Affinage

F2RL1

Proteinase-activated receptor 2 · UniProt P55085

Length
397 aa
Mass
44.1 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

F2RL1 (PAR2) is a protease-activated G protein-coupled receptor that transduces extracellular proteolytic signals into diverse intracellular cascades governing inflammation, pain, tissue remodeling, and metabolic homeostasis. Serine proteases (trypsin, tryptase, coagulation factors VIIa/Xa, kallikrein 6, proteinase 3, CAP1/Prss8) and the cysteine protease cathepsin S cleave the PAR2 N-terminus at distinct sites to unmask different tethered ligands, producing biased signaling: canonical cleavage at Arg36 activates Gαq/Gα12/13/Gαi and β-arrestin pathways driving PLC–PIP2 hydrolysis, RhoA/Rho kinase, MEK–ERK1/2, PI3K–Akt, and NF-κB, whereas cathepsin S cleavage at Glu56 selectively engages Gαs/cAMP/PKA to sensitize TRPV4 channels (PMID:17571167, PMID:25118282, PMID:23825105, PMID:33226635). PAR2 forms functional heterodimers with PAR1, PAR3, and PAR4 that alter receptor trafficking, β-arrestin–mediated endosomal ERK signaling, and immune regulation—including activated protein C–driven Treg expansion via PAR2/PAR3 heterodimers—and dynamin-2-dependent endocytosis sustains PAR2 endosomal signaling complexes required for colonic inflammation and hyperalgesia (PMID:23476015, PMID:22411985, PMID:28827518, PMID:35110404). In metabolic tissues, hepatic PAR2 suppresses glucose uptake through Gq–MAPK–FoxA3-dependent GLUT2 downregulation and Gq–CaMKK2-mediated inhibition of insulin–Akt signaling, while PAR2–Gi–JNK1/2 signaling regulates cholesterol synthesis and reverse cholesterol transport (PMID:35603482, PMID:31668396).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 Medium

    Identifying TF/FVIIa as a PAR2 ligand in vascular cells established that coagulation proteases drive PAR2-dependent cell migration, linking hemostasis to vascular remodeling.

    Evidence Boyden chamber migration assay with PAR2-activating peptide and neutralizing antisera in smooth muscle cells

    PMID:12479889

    Open questions at the time
    • Downstream signaling pathway not dissected
    • Single cell type tested
    • No genetic confirmation
  2. 2007 High

    Demonstrating that PAR2 sensitizes TRPA1 through PLC-mediated PIP2 hydrolysis resolved how protease signaling couples to nociceptive ion channels and provided a molecular mechanism for inflammatory pain.

    Evidence Electrophysiology in HEK293 cells and DRG neurons with PLC inhibitors and PIP2 antibody sequestration

    PMID:17571167

    Open questions at the time
    • In vivo behavioral validation of PIP2 mechanism not shown in this study
    • Whether TRPV1 is co-regulated by the same mechanism unclear
  3. 2008 Medium

    Identification of two independent, non-overlapping PAR2 signaling branches—MEK/ERK and PI3K/Akt—converging on IL-8 release revealed how PAR2 achieves robust inflammatory cytokine output through pathway redundancy.

    Evidence Pharmacological inhibition of MEK and PI3K with phospho-protein and cytokine readouts in GI epithelial cells

    PMID:18854173

    Open questions at the time
    • No genetic knockdown confirmation
    • G protein coupling to each branch not identified
  4. 2011 High

    Genetic epistasis showing that the skin pathology of CAP1/Prss8 overexpression is completely abolished on a PAR2-null background established PAR2 as the obligate downstream effector of this protease in epidermal homeostasis.

    Evidence Transgenic K14-CAP1/Prss8 mice crossed to PAR2-null background; histology, barrier function, and cytokine assays

    PMID:21245842

    Open questions at the time
    • Direct cleavage of PAR2 by CAP1/Prss8 not biochemically demonstrated
    • Downstream PAR2 signaling pathway in keratinocytes not identified
  5. 2012 High

    Discovery that PAR2 promotes PAR4 plasma membrane delivery by disrupting β-COP1-mediated ER retention and recruiting 14-3-3ζ revealed PAR2's role as a chaperone for other PARs, expanding the concept of GPCR heterodimerization beyond co-signaling to trafficking control.

    Evidence FRET, co-immunoprecipitation, mutagenesis of PAR4 RXR ER-retention motif, glycosylation and signaling assays

    PMID:22411985

    Open questions at the time
    • Whether PAR2 similarly chaperones PAR3 unknown
    • Structural basis of PAR2-PAR4 interface not resolved
  6. 2013 High

    Characterization of PAR1–PAR2 heterodimer constitutive internalization and endosomal β-arrestin–ERK signaling, together with the finding that PAR2 couples to Gq/G13/Gi with RhoA feedback inhibition via NF-κB–PKA in smooth muscle, defined how heterodimerization and G protein multiplicity shape PAR2 signaling output.

    Evidence BRET, co-IP, and ERK assays for PAR1–PAR2 heterodimers; siRNA/minigene/pertussis toxin dissection in gastric smooth muscle

    PMID:23476015 PMID:23825105

    Open questions at the time
    • Structural determinants of PAR1–PAR2 heterodimerization interface not defined
    • Whether RhoA–PKA feedback operates outside smooth muscle untested
  7. 2014 High

    Identification of cathepsin S as a biased agonist cleaving PAR2 at a non-canonical site (Glu56↓Thr57) to selectively engage Gαs/cAMP without β-arrestin or Ca²⁺ mobilization fundamentally changed the model of PAR2 activation from a single tethered-ligand mechanism to protease-specific biased agonism.

    Evidence Cleavage-site mapping, cAMP/Ca²⁺/β-arrestin assays, TRPV4 functional assay in oocytes, PAR2/TRPV4 KO mice

    PMID:24964046 PMID:25118282

    Open questions at the time
    • Whether other cysteine proteases produce similar bias unknown
    • Structural basis for bias at receptor level not resolved
  8. 2014 High

    Demonstration that PAR2 protects epithelial cells from cytokine-induced apoptosis through convergent MEK–BAD(Ser112) and PI3K–BAD(Ser136) phosphorylation established a cytoprotective function for PAR2 and explained why both pathways must be inhibited simultaneously to block survival signaling.

    Evidence Caspase/PARP cleavage, annexin V, phospho-BAD immunoblotting, PAR2 siRNA, MEK/PI3K inhibitors

    PMID:25331954

    Open questions at the time
    • Upstream G protein coupling to each survival branch not identified
    • In vivo relevance of anti-apoptotic function not tested
  9. 2015 High

    Two studies established PAR2 as a critical mediator in fibrosis and innate immunity: PAR2 was shown to be required for PAR1-dependent pulmonary fibrosis, and EPCR-dependent PAR2 activation by the TF–VIIa–Xa complex was found to initiate an interferon gene program via Pellino-1/IRF8.

    Evidence PAR2-KO mice in bleomycin fibrosis model; PAR2/EPCR-KO mice with LPS challenge and mRNA profiling

    PMID:25689283 PMID:25733582

    Open questions at the time
    • Whether PAR1–PAR2 heterodimerization is the mechanism underlying PAR2 requirement in fibrosis not directly tested
    • How EPCR scaffolding alters PAR2 cleavage specificity unknown
  10. 2017 High

    Discovery that activated protein C signals through PAR2/PAR3 heterodimers on Tregs to restrain alloreactive T cells and ameliorate graft-versus-host disease linked PAR2 to adaptive immune regulation and established a non-inflammatory, immunosuppressive role for PAR2.

    Evidence PAR2/PAR3-KO mice; allogeneic HSCT model; humanized NSG mouse model; Treg frequency analysis

    PMID:28827518

    Open questions at the time
    • Downstream signaling pathway in Tregs not dissected
    • Whether aPC-PAR2/PAR3 axis operates in solid organ transplant tolerance unknown
  11. 2018 Medium

    Multiple studies in 2018 expanded PAR2's tissue-specific roles: plasma kallikrein activates PAR2 to disrupt the blood-brain barrier via ICAM-1/VCAM-1; PAR2 drives FOXO1-dependent M1 macrophage polarization; mast cell tryptase signals through PAR2–PPARγ to promote atrial fibrosis; and PAR2 on trigeminal neurons mediates migraine-like pain.

    Evidence Endothelial PAR2 activation with prekallikrein-KO EAE model; macrophage FOXO1 siRNA; atrial fibroblast PAR2/PPARγ antagonism; dural PAR2-KO mice with behavioral pain assays

    PMID:29848111 PMID:30552714 PMID:30559188 PMID:30580879

    Open questions at the time
    • Integration of these tissue-specific findings into a unified signaling framework lacking
    • Whether migraine mechanism involves endosomal PAR2 signaling unknown
    • PPARγ link to canonical PAR2 G protein pathways not established
  12. 2019 High

    Identification of furin as the principal proprotein convertase processing PAR2 at Arg36, modulated by N-glycosylation at Asn30, revealed a post-translational regulatory layer controlling PAR2 activation efficiency and selectivity, with functional consequences in HIV-1-associated neurotoxicity.

    Evidence In vitro cleavage assays with site-directed mutagenesis; neuroblastoma-macrophage co-culture with HIV-1

    PMID:30683917

    Open questions at the time
    • Whether furin activates PAR2 in trans at the cell surface or in the secretory pathway not distinguished
    • Relevance of this processing to other PAR2 disease contexts untested
  13. 2019 High

    Demonstration that PAR2-KO mice have ~50% reduced plasma and hepatic cholesterol via decreased synthesis genes and increased reverse cholesterol transport, mediated by Gi–JNK1/2 signaling, established PAR2 as a metabolic regulator of cholesterol homeostasis.

    Evidence PAR2-KO mice on normal and high-fat diets; plasma/liver lipid profiling; fecal bile acid output; pathway inhibitors

    PMID:31668396

    Open questions at the time
    • Whether hepatocyte-specific or systemic PAR2 deletion is responsible not resolved
    • Identity of the endogenous activating protease in metabolic context unknown
  14. 2020 High

    CRISPR-based dissection of PAR2 signaling in ovarian cancer revealed that migration/invasion absolutely requires cooperative Gαq/11, Gα12/13, and β-arrestin1/2 engagement driving Src–EGFR transactivation–MEK–ERK–transcription factor cascades, while a negative allosteric modulator selectively blocking Gαq/Gα12/13 was sufficient to suppress inflammation in vivo.

    Evidence CRISPR-KO of individual G proteins and β-arrestins in cancer cells; BRET signaling profiling of PAR2 inhibitor I-287; in vivo inflammation model

    PMID:33226635 PMID:33247181

    Open questions at the time
    • Whether pathway cooperativity requirement is cancer-type specific untested
    • Structural basis for allosteric modulator selectivity not resolved
  15. 2022 High

    Three 2022 studies completed the picture of PAR2 compartmentalized signaling and metabolic function: endosomal PAR2 assemblies (Gαq/Gαi/β-arrestin) in colonocytes sustain colitis; GPR97 allosterically activates mPR3 within a CD177/GPR97/PAR2/CD16b neutrophil complex; and liver-specific PAR2-KO rescues glucose/glycogen defects by restoring GLUT2 and insulin-Akt signaling.

    Evidence PAR2-muGFP knockin mice with dynamin inhibition in colitis; GPR97 crystal structure with co-IP and neutrophil activation; liver-specific PAR2-KO with pepducin treatment and metabolic phenotyping

    PMID:35110404 PMID:35603482 PMID:36302784

    Open questions at the time
    • How endosomal vs. surface PAR2 signals are decoded differently at the transcriptional level unknown
    • Whether CD177/GPR97/PAR2 complex exists outside neutrophils not tested
    • Identity of endogenous hepatic PAR2 activating protease still unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the identity of endogenous PAR2-activating proteases in hepatic metabolic regulation, the structural basis for protease-specific biased agonism at the receptor level, how endosomal versus surface PAR2 signals are differentially decoded, and whether PAR2 heterodimer combinations produce distinct functional outcomes across additional tissue contexts.
  • No high-resolution PAR2 structure in complex with tethered ligand variants
  • Endogenous protease activating hepatic PAR2 unknown
  • Systematic comparison of heterodimer signaling profiles lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-168256 Immune System 5 R-HSA-112316 Neuronal System 3 R-HSA-109582 Hemostasis 2 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ADGRF5F2RF2RL2F2RL3PROCRTGFBR1TRPA1TRPV4
Complex memberships
CD177/GPR97/PAR2/CD16b complexPAR1-PAR2 heterodimerPAR2-PAR3 heterodimerPAR2-PAR4 heterodimer

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 PAR2 activation sensitizes TRPA1 channels in DRG neurons via PLC-mediated hydrolysis of plasma membrane PIP2, relieving tonic PIP2 inhibition of TRPA1 and increasing TRPA1 currents; this mechanism contributes to inflammatory pain. Electrophysiology in HEK293 cells transfected with TRPA1 and DRG neurons; PLC inhibitors and antibody sequestration of PIP2; colocalization immunofluorescence The Journal of clinical investigation High 17571167
2014 Cathepsin S acts as a biased agonist of PAR2 by cleaving at E56↓T57 (distinct from canonical trypsin cleavage at R36↓S37), exposing a novel tethered ligand that selectively couples PAR2 to Gαs/cAMP but not Ca2+ mobilization, β-arrestin recruitment, or ERK1/2 activation; Cat-S–activated PAR2 then stimulates TRPV4 and causes hyperalgesia via adenylyl cyclase/PKA. Cleavage-site mapping; cAMP assay; Ca2+ mobilization assay; β-arrestin recruitment assay; Xenopus oocyte TRPV4 functional assay; PAR2/TRPV4 knockout mice; in vivo paw inflammation model The Journal of biological chemistry High 25118282
2014 Cathepsin S cleaves PAR2 near the N-terminus to expose a novel tethered ligand sequence KVDGTS; mutation of the cathepsin S cleavage site prevents receptor activation by the protease while the hexapeptide KVDGTS retains PAR2 signaling activity. Protease cleavage assay; site-directed mutagenesis of PAR2 cleavage site; peptide functional assay in cells expressing PAR2 PloS one High 24964046
2013 PAR1 and PAR2 form a stable heterodimer that exhibits constitutive internalization driven by PAR1 C-terminal tail sorting motifs; thrombin-activated PAR1-PAR2 heterodimers co-internalize, recruit β-arrestins to endosomes, and enhance cytoplasmic (not nuclear) β-arrestin-mediated ERK1/2 activation. BRET; immunofluorescence microscopy; co-immunoprecipitation; cells expressing receptors exogenously and endogenously; ERK1/2 activation assays The Journal of biological chemistry High 23476015
2012 PAR2 facilitates plasma membrane delivery of PAR4 by disrupting PAR4's ER-retention complex with β-COP1 and promoting interaction with chaperone 14-3-3ζ; PAR2-PAR4 heterodimerization was confirmed by intermolecular FRET, and PAR2 co-expression enhanced PAR4 glycosylation and signaling. FRET; co-immunoprecipitation; mutagenesis of PAR4 RXR ER-retention sequence; immunofluorescence; glycosylation analysis; signaling assays The Journal of biological chemistry High 22411985
2013 In gastric smooth muscle cells, PAR2 couples to Gq, G13, and Gi1, stimulating PI hydrolysis (via Gαq/Gαi), Rho kinase activation (via Gα13), and biphasic contraction; PAR2-activated RhoA is subject to feedback inhibition via NF-κB–dependent release of PKA catalytic subunit, which phosphorylates RhoA at Ser188. PAR2/Gα siRNA knockdown; Gα minigene expression; pertussis toxin; dominant-negative mutants; Rho kinase activity assay; contractility assay; phospho-immunoblotting PloS one High 23825105
2022 In colitis, PAR2 redistributes from the basolateral membrane of colonocytes to early endosomes; endosomal PAR2 assembles signaling complexes containing Gαq, Gαi, and β-arrestin; dynamin-2-dependent endocytosis is required for PAR2-evoked colonic inflammation and hyperalgesia. Knockin mice expressing PAR2-muGFP; immunostaining; RNAScope in situ hybridization; confocal microscopy; Dnm2 siRNA knockdown; dynamin inhibitors; cytokine release assays; mouse colitis models Proceedings of the National Academy of Sciences of the United States of America High 35110404
2015 EPCR-dependent activation of PAR2 by the ternary TF-VIIa-Xa coagulation complex is required for LPS-induced expression of Pellino-1 and IRF8, thereby initiating an interferon-regulated gene expression program; mice lacking EPCR or PAR2 fail to mount this interferon response. Bone marrow-derived myeloid cell cultures; RAW264.7 cells; PAR2/EPCR knockout mice; LPS challenge in vivo; mRNA profiling Blood High 25733582
2011 Genetic epistasis in mouse skin demonstrates that PAR2 is a downstream effector of the serine protease CAP1/Prss8: transgenic overexpression of CAP1/Prss8 causes epidermal hyperplasia, ichthyosis, and skin inflammation that is completely abolished on a PAR2-null background. Transgenic mouse models (K14-CAP1/Prss8); PAR2-null background; histology; barrier function assays; cytokine measurement Nature communications High 21245842
2017 Activated protein C (aPC) signals through a PAR2/PAR3 heterodimer on regulatory T cells (CD4+FOXP3+) to restrict allogenic T-cell activation and expand Tregs, thereby ameliorating graft-vs.-host disease. PAR2/PAR3 knockout mice; Treg frequency measurement; allogeneic HSC transplantation model; humanized mouse model (NSG-AB°DR4) Nature communications High 28827518
2022 GPR97 allosterically activates CD177-associated membrane proteinase 3 (mPR3) within a macromolecular CD177/GPR97/PAR2/CD16b complex on neutrophils; mPR3 activation within this complex cleaves and activates PAR2, triggering inflammatory activation, ICAM-1/VCAM-1 upregulation, and endothelial dysfunction. Crystallography of GPR97 extracellular domain; deletion analysis; co-immunoprecipitation; functional neutrophil activation assays; PAR2 activation readouts Nature communications High 36302784
2020 PAR2-induced ovarian cancer cell migration and invasion requires cooperative signaling through Gαq/11, Gα12/13, and β-arrestin1/2 (not Gαs or Gαi), leading to serial activation of Src kinases, EGFR transactivation, and downstream MEK-ERK1/2-FOS/MYC/STAT3-COX2; loss of any single pathway component abolishes motility. CRISPR-Cas9 knockouts of PAR2, Gα proteins, and β-arrestin1/2; pharmacological inhibitors; western blots; migration/invasion assays British journal of pharmacology High 33226635
2019 Furin is the principal proprotein convertase that cleaves PAR2 at Arg36↓; N-glycosylation of PAR2 at Asn30 reduces the efficiency but enhances selectivity of Furin cleavage; Furin expression enhances neuronal cell viability against PAR2-induced cytotoxicity in the context of HIV-1 infection. In vitro cleavage assays; site-directed mutagenesis of PAR2 (Arg36, Asn30); co-culture of neuroblastoma cells with HIV-1-infected macrophages; PACS1 trafficking studies Cell death and differentiation High 30683917
2015 PAR2 deficiency in mice (PAR-2 knockout) prevents PAR1-dependent pro-fibrotic responses in bleomycin-induced pulmonary fibrosis; PAR1 signaling in fibroblasts requires the presence of PAR2, establishing PAR2 as necessary for PAR1-dependent signaling in this context. PAR2-knockout mice; bleomycin lung fibrosis model; fibroblast stimulation with PAR1/PAR2 agonists; PAR1 antagonist (P1pal-12); collagen/SMA western blot; hydroxyproline quantification Journal of cellular and molecular medicine High 25689283
2020 The PAR2 inhibitor I-287 acts as a negative allosteric modulator selectively blocking Gαq and Gα12/13 signaling and their downstream effectors while having no effect on Gi/o signaling or β-arrestin2 engagement; selective inhibition of only the Gαq/Gα12/13 pathways is sufficient to block PAR2-driven inflammation in vivo. BRET-based signaling pathway profiling; in vivo inflammatory model; selective PAR2 inhibitor characterization Communications biology High 33247181
2022 PAR2 activation downregulates the hepatic glucose transporter GLUT2 through a Gq-MAPK-FoxA3 pathway and inhibits insulin-Akt signaling through a Gq-calcium-CaMKK2 pathway, thereby suppressing glucose internalization and glycogen storage; liver-specific PAR2 knockout rescues these defects. Whole-body and liver-specific PAR2-KO mice; mechanistic pathway inhibitors; GLUT2/FoxA3 expression assays; Akt phosphorylation assays; glycogen storage measurements; pepducin therapeutic dosing Hepatology (Baltimore, Md.) High 35603482
2019 PAR2 deficiency in mice reduces plasma and total liver cholesterol by ~50% through decreased expression of hepatic cholesterol synthesis genes and induction of reverse cholesterol transport; Gi-Jnk1/2 signaling downstream of PAR2 was identified as the key effector pathway regulating lipid and cholesterol homeostasis in liver. PAR2-KO mice (C57BL/6 F2rl1-/-); normal/high-fat diet feeding; plasma/liver lipid assays; hepatic gene expression; fecal bile acid output; pathway inhibitor studies Molecular metabolism High 31668396
2017 PAR2 expression is required for TGF-β1-induced ERK1/2 activation (but not SMAD activation) and cell migration; PAR2 physically interacts with ALK5 (TGF-β type I receptor) as shown by co-immunoprecipitation, and ERK inhibition abolishes PAR2-AP- and TGF-β1-induced migration. siRNA depletion of PAR2; xCELLigence cell migration assay; phospho-immunoblotting for ERK1/2 and SMAD; co-immunoprecipitation of PAR2 with ALK5; MEK inhibitor U0126 International journal of molecular sciences Medium 29261154
2002 TF/FVIIa complex mediates vascular smooth muscle cell migration via PAR2; PAR2-activating peptide SLIGKV (but not PAR1-AP or PAR4-AP) stimulates SMC migration comparable to TF/FVIIa, and anti-PAR2-AP antisera blocks TF/FVIIa-induced migration. Modified Boyden chamber migration assay; PAR2-activating peptide; neutralizing antisera; immunostaining of human coronary arteries Thrombosis research Medium 12479889
2008 PAR2 triggers IL-8 release from GI epithelial cells via two independent, non-overlapping signaling pathways: MEK/ERK and PI3-kinase/Akt; inhibition of MEK blocks ERK but not Akt phosphorylation, and vice versa. PAR2-activating peptide stimulation; MEK inhibitor U0126; PI3K inhibitor LY294002; ERK and Akt phosphorylation by immunoblot; IL-8 ELISA Biochemical and biophysical research communications Medium 18854173
2014 PAR2 activation reduces cytokine-induced epithelial apoptosis via concurrent stimulation of MEK1/2 (leading to BAD phosphorylation at Ser112) and PI3K (leading to BAD phosphorylation at Ser136); simultaneous inhibition of both pathways is required to abolish the anti-apoptotic effect; PAR2 siRNA knockdown eliminates this protection. Caspase-3/8/9 cleavage assays; PARP cleavage; annexin V staining; siRNA knockdown of PAR2, BAD, MCL-1; MEK and PI3K inhibitors; phospho-BAD immunoblotting The Journal of biological chemistry High 25331954
2014 PAR2-induced TRPV4 channel activation is dependent on tyrosine kinases and PI3K but not Gαq or store-operated calcium entry (thapsigargin-insensitive); the tyrosine kinase inhibitor bafetinib, but not dasatinib, blocks PAR2-induced TRPV4 gating and mechanical hyperalgesia in vivo. Calcium imaging in HEK293 cells; TRPV4 transfection; pharmacological inhibitors; in vivo mechanical hyperalgesia assay British journal of pharmacology Medium 24779362
2018 PAR2 activation promotes M1-like macrophage polarization and proinflammatory cytokine expression through a FOXO1-dependent pathway; FOXO1 nuclear accumulation is required for PAR2-induced transcription of IL-1β, IL-6, MCP-1, and TNF-α, and FOXO1 siRNA knockdown abolishes this effect. Bone marrow-derived macrophages; PAR2 agonist stimulation; transcription factor microarray; qRT-PCR; western blot; immunofluorescence for FOXO1 localization; siRNA knockdown of FOXO1 Journal of cellular biochemistry Medium 30552714
2018 Plasma kallikrein modulates blood-brain barrier integrity via PAR2 on endothelial cells, leading to upregulation of ICAM-1 and VCAM-1 and amplified leukocyte trafficking; prekallikrein deficiency or blockade reduces BBB disruption and CNS inflammation in experimental autoimmune encephalomyelitis. In vitro endothelial cell PAR2 activation; ICAM-1/VCAM-1 upregulation assays; prekallikrein-deficient mice; EAE model; leukocyte trafficking quantification Proceedings of the National Academy of Sciences of the United States of America Medium 30559188
2013 Kallikrein 6 (Klk6) signals through both PAR1 and PAR2 to activate ERK1/2 in neurons via phosphoinositide 3-kinase and MEK-dependent pathways, exacerbating glutamate neurotoxicity; lipopeptide inhibitors of PAR1 or PAR2, and PAR1 genetic deletion, each reduce Klk6-ERK1/2 activation. Recombinant Klk6 treatment of cerebellar granule neurons and NSC34 cells; PAR1/PAR2 lipopeptide inhibitors; PAR1 knockout mice; ERK1/2 activation assays; LDH/caspase assays Journal of neurochemistry Medium 23647384
2020 PAR2 activation by tissue factor releases PTEN from its MAGI1-3 protein complex (demonstrated by proximity ligation assay and co-IP), transiently increasing PTEN lipid phosphatase activity and reducing Akt activity; prolonged TF exposure reduces PTEN antigen levels with concurrent Akt activation and increased proliferation. Proximity ligation assay; co-immunoprecipitation; PTEN/Akt phosphorylation assays; PAR2-agonist peptide; recombinant TF treatment; seven cancer cell lines Scientific reports Medium 33262514
2018 Mast cell tryptase promotes profibrotic phenotype in atrial fibroblasts via PAR2 and PPARγ pathways; the PAR2 antagonist FSLLRY-NH2 or PPARγ antagonist GW9662 abolishes tryptase-induced collagen I, fibronectin, laminin accumulation, and MMP upregulation. Primary atrial fibroblast culture; tryptase treatment; PAR2 antagonist; PPARγ antagonist; collagen/fibronectin/MMP western blots; cell proliferation and migration assays Archives of medical research Medium 30580879
2022 PAR2 activation in renal tubular epithelial cells induces chemokine (MCP1, MCP3) upregulation via the MAPK-NF-κB signaling pathway, driving inflammatory cell recruitment; PAR2-knockout mice are protected from adenine diet-induced renal fibrosis and inflammation. PAR2-knockout mice; adenine diet model; NRK52E epithelial cells; PAR2 agonist; MAPK and NF-κB inhibitors; qRT-PCR for chemokines; macrophage migration assay Archives of pharmacal research Medium 35334088
2018 PAR2 deficiency in MDSCs directly enhances their immunosuppressive activity through STAT3-mediated reactive oxygen species production, reshaping the tumor microenvironment to promote colorectal tumorigenesis. PAR2-KO mice; AOM/DSS colitis-associated cancer model; flow cytometry for MDSC/macrophage/T-cell infiltration; STAT3 pathway analysis; ROS measurement Cancer letters Medium 31733286
2016 PAR2 pepducin PZ-235, designed to mimic the juxtamembrane helical region of TM6/third intracellular loop, forms a well-structured α-helix and blocks PAR2-mediated reactive oxygen species production in hepatocytes and stellate cell activation, suppressing liver fibrosis, collagen deposition, and inflammation. NMR structure of PZ-235 peptide; mouse CCl4 and MCD diet fibrosis models; pepducin treatment; stellate cell activation assays; ROS assay; histology; collagen quantification The Journal of biological chemistry Medium 27613872
2018 PAR2 activation causes migraine-like pain behaviors (facial grimace and mechanical allodynia) upon dural application in mice; functional PAR2 is expressed on trigeminal neurons and dural fibroblasts; the effect is attenuated by PAR2 antagonist C391 and is absent in PAR2-/- mice. Ca2+ imaging of trigeminal neurons and dural fibroblasts; behavioral assays (grimace scale, von Frey); PAR2-KO mice; PAR2 antagonist C391; sumatriptan comparison Cephalalgia : an international journal of headache Medium 29848111
2018 In differentiated human keratinocytes, PAR2-evoked Ca2+ store depletion and downstream inflammatory mediator production (IL-1β, TNF-α, TSLP) require both InsP3R and TRPV1 in intracellular Ca2+ stores, rather than ORAI1-mediated store-operated Ca2+ entry; PLC inhibition abolishes these responses. Ca2+ imaging; TRPV1/InsP3R/ORAI1 inhibitors; NF-κB activity assay; cytokine ELISA; PAR2-activating peptide SLIGKV in primary keratinocytes The Journal of investigative dermatology Medium 29458120
2013 MicroRNA-34a mediates PAR2-induced upregulation of Cyclin D1 in colon cancer cells; TGF-β contributes to PAR2 regulation of miR-34a; PAR2 knockdown or inactivation of its autocrine activating proteinase reduces proliferation in vitro and tumorigenicity in vivo. siRNA knockdown of PAR2; miR-34a inhibitor; Cyclin D1 expression; in vitro proliferation; xenograft mouse model; TGF-β pathway analysis PloS one Medium 23991105

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. The Journal of clinical investigation 355 17571167
2014 Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4. The Journal of biological chemistry 158 25118282
2009 Tissue factor and PAR2 signaling in the tumor microenvironment. Arteriosclerosis, thrombosis, and vascular biology 98 19661489
2001 Protease-activated receptor-2 (PAR2) in the airways. Pulmonary pharmacology & therapeutics 98 11448145
2011 PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin. Nature communications 95 21245842
2011 Alternaria alternata serine proteases induce lung inflammation and airway epithelial cell activation via PAR2. American journal of physiology. Lung cellular and molecular physiology 92 21296894
2013 Transactivation of the PAR1-PAR2 heterodimer by thrombin elicits β-arrestin-mediated endosomal signaling. The Journal of biological chemistry 79 23476015
2015 EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice. Blood 72 25733582
2013 Toward drugs for protease-activated receptor 2 (PAR2). Journal of medicinal chemistry 70 23895492
2012 Novel animal models of acute and chronic cancer pain: a pivotal role for PAR2. The Journal of neuroscience : the official journal of the Society for Neuroscience 69 23055487
2002 Expression of protease activated receptor-2 (PAR-2) in central airways of smokers and non-smokers. Thorax 64 11828045
2002 Protease-activated receptor 2 (PAR2) mediates vascular smooth muscle cell migration induced by tissue factor/factor VIIa complex. Thrombosis research 60 12479889
2018 PAR2 promotes M1 macrophage polarization and inflammation via FOXO1 pathway. Journal of cellular biochemistry 59 30552714
2013 Both PHYTOCHROME RAPIDLY REGULATED1 (PAR1) and PAR2 promote seedling photomorphogenesis in multiple light signaling pathways. Plant physiology 55 24335334
2009 Increased mast cell expression of PAR-2 in skin inflammatory diseases and release of IL-8 upon PAR-2 activation. Experimental dermatology 55 19889021
2020 Macrophage TLR4 and PAR2 Signaling: Role in Regulating Vascular Inflammatory Injury and Repair. Frontiers in immunology 54 33072072
2018 PAR2 Pepducin-Based Suppression of Inflammation and Itch in Atopic Dermatitis Models. The Journal of investigative dermatology 53 30287285
2013 Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity. Journal of neurochemistry 53 23647384
2016 Targeting Liver Fibrosis with a Cell-penetrating Protease-activated Receptor-2 (PAR2) Pepducin. The Journal of biological chemistry 51 27613872
2014 Cathepsin S signals via PAR2 and generates a novel tethered ligand receptor agonist. PloS one 50 24964046
2014 Proteinase-activated receptor 2 (PAR2) decreases apoptosis in colonic epithelial cells. The Journal of biological chemistry 49 25331954
2008 PAR2 triggers IL-8 release via MEK/ERK and PI3-kinase/Akt pathways in GI epithelial cells. Biochemical and biophysical research communications 49 18854173
2006 Induction of IL-6 release from human T cells by PAR-1 and PAR-2 agonists. Immunology and cell biology 49 16869943
2015 Functional inhibition of PAR2 alleviates allergen-induced airway hyperresponsiveness and inflammation. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 48 26312432
2018 Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer. International journal of molecular sciences 47 29795022
2014 The tyrosine kinase inhibitor bafetinib inhibits PAR2-induced activation of TRPV4 channels in vitro and pain in vivo. British journal of pharmacology 47 24779362
2019 Protease-activated receptor 2 (PAR-2) antagonist AZ3451 as a novel therapeutic agent for osteoarthritis. Aging 45 31841119
2018 PAR2 (Protease-Activated Receptor 2) Deficiency Attenuates Atherosclerosis in Mice. Arteriosclerosis, thrombosis, and vascular biology 45 29599135
2018 Plasma kallikrein modulates immune cell trafficking during neuroinflammation via PAR2 and bradykinin release. Proceedings of the National Academy of Sciences of the United States of America 44 30559188
2018 Protease activated receptor 2 (PAR2) activation causes migraine-like pain behaviors in mice. Cephalalgia : an international journal of headache 42 29848111
2013 MicroRNA-34a mediates the autocrine signaling of PAR2-activating proteinase and its role in colonic cancer cell proliferation. PloS one 42 23991105
2005 Proteinase-activated receptor-2 (PAR2) agonist causes periodontitis in rats. Journal of dental research 41 15668333
2022 PAR2 promotes impaired glucose uptake and insulin resistance in NAFLD through GLUT2 and Akt interference. Hepatology (Baltimore, Md.) 40 35603482
2014 Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma. Current opinion in pharmacology 40 24907413
2012 Novel role for proteinase-activated receptor 2 (PAR2) in membrane trafficking of proteinase-activated receptor 4 (PAR4). The Journal of biological chemistry 40 22411985
2013 Distinctive G Protein-Dependent Signaling by Protease-Activated Receptor 2 (PAR2) in Smooth Muscle: Feedback Inhibition of RhoA by cAMP-Independent PKA. PloS one 39 23825105
2017 Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. Nature communications 38 28827518
2022 Mice expressing fluorescent PAR2 reveal that endocytosis mediates colonic inflammation and pain. Proceedings of the National Academy of Sciences of the United States of America 37 35110404
2006 Expression of protease activated receptor-2 (PAR-2) in gastric cancer. Journal of surgical oncology 37 16425301
2002 PAR-2: structure, function and relevance to human diseases of the gastric mucosa. Expert reviews in molecular medicine 36 14585156
2004 Protease-activated receptor-2 (PAR-2) expression in human fibroblasts is regulated by growth factors and extracellular matrix. The Journal of investigative dermatology 35 15482468
2020 PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR. British journal of pharmacology 34 33226635
2018 Major Role for TRPV1 and InsP3R in PAR2-Elicited Inflammatory Mediator Production in Differentiated Human Keratinocytes. The Journal of investigative dermatology 34 29458120
2024 Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation. Nature communications 33 38228638
2010 Protease-activated receptor-2 (PAR(2)) in human periodontitis. Journal of dental research 33 20530726
2015 The novel PAR2 ligand C391 blocks multiple PAR2 signalling pathways in vitro and in vivo. British journal of pharmacology 32 26140338
2002 Ion transport induced by proteinase-activated receptors (PAR2) in colon and airways. Cell biochemistry and biophysics 32 12139406
2019 PAR2 deficiency enhances myeloid cell-mediated immunosuppression and promotes colitis-associated tumorigenesis. Cancer letters 31 31733286
2018 Mechanisms of Probiotic VSL#3 in a Rat Model of Visceral Hypersensitivity Involves the Mast Cell-PAR2-TRPV1 Pathway. Digestive diseases and sciences 31 30560330
2019 PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling. Oncology research 29 30841957
2022 GPR97 triggers inflammatory processes in human neutrophils via a macromolecular complex upstream of PAR2 activation. Nature communications 28 36302784
2020 The PAR2 inhibitor I-287 selectively targets Gαq and Gα12/13 signaling and has anti-inflammatory effects. Communications biology 28 33247181
2015 Protease-activated receptor (PAR)-2 is required for PAR-1 signalling in pulmonary fibrosis. Journal of cellular and molecular medicine 27 25689283
2022 Renal tubular PAR2 promotes interstitial fibrosis by increasing inflammatory responses and EMT process. Archives of pharmacal research 26 35334088
2019 PAR2 controls cholesterol homeostasis and lipid metabolism in nonalcoholic fatty liver disease. Molecular metabolism 26 31668396
2017 The Role of PAR2 in TGF-β1-Induced ERK Activation and Cell Motility. International journal of molecular sciences 26 29261154
2012 PAR(2) expression in peripheral blood monocytes of patients with rheumatoid arthritis. Annals of the rheumatic diseases 26 22294633
2012 Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping. Journal of hypertension 26 22914544
2010 PAR1- and PAR2-induced innate immune markers are negatively regulated by PI3K/Akt signaling pathway in oral keratinocytes. BMC immunology 26 21029417
2005 RNA interference decreases PAR-2 expression and function in human airway smooth muscle cells. American journal of respiratory cell and molecular biology 26 16195539
2020 Punicalagin Ameliorates Lupus Nephritis via Inhibition of PAR2. International journal of molecular sciences 25 32674502
2020 Characterization and preclinical evaluation of a protease activated receptor 2 (PAR2) monoclonal antibody as a preventive therapy for migraine. Cephalalgia : an international journal of headache 25 33131305
2011 Potent agonists of the protease activated receptor 2 (PAR2). Journal of medicinal chemistry 25 21294569
2004 Proteinase-activated Receptor 2 (PAR2): a challenging new target for treatment of vascular diseases. Current pharmaceutical design 25 15320742
2017 Astragaloside Alleviates Hepatic Fibrosis Function via PAR2 Signaling Pathway in Diabetic Rats. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 24 28245465
2008 PAR1 and PAR2 integrate shade and hormone transcriptional networks. Plant signaling & behavior 24 19704482
2007 Protease-activated receptor-2 (PAR-2) in cervical cancer proliferation. Gynecologic oncology 24 17936340
2006 The protease-activated receptor2 (PAR2)-prostaglandin E2-prostanoid EP receptor axis: a potential bronchoprotective unit in the respiratory tract? European journal of pharmacology 24 16483565
2023 Crohn's disease proteolytic microbiota enhances inflammation through PAR2 pathway in gnotobiotic mice. Gut microbes 23 37131291
2016 Protease activated receptor 2 (PAR2) modulators: a patent review (2010-2015). Expert opinion on therapeutic patents 23 26936077
2014 Protease-activated receptor 2 (PAR2) is upregulated by Acanthamoeba plasminogen activator (aPA) and induces proinflammatory cytokine in human corneal epithelial cells. Investigative ophthalmology & visual science 22 24876278
2019 Aspergillus fumigatus induction of IL-33 expression in chronic rhinosinusitis is PAR2-dependent. The Laryngoscope 21 30973971
2019 House dust mite-treated PAR2 over-expressor mouse: A novel model of atopic dermatitis. Experimental dermatology 21 31487753
2022 Candida albicans Sap6 Initiates Oral Mucosal Inflammation via the Protease Activated Receptor PAR2. Frontiers in immunology 20 35844627
2016 Cortical Polarity of the RING Protein PAR-2 Is Maintained by Exchange Rate Kinetics at the Cortical-Cytoplasmic Boundary. Cell reports 20 27524610
2016 PAR2 regulates regeneration, transdifferentiation, and death. Cell death & disease 20 27809303
2008 Proteinase-activated receptor 2 (PAR-2) in gastrointestinal and pancreatic pathophysiology, inflammation and neoplasia. Scandinavian journal of gastroenterology 20 19086162
2018 Tryptase Promotes the Profibrotic Phenotype Transfer of Atrial Fibroblasts by PAR2 and PPARγ Pathway. Archives of medical research 19 30580879
2007 Protease-activated receptor-1 (PAR1) and PAR2 but not PAR4 mediate relaxations in lower esophageal sphincter. Regulatory peptides 19 17335921
2005 Protease-activated receptor-2 (PAR2) in cardiovascular system. Vascular pharmacology 19 16183333
2023 Excess pancreatic elastase alters acinar-β cell communication by impairing the mechano-signaling and the PAR2 pathways. Cell metabolism 17 37339634
2022 Activation of PAR2 promotes high-fat diet-induced renal injury by inducing oxidative stress and inflammation. Biochimica et biophysica acta. Molecular basis of disease 17 35772632
2019 HIV-induced neuroinflammation: impact of PAR1 and PAR2 processing by Furin. Cell death and differentiation 17 30683917
2024 PAR2 on oral cancer cells and nociceptors contributes to oral cancer pain that can be relieved by nanoparticle-encapsulated AZ3451. Biomaterials 16 39418848
2021 Genetic priming of sensory neurons in mice that overexpress PAR2 enhances allergen responsiveness. Proceedings of the National Academy of Sciences of the United States of America 16 33602818
2021 A re-innervated in vitro skin model of non-histaminergic itch and skin neurogenic inflammation: PAR2-, TRPV1- and TRPA1-agonist induced functionality. Skin health and disease 16 35663777
2012 Transient early neurotrophin release and delayed inflammatory cytokine release by microglia in response to PAR-2 stimulation. Journal of neuroinflammation 16 22731117
2024 PAR2-mediated cellular senescence promotes inflammation and fibrosis in aging and chronic kidney disease. Aging cell 15 38687090
2024 Par2-mediated responses in inflammation and regeneration: choosing between repair and damage. Inflammation and regeneration 15 38816842
2019 Mast Cell/Proteinase Activated Receptor 2 (PAR2) Mediated Interactions in the Pathogenesis of Discogenic Back Pain. Frontiers in cellular neuroscience 15 31333416
2016 Role of PAR2 in the Development of Lower Urinary Tract Dysfunction. The Journal of urology 15 26860791
2015 Regulation of SPRY3 by X chromosome and PAR2-linked promoters in an autism susceptibility region. Human molecular genetics 15 26089202
2014 Per a 10 activates human derived epithelial cell line in a protease dependent manner via PAR-2. Immunobiology 15 25468564
2010 PAR(2) and temporomandibular joint inflammation in the rat. Journal of dental research 15 20651095
2020 Is There a Trojan Horse to Aggressive Pancreatic Cancer Biology? A Review of the Trypsin-PAR2 Axis to Proliferation, Early Invasion, and Metastasis. Journal of pancreatic cancer 14 32064449
2020 Activation of PAR2 by tissue factor induces the release of the PTEN from MAGI proteins and regulates PTEN and Akt activities. Scientific reports 14 33262514
2016 PAR2 Modulators Derived from GB88. ACS medicinal chemistry letters 13 27994760
2015 Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists. Bioorganic & medicinal chemistry 13 26631441
2023 Role of the protease-activated receptor-2 (PAR2) in the exacerbation of house dust mite-induced murine allergic lung disease by multi-walled carbon nanotubes. Particle and fibre toxicology 12 37580758
2018 Protease-activated receptor 2 (PAR2) upregulates granulocyte colony stimulating factor (G-CSF) expression in breast cancer cells. Biochemical and biophysical research communications 12 30172372