Affinage

FPR3

N-formyl peptide receptor 3 · UniProt P25089

Length
353 aa
Mass
40.0 kDa
Annotated
2026-04-28
27 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FPR3 encodes a G protein-coupled chemoattractant receptor that is constitutively phosphorylated and predominantly localized to intracellular vesicles through clathrin-independent constitutive internalization governed by its N-terminal/first-transmembrane domain (residues 1–53) (PMID:21543323). The receptor is specifically activated by the endogenous ligand F2L (an acetylated peptide from heme-binding protein), signaling through Gi proteins to mobilize intracellular calcium, inhibit cAMP, activate ERK1/2, and drive chemotaxis of monocytes and dendritic cells (PMID:15623572, PMID:11285256). In mouse vomeronasal sensory neurons, the ortholog Fpr3/Fpr-rs1 detects bacterial peptides derived from MgrB and drives innate pathogen-avoidance behavior (PMID:31653840). The budding yeast ortholog Fpr3 is a nucleolar FKBP-family PPIase that binds and regulates PP1 to maintain the meiotic recombination checkpoint, promotes proteasomal degradation of centromeric histone Cse4, and is regulated by CK2-mediated phosphorylation at Tyr-184 (PMID:16179256, PMID:24514906, PMID:9148902).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1994 High

    Identification of Fpr3 as a nucleolar PPIase established the gene product as an FKBP-family immunophilin with a defined enzymatic activity and specific subnuclear localization, distinguishing it from cytoplasmic immunophilins.

    Evidence Protein purification from E. coli, PPIase activity assay, indirect immunofluorescence in yeast

    PMID:7525596 PMID:7925954

    Open questions at the time
    • Whether PPIase activity is required for in vivo function was not established
    • Substrates of PPIase activity in the nucleolus unknown
  2. 1997 High

    Demonstrating that CK2 phosphorylates Fpr3 at Tyr-184 via a sequential two-step mechanism and that multiple phosphatases (Ptp1, Ltp1, Stp1) reverse this modification revealed a regulated phosphorylation cycle controlling Fpr3 function and localization in yeast.

    Evidence In vitro reconstitution with purified CK2, mutagenesis, metabolic labeling in vivo, co-immunoprecipitation with phosphatases

    PMID:10506183 PMID:15141303 PMID:15358193 PMID:7559654 PMID:9148902

    Open questions at the time
    • How Tyr-184 phosphorylation status alters Fpr3 activity or binding partners is incompletely defined
    • Whether phosphorylation directly regulates nucleolar retention versus release is unclear
  3. 2001 High

    Establishing that human FPR3 (FPRL2) is a functional chemoattractant GPCR that mobilizes calcium, mediates chemotaxis, and is constitutively phosphorylated defined its basic signaling identity and distinguished it from other FPR family members.

    Evidence Calcium flux, chemotaxis, and radioligand binding in transfected HL-60 cells; metabolic labeling for phosphorylation

    PMID:11285256

    Open questions at the time
    • Endogenous ligand not yet identified
    • Mechanism of constitutive phosphorylation unknown
  4. 2004 High

    Identification of F2L as the first endogenous high-affinity agonist specific for FPR3, coupled with Gi pathway dissection, resolved the long-standing question of what physiological signal FPR3 detects and established its signaling cascade (calcium, cAMP inhibition, ERK1/2).

    Evidence Peptide isolation from spleen extract, calcium mobilization, cAMP assay, ERK1/2 phosphorylation, pertussis toxin sensitivity, chemotaxis assay in monocytes/dendritic cells

    PMID:15623572

    Open questions at the time
    • In vivo physiological role of F2L–FPR3 axis in immune regulation not demonstrated
    • Whether F2L is the sole or dominant endogenous ligand is unknown
  5. 2005 High

    Showing that yeast Fpr3 binds PP1 through its PPIase domain and regulates PP1 localization to maintain the meiotic recombination checkpoint established a direct mechanistic link between an immunophilin and cell-cycle checkpoint control.

    Evidence Reciprocal co-immunoprecipitation, PP1 localization assay, fpr3Δ and rapamycin-treated meiotic checkpoint assays

    PMID:16179256

    Open questions at the time
    • Whether Fpr3 isomerizes a specific proline in PP1 or acts as a non-enzymatic scaffold is unresolved
    • Checkpoint substrates of the Fpr3-regulated PP1 pool not identified
  6. 2009 Medium

    Demonstrating that Fpr3 and Zip3 prevent centromeric synaptonemal complex assembly in the absence of recombination initiation extended Fpr3's meiotic role from checkpoint signaling to spatial regulation of chromosome synapsis.

    Evidence Double/triple mutant analysis (fpr3Δ zip3Δ with spo11Δ), cytological analysis of SC assembly

    PMID:19765989

    Open questions at the time
    • Whether Fpr3 acts directly at centromeres or indirectly through PP1 is unresolved
    • Mechanism by which Fpr3 blocks centromeric synapsis initiation is unknown
  7. 2011 High

    Mapping the determinant of constitutive FPR3 internalization to its N-terminal/first-TM domain (residues 1–53) and showing clathrin-independent uptake explained why FPR3 is predominantly intracellular, resolving a key cell biological distinction from other formyl peptide receptors.

    Evidence Domain-swap chimeras between FPR3 and FPR2/ALX, antibody uptake assay, pharmacological inhibition of internalization pathways

    PMID:21543323

    Open questions at the time
    • The specific coat/adaptor machinery mediating clathrin-independent internalization is unidentified
    • Functional significance of intracellular pool versus surface pool remains unclear
  8. 2014 Medium

    Finding that Fpr3 PPIase activity is required for polyubiquitylation and proteasomal degradation of centromeric histone Cse4 identified a direct chromatin substrate and connected Fpr3 to centromere maintenance.

    Evidence fpr3Δ deletion, Cse4 ubiquitylation and stability assays, genetic interaction with psh1Δ

    PMID:24514906

    Open questions at the time
    • Whether Fpr3 directly isomerizes a proline in Cse4 has not been shown biochemically
    • Whether this function is specific to Cse4 or extends to other histone variants is unknown
  9. 2019 High

    Showing that mouse Fpr3 in vomeronasal neurons detects bacterial MgrB-derived peptides and drives innate avoidance behavior established a sensory chemoreception function for FPR3 orthologs in pathogen detection.

    Evidence Ligand functional screen, Fpr3 knockout mouse behavioral assays, in vivo calcium imaging in freely behaving mice

    PMID:31653840

    Open questions at the time
    • Whether human FPR3 has analogous sensory functions is unknown
    • Full spectrum of bacterial ligands recognized by mouse Fpr3 not mapped
  10. 2024 Medium

    Linking FPR3 overexpression to suppression of calcium-NFATc1-NOTCH3-AKT/mTORC1 signaling and glycolysis in gastric cancer cells suggested a tumor-suppressive signaling axis, while FPR3 in tumor-associated macrophages activates Wnt/PCP-JNK to promote immunosuppressive polarization.

    Evidence FPR3 overexpression/knockdown with calcium flux, ChIP, AKT/mTORC1 readouts in cancer cells; shRNA knockdown with JNK pathway assays in macrophages

    PMID:38614385 PMID:40987893

    Open questions at the time
    • Opposing roles in cancer cells versus macrophages are not reconciled mechanistically
    • Whether FPR3 signals through canonical Gi in the tumor microenvironment is untested
    • In vivo validation in FPR3-deficient tumor models is lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the machinery mediating FPR3 constitutive clathrin-independent internalization, the in vivo immune function of the F2L–FPR3 axis, whether yeast Fpr3 PPIase activity directly isomerizes identified substrates, and the structural basis for FPR3 ligand selectivity.
  • No structural model of FPR3 or Fpr3 bound to ligands or PP1
  • No genetic disease association established for human FPR3
  • In vivo immune phenotype of FPR3 knockout in mammals not reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0031410 cytoplasmic vesicle 2 GO:0005730 nucleolus 1
Pathway
R-HSA-162582 Signal Transduction 3 GO:0060089 molecular transducer activity 2 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 1
Partners
CK2CSE4GNG2PP1PSH1PTP1ZIP3

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Yeast Fpr3 is a nucleolarly localized FK506- and rapamycin-binding protein with peptidyl-prolyl cis-trans isomerase (PPIase) activity; both full-length Fpr3 and its isolated C-terminal FKBP domain exhibit PPIase activity when expressed in E. coli, and Fpr3 localizes exclusively to the nucleolus as shown by indirect immunofluorescence. Protein purification from E. coli, PPIase activity assay, indirect immunofluorescence, deletion mutant analysis The Journal of cell biology High 7525596 7925954
1994 Overexpression of full-length Fpr3 (but not the isolated C-terminal domain) is growth-inhibitory in yeast, and this toxicity is suppressed by rapamycin in fpr1Δ cells; the C-terminal domain alone (not full-length) restores rapamycin sensitivity in fpr1Δ cells, indicating distinct functional roles for the N- and C-terminal domains. GAL1-driven overexpression, fpr1Δ genetic background, rapamycin sensitivity assay The Journal of cell biology Medium 7525596
1995 Yeast Fpr3 is phosphorylated at Tyr-184 in vivo and is a physiological substrate of the tyrosine phosphatase Ptp1; immobilized phosphotyrosyl Fpr3 is directly dephosphorylated by recombinant Ptp1 in vitro, and Tyr-184 was confirmed as the phosphorylation site by site-directed mutagenesis. Protein purification, site-directed mutagenesis, in vitro phosphatase assay, ptp1 mutant yeast analysis The Journal of biological chemistry High 7559654
1997 Casein kinase II (CK2) phosphorylates yeast Fpr3 at Tyr-184 and adjacent Ser/Thr residues both in vitro and in vivo via a two-step mechanism in which prior phosphorylation at Ser-186 (position +2) provides a negatively-charged determinant that enables subsequent CK2-mediated Tyr-184 phosphorylation. In vitro phosphorylation assay with purified CK2 (yeast and human), CK2 overexpression/temperature-sensitive allele in vivo, synthetic peptide substrates, metabolic labeling The Journal of biological chemistry High 9148902
1999 CK2 can phosphorylate Fpr3 at Tyr-184 using structural features partially distinct from its canonical Ser/Thr consensus; the Asp at n+1 and Ile at n-1 around Tyr-184 are critical determinants that differentiate CK2-mediated Tyr versus Ser phosphorylation. In vitro kinase assay with synthetic peptide substrates and purified CK2, kinetic analysis (Km, Vmax), systematic residue substitutions The Journal of biological chemistry High 10506183
2000 Fpr3 (and Fpr4) suppress temperature-sensitive growth defects of tom1Δ (E3 ubiquitin ligase) mutants when overexpressed; suppression requires the conserved ~170-residue N-terminal acidic domain, not the PPIase domain, indicating a chaperone-like function of the N-terminus independent of isomerase activity. Multicopy suppressor screen, domain deletion analysis, growth assay in tom1Δ background Molecular & general genetics Medium 10821187
2001 Human FPRL2 (FPR3) is a functional chemoattractant receptor on monocytes that signals through calcium mobilization and mediates cell migration in response to the synthetic hexapeptide WKYMVm; FPRL2 is constitutively phosphorylated in unstimulated cells and undergoes internalization upon agonist stimulation. Calcium flux assay in HL-60 cells transfected with FPRL2, chemotaxis assay, radioligand binding, metabolic labeling/phosphorylation assay, receptor internalization assay The Journal of biological chemistry High 11285256
2004 F2L, an acetylated N-terminal peptide derived from the human heme-binding protein, is the first identified endogenous high-affinity agonist specific for FPRL2 (FPR3); F2L activates FPRL2 in the low nanomolar range, triggering intracellular calcium release, cAMP inhibition, and ERK1/2 phosphorylation via Gi-class heterotrimeric G proteins, and promotes chemotaxis of monocytes and dendritic cells. Peptide isolation from spleen extract, calcium mobilization assay, cAMP assay, ERK1/2 phosphorylation assay, Gi inhibitor (pertussis toxin) experiments, chemotaxis assay The Journal of experimental medicine High 15623572
2004 Yeast LMW-PTP Ltp1 dephosphorylates Fpr3 at Tyr-184 in vivo, and its phosphorylation status influences Fpr3 subcellular localization. In vivo phosphorylation analysis, LMW-PTP activity assay, localization studies Biochemical and biophysical research communications Medium 15358193
2004 Yeast Stp1 LMW-PTP interacts with and dephosphorylates Fpr3 in vivo; combined blockage of CK2 and overexpression of Stp1 cooperatively induces a severe growth-defective phenotype, indicating that CK2-mediated phosphorylation and LMW-PTP-mediated dephosphorylation of Fpr3 together regulate cell growth and budding. Co-immunoprecipitation, in vivo phosphorylation analysis, CK2 inhibitor treatment, growth phenotype assay Cellular and molecular life sciences Medium 15141303
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 in vivo; loss of FPR3 or inhibition by rapamycin causes premature adaptation to DNA damage and impaired checkpoint function. fpr3Δ deletion analysis, rapamycin treatment, co-immunoprecipitation of Fpr3 and PP1, PP1 localization assay, meiotic checkpoint assay Cell High 16179256
2009 Yeast Fpr3 (together with SUMO ligase Zip3) functions in a checkpoint-like pathway to ensure that synaptonemal complex (SC) assembly is contingent on meiotic recombination initiation; Fpr3 and Zip3 specifically prevent synapsis initiation at centromeric sites, and their absence allows synapsis even when recombination initiation is blocked. Double and triple mutant analysis (fpr3Δ zip3Δ combined with recombination initiation mutants), cytological analysis of SC assembly Current biology Medium 19765989
2011 Human FPR3 is constitutively phosphorylated at basal state and localizes predominantly in intracellular vesicles (not plasma membrane) in unstimulated cells due to constitutive, clathrin-independent (possibly caveolae-dependent) internalization; domain-swap experiments mapping the N-terminal extracellular region and first transmembrane domain (residues 1–53) identified this region as the determinant controlling subcellular distribution, distinguishing FPR3 from FPR2/ALX. Domain-swap chimera expression, receptor-bound antibody uptake assay, pharmacological inhibition of internalization pathways, phosphorylation analysis by metabolic labeling The Journal of biological chemistry High 21543323
2013 Yeast Fpr3 PPIase domain represses transcription when tethered to a promoter and modulates expression of a large number of genes genome-wide, resembling the function of histone chaperones CAF1 and Asf1, indicating Fpr3 acts on non-histone chromatin components. Transcriptional profiling of fpr3Δ cells, tethered PPIase domain reporter assay Molecular genetics and genomics Medium 24297734
2014 Yeast Fpr3 proline isomerase is required for proteasome-dependent polyubiquitylation and degradation of centromeric histone H3 variant Cse4; Fpr3-mediated structural change in Cse4 appears important for the interaction between Cse4 and E3 ubiquitin ligase Psh1. fpr3Δ deletion analysis, Cse4 ubiquitylation and stability assay, genetic interaction analysis with psh1Δ Genetics Medium 24514906
2019 Mouse Fpr3 (Fpr-rs1) expressed in vomeronasal sensory neurons (VSNs) recognizes the core peptide motif f-MKKFRW from the bacterial protein MgrB (a virulence regulator of Enterobacteriaceae), activates VSNs, and drives innate avoidance behavior; Fpr3 is required for neuronal detection of this bacterial peptide. Ligand identification by functional screening, VSN activation assay, Fpr3 knockout mouse behavioral assay, in vivo calcium imaging in freely behaving mice Nature communications High 31653840
2024 Human FPR3 overexpression in gastric cancer cells impedes cytoplasmic calcium ion flux, preventing NFATc1 nuclear translocation; this reduces NFATc1-driven transcription of NOTCH3, suppresses AKT/mTORC1 signaling, and downregulates glycolysis and cancer cell stemness. FPR3 overexpression/knockdown, calcium flux assay, NFATc1 nuclear translocation assay, chromatin immunoprecipitation (NFATc1 binding to SOX2/NOTCH3 promoters), AKT/mTORC1 signaling readouts, glycolysis assay Cancer letters Medium 38614385
2025 FPR3 in tumor-associated macrophages upregulates FZD7 and CCDC88C, leading to activation of the intracellular Wnt/PCP pathway and downstream JNK signaling, thereby promoting TAM development and immunosuppressive polarization in gastric adenocarcinoma. shRNA-mediated FPR3 knockdown, specific agonist treatment, pathway activation assays (JNK signaling), single-cell analysis of TAM subsets Oncogene Medium 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 156 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 87 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 58 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 52 21543323
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
2009 Fpr3 and Zip3 ensure that initiation of meiotic recombination precedes chromosome synapsis in budding yeast. Current biology : CB 51 19765989
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 26 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