensory neurobiology and oncology.

    Evidence Intrathecal EP4 shRNA knockdown plus antagonist in DRG electrophysiology and behavioral pain; EP4 antagonism in syngeneic breast cancer metastasis models

    PMID:16540639 PMID:16966471

    Open questions at the time
    • EP4 interaction partners in DRG not mapped
    • Breast cancer metastasis study lacked genetic confirmation
  6. 2008 High

    Hematopoietic EP4 deletion and transcriptional regulation studies established that EP4 sustains macrophage survival via PI3K/Akt/NF-κB in atherosclerosis and that PTGER4 transcription is controlled by Sp-1 binding sites subject to ERK-mediated phosphorylation.

    Evidence EP4−/− fetal liver chimeras in LDLR−/− mice on Western diet; EP4 promoter luciferase reporters with Sp-1 site mutations and ChIP

    PMID:18346464 PMID:19041765

    Open questions at the time
    • Whether Sp-1 regulation is tissue-specific not addressed
    • Atherosclerosis findings limited to early lesion stage
  7. 2009 High

    Quantitative BRET assays revealed that EP4 exhibits ligand-dependent functional selectivity across Gαs, Gαi, and β-arrestin pathways, and conditional KO identified fibroblast EP4 as the driver of RANKL-dependent osteoclastogenesis.

    Evidence BRET assays with panel of ligands in living cells; FSP1-Cre EP4 conditional KO with RANKL mRNA and osteolysis assays

    PMID:19419302 PMID:19584306 PMID:19880670

    Open questions at the time
    • Structural basis for biased agonism at EP4 not determined
    • Whether β-arrestin bias translates to differential in vivo outcomes untested
  8. 2010 High

    The EP4–β-arrestin1–c-Src signaling complex was identified as the mechanism driving PGE2-induced cancer cell migration, establishing a G protein–independent oncogenic signalome for EP4.

    Evidence shRNA knockdown of EP4 and β-arrestin1 with c-Src kinase activity and cell migration assays in lung cancer cells

    PMID:20353998

    Open questions at the time
    • Whether EP4–β-arrestin1–c-Src complex forms constitutively or only upon ligand binding not resolved
    • Stoichiometry of the complex unknown
  9. 2011 High

    EP4 was established as the key receptor mediating COX-2–dependent renin secretion by macula densa and PGE2-driven angiogenesis via PKA/Rap1/eNOS, broadening its cardiovascular roles.

    Evidence Epistasis panel of COX-2, mPGES1/2, EP2, EP4, IP KO mice with furosemide challenge; siRNA knockdown of EP4/PKA subunits in tube formation, aortic ring, and Matrigel plug assays

    PMID:21835766 PMID:21926356

    Open questions at the time
    • Whether EP4 directly signals in juxtaglomerular cells or acts indirectly via macula densa not fully dissected
    • Relative contribution of eNOS vs Rap1A in angiogenesis not quantified
  10. 2012 High

    Post-transcriptional regulation of EP4 by miR-101 was demonstrated, and EP4 signaling in vascular smooth muscle was linked to MMP-2/IL-6 and abdominal aortic aneurysm progression.

    Evidence Luciferase reporter with wild-type and mutant EP4 3′-UTR for miR-101 binding; EP4 antagonist and EP4+/− mice in multiple AAA models

    PMID:22353936 PMID:22570740

    Open questions at the time
    • Whether miR-101 regulation of EP4 is tissue-restricted not determined
    • Direct EP4 target cells in the AAA wall not identified by cell-type-specific KO
  11. 2014 High

    Conditional microglial EP4 deletion in an Alzheimer's disease model revealed EP4 as an anti-inflammatory and pro-phagocytic receptor in microglia, suppressing IRF1/IRF7/NF-κB while enhancing Aβ clearance.

    Evidence Microglial EP4 conditional KO in APP-PS1 mice with microarray profiling and Aβ deposition measurement; EP4 agonist in cultured microglia

    PMID:24760848

    Open questions at the time
    • Signaling intermediary between EP4 and IRF1/IRF7 not identified
    • Long-term disease progression effects not reported
  12. 2016 High

    EP4 was linked to cancer stemness via PI3K/AKT–NOTCH/WNT in breast cancer, to pro-tumorigenic myeloid M1-to-M2 switching via mTOR/ERK in colorectal cancer, and to Th17 differentiation in ankylosing spondylitis, expanding its roles in adaptive immunity and tumor immunology.

    Evidence EP4 antagonist/siRNA with PI3K/NOTCH/WNT inhibitors in breast CSC assays and xenografts; myeloid-specific EP4 cKO in ApcMin/+ mice; EP4 agonist with IL-23R/STAT3/FoxO1 analysis in patient Th17 cells

    PMID:26378024 PMID:27301070 PMID:31253169

    Open questions at the time
    • Whether EP4-driven CSC properties require cell-autonomous signaling or microenvironmental cues not resolved
    • Th17 study based on pharmacological agonist without genetic validation
  13. 2017 High

    Endothelial-specific EP4 deletion demonstrated that EP4 maintains vascular barrier integrity through Rap1/Rac1 and suppresses NF-κB-driven adhesion molecule expression, providing a mechanistic basis for EP4's protective role in acute lung injury.

    Evidence Endothelial EP4 cKO mice in ALI models, Rap1/Rac1 GTPase activity assays, EP4 siRNA and pharmacological inhibition

    PMID:28428256

    Open questions at the time
    • Whether EP4 barrier protection involves junctional complex remodeling beyond VE-cadherin not fully explored
    • Role of β-arrestin in endothelial EP4 signaling not addressed
  14. 2019 High

    Endothelial EP4 was shown to regulate systemic blood pressure via AMPK-dependent eNOS phosphorylation and to protect against myocardial ischemia-reperfusion injury by maintaining microvascular perfusion, establishing EP4 as a cardioprotective endothelial receptor.

    Evidence EC-specific EP4 KO and overexpression mice with BP measurement and eNOS/AMPK pathway analysis; mPges-1 KO and EC-EP4 KO mice in MI/R models with vascular reactivity and leukocyte adhesion assays

    PMID:31015404 PMID:32641583

    Open questions at the time
    • Whether AMPK activation by EP4 is cAMP-dependent or involves alternative upstream signals not fully resolved
    • Specific prostanoid source (COX-1 vs COX-2) feeding endothelial EP4 in different vascular beds not systematically compared
  15. 2019 High

    EP4 was found to form a complex with Orai1/TRPC1 channels to drive PI3K-dependent calcium influx and ERK-mediated MMP activation in oral cancer migration, revealing a non-canonical ion channel partnership.

    Evidence Co-immunoprecipitation of EP4–Orai1–TRPC1, siRNA knockdown, calcium imaging, in vivo lung metastasis model

    PMID:31755615

    Open questions at the time
    • Whether EP4–Orai1 interaction is direct or mediated by adaptor proteins not determined
    • STIM1-independent Orai1 activation mechanism not structurally characterized
  16. 2020 High

    The cryo-EM structure of EP4 bound to Gs at 3.3 Å provided the first atomic-level view of prostanoid receptor–G protein coupling, revealing a restrained TM6 outward displacement and a Gs C-terminal hook structure mediated by conserved residues Phe54 and Trp327.

    Evidence Cryo-EM structure determination at 3.3 Å global resolution

    PMID:33264604

    Open questions at the time
    • No structure of EP4 bound to Gαi or β-arrestin available
    • Ligand-bound inactive state structure not determined
    • Structural basis for functional selectivity not addressed
  17. 2021 High

    Macrophage-specific PTGER4 deletion revealed EP4/MAPK/CXCL1 as a paracrine axis driving epithelial regeneration in colitis, and TNF-α was shown to impair EP4 signaling via TRAF2-mediated GRK2 recruitment and receptor internalization.

    Evidence Csf1r-iCre Ptger4fl/fl conditional KO in DSS colitis with organoid assays and CXCL1 pathway analysis; cAMP FRET biosensor, TRAF2 siRNA, and co-IP of TRAF2-GRK2 in FLS with CIA model validation

    PMID:33558271 PMID:33859345

    Open questions at the time
    • Whether TRAF2-GRK2 desensitization mechanism operates in cell types beyond synoviocytes not tested
    • Epithelial CXCL1 receptor identity not confirmed
  18. 2022 High

    Cell-type-specific EP4 functions in bone were dissected: osteoclast EP4 promotes OA via Gαs/PI3K/AKT/MAPK-driven osteoclastogenesis and sensory innervation, while cartilage EP4 antagonism promotes chondrogenesis via cAMP/PKA/CREB/Sox9, and tumor EP4 drives dual pro-inflammatory and immunosuppressive programs.

    Evidence Osteoclast-specific EP4 cKO and cartilage-specific EP4 cKO in OA models with pathway analysis; EP2/EP4 antagonists with scRNAseq in tumor models

    PMID:35256606 PMID:35260562 PMID:35675777

    Open questions at the time
    • How EP4 activation produces opposite cAMP/PKA outcomes in osteoclasts vs chondrocytes not mechanistically explained
    • EP4 vs EP2 contribution to mregDC-Treg axis not fully separated
  19. 2023 High

    Microglial EP4 was identified as a metabolic regulator: it maintains a phagocytic microglial state in the hypothalamus that reduces POMC neurite density and promotes diet-induced obesity, revealing a neuroimmune metabolic role.

    Evidence Microglia-specific EP4 knockout mice on high-fat diet with metabolic phenotyping, CD68/phagocytosis assays, and POMC neurite analysis

    PMID:36318114

    Open questions at the time
    • Whether EP4-driven microglial phagocytosis targets POMC neurites directly or acts indirectly not determined
    • Downstream signaling pathway (cAMP vs PI3K) mediating phagocytic phenotype not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for EP4 functional selectivity (no Gαi- or β-arrestin-bound structures), the molecular identity of adaptors linking EP4 to PI3K, and how identical cAMP signaling produces opposing outcomes in different cell types (e.g., osteoclasts vs chondrocytes).
  • No EP4–Gαi or EP4–β-arrestin structure available
  • Adaptor linking EP4 to PI3K unknown
  • Cell-type-specific signal interpretation mechanisms not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 1
Partners
ARRB1GNASGRK2ORAI1SRCTRAF2TRPC1

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 EP4 receptor couples to Gs to increase intracellular cAMP, and also activates PI3K and ERK1/2 (but not EP2) leading to induction of EGR-1 transcription factor, distinct from the cAMP-PKA pathway used by EP2. Pharmacological receptor subtype-selective ligand studies, signaling assays in transfected cells Life sciences Medium 14607241
1998 EP4 receptor knockout mice develop patent ductus arteriosus and neonatal death, establishing that EP4 signaling is required for closure of the ductus arteriosus in neonatal circulatory adaptation; EP4 mRNA was confirmed by in situ hybridization in the ductus. Gene targeting (knockout mice), histological examination, in situ hybridization Biochemical and biophysical research communications High 9600059
2006 EP4 receptor on primary sensory DRG neurons mediates PGE2-induced sensitization of capsaicin-evoked currents and inflammatory pain hypersensitivity; EP4 levels increase in DRG after peripheral inflammation. Intrathecal shRNA knockdown, EP4 antagonist (AH23848), in vitro DRG neuron electrophysiology, behavioral pain assays The Journal of pharmacology and experimental therapeutics High 16966471
2015 EP4 receptor mediates PGE2 inhibition of NLRP3 inflammasome activation in human macrophages through elevation of intracellular cAMP, independently of PKA or Epac. EP4-specific agonist/antagonist pharmacology, EP4 knockdown (siRNA), adenylate cyclase inhibitor, cAMP measurement, NLRP3 inflammasome activation assays in human monocyte-derived macrophages Journal of immunology High 25917098
2004 EP4 receptor mediates PGE2-induced colon adenocarcinoma cell proliferation via PI3K/ERK activation; selective EP4 agonist PGE1-OH rescues anti-proliferative effects of COX inhibition through this pathway. Selective EP receptor agonists, PI3K/ERK inhibitors, cell proliferation assays, in vivo tumor model The Journal of biological chemistry High 15123663
2010 EP4 receptor promotes lung cancer cell migration via a signaling complex of EP4–βArrestin1–c-Src; knockdown of βArrestin1 impairs PGE2-induced c-Src activation and cell migration. EP subtype-selective agonists, shRNA knockdown of EP4 and βArrestin1, c-Src kinase activity assays, cell migration assays Molecular cancer research High 20353998
2011 EP4 receptor couples to Gαs to activate PKA catalytic subunit γ, which promotes in vitro tube formation, ex vivo vessel outgrowth, and in vivo angiogenesis; downstream PKA substrates Rap1A, HSPB6, and eNOS promote angiogenesis while RhoA and GSK3β are inhibitory. EP subtype-selective agonists/antagonists, siRNA knockdown of EP4 and PKA subunits, tube formation and aortic ring assays, in vivo Matrigel plug assay Blood High 21926356
2022 PGE2 activates EP4 on osteoclasts to promote migration, osteoclastogenesis, Netrin-1/CGRP sensory innervation, and PDGF-BB-driven type H vessel formation in subchondral bone via Gαs/PI3K/AKT/MAPK signaling, promoting OA progression. Osteoclast-specific EP4 conditional knockout (EP4LysM), pharmacological EP4 antagonist (HL-43), in vitro migration/osteoclastogenesis assays, OA mouse models, signaling pathway inhibitors Bone research High 35260562
2016 COX-2/EP4 signaling induces cancer stem-like cells in breast cancer via PI3K/AKT activation of NOTCH/WNT signaling pathways. COX-2 overexpression, EP4 antagonist and siRNA knockdown, PI3K/AKT inhibitors, NOTCH/WNT inhibitors, spheroid/ALDH assays, xenograft tumor models Stem cells High 27301070
2022 PGE2-EP2/EP4 signaling simultaneously promotes NF-κB-driven active inflammation in myeloid cells and drives the mregDC-Treg axis for immunosuppression in the tumor microenvironment. Immune checkpoint inhibitor-insensitive mouse cancer model, single-cell RNA sequencing, EP2/EP4 antagonists Cell reports Medium 35675777
2008 Macrophage EP4 deficiency increases sensitivity to apoptotic stimuli (palmitic acid, free cholesterol) by suppressing PI3K/Akt and NF-κB pathway activity, reducing early atherosclerosis. Fetal liver cell transplantation into LDLR-/- mice (EP4-/- hematopoietic chimeras), Western diet feeding, apoptosis assays, signaling pathway analysis Cell metabolism High 19041765
2009 EP4 receptor exhibits functional selectivity: PGE2 preferentially activates Gαs; PGF2α preferentially activates Gαi1; PGE1-alcohol is biased toward β-arrestin. EP4 also couples to pertussis toxin-sensitive Gαi and β-arrestin pathways. BRET-based assays for Gαs, Gαi, and β-arrestin activation in living cells with a panel of EP4 ligands The Journal of pharmacology and experimental therapeutics High 19584306
2014 Microglial EP4 stimulation suppresses Aβ42-induced inflammatory gene expression (targeting IRF1, IRF7, NF-κB pathways) and potentiates Aβ42 phagocytosis; conditional microglial EP4 deletion in APP-PS1 mice increases inflammatory gene expression and Aβ deposition at early pathology stages. EP4 agonist treatment of cultured microglia, microarray gene expression analysis, conditional microglial EP4 knockout in APP-PS1 mice, oxidative protein modification and Aβ measurement The Journal of neuroscience High 24760848
2011 EP4 receptor mediates PGE2-induced relaxation of human airways (bronchodilation); EP2 mediates this effect in guinea pig and mouse but not human airways. Pharmacological EP-subtype selective agonists/antagonists in isolated airway preparations from multiple species; EP2-knockout mice Thorax High 21606476
2004 EP4 receptor mediates PGE2-induced suppression of 3T3-L1 preadipocyte differentiation by increasing cAMP and suppressing expression of differentiation markers (resistin, PPARγ). EP4-selective agonist (AE1-329) and antagonist (AE3-208), cAMP measurement, RT-PCR for differentiation markers Biochemical and biophysical research communications Medium 15336573
2021 PTGER4-expressing intestinal macrophages secrete CXCL1 via MAPK signaling upon PGE2 stimulation, driving epithelial cell differentiation and proliferation to support mucosal healing; macrophage-specific PTGER4 deletion impairs epithelial barrier regeneration in DSS colitis. Conditional macrophage-specific Ptger4 knockout (Csf1r-iCre Ptger4fl/fl), DSS colitis model, MAPK pathway analysis, epithelial organoid differentiation assays, liposome-mediated therapeutic targeting Gut High 33558271
2004 EP4 receptor induces cardiac myocyte hypertrophy independently of PKA by transactivating EGFR, leading to p42/44 MAPK activation and increased protein synthesis; the EP4 antagonist blocks EGFR phosphorylation and MAPK activation. EP4 antagonist, EGFR selective inhibitor (AG-1478), PKA inhibitor, immunoprecipitation for EGFR phosphorylation, [3H]leucine incorporation, p42/44 MAPK phosphorylation assays in neonatal ventricular myocytes American journal of physiology. Heart and circulatory physiology High 15626689
2009 EP4 signaling in fibroblasts (FSP1+ cells) upregulates RANKL expression in response to PGE2 or wear debris, stimulating osteoclastogenesis and periprosthetic osteolysis; conditional fibroblast-specific EP4 knockout abolishes this response. Conditional knockout of EP4 in FSP1+ fibroblasts, in vitro PGE2 stimulation with RANKL mRNA measurement, osteoclast and osteolysis assays, comparison with EP1-/- and EP2-/- mice Journal of bone and mineral research High 19419302
2019 Endothelial EP4 receptor is essential for blood pressure homeostasis by promoting eNOS phosphorylation at Ser1177 and NO production via the AMPK pathway; EC-specific EP4 knockout elevates blood pressure and reduces vasorelaxant responses. Endothelial-specific EP4 knockout and overexpression mice, eNOS phosphorylation assays, AMPK pathway inhibitors, blood pressure measurements, vascular reactivity assays JCI insight High 32641583
2019 COX-1/mPGES-1-derived PGE2 acting on endothelial EP4 receptor constrains myocardial ischemia-reperfusion injury by maintaining microvascular perfusion and suppressing leukocyte-endothelial interactions; endothelium-restricted EP4 deletion exacerbates MI/R injury. mPges-1 knockout mice, endothelium-restricted Ep4 knockout mice, in vivo and ex vivo vascular reactivity assays, leukocyte-endothelial interaction assays, EP4 agonist treatment Nature communications High 31015404
2011 EP4 receptor is the primary mediator of COX-2-dependent renin stimulation by the macula densa; EP4 knockout mice show ~70% reduction in furosemide-induced renin mRNA upregulation, while EP2 and IP receptor knockouts are unaffected. Panel of gene-targeted mice (COX-2, mPGES1, mPGES2, EP2, EP4, IP knockouts), furosemide challenge, real-time RT-PCR for renin mRNA American journal of physiology. Renal physiology High 21835766
2009 EP4 receptor in neonatal ventricular myocytes signals through a PKA→Rap1→ERK1/2→p90RSK cascade to regulate brain natriuretic peptide, c-Fos, and EGR-1 expression and to increase cell size; Rap dominant-negative mutant blocks PGE2-induced ERK activation. Dominant negative Rap mutant transfection, PKA inhibitor, Rap and p90RSK activation assays, BNP promoter reporter, cell size measurement in neonatal ventricular myocytes with EP4 overexpression American journal of physiology. Heart and circulatory physiology High 19880670
2020 Cryo-EM structure of EP4 coupled to heterotrimeric Gs at 3.3 Å resolution reveals that compared to other class A GPCRs, EP4 TM6 shifts less outward, but the Gs C-terminal helix inserts toward TM2 and forms an extended hook structure, mediated by conserved prostanoid receptor residues Phe54(2.39) and Trp327(7.51). Cryo-electron microscopy (cryo-EM) structure determination at 3.3 Å global resolution Structure High 33264604
2017 EP4 receptor mediates barrier-protective effects of prostaglandin A2 on lung endothelial cells via Rap1/Rac1 GTPase and PKA targets (VE-cadherin, p120-catenin, ZO-1, cortactin, VASP) and suppresses NF-κB-driven ICAM1/VCAM1 expression; endothelial-specific EP4 knockout abolishes protection in ALI models. EP4 siRNA and pharmacological inhibition, endothelial-specific EP4 knockout mice, Rap1/Rac1 GTPase activity assays, permeability measurements, two in vivo ALI models Molecular biology of the cell High 28428256
2008 EP4 receptor functions as a tumor suppressor in B cells by acting as a negative feedback regulator of BCR-mediated proliferation; EP4 knockdown accelerates B cell lymphoma growth in mice while EP4 overexpression is protective. Stable EP4 shRNA knockdown and overexpression in B cell lymphoma lines, in vivo tumor spread assays, microarray gene expression The Journal of experimental medicine High 19075289
2006 EP4 receptor antagonism inhibits breast cancer metastasis; mammary tumor cells migrate in response to PGE2 via a cAMP-elevating EP4 mechanism; EP4 antagonists block both tumor migration and proliferation in vitro. EP4-selective antagonists (AH23848, ONO-AE3-208), in vivo metastasis models (syngeneic), in vitro migration and proliferation assays Cancer research Medium 16540639
2012 EP4 receptor signaling in aortic smooth muscle cells increases MMP-2 activity and IL-6 production; genetic or pharmacological EP4 inhibition attenuates AAA formation in multiple mouse models by reducing MMP activity and cytokine release. EP4 agonist stimulation of human ASMCs, MMP-2 activity assays, EP4 antagonist (ONO-AE3-208) in ApoE-/- AAA mouse model, EP4+/- mice, CaCl2 AAA model, human AAA tissue organ cultures PloS one High 22570740
2010 EP4 receptor activation or inhibition regulates colonic epithelial barrier integrity; apical EP4 receptors on T84 cells mediate PGE2-induced barrier disruption, and prostaglandin transporter (PGT) vectorially transports basolateral PGE2 to apical EP4 receptors. EP4 receptor antagonist, immunolocalization of EP4 in polarized T84 cells and human biopsies, PGT siRNA/inhibitor, [3H]-PGE2 vectorial transport assays American journal of physiology. Gastrointestinal and liver physiology Medium 20813914
2012 miR-101 post-transcriptionally represses EP4 receptor expression by binding to the 3'-UTR of EP4 mRNA; loss of miR-101 leads to elevated EP4 and increased colon cancer cell proliferation and motility. Luciferase reporter assay with EP4 3'-UTR (wild-type and mutant), miR-101 transfection, EP4 rescue co-transfection, cell proliferation and migration assays Cancer biology & therapy High 22353936
2008 EP4 expression is regulated transcriptionally by Sp-1 binding sites in the human EP4 promoter (-197 to -160); troglitazone suppresses EP4 by activating ERK-mediated Sp-1 phosphorylation, which reduces Sp-1 DNA binding. Luciferase reporter with EP4 promoter constructs, Sp-1 site mutations, MEK-1/ERK inhibitor (PD98059), immunoprecipitation-Western for Sp-1 phosphorylation, ChIP assay Biochimica et biophysica acta High 18346464
2019 EP4 receptor promotes oral cancer cell migration by activating PI3K and inducing Ca2+ influx through Orai1 channel (independently of STIM1 store depletion), leading to ERK phosphorylation and MMP-2/9 activation; EP4 forms a complex with Orai1 and TRPC1. EP4 agonist/antagonist, siRNA knockdown of EP4 and Orai1, co-immunoprecipitation of EP4-Orai1-TRPC1, Ca2+ imaging, ERK phosphorylation, MMP activity assays, in vivo lung metastasis model Cancer science High 31755615
2020 EP4/AC/cAMP/PKA signaling mediates GRK2 translocation to the plasma membrane in endothelial cells, decreasing GRK2-ERK1/2 interaction and allowing ERK1/2 activation to promote PGE2-induced angiogenesis; specific GRK2 residues Lys220 and Ser685 regulate this translocation. GRK2 siRNA, GRK2 site-directed mutants (Lys220, Ser685), EP4 inhibition, PKA inhibition, HUVEC migration and tube formation assays, in vivo Matrigel angiogenesis with GRK2-deficient aortic segments Clinical science High 31967309
2016 EP4 receptor activation promotes Th17 cell development in ankylosing spondylitis by upregulating IL-23R expression, suppressing the RORγt inhibitor FoxO1, and enhancing STAT3 phosphorylation, in a positive feedback loop that further increases EP4 expression. EP4-specific agonists, flow cytometry for EP4 expression in Th17 cells, Western blot, quantitative RT-PCR, ex vivo functional analysis of Th17 differentiation from AS patients Arthritis research & therapy Medium 31253169
2021 TNF-α impairs EP4 signaling in fibroblast-like synoviocytes by recruiting TRAF2 to the membrane, which brings GRK2 to the membrane; GRK2 then separates and phosphorylates/internalizes EP4, reducing cAMP production. cAMP FRET biosensor (PM-ICUE3), TRAF2 siRNA, co-immunoprecipitation of TRAF2-GRK2, GRK2 inhibitor (paroxetine), EP4 membrane distribution assays, CIA rat model Acta pharmacologica Sinica High 33859345
2021 EP4 signaling in dendritic cells (cDC2s) drives upregulation of activation markers (CD80, CD86, CD83, MHC-II) and IL-10/IL-23 production, promotes CCR7-based migration, and drives expansion of suppressive (rather than pro-inflammatory) T-cell populations. EP2 and EP4 selective antagonists on human cDC2s, flow cytometry for activation markers, cytokine measurement, T-cell co-culture assays European journal of immunology Medium 38088451
2022 EP4 receptor antagonism in cartilage promotes chondrogenesis and cartilage anabolism through the cAMP/PKA/CREB/Sox9 signaling pathway; cartilage-specific EP4 knockout or EP4 antagonist (HL-43) enhances articular cartilage regeneration and reduces fibrocartilage formation. Cartilage-specific EP4 conditional knockout, EP4 antagonist HL-43, multiple OA/cartilage defect mouse and rat models, cAMP/PKA/CREB/Sox9 pathway analysis, human cartilage explant assays Cell discovery High 35256606
2016 EP4 receptor activation increases expression of oncogenic miR-526b via downstream PI3K/AKT, cAMP/PKA, and NF-κB signaling pathways in breast cancer cells. EP4 agonist/antagonist, COX-2 overexpression, PI3K-AKT inhibitors, NF-κB inhibitor, miR-526b stable overexpression/knockdown, in vivo lung colonization model Molecular cancer research Medium 25733698
2017 EP4 receptor in myeloid cells promotes colorectal tumorigenesis by driving an anti-tumorigenic M1-to-M2 phenotype switch and activating mTOR and ERK signaling; myeloid-specific EP4 deletion or pharmacological EP4 inhibition markedly reduces adenoma number and size in ApcMin/+ mice. Myeloid-specific EP4 conditional knockout crossed to ApcMin/+ mice, EP4 antagonist treatment, mTOR/ERK signaling analysis, macrophage/DC phenotyping Oncotarget High 26378024
2023 Microglial EP4 signaling promotes diet-induced obesity by maintaining a phagocytic microglial state (elevated CD68) that reduces POMC neurite contacts with the paraventricular nucleus; microglial-specific EP4 deletion reduces weight gain, food intake, and improves insulin sensitivity in HFD-fed mice. Microglia-specific EP4 knockout mice (MG-EP4 KO), high-fat diet feeding, metabolic phenotyping, microglial CD68/phagocytosis assays, POMC neurite density analysis Diabetes High 36318114
2001 Canine EP4 receptor (90% amino acid identity to human EP4) couples to adenylate cyclase to increase cAMP upon PGE2 binding; short-term PGE2-induced desensitization does not require the intracellular C-terminal tail, in contrast to the reported mechanism for the human receptor. cDNA library screening, CHO-K1 transfection, Scatchard binding analysis, cAMP accumulation assays, truncated C-terminus receptor construct comparison Prostaglandins & other lipid mediators Medium 11444589
2016 PTGER4 promoter demethylation in AI-resistant breast cancer cells leads to EP4 upregulation, and EP4 signaling promotes estrogen-independent growth likely via ligand-independent activation of ERα cofactor CARM1. Genome-wide DNA methylation and expression analysis, EP4 knockdown, EP4 inhibitor studies, downstream CARM1 signaling assay Oncogene Medium 27869171
2002 EP4 receptor mediates PGE2-stimulated osteoclastogenesis and bone resorption by inducing RANKL mRNA in osteoblasts and increasing cAMP; selective EP4 antagonism also reduces 1,25D- and PTH-stimulated osteoclast formation, suggesting EP4 plays a general role in osteoclastic bone resorption. EP4-selective antagonist (EP4RA) in murine marrow cultures and fetal rat long bone organ cultures, TRAP+ multinucleated cell counting, cAMP measurement, RANKL mRNA quantification, 45Ca release assay Bone Medium 11792579
2021 EP4 and EP2 signaling show distinct cAMP kinetics in dendritic cells: EP4 induces transient cAMP and EP2 induces sustained cAMP; simultaneous EP2+EP4 stimulation attenuates cAMP production (crosstalk); EP4 primarily mediates podosome dissolution in DCs; both receptors require intact microtubule networks for efficient signaling. Quantitative live-cell cAMP imaging (FRET), podosome dissolution assays, microtubule disruption, EP2/EP4 selective antagonists Frontiers in immunology Medium 33643295

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 EP2 and EP4 prostanoid receptor signaling. Life sciences 365 14607241
1998 Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4-deficient mice. Biochemical and biophysical research communications 253 9600059
2006 Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity. The Journal of pharmacology and experimental therapeutics 194 16966471
2015 Prostaglandin E2 Inhibits NLRP3 Inflammasome Activation through EP4 Receptor and Intracellular Cyclic AMP in Human Macrophages. Journal of immunology (Baltimore, Md. : 1950) 146 25917098
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