F2rl2 encodes proteinase-activated receptor 3 (PAR-3), a seven-transmembrane G protein-coupled receptor activated by thrombin-mediated proteolytic cleavage of its N-terminal extracellular domain. In mouse platelets, PAR3 does not independently mediate transmembrane signaling but instead functions as a cofactor that binds thrombin and promotes productive cleavage and activation of PAR4. PAR3-deficient mice are protected against thrombosis, demonstrating the in vivo importance of this cofactor function. The proteolytic cleavage of PAR3 exposes a tethered ligand peptide (SFNGGP) that can activate signaling through phospholipase C and Ca2+ release from intracellular stores, stimulating insulin secretion from pancreatic beta cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAR3 is a seven-transmembrane GPCR belonging to the rhodopsin-like family, with canonical GPCR architecture confirmed by InterPro domain analysis. Reason: PAR3 has the defining structural features of a GPCR (7TM rhodopsin-like domain, G protein coupling). Although mouse PAR3 acts primarily as a cofactor for PAR4 rather than signaling independently, it retains GPCR structure. Supporting Evidence: PMID:9087410 cloning and characterization of a new human thrombin receptor, designated protease-activated receptor 3 (PAR3). PAR3 can mediate thrombin-triggered phosphoinositide hydrolysis file:mouse/F2rl2/F2rl2-deep-research-bioreason-sft.md 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. file:mouse/F2rl2/F2rl2-deep-research-falcon.md The target is **mouse F2rl2 (Par3)** encoding **proteinase-activated receptor 3 (PAR3)**, a rhodopsin-like **7-transmembrane GPCR** activated by proteolysis |
| GO:0007186 G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAR3 participates in GPCR signaling, though in mouse platelets it acts primarily as a cofactor for PAR4 activation rather than signaling independently. Reason: PAR3 is part of the thrombin-PAR signaling cascade in mouse platelets. The PAR3 tethered ligand peptide also directly activates GPCR signaling in pancreatic beta cells via PLC and Ca2+ mobilization. Falcon deep research confirms the context-dependence - in mouse platelets PAR3 acts as a cofactor that does not itself signal, but in non-platelet contexts (islets) PAR3 activation engages a Gq-PLC-Ca2+/PKC module. Supporting Evidence: PMID:26742564 Treatment with a peptide corresponding to the PAR3 tethered ligand stimulated islet insulin secretion and single beta-cell exocytosis by a mechanism that involves activation of phospholipase C and Ca(2+) release from intracellular stores file:mouse/F2rl2/F2rl2-deep-research-falcon.md Pharmacology and Ca2+ imaging support signaling via **Gq β PLC β IP3/DAG**, with **Ca2+ release from intracellular stores** and involvement of **PKC** |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAR3 is a multi-pass integral membrane protein localized to the plasma membrane as annotated by UniProt. Reason: UniProt annotates PAR3 as a cell membrane multi-pass membrane protein with 7 transmembrane helices. Supporting Evidence: UniProtKB:O08675 Cell membrane; Multi-pass membrane protein. file:mouse/F2rl2/F2rl2-deep-research-falcon.md 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 |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based annotation consistent with rhodopsin-like GPCR domain architecture. Reason: PAR3 contains IPR000276 (rhodopsin-like GPCR) and IPR017452 (GPCR 7TM domain). Supporting Evidence: UniProtKB:O08675 Belongs to the G-protein coupled receptor 1 family. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping confirms plasma membrane localization. Reason: Consistent with multi-pass membrane protein topology. Supporting Evidence: UniProtKB:O08675 Cell membrane; Multi-pass membrane protein. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based annotation for GPCR signaling pathway participation. Reason: Consistent with GPCR family membership and documented signaling functions. Supporting Evidence: UniProtKB:O08675 High affinity receptor for activated thrombin coupled to G proteins that stimulate phosphoinositide hydrolysis. |
| GO:0007596 blood coagulation | IEA GO_REF:0000002 | ACCEPT | Summary: PAR3 has a well-documented role in hemostasis via its cofactor function for PAR4 on mouse platelets. Reason: Par3-/- mice are protected against thrombosis, confirming a functional role in coagulation. PAR3 promotes thrombin-mediated activation of PAR4 on platelets. Supporting Evidence: PMID:12384423 Par3(-/-) mice were protected against ferric chloride-induced thrombosis of mesenteric arterioles and against thromboplastin-induced pulmonary embolism file:mouse/F2rl2/F2rl2-deep-research-falcon.md 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 |
| GO:0015057 thrombin-activated receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: PAR3 is directly cleaved and activated by thrombin at its N-terminal extracellular domain. Reason: Thrombin cleaves PAR3 between residues 37-38 to expose the tethered ligand peptide. This is the defining feature of thrombin-activated receptors. Supporting Evidence: PMID:9087410 cloning and characterization of a new human thrombin receptor, designated protease-activated receptor 3 (PAR3). PAR3 can mediate thrombin-triggered phosphoinositide hydrolysis PMID:26742564 We treated mouse islets with the 6-aa PAR3-activating peptide (PAR3-AP;SFNGGP) |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Generic membrane annotation; plasma membrane is more specific. Reason: PAR3 is a multi-pass membrane protein, but the plasma membrane annotation is more informative. This broader term is retained as non-core. Supporting Evidence: UniProtKB:O08675 Cell membrane; Multi-pass membrane protein. |
| GO:0070493 thrombin-activated receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: PAR3 participates in thrombin-activated receptor signaling as a cofactor for PAR4 activation on mouse platelets. Reason: PAR3 is essential for efficient thrombin signaling at low thrombin concentrations in mouse platelets, functioning as a cofactor for PAR4. Supporting Evidence: PMID:10766244 mPAR3 does not itself mediate transmembrane signalling but instead functions as a cofactor for the cleavage and activation of mPAR4 by thrombin file:mouse/F2rl2/F2rl2-deep-research-falcon.md PAR3 itself is stated to **not mediate signal transduction upon thrombin cleavage**, instead acting as a **cofactor enabling PAR4 signaling** |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from human PAR3 (O00254). PAR3 forms constitutive homodimers and heterodimers with PAR4. Reason: BRET experiments demonstrate that PAR3 forms constitutive homodimers and heterodimers with PAR4 on mouse platelets. Supporting Evidence: PMID:23405206 PAR3 and PAR4 form constitutive homodimers and heterodimers PMID:23405206 PAR3 negatively regulates PAR4-mediated maximum Ca(2+) mobilization and PKC activation in mouse platelets by physical interaction |
| GO:0032991 protein-containing complex | ISO GO_REF:0000119 | ACCEPT | Summary: Ortholog-based transfer from human PAR3. Consistent with PAR3-PAR4 complex formation. Reason: PAR3 forms complexes with PAR4 as demonstrated by BRET in mouse platelets. Supporting Evidence: PMID:23405206 PAR3 and PAR4 form constitutive homodimers and heterodimers |
| GO:0001648 proteinase-activated receptor activity | IGI PMID:26742564 Thrombin stimulates insulin secretion via protease-activated... | ACCEPT | Summary: IGI annotation from PMID:26742564 showing PAR3 receptor activity in context of thrombin-mediated insulin secretion, with F2r (PAR1, MGI:88380) as the interacting gene. Reason: PAR3 activation by thrombin and the PAR3-activating peptide stimulates insulin secretion via PLC and Ca2+ signaling. The IGI evidence involves interaction with PAR1 in the signaling context. Supporting Evidence: PMID:26742564 thrombin stimulates insulin secretion, an effect that was prevented by an antibody that blocks the thrombin cleavage site of PAR3 file:mouse/F2rl2/F2rl2-deep-research-falcon.md 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 |
| GO:0007186 G protein-coupled receptor signaling pathway | IDA PMID:26742564 Thrombin stimulates insulin secretion via protease-activated... | ACCEPT | Summary: Direct assay showing PAR3 tethered ligand peptide activates GPCR signaling (PLC activation, Ca2+ release) in mouse islets. Reason: PAR3-AP (SFNGGP) stimulates insulin secretion via Gq-PLC-IP3-Ca2+ pathway, demonstrating GPCR signaling activity. Supporting Evidence: PMID:26742564 the stimulatory effect of PAR3-AP was abolished in the presence of U73122 |
| GO:0007186 G protein-coupled receptor signaling pathway | IGI PMID:26742564 Thrombin stimulates insulin secretion via protease-activated... | ACCEPT | Summary: IGI annotation with F2r (PAR1) as interacting gene for GPCR signaling. Reason: PAR3 signaling in the insulin secretion context involves interaction with other PARs, consistent with the known PAR crosstalk mechanisms. Supporting Evidence: PMID:26742564 Treatment with a peptide corresponding to the PAR3 tethered ligand stimulated islet insulin secretion and single beta-cell exocytosis by a mechanism that involves activation of phospholipase C and Ca(2+) release from intracellular stores |
| GO:0048018 receptor ligand activity | IDA PMID:26742564 Thrombin stimulates insulin secretion via protease-activated... | ACCEPT | Summary: PAR3 tethered ligand peptide (SFNGGP) acts as an agonist that activates signaling. After proteolytic cleavage, the new N-terminus functions as an intrinsic receptor ligand. Reason: The PAR3-activating peptide (corresponding to the tethered ligand exposed after thrombin cleavage) directly stimulates insulin secretion and exocytosis, demonstrating receptor ligand activity. Supporting Evidence: PMID:26742564 PAR3 is cleaved by thrombin, which exposes a 6-amino acid sequence that acts as a βtethered ligandβ to regulate cellular signaling |
| GO:0016324 apical plasma membrane | IDA PMID:16892058 The Rho-GTPase cdc42 regulates neural progenitor fate at the... | UNDECIDED | Summary: Cannot be adjudicated here: PMID:16892058 is cached abstract-only. Prior observation, not a verdict: This annotation appears to be erroneous. PMID:16892058 (Cappello et al., 2006) studies the Rho-GTPase Cdc42 and neural progenitor fate. The paper discusses the "Par complex" (aPKC-Par3-Par6) at the apical surface, but this refers to the cell polarity protein PARD3, not the thrombin receptor F2rl2/PAR3. The two proteins share the name "Par3" but are entirely different genes. Reason: PMID:16892058 is cached abstract-only, so the curator's experimental evidence cannot be inspected here; per CLAUDE.md an experimental annotation is not overruled on that basis. Recorded observation, not a verdict: PMID:16892058 does not study F2rl2 (thrombin receptor PAR3). The "Par3" referenced in this paper is the cell polarity protein Pard3 (Q99NH2). This annotation appears to result from a gene name confusion between PAR3/PARD3 (polarity) and PAR3/F2rl2 (thrombin receptor). Supporting Evidence: PMID:16892058 the apical location of the Par complex and adherens junctions are gradually lost |
| GO:0032024 positive regulation of insulin secretion | IDA PMID:26742564 Thrombin stimulates insulin secretion via protease-activated... | NEW | Summary: PAR3-activating peptide (SFNGGP) stimulates insulin secretion from mouse islets by 90% at basal glucose and 130% at high glucose, via PLC and Ca2+ release from intracellular stores. Reason: PMID:26742564 directly demonstrates that the PAR3 tethered ligand stimulates insulin secretion from mouse islets. This is a novel annotation not currently present in GOA for F2rl2. Supporting Evidence: PMID:26742564 PAR3-AP stimulated insulin secretion by 90% at basal glucose... Moreover, PAR3-AP stimulated insulin secretion by 130% at high glucose file:mouse/F2rl2/F2rl2-deep-research-falcon.md 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%**) |
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Download this section (compressed HTML)Q: Is the GO annotation of F2rl2 to apical plasma membrane (GO:0016324) based on PMID:16892058 a case of gene name confusion with the cell polarity protein PARD3? Should this annotation be removed from F2rl2?
Suggested experts: Cappello S
Q: Are the UniProt-annotated protein interactions of O08675 with INSC and GPSM2 (citing PMID:16094321) actually interactions of the cell polarity protein PARD3 rather than the thrombin receptor F2rl2?
Suggested experts: Lechler T, Fuchs E
Experiment: Test the effect of PAR3-activating peptide on insulin secretion from Par4-/- mouse islets to determine whether PAR3 tethered ligand signaling in beta cells is PAR4-independent. Combine with siRNA knockdown of PAR3 itself to confirm specificity.
Hypothesis: Mouse PAR3 tethered ligand peptide acts on beta cells independently of PAR4, via a distinct GPCR signaling mechanism.
Experiment: Use peptide competition assays or domain-swap chimeras between mouse and human PAR3 to map the cofactor interaction surface between PAR3 and PAR4 that enables thrombin presentation. This could clarify the species-specific difference in PAR3 signaling.
Hypothesis: The PAR3 cofactor function for PAR4 involves specific extracellular domain interactions that could be disrupted by targeted peptides.
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