{"gene":"FPR3","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":1994,"finding":"Yeast Fpr3 (FPR3 gene product) is a peptidylprolyl cis-trans isomerase (PPIase) localized exclusively to the nucleolus; both full-length Fpr3 and its isolated C-terminal FKBP domain exhibit PPIase activity in vitro, and the protein binds FK506 and rapamycin.","method":"Purification from E. coli, PPIase activity assay, indirect immunofluorescence localization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with domain dissection, confirmed by two independent groups (PMID:7525596 and PMID:7925954)","pmids":["7525596","7925954"],"is_preprint":false},{"year":1995,"finding":"Yeast Fpr3 is phosphorylated on Tyr-184 by endogenous kinases and is a direct physiological substrate of the tyrosine phosphatase Ptp1; immobilized phosphotyrosyl Fpr3 is dephosphorylated by recombinant Ptp1 in vitro, and the phosphorylation site was confirmed by site-directed mutagenesis.","method":"Protein purification, in vitro phosphatase assay, site-directed mutagenesis, ptp1 mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis identifying the exact phosphosite, confirmed in vivo by genetic correlation","pmids":["7559654"],"is_preprint":false},{"year":1997,"finding":"Casein kinase II (CKII) phosphorylates yeast Fpr3 at Tyr-184 and Ser-186 both in vitro and in vivo; phosphorylation at Tyr-184 by CKII occurs via a two-step mechanism where prior phosphorylation at Ser-186 (position +2) provides a specificity determinant for subsequent tyrosine phosphorylation.","method":"In vitro kinase assay with purified yeast and human CKII, metabolic phospholabeling, temperature-sensitive CKII allele, overexpression of heterologous CKII","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with synthetic peptide substrates and mutagenesis, corroborated in vivo by genetic manipulation of CKII","pmids":["9148902"],"is_preprint":false},{"year":1999,"finding":"CK2 can phosphorylate a tyrosyl residue (Tyr-184) in Fpr3 using partially distinct structural determinants compared to Ser/Thr phosphorylation; the surrounding sequence DEDADIY(184)DEEDYDL allows CK2 tyrosine phosphorylation but with much higher Km and lower Vmax than the equivalent serine-containing peptide.","method":"In vitro kinase assay with synthetic peptide substrates and site-substitution variants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with systematic peptide mutagenesis, single lab but multiple peptide variants tested","pmids":["10506183"],"is_preprint":false},{"year":2001,"finding":"Human FPR3 (FPRL2) functions as a G protein-coupled chemoattractant receptor on monocytes; it is activated by the synthetic hexapeptides WKYMVm and WKYMVm (l-conformer) to mobilize calcium and drive chemotaxis in HL-60-FPRL2 transfected cells; FPR3 is constitutively phosphorylated in resting cells and both conformers induce receptor internalization.","method":"Calcium flux assay in transfected HL-60 cells, chemotaxis assay, radioligand binding (125I-WKYMVm), metabolic phospholabeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (calcium, chemotaxis, binding, phosphorylation) in receptor-transfected cells","pmids":["11285256"],"is_preprint":false},{"year":2004,"finding":"F2L, an acetylated N-terminal peptide derived from cleavage of human heme-binding protein, is a specific endogenous agonist of FPR3 (FPRL2); F2L binds and activates FPR3 in the low nanomolar range, triggering intracellular calcium release, inhibition of cAMP accumulation, ERK1/2 phosphorylation via Gi proteins, and chemotaxis of monocytes and dendritic cells.","method":"Peptide isolation from spleen extract, radioligand competition binding, calcium mobilization assay, cAMP assay, ERK phosphorylation assay, chemotaxis assay, Gi inhibition with pertussis toxin","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — natural ligand isolated and reconstituted with multiple orthogonal signaling assays; Gi coupling confirmed pharmacologically","pmids":["15623572"],"is_preprint":false},{"year":2004,"finding":"Yeast Fpr3 interacts with and is dephosphorylated by the LMW-PTP Stp1 in vivo; Fpr3 dephosphorylation by Stp1, synergized with CK2 inhibition, induces a severe growth-defective phenotype.","method":"In vivo co-immunoprecipitation, yeast genetics, CK2 inhibitor treatment","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, Co-IP plus genetic/pharmacological evidence, two orthogonal approaches","pmids":["15141303"],"is_preprint":false},{"year":2004,"finding":"The LMW-PTP Ltp1 dephosphorylates yeast Fpr3 at Tyr-184 in vivo; tyrosine phosphorylation state of Fpr3 influences its subcellular localization.","method":"In vivo phosphorylation analysis, site identification, localization assay in ltp1 mutants","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single method per claim; phosphosite confirmed but localization mechanistic link is partial","pmids":["15358193"],"is_preprint":false},{"year":2005,"finding":"Yeast Fpr3 maintains meiotic recombination checkpoint activity by interacting with protein phosphatase 1 (PP1) through its PPIase domain, regulating PP1 localization and counteracting PP1 activity; fpr3 deletion or rapamycin treatment (which binds the PPIase domain) causes premature adaptation to checkpoint-activating damage.","method":"Genetic deletion analysis, epistasis, rapamycin treatment, co-immunoprecipitation of Fpr3-PP1 interaction, PP1 localization by microscopy","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and biochemical evidence (Co-IP, localization, rapamycin domain-specific inhibition, epistasis) in multiple genetic backgrounds","pmids":["16179256"],"is_preprint":false},{"year":2002,"finding":"Human FPR3 (FPRL2) protein is expressed on both immature and mature dendritic cells; WKYMVm-induced FPR3 internalization occurs in both DC types, and mature DCs—which lack other FPR family members—respond to WKYMVm exclusively through FPR3.","method":"RT-PCR, protein expression analysis, calcium mobilization assay, receptor internalization assay using receptor-bound antibody uptake","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — expression plus functional internalization assay; attribution to FPR3 relies on absence of other receptors in mature DCs","pmids":["12223529"],"is_preprint":false},{"year":2009,"finding":"Yeast Fpr3 and the SUMO ligase Zip3 function in parallel pathways to ensure that synaptonemal complex (SC) assembly is contingent on recombination initiation; in fpr3 zip3 double mutants, synapsis occurs even without recombination initiation, and Fpr3 specifically prevents premature SC initiation at centromeric sites.","method":"Genetic epistasis using fpr3, zip3 double mutants combined with recombination-initiation mutants; cytological analysis of SC assembly","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with multiple double and triple mutant combinations and cytological readouts","pmids":["19765989"],"is_preprint":false},{"year":2011,"finding":"Human FPR3 undergoes constitutive internalization in unstimulated cells that is independent of C-terminus phosphorylation; the N-terminal extracellular region and first transmembrane domain (residues 1–53) determine intracellular vesicular localization, and constitutive internalization proceeds via a clathrin-independent, possibly caveolae-dependent mechanism. FPR3 also displays basal phosphorylation that is only slightly increased upon agonist stimulation, unlike FPR2/ALX.","method":"Chimeric receptor domain-swap experiments, receptor-bound antibody uptake assay, clathrin/caveolae inhibitor treatment, phosphorylation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic domain-swap mutagenesis combined with multiple orthogonal functional assays (internalization, phosphorylation, inhibitor pharmacology)","pmids":["21543323"],"is_preprint":false},{"year":2014,"finding":"Yeast Fpr3 proline isomerase activity is required for proteolysis of the centromeric histone H3 variant Cse4; Fpr3-mediated structural change in Cse4 is proposed to facilitate Cse4 interaction with the E3 ubiquitin ligase Psh1, leading to polyubiquitylation and proteasome-dependent degradation.","method":"Genetic deletion (fpr3 mutant), co-immunoprecipitation of Cse4-Psh1 interaction, ubiquitylation assay","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — genetic evidence with Co-IP; mechanistic interpretation of isomerase activity requirement is partially inferred from genetic data","pmids":["24514906"],"is_preprint":false},{"year":2000,"finding":"The N-terminal acidic domain (~170 residues) of yeast Fpr3 (not its PPIase domain) is sufficient to suppress temperature-sensitive growth and mating defects of tom1 (E3 ubiquitin ligase) deletion strains when overexpressed, placing Fpr3 in a functional relationship with ubiquitin-mediated pathways.","method":"Multicopy suppression screen, domain deletion/truncation analysis, genetic epistasis","journal":"Molecular & general genetics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain dissection with multiple genetic controls showing suppression specificity","pmids":["10821187"],"is_preprint":false},{"year":2019,"finding":"Mouse Fpr3 (Fpr-rs1), expressed in vomeronasal sensory neurons, recognizes the bacterial peptide motif f-MKKFRW derived from the MgrB signal sequence of Enterobacteriaceae; Fpr3 is required for neuronal detection of this peptide and for innate avoidance behavior in freely behaving mice.","method":"Vomeronasal neuron calcium imaging, Fpr3 knockout mouse behavioral assay (avoidance), peptide specificity testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined behavioral phenotype, combined with neuronal activation assay and peptide specificity characterization","pmids":["31653840"],"is_preprint":false},{"year":2022,"finding":"FPR3 overexpression in fibroblasts activates the PKA/Rap1/ERK1/2 axis to promote cell viability and myofibroblast transformation, and phosphorylates IκB to reduce NF-κB inhibition, increasing secretion of IL-1β, TNF-α, and IL-6, thereby driving capsular contracture.","method":"Western blot, qRT-PCR, CCK-8 viability assay, wound healing migration assay, ELISA for cytokines","journal":"Tissue & cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression only, pathway assignments based on downstream marker measurements without direct pathway reconstitution","pmids":["36527787"],"is_preprint":false},{"year":2024,"finding":"FPR3 suppresses glycolytic capacity and stemness in gastric cancer cells by impeding cytoplasmic calcium flux, which prevents NFATc1 nuclear translocation, reducing NFATc1-driven transcription of NOTCH3 and SOX2 and suppressing AKT/mTORC1 signaling.","method":"FPR3 overexpression/knockdown, calcium flux measurement, NFATc1 nuclear translocation assay, chromatin/promoter binding assay, Western blot for pathway components","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple downstream readouts with both gain- and loss-of-function, but pathway intermediates confirmed by reporter/binding assays rather than reconstitution","pmids":["38614385"],"is_preprint":false},{"year":2025,"finding":"FPR3 in tumor-associated macrophages upregulates FZD7 and CCDC88C, activating the Wnt/PCP pathway and downstream JNK signaling to promote macrophage proliferation, immunosuppressive polarization, and TAM maintenance in gastric adenocarcinoma.","method":"shRNA knockdown, FPR3 agonist treatment, gene expression analysis, pathway inhibition","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, shRNA knockdown with pathway marker measurements; no direct reconstitution or epistasis for Wnt/PCP assignment","pmids":["40987893"],"is_preprint":false}],"current_model":"FPR3 encodes two functionally distinct proteins sharing the symbol: (1) human FPR3 (also FPRL2/FPRH1), a G protein-coupled chemoattractant receptor on monocytes and dendritic cells that couples through Gi to calcium mobilization, ERK1/2 activation, and chemotaxis in response to its specific endogenous agonist F2L (a peptide from heme-binding protein), undergoes constitutive clathrin-independent internalization driven by its N-terminal/TM1 domain, and displays constitutive basal phosphorylation; (2) yeast Fpr3, a nucleolar FK506/rapamycin-binding protein with PPIase activity that is phosphorylated at Tyr-184 by CK2 and dephosphorylated by Ptp1/Ltp1/Stp1, interacts with PP1 through its PPIase domain to maintain meiotic recombination checkpoint activity by controlling PP1 localization, and also regulates centromeric histone Cse4 proteolysis and ensures that chromosome synapsis is contingent on recombination initiation."},"narrative":{"mechanistic_narrative":"The FPR3 symbol denotes two unrelated proteins, and the timeline coherently resolves both. In the human and rodent literature, FPR3 is a Gi-coupled G protein-coupled chemoattractant receptor of myeloid cells: it is activated by the synthetic hexapeptide WKYMVm and by its specific endogenous agonist F2L (an acetylated N-terminal peptide from heme-binding protein), driving intracellular calcium mobilization, inhibition of cAMP, ERK1/2 phosphorylation, and chemotaxis of monocytes and dendritic cells [PMID:11285256, PMID:15623572]. The receptor is expressed on both immature and mature dendritic cells and is the exclusive WKYMVm responder in mature DCs [PMID:12223529]. FPR3 displays constitutive basal phosphorylation that is only marginally increased by agonist, and it undergoes constitutive, clathrin-independent (caveolae-associated) internalization directed by its N-terminal/TM1 region rather than C-terminal phosphorylation [PMID:11285256, PMID:21543323]. In olfaction, mouse Fpr3 acts in vomeronasal sensory neurons as a detector of the bacterial peptide motif f-MKKFRW and is required for innate avoidance behavior [PMID:31653840]. In contrast, yeast Fpr3 is a nucleolar FK506/rapamycin-binding peptidylprolyl cis-trans isomerase (PPIase) whose C-terminal FKBP domain carries the isomerase activity [PMID:7525596, PMID:7925954]. Through its PPIase domain it binds protein phosphatase 1 (PP1) to control PP1 localization and sustain the meiotic recombination checkpoint, such that fpr3 deletion or rapamycin causes premature checkpoint adaptation [PMID:16179256]. Fpr3 acts in parallel with the SUMO ligase Zip3 to make synaptonemal complex assembly contingent on recombination initiation, preventing premature synapsis at centromeres [PMID:19765989], and its isomerase activity promotes Psh1-dependent proteolysis of the centromeric histone variant Cse4 [PMID:24514906]. Yeast Fpr3 is phosphorylated at Tyr-184 (and Ser-186) by casein kinase II through a two-step ordered mechanism and is dephosphorylated by the LMW tyrosine phosphatases Ptp1, Ltp1, and Stp1, with phosphorylation state influencing its localization [PMID:7559654, PMID:9148902, PMID:15358193].","teleology":[{"year":1994,"claim":"Established the biochemical identity of yeast Fpr3 as a nucleolar PPIase, distinguishing it from the unrelated mammalian receptor sharing the symbol.","evidence":"Recombinant purification, in vitro PPIase activity assay with domain dissection, and immunofluorescence localization","pmids":["7525596","7925954"],"confidence":"High","gaps":["In vitro substrates of the PPIase activity not defined","Function of the N-terminal acidic domain not addressed"]},{"year":1995,"claim":"Identified Fpr3 as an in vivo tyrosine-phosphorylated protein and a physiological substrate of the phosphatase Ptp1, opening the question of its regulatory phospho-cycle.","evidence":"Protein purification, in vitro phosphatase assay, and site-directed mutagenesis mapping Tyr-184 in ptp1 mutants","pmids":["7559654"],"confidence":"High","gaps":["Kinase responsible not yet identified","Functional consequence of Tyr-184 phosphorylation unknown"]},{"year":1997,"claim":"Resolved the kinase and mechanism of Fpr3 phosphorylation, showing CKII phosphorylates Tyr-184 via an ordered process primed by Ser-186.","evidence":"In vitro kinase assays with purified CKII, metabolic phospholabeling, and temperature-sensitive CKII alleles","pmids":["9148902","10506183"],"confidence":"High","gaps":["Cellular trigger for CKII phosphorylation of Fpr3 unknown","Downstream effect of dual phosphorylation on PPIase function not established"]},{"year":2000,"claim":"Placed the Fpr3 N-terminal acidic domain in a functional relationship with ubiquitin-mediated pathways, distinct from its catalytic PPIase domain.","evidence":"Multicopy suppression of tom1 E3 ligase deletion phenotypes with domain truncation analysis","pmids":["10821187"],"confidence":"Medium","gaps":["Direct biochemical link between Fpr3 and Tom1 not shown","Mechanism of suppression unresolved"]},{"year":2001,"claim":"Defined human FPR3 (FPRL2) as a functional GPCR chemoattractant receptor on monocytes activated by WKYMVm.","evidence":"Calcium flux, chemotaxis, radioligand binding, and phospholabeling in receptor-transfected HL-60 cells","pmids":["11285256"],"confidence":"High","gaps":["Endogenous agonist not yet identified","G protein coupling not directly demonstrated"]},{"year":2002,"claim":"Showed FPR3 is the exclusive WKYMVm-responsive receptor on mature dendritic cells, indicating a role in DC signaling.","evidence":"RT-PCR, calcium mobilization, and antibody-uptake internalization in immature and mature DCs","pmids":["12223529"],"confidence":"Medium","gaps":["Attribution relies on absence of other FPRs rather than direct knockout","Physiological agonist in DCs not defined"]},{"year":2004,"claim":"Identified F2L as the specific endogenous agonist of FPR3 and established Gi coupling to calcium, cAMP, and ERK signaling.","evidence":"Peptide isolation from spleen, competition binding, calcium/cAMP/ERK assays, chemotaxis, and pertussis toxin block","pmids":["15623572"],"confidence":"High","gaps":["Physiological context of F2L generation not defined","Structural basis of F2L recognition unknown"]},{"year":2004,"claim":"Extended the Fpr3 phospho-regulatory network to additional LMW phosphatases and linked phospho-state to localization.","evidence":"In vivo co-immunoprecipitation, ltp1/stp1 mutant phospho- and localization analysis, and CK2 inhibitor synergy","pmids":["15141303","15358193"],"confidence":"Medium","gaps":["Single-lab Co-IP evidence for Stp1 interaction","Mechanistic link between Tyr-184 phosphorylation and localization only partial"]},{"year":2005,"claim":"Defined a meiotic role for Fpr3, showing its PPIase domain binds PP1 to control PP1 localization and sustain the recombination checkpoint.","evidence":"Genetic deletion, epistasis, rapamycin domain-specific inhibition, Fpr3-PP1 Co-IP, and PP1 localization microscopy","pmids":["16179256"],"confidence":"High","gaps":["PPIase substrate within the checkpoint not identified","How rapamycin binding disrupts PP1 interaction structurally unresolved"]},{"year":2009,"claim":"Established that Fpr3 acts in parallel with Zip3 to couple synaptonemal complex assembly to recombination initiation, preventing premature centromeric synapsis.","evidence":"Genetic epistasis with fpr3 zip3 double/triple mutants and cytological SC analysis","pmids":["19765989"],"confidence":"High","gaps":["Molecular target of Fpr3 at centromeres unknown","Relationship to PP1 checkpoint role not integrated"]},{"year":2011,"claim":"Showed human FPR3 internalizes constitutively via a clathrin-independent mechanism driven by its N-terminus/TM1, distinct from C-terminal phosphorylation-driven receptors.","evidence":"Chimeric domain-swap, antibody-uptake internalization, clathrin/caveolae inhibitor pharmacology, and phosphorylation analysis","pmids":["21543323"],"confidence":"High","gaps":["Exact endocytic adaptor not identified","Functional significance of constitutive internalization unclear"]},{"year":2014,"claim":"Linked Fpr3 PPIase activity to centromeric chromatin turnover through promotion of Cse4 proteolysis.","evidence":"fpr3 deletion, Cse4-Psh1 Co-IP, and ubiquitylation assays","pmids":["24514906"],"confidence":"Medium","gaps":["Direct isomerization of Cse4 by Fpr3 not demonstrated","Mechanism inferred from genetic and Co-IP data"]},{"year":2019,"claim":"Defined a sensory role for mouse Fpr3 as a vomeronasal detector of a bacterial peptide motif driving innate avoidance.","evidence":"Vomeronasal neuron calcium imaging, Fpr3 knockout behavioral assay, and peptide specificity testing","pmids":["31653840"],"confidence":"High","gaps":["Downstream signaling in VSNs not detailed","Relationship to myeloid FPR3 signaling not addressed"]},{"year":2024,"claim":"Assigned a tumor-suppressive signaling role to FPR3 via calcium/NFATc1 control of stemness and glycolysis in gastric cancer.","evidence":"FPR3 gain/loss-of-function, calcium flux, NFATc1 translocation, promoter binding, and pathway Western blots","pmids":["38614385"],"confidence":"Medium","gaps":["Pathway intermediates not reconstituted","Ligand driving this signaling in tumor cells not defined"]},{"year":null,"claim":"How the constitutively internalizing, Gi-coupled human receptor and the nucleolar yeast PPIase relate functionally, and whether human FPR3 signaling outputs in disease contexts are driven by defined endogenous agonists, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Disease-context FPR3 pathway claims rest on overexpression in single labs","No structural data on either protein in the timeline","PPIase substrate spectrum of yeast Fpr3 undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[0,8,12]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,5,14]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[5,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,9,11]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,9]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[8,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,10,12]}],"complexes":[],"partners":["PP1","PSH1","CSE4","PTP1","LTP1","STP1","ZIP3","CK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P25089","full_name":"N-formyl peptide receptor 3","aliases":["FMLP-related receptor II","FMLP-R-II","Formyl peptide receptor-like 2"],"length_aa":353,"mass_kda":40.0,"function":"May function as a pattern recognition G-protein coupled receptor (PRR/GPCR) involved in innate recognition of peptides derived from a specific set of bacterial pathogens or host mitochondria as pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) (PubMed:24108355, PubMed:25605714). Low affinity receptor for a restricted repertoire of bacterial N-formylated peptides including fMKKIML from L. monocytogenes and fMPKLNR from V. cholerae. Contrary to FPR1 and FPR2 does not act as a receptor for fMLF peptide (PubMed:15187149, PubMed:25605714). High affinity receptor for N-acetylated F2L peptide derived from the cleavage of heme-binding protein HEBP1. F2L peptide binding may trigger chemotaxis of monocytes and dendritic cells to facilitate tissue repair (PubMed:15623572). Low affinity receptor for N-acetylated Ac2-26 peptide derived from ANXA1, an anti-inflammatory and pro-resolving agonist. Ac2-26 peptide binding can direct myeloid cell chemotaxis within the inflammatory site where ANXA1 is at high concentrations, but it can also lead to receptor desensitization to limit the inflammatory response (PubMed:15187149). Receptor for MT-RNR2/humanin, a mitochondrial-derived peptide that has an anti-inflammatory role in resolution of inflammation (PubMed:15465011). Peptide binding leads to conformational changes coupled to heterotrimeric G(i) protein signaling. Upon GDP to GTP conversion, G(i)-alpha subunit dissociates from G-beta and G-gamma subunits. Free G(i)-alpha subunit inhibits cyclic adenylate cyclase and cAMP synthesis whereas the G-beta and G-gamma dimer activates downstream phospholipase C-beta and phosphoinositide 3-kinase signaling cascades leading to Ca(2+) influx (PubMed:15187149, PubMed:15465011, PubMed:15623572, PubMed:25605714)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P25089/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FPR3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FPR3","total_profiled":1310},"omim":[{"mim_id":"605826","title":"HEME-BINDING PROTEIN 1; HEBP1","url":"https://www.omim.org/entry/605826"},{"mim_id":"136539","title":"FORMYL PEPTIDE RECEPTOR 3; FPR3","url":"https://www.omim.org/entry/136539"},{"mim_id":"136538","title":"FORMYL PEPTIDE RECEPTOR 2; FPR2","url":"https://www.omim.org/entry/136538"},{"mim_id":"136537","title":"FORMYL PEPTIDE RECEPTOR 1; FPR1","url":"https://www.omim.org/entry/136537"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":26.6}],"url":"https://www.proteinatlas.org/search/FPR3"},"hgnc":{"alias_symbol":["FPRH1","FMLPY","RMLP-R-I"],"prev_symbol":["FPRL2"]},"alphafold":{"accession":"P25089","domains":[{"cath_id":"1.20.1070.10","chopping":"19-314","consensus_level":"medium","plddt":91.0183,"start":19,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25089","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25089-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25089-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FPR3","jax_strain_url":"https://www.jax.org/strain/search?query=FPR3"},"sequence":{"accession":"P25089","fasta_url":"https://rest.uniprot.org/uniprotkb/P25089.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25089/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25089"}},"corpus_meta":[{"pmid":"11285256","id":"PMC_11285256","title":"The synthetic peptide Trp-Lys-Tyr-Met-Val-Met-NH2 specifically activates neutrophils through FPRL1/lipoxin A4 receptors and is an agonist for the orphan monocyte-expressed chemoattractant receptor FPRL2.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11285256","citation_count":157,"is_preprint":false},{"pmid":"1612600","id":"PMC_1612600","title":"Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19.","date":"1992","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1612600","citation_count":115,"is_preprint":false},{"pmid":"16179256","id":"PMC_16179256","title":"The FK506 binding protein Fpr3 counteracts protein phosphatase 1 to maintain meiotic recombination checkpoint activity.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16179256","citation_count":111,"is_preprint":false},{"pmid":"15623572","id":"PMC_15623572","title":"Identification and characterization of an endogenous chemotactic ligand specific for FPRL2.","date":"2004","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15623572","citation_count":96,"is_preprint":false},{"pmid":"9148902","id":"PMC_9148902","title":"Casein kinase II catalyzes tyrosine phosphorylation of the yeast nucleolar immunophilin Fpr3.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9148902","citation_count":88,"is_preprint":false},{"pmid":"7525596","id":"PMC_7525596","title":"A novel FK506- and rapamycin-binding protein (FPR3 gene product) in the yeast Saccharomyces cerevisiae is a proline rotamase localized to the nucleolus.","date":"1994","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7525596","citation_count":74,"is_preprint":false},{"pmid":"12223529","id":"PMC_12223529","title":"Human dendritic cells express functional formyl peptide receptor-like-2 (FPRL2) throughout maturation.","date":"2002","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/12223529","citation_count":59,"is_preprint":false},{"pmid":"21543323","id":"PMC_21543323","title":"N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21543323","citation_count":53,"is_preprint":false},{"pmid":"19765989","id":"PMC_19765989","title":"Fpr3 and Zip3 ensure that initiation of meiotic recombination precedes chromosome synapsis in budding yeast.","date":"2009","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/19765989","citation_count":52,"is_preprint":false},{"pmid":"10506183","id":"PMC_10506183","title":"Tyrosine versus serine/threonine phosphorylation by protein kinase casein kinase-2. A study with peptide substrates derived from immunophilin Fpr3.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10506183","citation_count":52,"is_preprint":false},{"pmid":"31653840","id":"PMC_31653840","title":"Bacterial MgrB peptide activates chemoreceptor Fpr3 in mouse accessory olfactory system and drives avoidance behaviour.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31653840","citation_count":32,"is_preprint":false},{"pmid":"24514906","id":"PMC_24514906","title":"Degradation of centromeric histone H3 variant Cse4 requires the Fpr3 peptidyl-prolyl Cis-Trans isomerase.","date":"2014","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24514906","citation_count":27,"is_preprint":false},{"pmid":"7925954","id":"PMC_7925954","title":"Purification of FKBP-70, a novel immunophilin from Saccharomyces cerevisiae, and cloning of its structural gene, FPR3.","date":"1994","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/7925954","citation_count":26,"is_preprint":false},{"pmid":"7559654","id":"PMC_7559654","title":"The yeast immunophilin Fpr3 is a physiological substrate of the tyrosine-specific phosphoprotein phosphatase Ptp1.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7559654","citation_count":22,"is_preprint":false},{"pmid":"33679387","id":"PMC_33679387","title":"Identification of FPR3 as a Unique Biomarker for Targeted Therapy in the Immune Microenvironment of Breast Cancer.","date":"2021","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33679387","citation_count":19,"is_preprint":false},{"pmid":"38614385","id":"PMC_38614385","title":"FPR3 reprograms glycolytic metabolism and stemness in gastric cancer via calcium-NFATc1 pathway.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38614385","citation_count":16,"is_preprint":false},{"pmid":"10821187","id":"PMC_10821187","title":"The yeast peptidyl proline isomerases FPR3 and FPR4, in high copy numbers, suppress defects resulting from the absence of the E3 ubiquitin ligase TOM1.","date":"2000","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/10821187","citation_count":13,"is_preprint":false},{"pmid":"15141303","id":"PMC_15141303","title":"Expression of the Stp1 LMW-PTP and inhibition of protein CK2 display a cooperative effect on immunophilin Fpr3 tyrosine phosphorylation and Saccharomyces cerevisiae growth.","date":"2004","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/15141303","citation_count":12,"is_preprint":false},{"pmid":"24297734","id":"PMC_24297734","title":"Nuclear FKBPs, Fpr3 and Fpr4 affect genome-wide genes transcription.","date":"2013","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/24297734","citation_count":7,"is_preprint":false},{"pmid":"36527787","id":"PMC_36527787","title":"The activation of FPR3/PKA/Rap1/ERK1/2 and FPR3/p-IκB/NF-κB axis in fibroblasts promote capsular contracture after rhinoplasty.","date":"2022","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/36527787","citation_count":6,"is_preprint":false},{"pmid":"21717223","id":"PMC_21717223","title":"Transcriptional variations mediated by an alternative promoter of the FPR3 gene.","date":"2011","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/21717223","citation_count":6,"is_preprint":false},{"pmid":"36936958","id":"PMC_36936958","title":"Nocardia rubra cell-wall skeleton activates an immune response in cervical tissue via stimulating FPR3 to enhance dendritic cell-mediated Th1 differentiation.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36936958","citation_count":5,"is_preprint":false},{"pmid":"15358193","id":"PMC_15358193","title":"The in vivo tyrosine phosphorylation level of yeast immunophilin Fpr3 is influenced by the LMW-PTP Ltp1.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15358193","citation_count":5,"is_preprint":false},{"pmid":"22008079","id":"PMC_22008079","title":"Monoclonal antibodies directed against Fpr3 protein as molecular chaperones.","date":"2011","source":"Hybridoma (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/22008079","citation_count":4,"is_preprint":false},{"pmid":"40848578","id":"PMC_40848578","title":"Blocking Fpr3 ameliorates osteoarthritis by inhibiting NLRP3-mediated chondrocyte pyroptosis.","date":"2025","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/40848578","citation_count":2,"is_preprint":false},{"pmid":"40987893","id":"PMC_40987893","title":"FPR3 sustains the immunosuppression of tumor-associated macrophages and accelerates the progression of gastric adenocarcinoma.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40987893","citation_count":2,"is_preprint":false},{"pmid":"41667046","id":"PMC_41667046","title":"The role of FPR3 in remodeling the immune microenvironment and lung metastasis of colon adenocarcinoma.","date":"2026","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41667046","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.21.644686","title":"Redirecting cytotoxic lymphocytes to breast cancer tumors via metabolite-sensing receptors","date":"2025-03-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.21.644686","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15399,"output_tokens":4509,"usd":0.056916,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12522,"output_tokens":4467,"usd":0.087142,"stage2_stop_reason":"end_turn"},"total_usd":0.144058,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Yeast Fpr3 (FPR3 gene product) is a peptidylprolyl cis-trans isomerase (PPIase) localized exclusively to the nucleolus; both full-length Fpr3 and its isolated C-terminal FKBP domain exhibit PPIase activity in vitro, and the protein binds FK506 and rapamycin.\",\n      \"method\": \"Purification from E. coli, PPIase activity assay, indirect immunofluorescence localization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with domain dissection, confirmed by two independent groups (PMID:7525596 and PMID:7925954)\",\n      \"pmids\": [\"7525596\", \"7925954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Yeast Fpr3 is phosphorylated on Tyr-184 by endogenous kinases and is a direct physiological substrate of the tyrosine phosphatase Ptp1; immobilized phosphotyrosyl Fpr3 is dephosphorylated by recombinant Ptp1 in vitro, and the phosphorylation site was confirmed by site-directed mutagenesis.\",\n      \"method\": \"Protein purification, in vitro phosphatase assay, site-directed mutagenesis, ptp1 mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis identifying the exact phosphosite, confirmed in vivo by genetic correlation\",\n      \"pmids\": [\"7559654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Casein kinase II (CKII) phosphorylates yeast Fpr3 at Tyr-184 and Ser-186 both in vitro and in vivo; phosphorylation at Tyr-184 by CKII occurs via a two-step mechanism where prior phosphorylation at Ser-186 (position +2) provides a specificity determinant for subsequent tyrosine phosphorylation.\",\n      \"method\": \"In vitro kinase assay with purified yeast and human CKII, metabolic phospholabeling, temperature-sensitive CKII allele, overexpression of heterologous CKII\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with synthetic peptide substrates and mutagenesis, corroborated in vivo by genetic manipulation of CKII\",\n      \"pmids\": [\"9148902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CK2 can phosphorylate a tyrosyl residue (Tyr-184) in Fpr3 using partially distinct structural determinants compared to Ser/Thr phosphorylation; the surrounding sequence DEDADIY(184)DEEDYDL allows CK2 tyrosine phosphorylation but with much higher Km and lower Vmax than the equivalent serine-containing peptide.\",\n      \"method\": \"In vitro kinase assay with synthetic peptide substrates and site-substitution variants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with systematic peptide mutagenesis, single lab but multiple peptide variants tested\",\n      \"pmids\": [\"10506183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human FPR3 (FPRL2) functions as a G protein-coupled chemoattractant receptor on monocytes; it is activated by the synthetic hexapeptides WKYMVm and WKYMVm (l-conformer) to mobilize calcium and drive chemotaxis in HL-60-FPRL2 transfected cells; FPR3 is constitutively phosphorylated in resting cells and both conformers induce receptor internalization.\",\n      \"method\": \"Calcium flux assay in transfected HL-60 cells, chemotaxis assay, radioligand binding (125I-WKYMVm), metabolic phospholabeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (calcium, chemotaxis, binding, phosphorylation) in receptor-transfected cells\",\n      \"pmids\": [\"11285256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"F2L, an acetylated N-terminal peptide derived from cleavage of human heme-binding protein, is a specific endogenous agonist of FPR3 (FPRL2); F2L binds and activates FPR3 in the low nanomolar range, triggering intracellular calcium release, inhibition of cAMP accumulation, ERK1/2 phosphorylation via Gi proteins, and chemotaxis of monocytes and dendritic cells.\",\n      \"method\": \"Peptide isolation from spleen extract, radioligand competition binding, calcium mobilization assay, cAMP assay, ERK phosphorylation assay, chemotaxis assay, Gi inhibition with pertussis toxin\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — natural ligand isolated and reconstituted with multiple orthogonal signaling assays; Gi coupling confirmed pharmacologically\",\n      \"pmids\": [\"15623572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Yeast Fpr3 interacts with and is dephosphorylated by the LMW-PTP Stp1 in vivo; Fpr3 dephosphorylation by Stp1, synergized with CK2 inhibition, induces a severe growth-defective phenotype.\",\n      \"method\": \"In vivo co-immunoprecipitation, yeast genetics, CK2 inhibitor treatment\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, Co-IP plus genetic/pharmacological evidence, two orthogonal approaches\",\n      \"pmids\": [\"15141303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The LMW-PTP Ltp1 dephosphorylates yeast Fpr3 at Tyr-184 in vivo; tyrosine phosphorylation state of Fpr3 influences its subcellular localization.\",\n      \"method\": \"In vivo phosphorylation analysis, site identification, localization assay in ltp1 mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method per claim; phosphosite confirmed but localization mechanistic link is partial\",\n      \"pmids\": [\"15358193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Yeast Fpr3 maintains meiotic recombination checkpoint activity by interacting with protein phosphatase 1 (PP1) through its PPIase domain, regulating PP1 localization and counteracting PP1 activity; fpr3 deletion or rapamycin treatment (which binds the PPIase domain) causes premature adaptation to checkpoint-activating damage.\",\n      \"method\": \"Genetic deletion analysis, epistasis, rapamycin treatment, co-immunoprecipitation of Fpr3-PP1 interaction, PP1 localization by microscopy\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and biochemical evidence (Co-IP, localization, rapamycin domain-specific inhibition, epistasis) in multiple genetic backgrounds\",\n      \"pmids\": [\"16179256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human FPR3 (FPRL2) protein is expressed on both immature and mature dendritic cells; WKYMVm-induced FPR3 internalization occurs in both DC types, and mature DCs—which lack other FPR family members—respond to WKYMVm exclusively through FPR3.\",\n      \"method\": \"RT-PCR, protein expression analysis, calcium mobilization assay, receptor internalization assay using receptor-bound antibody uptake\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — expression plus functional internalization assay; attribution to FPR3 relies on absence of other receptors in mature DCs\",\n      \"pmids\": [\"12223529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Yeast Fpr3 and the SUMO ligase Zip3 function in parallel pathways to ensure that synaptonemal complex (SC) assembly is contingent on recombination initiation; in fpr3 zip3 double mutants, synapsis occurs even without recombination initiation, and Fpr3 specifically prevents premature SC initiation at centromeric sites.\",\n      \"method\": \"Genetic epistasis using fpr3, zip3 double mutants combined with recombination-initiation mutants; cytological analysis of SC assembly\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with multiple double and triple mutant combinations and cytological readouts\",\n      \"pmids\": [\"19765989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human FPR3 undergoes constitutive internalization in unstimulated cells that is independent of C-terminus phosphorylation; the N-terminal extracellular region and first transmembrane domain (residues 1–53) determine intracellular vesicular localization, and constitutive internalization proceeds via a clathrin-independent, possibly caveolae-dependent mechanism. FPR3 also displays basal phosphorylation that is only slightly increased upon agonist stimulation, unlike FPR2/ALX.\",\n      \"method\": \"Chimeric receptor domain-swap experiments, receptor-bound antibody uptake assay, clathrin/caveolae inhibitor treatment, phosphorylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic domain-swap mutagenesis combined with multiple orthogonal functional assays (internalization, phosphorylation, inhibitor pharmacology)\",\n      \"pmids\": [\"21543323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Yeast Fpr3 proline isomerase activity is required for proteolysis of the centromeric histone H3 variant Cse4; Fpr3-mediated structural change in Cse4 is proposed to facilitate Cse4 interaction with the E3 ubiquitin ligase Psh1, leading to polyubiquitylation and proteasome-dependent degradation.\",\n      \"method\": \"Genetic deletion (fpr3 mutant), co-immunoprecipitation of Cse4-Psh1 interaction, ubiquitylation assay\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic evidence with Co-IP; mechanistic interpretation of isomerase activity requirement is partially inferred from genetic data\",\n      \"pmids\": [\"24514906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The N-terminal acidic domain (~170 residues) of yeast Fpr3 (not its PPIase domain) is sufficient to suppress temperature-sensitive growth and mating defects of tom1 (E3 ubiquitin ligase) deletion strains when overexpressed, placing Fpr3 in a functional relationship with ubiquitin-mediated pathways.\",\n      \"method\": \"Multicopy suppression screen, domain deletion/truncation analysis, genetic epistasis\",\n      \"journal\": \"Molecular & general genetics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain dissection with multiple genetic controls showing suppression specificity\",\n      \"pmids\": [\"10821187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mouse Fpr3 (Fpr-rs1), expressed in vomeronasal sensory neurons, recognizes the bacterial peptide motif f-MKKFRW derived from the MgrB signal sequence of Enterobacteriaceae; Fpr3 is required for neuronal detection of this peptide and for innate avoidance behavior in freely behaving mice.\",\n      \"method\": \"Vomeronasal neuron calcium imaging, Fpr3 knockout mouse behavioral assay (avoidance), peptide specificity testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined behavioral phenotype, combined with neuronal activation assay and peptide specificity characterization\",\n      \"pmids\": [\"31653840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FPR3 overexpression in fibroblasts activates the PKA/Rap1/ERK1/2 axis to promote cell viability and myofibroblast transformation, and phosphorylates IκB to reduce NF-κB inhibition, increasing secretion of IL-1β, TNF-α, and IL-6, thereby driving capsular contracture.\",\n      \"method\": \"Western blot, qRT-PCR, CCK-8 viability assay, wound healing migration assay, ELISA for cytokines\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression only, pathway assignments based on downstream marker measurements without direct pathway reconstitution\",\n      \"pmids\": [\"36527787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FPR3 suppresses glycolytic capacity and stemness in gastric cancer cells by impeding cytoplasmic calcium flux, which prevents NFATc1 nuclear translocation, reducing NFATc1-driven transcription of NOTCH3 and SOX2 and suppressing AKT/mTORC1 signaling.\",\n      \"method\": \"FPR3 overexpression/knockdown, calcium flux measurement, NFATc1 nuclear translocation assay, chromatin/promoter binding assay, Western blot for pathway components\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple downstream readouts with both gain- and loss-of-function, but pathway intermediates confirmed by reporter/binding assays rather than reconstitution\",\n      \"pmids\": [\"38614385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FPR3 in tumor-associated macrophages upregulates FZD7 and CCDC88C, activating the Wnt/PCP pathway and downstream JNK signaling to promote macrophage proliferation, immunosuppressive polarization, and TAM maintenance in gastric adenocarcinoma.\",\n      \"method\": \"shRNA knockdown, FPR3 agonist treatment, gene expression analysis, pathway inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, shRNA knockdown with pathway marker measurements; no direct reconstitution or epistasis for Wnt/PCP assignment\",\n      \"pmids\": [\"40987893\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FPR3 encodes two functionally distinct proteins sharing the symbol: (1) human FPR3 (also FPRL2/FPRH1), a G protein-coupled chemoattractant receptor on monocytes and dendritic cells that couples through Gi to calcium mobilization, ERK1/2 activation, and chemotaxis in response to its specific endogenous agonist F2L (a peptide from heme-binding protein), undergoes constitutive clathrin-independent internalization driven by its N-terminal/TM1 domain, and displays constitutive basal phosphorylation; (2) yeast Fpr3, a nucleolar FK506/rapamycin-binding protein with PPIase activity that is phosphorylated at Tyr-184 by CK2 and dephosphorylated by Ptp1/Ltp1/Stp1, interacts with PP1 through its PPIase domain to maintain meiotic recombination checkpoint activity by controlling PP1 localization, and also regulates centromeric histone Cse4 proteolysis and ensures that chromosome synapsis is contingent on recombination initiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The FPR3 symbol denotes two unrelated proteins, and the timeline coherently resolves both. In the human and rodent literature, FPR3 is a Gi-coupled G protein-coupled chemoattractant receptor of myeloid cells: it is activated by the synthetic hexapeptide WKYMVm and by its specific endogenous agonist F2L (an acetylated N-terminal peptide from heme-binding protein), driving intracellular calcium mobilization, inhibition of cAMP, ERK1/2 phosphorylation, and chemotaxis of monocytes and dendritic cells [#4, #5]. The receptor is expressed on both immature and mature dendritic cells and is the exclusive WKYMVm responder in mature DCs [#9]. FPR3 displays constitutive basal phosphorylation that is only marginally increased by agonist, and it undergoes constitutive, clathrin-independent (caveolae-associated) internalization directed by its N-terminal/TM1 region rather than C-terminal phosphorylation [#4, #11]. In olfaction, mouse Fpr3 acts in vomeronasal sensory neurons as a detector of the bacterial peptide motif f-MKKFRW and is required for innate avoidance behavior [#14]. In contrast, yeast Fpr3 is a nucleolar FK506/rapamycin-binding peptidylprolyl cis-trans isomerase (PPIase) whose C-terminal FKBP domain carries the isomerase activity [#0]. Through its PPIase domain it binds protein phosphatase 1 (PP1) to control PP1 localization and sustain the meiotic recombination checkpoint, such that fpr3 deletion or rapamycin causes premature checkpoint adaptation [#8]. Fpr3 acts in parallel with the SUMO ligase Zip3 to make synaptonemal complex assembly contingent on recombination initiation, preventing premature synapsis at centromeres [#10], and its isomerase activity promotes Psh1-dependent proteolysis of the centromeric histone variant Cse4 [#12]. Yeast Fpr3 is phosphorylated at Tyr-184 (and Ser-186) by casein kinase II through a two-step ordered mechanism and is dephosphorylated by the LMW tyrosine phosphatases Ptp1, Ltp1, and Stp1, with phosphorylation state influencing its localization [#1, #2, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the biochemical identity of yeast Fpr3 as a nucleolar PPIase, distinguishing it from the unrelated mammalian receptor sharing the symbol.\",\n      \"evidence\": \"Recombinant purification, in vitro PPIase activity assay with domain dissection, and immunofluorescence localization\",\n      \"pmids\": [\"7525596\", \"7925954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro substrates of the PPIase activity not defined\", \"Function of the N-terminal acidic domain not addressed\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified Fpr3 as an in vivo tyrosine-phosphorylated protein and a physiological substrate of the phosphatase Ptp1, opening the question of its regulatory phospho-cycle.\",\n      \"evidence\": \"Protein purification, in vitro phosphatase assay, and site-directed mutagenesis mapping Tyr-184 in ptp1 mutants\",\n      \"pmids\": [\"7559654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible not yet identified\", \"Functional consequence of Tyr-184 phosphorylation unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved the kinase and mechanism of Fpr3 phosphorylation, showing CKII phosphorylates Tyr-184 via an ordered process primed by Ser-186.\",\n      \"evidence\": \"In vitro kinase assays with purified CKII, metabolic phospholabeling, and temperature-sensitive CKII alleles\",\n      \"pmids\": [\"9148902\", \"10506183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular trigger for CKII phosphorylation of Fpr3 unknown\", \"Downstream effect of dual phosphorylation on PPIase function not established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Placed the Fpr3 N-terminal acidic domain in a functional relationship with ubiquitin-mediated pathways, distinct from its catalytic PPIase domain.\",\n      \"evidence\": \"Multicopy suppression of tom1 E3 ligase deletion phenotypes with domain truncation analysis\",\n      \"pmids\": [\"10821187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between Fpr3 and Tom1 not shown\", \"Mechanism of suppression unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined human FPR3 (FPRL2) as a functional GPCR chemoattractant receptor on monocytes activated by WKYMVm.\",\n      \"evidence\": \"Calcium flux, chemotaxis, radioligand binding, and phospholabeling in receptor-transfected HL-60 cells\",\n      \"pmids\": [\"11285256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous agonist not yet identified\", \"G protein coupling not directly demonstrated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed FPR3 is the exclusive WKYMVm-responsive receptor on mature dendritic cells, indicating a role in DC signaling.\",\n      \"evidence\": \"RT-PCR, calcium mobilization, and antibody-uptake internalization in immature and mature DCs\",\n      \"pmids\": [\"12223529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Attribution relies on absence of other FPRs rather than direct knockout\", \"Physiological agonist in DCs not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified F2L as the specific endogenous agonist of FPR3 and established Gi coupling to calcium, cAMP, and ERK signaling.\",\n      \"evidence\": \"Peptide isolation from spleen, competition binding, calcium/cAMP/ERK assays, chemotaxis, and pertussis toxin block\",\n      \"pmids\": [\"15623572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context of F2L generation not defined\", \"Structural basis of F2L recognition unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended the Fpr3 phospho-regulatory network to additional LMW phosphatases and linked phospho-state to localization.\",\n      \"evidence\": \"In vivo co-immunoprecipitation, ltp1/stp1 mutant phospho- and localization analysis, and CK2 inhibitor synergy\",\n      \"pmids\": [\"15141303\", \"15358193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP evidence for Stp1 interaction\", \"Mechanistic link between Tyr-184 phosphorylation and localization only partial\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined a meiotic role for Fpr3, showing its PPIase domain binds PP1 to control PP1 localization and sustain the recombination checkpoint.\",\n      \"evidence\": \"Genetic deletion, epistasis, rapamycin domain-specific inhibition, Fpr3-PP1 Co-IP, and PP1 localization microscopy\",\n      \"pmids\": [\"16179256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PPIase substrate within the checkpoint not identified\", \"How rapamycin binding disrupts PP1 interaction structurally unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that Fpr3 acts in parallel with Zip3 to couple synaptonemal complex assembly to recombination initiation, preventing premature centromeric synapsis.\",\n      \"evidence\": \"Genetic epistasis with fpr3 zip3 double/triple mutants and cytological SC analysis\",\n      \"pmids\": [\"19765989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of Fpr3 at centromeres unknown\", \"Relationship to PP1 checkpoint role not integrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed human FPR3 internalizes constitutively via a clathrin-independent mechanism driven by its N-terminus/TM1, distinct from C-terminal phosphorylation-driven receptors.\",\n      \"evidence\": \"Chimeric domain-swap, antibody-uptake internalization, clathrin/caveolae inhibitor pharmacology, and phosphorylation analysis\",\n      \"pmids\": [\"21543323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact endocytic adaptor not identified\", \"Functional significance of constitutive internalization unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked Fpr3 PPIase activity to centromeric chromatin turnover through promotion of Cse4 proteolysis.\",\n      \"evidence\": \"fpr3 deletion, Cse4-Psh1 Co-IP, and ubiquitylation assays\",\n      \"pmids\": [\"24514906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct isomerization of Cse4 by Fpr3 not demonstrated\", \"Mechanism inferred from genetic and Co-IP data\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a sensory role for mouse Fpr3 as a vomeronasal detector of a bacterial peptide motif driving innate avoidance.\",\n      \"evidence\": \"Vomeronasal neuron calcium imaging, Fpr3 knockout behavioral assay, and peptide specificity testing\",\n      \"pmids\": [\"31653840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling in VSNs not detailed\", \"Relationship to myeloid FPR3 signaling not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Assigned a tumor-suppressive signaling role to FPR3 via calcium/NFATc1 control of stemness and glycolysis in gastric cancer.\",\n      \"evidence\": \"FPR3 gain/loss-of-function, calcium flux, NFATc1 translocation, promoter binding, and pathway Western blots\",\n      \"pmids\": [\"38614385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway intermediates not reconstituted\", \"Ligand driving this signaling in tumor cells not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the constitutively internalizing, Gi-coupled human receptor and the nucleolar yeast PPIase relate functionally, and whether human FPR3 signaling outputs in disease contexts are driven by defined endogenous agonists, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Disease-context FPR3 pathway claims rest on overexpression in single labs\", \"No structural data on either protein in the timeline\", \"PPIase substrate spectrum of yeast Fpr3 undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0, 8, 12]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 5, 14]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [5, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 9, 11]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 10, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PP1\", \"Psh1\", \"Cse4\", \"Ptp1\", \"Ltp1\", \"Stp1\", \"Zip3\", \"CK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}