Affinage

FPR3

N-formyl peptide receptor 3 · UniProt P25089

Length
353 aa
Mass
40.0 kDa
Annotated
2026-06-09
27 papers in source corpus 19 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    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

    PMID:7525596 PMID:7925954

    Open questions at the time
    • In vitro substrates of the PPIase activity not defined
    • Function of the N-terminal acidic domain not addressed
  2. 1995 High

    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

    PMID:7559654

    Open questions at the time
    • Kinase responsible not yet identified
    • Functional consequence of Tyr-184 phosphorylation unknown
  3. 1997 High

    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

    PMID:10506183 PMID:9148902

    Open questions at the time
    • Cellular trigger for CKII phosphorylation of Fpr3 unknown
    • Downstream effect of dual phosphorylation on PPIase function not established
  4. 2000 Medium

    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

    PMID:10821187

    Open questions at the time
    • Direct biochemical link between Fpr3 and Tom1 not shown
    • Mechanism of suppression unresolved
  5. 2001 High

    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

    PMID:11285256

    Open questions at the time
    • Endogenous agonist not yet identified
    • G protein coupling not directly demonstrated
  6. 2002 Medium

    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

    PMID:12223529

    Open questions at the time
    • Attribution relies on absence of other FPRs rather than direct knockout
    • Physiological agonist in DCs not defined
  7. 2004 High

    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

    PMID:15623572

    Open questions at the time
    • Physiological context of F2L generation not defined
    • Structural basis of F2L recognition unknown
  8. 2004 Medium

    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

    PMID:15141303 PMID:15358193

    Open questions at the time
    • Single-lab Co-IP evidence for Stp1 interaction
    • Mechanistic link between Tyr-184 phosphorylation and localization only partial
  9. 2005 High

    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

    PMID:16179256

    Open questions at the time
    • PPIase substrate within the checkpoint not identified
    • How rapamycin binding disrupts PP1 interaction structurally unresolved
  10. 2009 High

    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

    PMID:19765989

    Open questions at the time
    • Molecular target of Fpr3 at centromeres unknown
    • Relationship to PP1 checkpoint role not integrated
  11. 2011 High

    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

    PMID:21543323

    Open questions at the time
    • Exact endocytic adaptor not identified
    • Functional significance of constitutive internalization unclear
  12. 2014 Medium

    Linked Fpr3 PPIase activity to centromeric chromatin turnover through promotion of Cse4 proteolysis.

    Evidence fpr3 deletion, Cse4-Psh1 Co-IP, and ubiquitylation assays

    PMID:24514906

    Open questions at the time
    • Direct isomerization of Cse4 by Fpr3 not demonstrated
    • Mechanism inferred from genetic and Co-IP data
  13. 2019 High

    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

    PMID:31653840

    Open questions at the time
    • Downstream signaling in VSNs not detailed
    • Relationship to myeloid FPR3 signaling not addressed
  14. 2024 Medium

    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

    PMID:38614385

    Open questions at the time
    • Pathway intermediates not reconstituted
    • Ligand driving this signaling in tumor cells not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016853 isomerase activity 3 GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005730 nucleolus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-1474165 Reproduction 2 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
CK2CSE4LTP1PP1PSH1PTP1STP1ZIP3

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 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. Purification from E. coli, PPIase activity assay, indirect immunofluorescence localization The Journal of cell biology High 7525596 7925954
1995 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. Protein purification, in vitro phosphatase assay, site-directed mutagenesis, ptp1 mutant analysis The Journal of biological chemistry High 7559654
1997 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. In vitro kinase assay with purified yeast and human CKII, metabolic phospholabeling, temperature-sensitive CKII allele, overexpression of heterologous CKII The Journal of biological chemistry High 9148902
1999 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. In vitro kinase assay with synthetic peptide substrates and site-substitution variants The Journal of biological chemistry High 10506183
2001 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. Calcium flux assay in transfected HL-60 cells, chemotaxis assay, radioligand binding (125I-WKYMVm), metabolic phospholabeling The Journal of biological chemistry High 11285256
2004 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. Peptide isolation from spleen extract, radioligand competition binding, calcium mobilization assay, cAMP assay, ERK phosphorylation assay, chemotaxis assay, Gi inhibition with pertussis toxin The Journal of experimental medicine High 15623572
2004 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. In vivo co-immunoprecipitation, yeast genetics, CK2 inhibitor treatment Cellular and molecular life sciences : CMLS Medium 15141303
2004 The LMW-PTP Ltp1 dephosphorylates yeast Fpr3 at Tyr-184 in vivo; tyrosine phosphorylation state of Fpr3 influences its subcellular localization. In vivo phosphorylation analysis, site identification, localization assay in ltp1 mutants Biochemical and biophysical research communications Medium 15358193
2005 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. Genetic deletion analysis, epistasis, rapamycin treatment, co-immunoprecipitation of Fpr3-PP1 interaction, PP1 localization by microscopy Cell High 16179256
2002 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. RT-PCR, protein expression analysis, calcium mobilization assay, receptor internalization assay using receptor-bound antibody uptake Journal of leukocyte biology Medium 12223529
2009 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. Genetic epistasis using fpr3, zip3 double mutants combined with recombination-initiation mutants; cytological analysis of SC assembly Current biology : CB High 19765989
2011 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. Chimeric receptor domain-swap experiments, receptor-bound antibody uptake assay, clathrin/caveolae inhibitor treatment, phosphorylation analysis The Journal of biological chemistry High 21543323
2014 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. Genetic deletion (fpr3 mutant), co-immunoprecipitation of Cse4-Psh1 interaction, ubiquitylation assay Genetics Medium 24514906
2000 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. Multicopy suppression screen, domain deletion/truncation analysis, genetic epistasis Molecular & general genetics : MGG Medium 10821187
2019 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. Vomeronasal neuron calcium imaging, Fpr3 knockout mouse behavioral assay (avoidance), peptide specificity testing Nature communications High 31653840
2022 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. Western blot, qRT-PCR, CCK-8 viability assay, wound healing migration assay, ELISA for cytokines Tissue & cell Low 36527787
2024 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. FPR3 overexpression/knockdown, calcium flux measurement, NFATc1 nuclear translocation assay, chromatin/promoter binding assay, Western blot for pathway components Cancer letters Medium 38614385
2025 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. shRNA knockdown, FPR3 agonist treatment, gene expression analysis, pathway inhibition Oncogene Low 40987893

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 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. The Journal of biological chemistry 157 11285256
1992 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. Genomics 115 1612600
2005 The FK506 binding protein Fpr3 counteracts protein phosphatase 1 to maintain meiotic recombination checkpoint activity. Cell 111 16179256
2004 Identification and characterization of an endogenous chemotactic ligand specific for FPRL2. The Journal of experimental medicine 96 15623572
1997 Casein kinase II catalyzes tyrosine phosphorylation of the yeast nucleolar immunophilin Fpr3. The Journal of biological chemistry 88 9148902
1994 A novel FK506- and rapamycin-binding protein (FPR3 gene product) in the yeast Saccharomyces cerevisiae is a proline rotamase localized to the nucleolus. The Journal of cell biology 74 7525596
2002 Human dendritic cells express functional formyl peptide receptor-like-2 (FPRL2) throughout maturation. Journal of leukocyte biology 59 12223529
2011 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. The Journal of biological chemistry 53 21543323
2009 Fpr3 and Zip3 ensure that initiation of meiotic recombination precedes chromosome synapsis in budding yeast. Current biology : CB 52 19765989
1999 Tyrosine versus serine/threonine phosphorylation by protein kinase casein kinase-2. A study with peptide substrates derived from immunophilin Fpr3. The Journal of biological chemistry 52 10506183
2019 Bacterial MgrB peptide activates chemoreceptor Fpr3 in mouse accessory olfactory system and drives avoidance behaviour. Nature communications 32 31653840
2014 Degradation of centromeric histone H3 variant Cse4 requires the Fpr3 peptidyl-prolyl Cis-Trans isomerase. Genetics 27 24514906
1994 Purification of FKBP-70, a novel immunophilin from Saccharomyces cerevisiae, and cloning of its structural gene, FPR3. FEBS letters 26 7925954
1995 The yeast immunophilin Fpr3 is a physiological substrate of the tyrosine-specific phosphoprotein phosphatase Ptp1. The Journal of biological chemistry 22 7559654
2021 Identification of FPR3 as a Unique Biomarker for Targeted Therapy in the Immune Microenvironment of Breast Cancer. Frontiers in pharmacology 19 33679387
2024 FPR3 reprograms glycolytic metabolism and stemness in gastric cancer via calcium-NFATc1 pathway. Cancer letters 16 38614385
2000 The yeast peptidyl proline isomerases FPR3 and FPR4, in high copy numbers, suppress defects resulting from the absence of the E3 ubiquitin ligase TOM1. Molecular & general genetics : MGG 13 10821187
2004 Expression of the Stp1 LMW-PTP and inhibition of protein CK2 display a cooperative effect on immunophilin Fpr3 tyrosine phosphorylation and Saccharomyces cerevisiae growth. Cellular and molecular life sciences : CMLS 12 15141303
2013 Nuclear FKBPs, Fpr3 and Fpr4 affect genome-wide genes transcription. Molecular genetics and genomics : MGG 7 24297734
2022 The activation of FPR3/PKA/Rap1/ERK1/2 and FPR3/p-IκB/NF-κB axis in fibroblasts promote capsular contracture after rhinoplasty. Tissue & cell 6 36527787
2011 Transcriptional variations mediated by an alternative promoter of the FPR3 gene. Mammalian genome : official journal of the International Mammalian Genome Society 6 21717223
2023 Nocardia rubra cell-wall skeleton activates an immune response in cervical tissue via stimulating FPR3 to enhance dendritic cell-mediated Th1 differentiation. Frontiers in immunology 5 36936958
2004 The in vivo tyrosine phosphorylation level of yeast immunophilin Fpr3 is influenced by the LMW-PTP Ltp1. Biochemical and biophysical research communications 5 15358193
2011 Monoclonal antibodies directed against Fpr3 protein as molecular chaperones. Hybridoma (2005) 4 22008079
2025 Blocking Fpr3 ameliorates osteoarthritis by inhibiting NLRP3-mediated chondrocyte pyroptosis. Cytokine 2 40848578
2025 FPR3 sustains the immunosuppression of tumor-associated macrophages and accelerates the progression of gastric adenocarcinoma. Oncogene 2 40987893
2026 The role of FPR3 in remodeling the immune microenvironment and lung metastasis of colon adenocarcinoma. Cellular signalling 0 41667046

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