Deep Research
Bioreason Pro
(F2rl2-deep-research-bioreason-sft.md)
Bioreason Pro
(F2rl2-deep-research-bioreason-sft.md)Thinking Trace
I begin by dissecting the InterPro architecture and its order along the sequence. Multiple family signatures specific to protease-activated receptor 3 cluster in the extreme N-terminus and early transmembrane-proximal regions: IPR003943 (Protease-activated receptor 3 family) appears at residues 2β22, 30β51, 56β73, 77β93, 118β132, 197β214, 232β243, and 292β337, while broader protease-activated receptor family marks (IPR003912) occur at 83β100, 150β164, 262β273 and 262β273. These N-terminal PAR3-specific motifs define a protease-cleavable segment that, once cut, exposes a tethered ligand (βactivation peptideβ) that folds back to engage and activate the receptor. Downstream, a canonical rhodopsin-like G protein-coupled receptor (GPCR) 7-transmembrane core is delineated by IPR017452 (GPCR, rhodopsin-like, 7TM domain) spanning residues 110β357, reinforced by multiple overlapping rhodopsin-like family signatures (IPR000276) at 95β119, 116β357, 127β148, 172β194, 208β229, 298β322 and 339β365. This arrangementβPAR3-specific N-terminus followed by a 7TM GPCR coreβcausally establishes a protease-gated GPCR whose activation mechanism is proteolytic unmasking of an intramolecular agonist.
From this architecture, the molecular function resolves as follows. The PAR3-specific N-terminus, once cleaved by trypsin-like serine proteases, generates an activation peptide that functions as an intrinsic ligand; this confers receptor ligand activity (GO:0048018) in the sense of an auto-ligand that binds the receptorβs own N-terminus. Engagement of the 7TM core initiates G protein coupling. The rhodopsin-like 7TM domain supports G protein activation; while the receptor is not a GTPase itself, its signaling complex recruits RGS proteins that accelerate GTP hydrolysis on GΞ± subunits. Through this scaffolding role, the receptor complex exerts GTPase activator activity (GO:0005096) via associated RGS proteins. The same GPCR signaling triggers phospholipase C-Ξ² activation (GO:0043532 phospholipase C activator activity) and protein kinase C activation (GO:0043537 protein kinase C activator activity) by coupling to Gq/11 and/or G12/13, respectively. Downstream, the pathway modulates calcium channels, providing calcium channel regulator activity (GO:0005246), and directly exhibits protein tyrosine kinase activator activity (GO:0043535) by engaging receptor-proximal tyrosine kinases such as Src. The receptorβs ability to functionally gate ion channels through GΞ²Ξ³ and second messengers supports ion channel regulator activity involved in ligand-gated ion channel signaling (GO:0099108). Collectively, these activities are the expected consequences of a PAR3-class rhodopsin-like GPCR.
These molecular activities drive specific biological processes. Proteolytic activation by trypsin-like enzymes (e.g., trypsin, matriptase, kallikreins) positions the receptor as a sensor of extracellular protease tone, translating protease availability into intracellular G protein signaling. The PLC/PKC axis and calcium channel regulation modulate excitability and secretion, aligning with participation in a ligand-gated ion channel signaling pathway (GO:1990806) via G proteinβdependent control of channel opening probability and trafficking. In endocrine contexts, the same signaling enhances secretory output, consistent with positive regulation of insulin secretion (GO:0032024). In epithelia, the receptorβs apical positioning and protease gating enable rapid responses to luminal proteases, shaping barrier function and inflammatory signaling.
The cellular component follows directly from the 7TM GPCR core and the PAR-specific N-terminus: the protein is a multi-pass integral membrane receptor at the plasma membrane. Epithelial polarity cues and protease access favor localization to the apical plasma membrane (GO:0016324), where luminal proteases can cleave the N-terminus and initiate signaling. The multi-pass nature is inherent to the rhodopsin-like 7TM domain.
Mechanistically, proteolytic cleavage of the N-terminal PAR3 module exposes the tethered ligand, which binds intramolecularly to the receptorβs extracellular loops/orthosteric pocket, stabilizing an active 7TM conformation. This conformation couples to heterotrimeric G proteins (primarily Gq/11 and G12/13), leading to PLCΞ² activation, IP3/DAG production, Ca2+ mobilization via calcium channels, PKC activation, and engagement of tyrosine kinases. RGS proteins bound to the receptor complex accelerate GTP hydrolysis on GΞ±, shaping signal timing. The receptor likely forms functional complexes with other protease-activated receptors, particularly Proteinase-activated receptor 4, to diversify responses to distinct protease cleavages. The activation peptide fragment 1 represents the intramolecular agonist generated by initial cleavage, and additional extracellular partners plausibly include trypsin-like serine proteases (trypsin, matriptase, kallikreins) and intracellular effectors such as PLCΞ² isoforms, GNAQ/GNA11, GNA12/GNA13, RGS proteins, Src-family kinases, and epithelial calcium channels that implement the downstream physiological outputs.
## Functional Summary
A multi-pass plasma membrane receptor in mouse that is activated by proteolytic cleavage of its N-terminus, exposing a tethered activation peptide that turns on a rhodopsin-like signaling core. Upon activation, it couples to heterotrimeric G proteins to stimulate phospholipase C, mobilize intracellular calcium, regulate ion channels, and activate protein kinase C and tyrosine kinases. These signaling outputs modulate epithelial and endocrine physiology, including enhancing insulin secretion and shaping responses to luminal proteases at the apical surface, with timing and amplitude tuned by associated GTPase-accelerating regulators and crosstalk with related protease-activated receptors.
## UniProt Summary
Receptor for trypsin. When proteolytically cleaved in the N-terminus, the activation peptide internally binds and activates the receptor.
## InterPro Domains
- IPR003943: Protease-activated receptor 3 (family) [2-22]
- IPR003943: Protease-activated receptor 3 (family) [30-51]
- IPR003943: Protease-activated receptor 3 (family) [56-73]
- IPR003943: Protease-activated receptor 3 (family) [77-93]
- IPR003912: Protease-activated receptor (family) [83-100]
- IPR000276: G protein-coupled receptor, rhodopsin-like (family) [95-119]
- IPR017452: GPCR, rhodopsin-like, 7TM (domain) [110-357]
- IPR000276: G protein-coupled receptor, rhodopsin-like (family) [116-357]
- IPR003943: Protease-activated receptor 3 (family) [118-132]
- IPR003912: Protease-activated receptor (family) [150-164]
- IPR000276: G protein-coupled receptor, rhodopsin-like (family) [172-194]
- IPR003943: Protease-activated receptor 3 (family) [197-214]
- IPR000276: G protein-coupled receptor, rhodopsin-like (family) [208-229]
- IPR003943: Protease-activated receptor 3 (family) [232-243]
- IPR003943: Protease-activated receptor 3 (family) [251-262]
- IPR000276: G protein-coupled receptor, rhodopsin-like (family) [262-285]
- IPR003912: Protease-activated receptor (family) [262-273]
- IPR003943: Protease-activated receptor 3 (family) [292-304]
- IPR000276: G protein-coupled receptor, rhodopsin-like (family) [298-322]
- IPR003912: Protease-activated receptor (family) [300-313]
- IPR003943: Protease-activated receptor 3 (family) [322-337]
- IPR003912: Protease-activated receptor (family) [323-336]
- IPR000276: G protein-coupled receptor, rhodopsin-like (family) [339-365]
## GO Term Predictions
### Molecular Function
### Biological Process
### Cellular Component
Falcon
(F2rl2-deep-research-falcon.md)
Falcon
(F2rl2-deep-research-falcon.md)The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Research report: Mouse F2rl2 (UniProt O08675) β Proteinase-activated receptor 3 (PAR3)
Scope and identity verification
The target is mouse F2rl2 (Par3) encoding proteinase-activated receptor 3 (PAR3), a rhodopsin-like 7-transmembrane GPCR activated by proteolysis and historically described as a thrombin receptor-like protein (UniProt O08675 context). Multiple independent sources explicitly map F2rl2/F2RL2 β PAR3 and describe canonical PAR-family activation by N-terminal cleavage and tethered-ligand exposure, consistent with this identity (hanzelmann2015thrombinstimulatesinsulin pages 4-8, knauss2024plateletactivationin pages 64-70).
1) Key concepts and current understanding
1.1 Protease-activated receptors (PARs): definition and βtethered ligandβ activation
PARs are GPCRs that are activated when a protease cleaves their N-terminus, unmasking a new N-terminal sequence that folds back as a tethered ligand to activate the receptor; synthetic peptides corresponding to the tethered ligand can substitute for proteolysis in many systems (hollenberg2015proteinasestheirreceptors pages 4-5, jakobschepolicht2025theroleof pages 6-8). PAR signaling is often described as βsingle-use/Kleenexβ because activation is irreversible and is followed by desensitization, internalization, and degradation; PARs can also signal from endosomes through Ξ²-arrestin signalosomes over longer timescales (minutesβtens of minutes) beyond the rapid membrane-proximal G-protein signaling (secondsβminutes) (hollenberg2015proteinasestheirreceptors pages 4-5).
1.2 PAR3 (F2rl2) molecular activation features
Mouse PAR3 is reported to have a hirudin-like thrombin-binding sequence that can bind thrombinβs exosite I, and it is cleaved at Lys38/Thr39, exposing a tethered ligand beginning with TFRGAPβ¦; a synthetic peptide TFRGAP is described as a PAR3-activating peptide in platelet-oriented literature (knauss2024plateletactivationin pages 64-70, thibeault2020molecularmechanismsregulating pages 62-69).
1.3 Two functional βmodesβ of PAR3 emphasized in the literature
A consistent theme is that PAR3 can act (i) as a thrombin-binding cofactor/modulator for other PARs (especially PAR4 on mouse platelets), and (ii) as a signaling receptor in certain non-platelet contexts where direct downstream signaling has been experimentally demonstrated (e.g., islets/Ξ² cells) (knauss2024plateletactivationin pages 70-76, hanzelmann2015thrombinstimulatesinsulin pages 8-11).
2) Recent developments and latest research (2023β2024 prioritized)
2.1 2024: F2rl2/PAR3 as an eosinophil βstate markerβ in atopic dermatitis niche biology
A 2024 mouse study of atopic dermatitis (AD) and hypodermal fibroblastβmacrophage matrices measured F2rl2 (PAR3) in eosinophils by bulk RNA-seq and intracellular flow cytometry. The authors report that dermal eosinophil F2rl2/PAR3 expression is reduced in AD and restored by laminin-211 (LN211) treatment (Fig. 7F) (li2024guidedmonocytefate pages 10-12, li2024guidedmonocytefate media 243f02b7). In an in vitro coculture system, eosinophils interacting with macrophages driven toward a non-S1 phenotype (IL4/TGFΞ²3-treated) showed substantially lower PAR3, quantified as β62 (Β±12)%, and this loss was rescued when macrophages were treated with IL4/TGFΞ²3 plus LN211 (li2024guidedmonocytefate pages 10-12, li2024guidedmonocytefate media 243f02b7). This positions F2rl2/PAR3 as a readout of eosinophil maladaptation versus restoration in a defined skin inflammatory microenvironment rather than as a general systemic marker (li2024guidedmonocytefate pages 10-12, li2024guidedmonocytefate pages 12-14).
2.2 2024: Emphasis on species differencesβmouse platelet thrombin signaling uses PAR3/PAR4
A 2024 platelet-focused synthesis emphasizes that mouse platelets lack PAR1, have high PAR3, and rely on a PAR3βPAR4 partnership for thrombin responsiveness, whereas human platelets use a PAR1/PAR4 dual receptor system and have low PAR3 (reported ~150β200 copies) (knauss2024plateletactivationin pages 70-76). This species difference is highlighted as crucial for interpreting mouse thrombosis/hemostasis models and translating antiplatelet strategies (knauss2024plateletactivationin pages 70-76).
3) Primary function, pathways, and mechanistic evidence
3.1 Primary function in mouse platelets: PAR3 as a thrombin-binding cofactor for PAR4
Across multiple authoritative sources, the dominant experimentally supported platelet role of mouse PAR3 is cofactoring PAR4 activation rather than acting as an autonomous signaling receptor.
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Cofactor role / heterodimerization: In mouse platelets, PAR4 can form a heterodimer with PAR3 that promotes thrombin-mediated platelet activity; PAR3 itself is stated to not mediate signal transduction upon thrombin cleavage, instead acting as a cofactor enabling PAR4 signaling (cunningham2016proteinaseactivatedreceptors(pars) pages 3-5). A mechanistic model is that PAR3βs hirudin-like/exosite-I thrombin binding recruits thrombin to facilitate cleavage of adjacent PAR4; dimerization is described as essential for this amplification of PAR4 cleavage (knauss2024plateletactivationin pages 70-76).
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Species difference matters: A 2019 review notes mouse platelets express a PAR3/PAR4 complex, while human platelets express PAR1 and PAR4, and thus phenotypes in Par1β/β mice should not be assumed to reflect platelet hyporesponsiveness to thrombin (posma2019rolesofcoagulation pages 1-2). This distinction is reiterated in later syntheses (knauss2024plateletactivationin pages 70-76).
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Expert consensus framing: A highly cited inflammation-focused PAR review summarizes that mouse PAR3 maintained thrombin recruitment activity but βlost receptor function,β reinforcing the concept of PAR3 as a thrombin-recruiting cofactor in mice (heuberger2019proteaseactivatedreceptors(pars) pages 1-3).
3.2 Direct signaling: PAR3 activation in pancreatic islets/Ξ² cells (PLC/Ca2+/PKC)
In contrast to the βnon-signaling cofactorβ view for platelets, a primary study demonstrated functional signaling downstream of PAR3 activation in islets.
In isolated mouse islets/Ξ² cells, thrombin and a PAR3 tethered-ligand peptide stimulated insulin secretion and Ξ²-cell exocytosis:
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Agonists and blockade supporting PAR3 cleavage mechanism: Thrombin-stimulated insulin secretion was prevented by an antibody blocking the thrombin cleavage site of PAR3, supporting proteolytic activation and tethered-ligand signaling (hanzelmann2015thrombinstimulatesinsulin pages 8-11).
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Quantitative functional outcomes: Thrombin (10 nM) increased insulin secretion by ~140% at 2 h (with diminishing effects at longer incubations), and a PAR3 activating peptide at 20 ΞΌM robustly increased insulin secretion (reported ~90% increase at basal glucose and ~130% at high glucose) and increased Ξ²-cell exocytosis (~70%) (hanzelmann2015thrombinstimulatesinsulin pages 4-8, hanzelmann2015thrombinstimulatesinsulin pages 8-11).
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Downstream pathway evidence: Pharmacology and Ca2+ imaging support signaling via Gq β PLC β IP3/DAG, with Ca2+ release from intracellular stores and involvement of PKC; multiple inhibitors (e.g., PLC, IP3 receptor, PKC blockade) prevented the PAR3 peptideβs effects, and the peptide increased intracellular Ca2+ about 2-fold (hanzelmann2015thrombinstimulatesinsulin pages 8-11).
This provides a concrete mechanistic pathway for PAR3-dependent cellular responses outside platelets and highlights the context dependence of PAR3 biology (hanzelmann2015thrombinstimulatesinsulin pages 8-11).
3.3 Canonical PAR signaling modules (general framework used for interpreting PAR3)
A mechanistic review of PAR signaling provides a widely used interpretive framework: rapid Gq-mediated Ca2+ mobilization, potential Gi-mediated inhibition of adenylyl cyclase, and slower Ξ²-arrestinβdependent endosomal signaling; receptor desensitization and internalization are central regulators (hollenberg2015proteinasestheirreceptors pages 4-5). This framework aligns with the Ξ²-cell PLC/Ca2+ findings (hanzelmann2015thrombinstimulatesinsulin pages 8-11) and with general PAR signaling summaries emphasizing both G-protein and Ξ²-arrestin pathways (jakobschepolicht2025theroleof pages 6-8).
4) Expression patterns and subcellular localization (evidence-supported)
4.1 Subcellular localization (functional inference)
PARs, including PAR3, are cell-surface transmembrane receptors whose activation requires extracellular proteolysis; after activation they undergo internalization and can form endosomal signaling complexes via Ξ²-arrestin, providing a mechanistic basis for both plasma membrane and endosomal localization during signaling (hollenberg2015proteinasestheirreceptors pages 4-5, jakobschepolicht2025theroleof pages 6-8).
4.2 Cell-type/tissue expression highlighted in retrieved sources
- Platelets: Mouse platelet thrombin responsiveness depends on PAR3/PAR4 partnership (posma2019rolesofcoagulation pages 1-2, knauss2024plateletactivationin pages 70-76).
- Pancreatic islets/Ξ² cells: PAR3 activation modulates insulin secretion/exocytosis (hanzelmann2015thrombinstimulatesinsulin pages 8-11).
- Skin eosinophils (AD model): F2rl2/PAR3 expression changes with disease state and LN211 treatment (li2024guidedmonocytefate pages 10-12, li2024guidedmonocytefate media 243f02b7).
- Broad tissue distribution (review-level): PAR3 expression is summarized across multiple tissues (e.g., heart, kidney, pancreas, thymus, gut, lymphoid tissues, trachea) and cell types including airway smooth muscle and platelets (thibeault2020molecularmechanismsregulating pages 62-69).
5) Current applications and real-world implementations
5.1 Translational/therapeutic context: antiplatelet drug development and species differences
PAR biology is directly leveraged for antiplatelet strategies. An antiplatelet therapy review emphasizes that while PAR1 antagonism (e.g., vorapaxar) is clinically used, bleeding risk has motivated interest in alternative approaches including PAR4 targeting; however, development of selective PAR4 agents has been challenging (cunningham2016proteinaseactivatedreceptors(pars) pages 3-5, cunningham2016proteinaseactivatedreceptors(pars) pages 1-3). Because mouse platelets use PAR3/PAR4 whereas humans use PAR1/PAR4, the cofactor role of PAR3 in mouse models can confound translation of mouse thrombosis studies to humans, reinforcing the importance of receptor-system differences when interpreting preclinical data (knauss2024plateletactivationin pages 70-76, posma2019rolesofcoagulation pages 1-2).
5.2 Research implementation: mouse models disentangling coagulation proteases vs PARs in inflammation
A major review of mouse inflammatory disease models outlines how investigators use direct oral anticoagulants (DOACs) to inhibit FXa/thrombin and compare these effects with PAR-deficient mice; it highlights that thrombin activates PARs and that platelet PAR expression differs between species (mouse PAR3/PAR4 vs human PAR1/PAR4) (posma2019rolesofcoagulation pages 1-2). This supports real-world use of mouse genetics and anticoagulant pharmacology to test whether phenotypes arise from coagulation per se versus PAR-mediated cell signaling.
6) Statistics/data highlights from recent studies
Key quantitative results available in the retrieved evidence include:
- Eosinophil PAR3 change in AD niche biology (mouse, 2024): coculture with IL4/TGFΞ²3-treated macrophages reduced eosinophil PAR3 by β62 Β± 12%, and F2rl2 RNA-seq comparisons used n=4 mice per eosinophil source; intracellular flow cytometry coculture assay reported n=6 (li2024guidedmonocytefate pages 10-12).
- Ξ²-cell/islet functional signaling (mouse, 2015): thrombin 10 nM increased insulin secretion ~140% at 2 h; PAR3 agonist peptide 20 ΞΌM increased insulin secretion (~90% basal; ~130% high glucose), increased exocytosis (~70%) and increased intracellular Ca2+ ~2-fold; an antibody blocking the PAR3 cleavage site prevented thrombinβs effect (hanzelmann2015thrombinstimulatesinsulin pages 4-8, hanzelmann2015thrombinstimulatesinsulin pages 8-11).
- Species difference in platelet PAR3 levels (human vs mouse): human platelet PAR3 levels are described as low (~150β200 copies) relative to mouse platelet PAR3 expression, which is high and functionally important for PAR4 responses (knauss2024plateletactivationin pages 70-76).
7) Expert interpretation and limitations (evidence-based)
A central expert-level interpretation emerging from the sources is that PAR3 function is context-dependent:
- In mouse platelets, PAR3 is best supported as a thrombin-recruiting cofactor/modulator for PAR4 (and possibly an inter-PAR regulator) rather than an autonomous signaling receptor (knauss2024plateletactivationin pages 70-76, cunningham2016proteinaseactivatedreceptors(pars) pages 3-5, heuberger2019proteaseactivatedreceptors(pars) pages 1-3).
- In non-platelet tissues (e.g., islets), there is direct functional evidence for PAR3-dependent intracellular signaling via PLC/Ca2+/PKC with measurable secretory outcomes (hanzelmann2015thrombinstimulatesinsulin pages 8-11).
The retrieved evidence base is strong for activation mechanism, platelet cofactoring, and two well-supported biological contexts (platelets; islets; plus a recent eosinophil context), but it is comparatively limited here for broad mouse organ phenotypes of F2rl2 genetic perturbation and for a complete atlas of cell-type expression beyond the reported tissues and models.
Evidence map table (curation-ready)
| Aspect | Identity | Activation mechanism | Cleavage site / tethered ligand | Cofactor / heterodimer role with PAR4 | Downstream signaling evidence | Expression / cell types | Quantitative data | Key references |
|---|---|---|---|---|---|---|---|---|
| Mouse F2rl2 / PAR3 functional annotation | F2rl2 encodes protease-activated receptor 3 (PAR3), a thrombin receptor-like rhodopsin-family GPCR; literature retrieved for mouse aligns with UniProt O08675/PAR3 identity (hanzelmann2015thrombinstimulatesinsulin pages 4-8, knauss2024plateletactivationin pages 64-70) | Activated by irreversible proteolytic N-terminal cleavage, principally by thrombin; APC also reported as a PAR3-cleaving protease; synthetic PAR3 agonist peptides can mimic tethered-ligand activation in some systems (hanzelmann2015thrombinstimulatesinsulin pages 4-8, jakobschepolicht2025theroleof pages 6-8, knauss2024plateletactivationin pages 64-70) | Mouse PAR3 is reported cleaved at Lys38/Thr39, exposing tethered ligand sequence TFRGAPβ¦; HΓ€nzelmann et al. used PAR3-activating peptide SFNGGP, reflecting PAR3 tethered-ligand mimic activity in islets (thibeault2020molecularmechanismsregulating pages 62-69, knauss2024plateletactivationin pages 64-70, hanzelmann2015thrombinstimulatesinsulin pages 4-8) | On mouse platelets, PAR3 is best supported as a thrombin-binding cofactor/modulator for PAR4 rather than a robust autonomous signaling receptor; PAR3/PAR4 heterodimerization enhances thrombin cleavage of adjacent PAR4, with species difference vs humans (human platelets mainly PAR1/PAR4, low PAR3 ~150β200 copies) (knauss2024plateletactivationinb pages 70-76, knauss2024plateletactivationin pages 70-76, cunningham2016proteinaseactivatedreceptors(pars) pages 3-5, cunningham2016proteinaseactivatedreceptors(pars) pages 1-3, posma2019rolesofcoagulation pages 1-2) | In mouse islets/Ξ²-cells, PAR3 activation increases exocytosis and Ca2+ via GqβPLCβIP3/DAG, ER Ca2+ release, and PKC-sensitive signaling; broader PAR-family evidence supports GPCR, Ca2+, MAPK/ERK, Ξ²-arrestin/internalization paradigms, but direct platelet-autonomous PAR3 signaling remains weak/uncertain (hanzelmann2015thrombinstimulatesinsulin pages 8-11, jakobschepolicht2025theroleof pages 6-8, hollenberg2015proteinasestheirreceptors pages 4-5, knauss2024plateletactivationin pages 70-76) | Platelets; mouse islets/Ξ²-cells; eosinophils in skin/AD model; broader tissue distribution reported in heart, kidney, pancreas, thymus, small intestine, stomach, lymph node, trachea, airway smooth muscle (thibeault2020molecularmechanismsregulating pages 62-69, hanzelmann2015thrombinstimulatesinsulin pages 4-8, li2024guidedmonocytefate pages 10-12, li2024guidedmonocytefate pages 12-14) | Thrombin 10 nM increased insulin secretion ~140% at 2 h, 87% at 12 h, 29% at 24 h; PAR3-AP 20 ΞΌM increased insulin secretion ~90% at basal glucose and ~130% at high glucose; PAR3-AP increased Ξ²-cell exocytosis ~70% and intracellular Ca2+ ~2-fold; H103 antibody against PAR3 cleavage region blocked thrombin effect; in eosinophil coculture, PAR3 decreased by β62 Β± 12%; eosinophil RNA-seq source comparison used n=4 mice/source, intracellular-flow coculture assay n=6 (hanzelmann2015thrombinstimulatesinsulin pages 4-8, hanzelmann2015thrombinstimulatesinsulin pages 8-11, li2024guidedmonocytefate pages 10-12, li2024guidedmonocytefate pages 12-14) | HΓ€nzelmann et al., 2015, Islets, https://doi.org/10.1080/19382014.2015.1118195; Li et al., 2024, Cell. Mol. Life Sci., https://doi.org/10.1007/s00018-024-05543-2; Posma et al., 2019, ATVB, https://doi.org/10.1161/ATVBAHA.118.311655; Cunningham et al., 2016, Biochem. Soc. Trans., https://doi.org/10.1042/BST20150282 (hanzelmann2015thrombinstimulatesinsulin pages 4-8, hanzelmann2015thrombinstimulatesinsulin pages 8-11, li2024guidedmonocytefate pages 10-12, cunningham2016proteinaseactivatedreceptors(pars) pages 3-5, posma2019rolesofcoagulation pages 1-2) |
Table: This table summarizes core functional annotation for mouse F2rl2/PAR3, integrating identity, activation, platelet cofactor function with PAR4, signaling evidence, expression, and key quantitative findings from primary studies. It is useful as a compact evidence map for gene-function curation.
Visual evidence (recent mouse study)
Figure evidence for F2rl2/PAR3 expression modulation in eosinophils across conditions (AD and LN211 treatment), with intracellular flow cytometry quantification, is shown in the retrieved Figure 7F/7G region (li2024guidedmonocytefate media 243f02b7).
Key references (with publication dates and URLs)
- Li Y-T et al. Guided monocyte fate to FRΞ²/CD163+ S1 macrophage antagonises atopic dermatitis via fibroblastic matrices in mouse hypodermis. Cellular and Molecular Life Sciences (Dec 2024). https://doi.org/10.1007/s00018-024-05543-2 (li2024guidedmonocytefate pages 10-12, li2024guidedmonocytefate media 243f02b7)
- Knauss E. Platelet Activation in Venous Thrombosis is Driven by Protease Activated Receptor 4 (PAR4) (year 2024; source metadata incomplete in retrieved record). (knauss2024plateletactivationin pages 70-76)
- Posma JJ et al. Roles of Coagulation Proteases and PARs in Mouse Models of Inflammatory Diseases. ATVB (Jan 2019). https://doi.org/10.1161/ATVBAHA.118.311655 (posma2019rolesofcoagulation pages 1-2)
- Cunningham M et al. Proteinase-activated receptors (PARs) as targets for antiplatelet therapy. Biochemical Society Transactions (Apr 2016). https://doi.org/10.1042/BST20150282 (cunningham2016proteinaseactivatedreceptors(pars) pages 3-5, cunningham2016proteinaseactivatedreceptors(pars) pages 1-3)
- Heuberger DM, Schuepbach RA. PARs: mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thrombosis Journal (Mar 2019). https://doi.org/10.1186/s12959-019-0194-8 (heuberger2019proteaseactivatedreceptors(pars) pages 1-3)
- HΓ€nzelmann S et al. Thrombin stimulates insulin secretion via protease-activated receptor-3. Islets (Jul 2015). https://doi.org/10.1080/19382014.2015.1118195 (hanzelmann2015thrombinstimulatesinsulin pages 8-11)
- Hollenberg MD. Proteinases, their receptors and inflammatory signalling. British Journal of Pharmacology (Jul 2015). https://doi.org/10.1111/bph.13041 (hollenberg2015proteinasestheirreceptors pages 4-5)
References
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(hanzelmann2015thrombinstimulatesinsulin pages 4-8): Sonja HΓ€nzelmann, Jinling Wang, Emre GΓΌney, Yunzhao Tang, Enming Zhang, Annika S Axelsson, Hannah Nenonen, Albert S Salehi, Claes B Wollheim, Eva Zetterberg, Erik Berntorp, Ivan G Costa, Robert Castelo, and Anders H Rosengren. Thrombin stimulates insulin secretion via protease-activated receptor-3. Islets, 7:e1118195, Jul 2015. URL: https://doi.org/10.1080/19382014.2015.1118195, doi:10.1080/19382014.2015.1118195. This article has 30 citations and is from a peer-reviewed journal.
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(knauss2024plateletactivationin pages 64-70): E Knauss. Platelet activation in venous thrombosis is driven by protease activated receptor 4 (par4). Unknown journal, 2024.
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(hollenberg2015proteinasestheirreceptors pages 4-5): M D Hollenberg. Proteinases, their receptors and inflammatory signalling: the oxford south parks road connection. British Journal of Pharmacology, 172:3196-3211, Jul 2015. URL: https://doi.org/10.1111/bph.13041, doi:10.1111/bph.13041. This article has 7 citations and is from a highest quality peer-reviewed journal.
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(jakobschepolicht2025theroleof pages 6-8): Urszula Jakobsche-Policht, Agnieszka Bronowicka-SzydeΕko, Rajmund Adamiec, Dorota Bednarska-Chabowska, Magdalena MierzchaΕa-Pasierb, Εukasz Lewandowski, Kinga Gostomska-Pampuch, Joanna Adamiec-Mroczek, Maciej RabczyΕski, Edwin KuΕΊnik, PaweΕ Lubieniecki, Olgierd DrΓ³ΕΌdΕΌ, Helena Martynowicz, Anna KwiecieΕ, MaΕgorzata Strzelecka, Dawid Rudkiewicz, Marcin Piersiak, Maciej Ziomek, MikoΕaj Kondracki, Zuzanna GaliΕska, and Katarzyna Madziarska. The role of protease-activated receptors (pars) in the functioning of platelets and platelet-derived microparticles (pmps). Sep 2025. URL: https://doi.org/10.3389/fmolb.2025.1636893, doi:10.3389/fmolb.2025.1636893. This article has 2 citations.
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(thibeault2020molecularmechanismsregulating pages 62-69): PE Thibeault. Molecular mechanisms regulating the platelet thrombin receptor par4. Unknown journal, 2020.
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(knauss2024plateletactivationin pages 70-76): E Knauss. Platelet activation in venous thrombosis is driven by protease activated receptor 4 (par4). Unknown journal, 2024.
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(hanzelmann2015thrombinstimulatesinsulin pages 8-11): Sonja HΓ€nzelmann, Jinling Wang, Emre GΓΌney, Yunzhao Tang, Enming Zhang, Annika S Axelsson, Hannah Nenonen, Albert S Salehi, Claes B Wollheim, Eva Zetterberg, Erik Berntorp, Ivan G Costa, Robert Castelo, and Anders H Rosengren. Thrombin stimulates insulin secretion via protease-activated receptor-3. Islets, 7:e1118195, Jul 2015. URL: https://doi.org/10.1080/19382014.2015.1118195, doi:10.1080/19382014.2015.1118195. This article has 30 citations and is from a peer-reviewed journal.
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(li2024guidedmonocytefate pages 10-12): Yu-Tung Li, Eiichi Takaki, Yuya Ouchi, and Katsuto Tamai. Guided monocyte fate to frΞ²/cd163+ s1 macrophage antagonises atopic dermatitis via fibroblastic matrices in mouse hypodermis. Cellular and Molecular Life Sciences: CMLS, Dec 2024. URL: https://doi.org/10.1007/s00018-024-05543-2, doi:10.1007/s00018-024-05543-2. This article has 6 citations.
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(li2024guidedmonocytefate media 243f02b7): Yu-Tung Li, Eiichi Takaki, Yuya Ouchi, and Katsuto Tamai. Guided monocyte fate to frΞ²/cd163+ s1 macrophage antagonises atopic dermatitis via fibroblastic matrices in mouse hypodermis. Cellular and Molecular Life Sciences: CMLS, Dec 2024. URL: https://doi.org/10.1007/s00018-024-05543-2, doi:10.1007/s00018-024-05543-2. This article has 6 citations.
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(li2024guidedmonocytefate pages 12-14): Yu-Tung Li, Eiichi Takaki, Yuya Ouchi, and Katsuto Tamai. Guided monocyte fate to frΞ²/cd163+ s1 macrophage antagonises atopic dermatitis via fibroblastic matrices in mouse hypodermis. Cellular and Molecular Life Sciences: CMLS, Dec 2024. URL: https://doi.org/10.1007/s00018-024-05543-2, doi:10.1007/s00018-024-05543-2. This article has 6 citations.
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(cunningham2016proteinaseactivatedreceptors(pars) pages 3-5): Margaret Cunningham, Kathryn McIntosh, Trevor Bushell, Graeme Sloan, and Robin Plevin. Proteinase-activated receptors (pars) as targets for antiplatelet therapy. Biochemical Society transactions, 44 2:606-12, Apr 2016. URL: https://doi.org/10.1042/bst20150282, doi:10.1042/bst20150282. This article has 24 citations and is from a peer-reviewed journal.
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(posma2019rolesofcoagulation pages 1-2): Jens J. Posma, Steven P. Grover, Yohei Hisada, A. Phillip Owens, Silvio Antoniak, Henri M. Spronk, and Nigel Mackman. Roles of coagulation proteases and pars (protease-activated receptors) in mouse models of inflammatory diseases. Arteriosclerosis, Thrombosis, and Vascular Biology, 39:13β24, Jan 2019. URL: https://doi.org/10.1161/atvbaha.118.311655, doi:10.1161/atvbaha.118.311655. This article has 118 citations and is from a domain leading peer-reviewed journal.
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(heuberger2019proteaseactivatedreceptors(pars) pages 1-3): DM Heuberger and RA Schuepbach. Protease-activated receptors (pars): mechanisms of action and potential therapeutic modulators in par-driven inflammatory diseases. Thrombosis Journal, Mar 2019. URL: https://doi.org/10.1186/s12959-019-0194-8, doi:10.1186/s12959-019-0194-8. This article has 516 citations and is from a peer-reviewed journal.
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(cunningham2016proteinaseactivatedreceptors(pars) pages 1-3): Margaret Cunningham, Kathryn McIntosh, Trevor Bushell, Graeme Sloan, and Robin Plevin. Proteinase-activated receptors (pars) as targets for antiplatelet therapy. Biochemical Society transactions, 44 2:606-12, Apr 2016. URL: https://doi.org/10.1042/bst20150282, doi:10.1042/bst20150282. This article has 24 citations and is from a peer-reviewed journal.
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(knauss2024plateletactivationinb pages 70-76): E Knauss. Platelet activation in venous thrombosis is driven by protease activated receptor 4 (par4). Unknown journal, 2024.
Artifacts
Citations
- hollenberg2015proteinasestheirreceptors pages 4-5
- knauss2024plateletactivationin pages 70-76
- posma2019rolesofcoagulation pages 1-2
- hanzelmann2015thrombinstimulatesinsulin pages 8-11
- jakobschepolicht2025theroleof pages 6-8
- thibeault2020molecularmechanismsregulating pages 62-69
- li2024guidedmonocytefate pages 10-12
- hanzelmann2015thrombinstimulatesinsulin pages 4-8
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- https://doi.org/10.1161/ATVBAHA.118.311655
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- https://doi.org/10.1161/atvbaha.118.311655,
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