{"gene":"CD177","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1991,"finding":"The NB1 (CD177) antigen is anchored to the neutrophil plasma membrane via a glycosyl-phosphatidylinositol (GPI) linkage, as demonstrated by release of the 58–64 kDa protein from the cell surface upon treatment with phosphatidylinositol-specific phospholipase C (PI-PLC) and shift in electrophoretic mobility under non-denaturing conditions.","method":"PI-PLC treatment of 125I-surface-labeled neutrophils, non-denaturing gel electrophoresis, endoglycosidase-F digestion","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution with PI-PLC, confirmed by multiple orthogonal methods (radiolabeling, gel mobility shift, endoglycosidase treatment), replicated by later studies","pmids":["1825110"],"is_preprint":false},{"year":1990,"finding":"The NB1 (CD177) antigen resides on a 58–64 kDa surface glycoprotein that is also present in secondary (but not primary) neutrophil granules; the NB1 epitope is protein-based (not carbohydrate), requires intact tertiary structure (disulfide bonds), and is lost upon reduction.","method":"SDS-PAGE, immunoblotting with alloantisera, immunoprecipitation of 125I-labeled neutrophil membranes and granule fractions prepared by nitrogen cavitation and differential centrifugation; periodate and reduction treatments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (immunoblot, immunoprecipitation, subcellular fractionation, chemical modification) in a single focused study","pmids":["2153425"],"is_preprint":false},{"year":2001,"finding":"The NB1 (CD177) glycoprotein is a ~50.6 kDa GPI-anchored glycoprotein (43 kDa after N-glycan removal) belonging to the uPAR/CD59/Ly-6 snake-toxin superfamily, with two cysteine-rich domains, three N-linked glycosylation sites, and a GPI attachment site; surface expression was confirmed in transfected COS-7 cells.","method":"Immunoaffinity chromatography, MALDI-TOF mass spectrometry, N-terminal amino acid sequencing, RACE-PCR, cDNA cloning, COS-7 transfection with flow cytometry","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — protein purification, mass spectrometry, sequencing, and functional validation in transfected cells in a single study","pmids":["11465086"],"is_preprint":false},{"year":2000,"finding":"PRV-1 (CD177) encodes a GPI-anchored cell-surface receptor of 437 amino acids with two cysteine-rich uPAR/Ly6 superfamily domains; the protein is N-glycosylated, shed into cell supernatants as a soluble form, and expressed specifically on myeloid/granulocytic cells; overexpression in polycythemia vera is not due to gene rearrangement.","method":"Subtractive hybridization, Northern blot, cDNA cloning, intron-exon structure determination, FACS of stably transfected cells, immunoblotting, flow cytometry of bone marrow and peripheral blood","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — molecular cloning with full biochemical characterization in the original discovery paper, multiple orthogonal methods","pmids":["10753836","12239154"],"is_preprint":false},{"year":2007,"finding":"CD177 (NB1) is a heterophilic counter-receptor for platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) on endothelial cells; the interaction is cation-dependent and involves PECAM-1 domain 6; blocking antibodies to CD177 or PECAM-1 domain 6 inhibit both cell adhesion and transendothelial migration of neutrophils.","method":"Flow cytometry, immunoprecipitation, surface plasmon resonance (real-time protein–protein interaction analysis), U937 cell adhesion assays with immobilized PECAM-1, transendothelial migration assays with blocking monoclonal antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — surface plasmon resonance plus reciprocal binding assays plus functional migration inhibition, replicated in subsequent studies","pmids":["17580308"],"is_preprint":false},{"year":2007,"finding":"NB1 (CD177) mediates surface expression of the autoantigen proteinase 3 (PR3) on human neutrophils; PR3 and NB1 co-immunoprecipitate and co-localize on the plasma membrane; enzymatic removal of GPI anchors reduces membrane PR3 expression; transfection of NB1 into HEK293 and HL60 cells confers specific surface PR3 binding.","method":"Flow cytometry, confocal microscopy, co-immunoprecipitation, Western blot, GPI anchor removal with phospholipase, transfection of HEK293 and HL60 cells, magnetic cell sorting of NB1+/NB1− subsets, cord blood stem cell differentiation model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-IP, co-localization, GPI removal, and transfection rescue all in one study; replicated by multiple independent labs","pmids":["17244676"],"is_preprint":false},{"year":2006,"finding":"CD177 and membrane PR3 are co-expressed exclusively on the same neutrophil subset; their surface expression increases or decreases in parallel during cell stimulation or apoptosis; both undergo rapid internalization and recirculation (all mPR3 replaced within 30 min), and their co-expression indicates shared storage in secondary granules and secretory vesicles (not primary granules).","method":"Flow cytometry of matched CD177/mPR3 expression, stimulation and apoptosis assays, kinetic internalization experiments","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple flow cytometry readouts in one lab; no reconstitution, but consistent with co-IP data from other labs","pmids":["17077162"],"is_preprint":false},{"year":2008,"finding":"A unique hydrophobic cluster in human PR3 (residues F166, W218, G219, L223 in the C-terminal half) mediates binding to the NB1 (CD177) receptor on the cell surface; the gibbon PR3 homolog, which lacks these residues, does not bind human NB1; NB1-bound PR3 retains enzymatic activity and is cleared from the surface by α1-protease inhibitor.","method":"Cloning of gibbon PR3 homolog, construction of human–gibbon PR3 hybrid proteins, NB1-binding assays, activity assays with α1-protease inhibitor","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain-swap mutagenesis plus functional binding and activity assays define the molecular determinant","pmids":["18854317"],"is_preprint":false},{"year":2010,"finding":"Mac-1 (CD11b/CD18) is an adaptor for NB1 (CD177)-mediated PR3-ANCA neutrophil activation: the NB1 signaling complex precipitated from plasma membranes contains Mac-1, as identified by MS/MS and immunoblotting; NB1 shows direct protein–protein interaction with CD11b and CD11a by SPR, but only Mac-1-transfected cells adhere to immobilized NB1; NB1, PR3, and Mac-1 reside in lipid rafts; CD11b blockade inhibits NB1-triggered degranulation and superoxide production.","method":"Membrane complex immunoprecipitation, MS/MS and immunoblotting identification of Mac-1, surface plasmon resonance, cell adhesion assays on transfected cells, lipid raft fractionation, confocal microscopy co-localization, functional assays (degranulation, oxidative burst) with blocking antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — SPR, MS/MS identification, transfection-based adhesion assay, and functional blocking experiments in one rigorous study","pmids":["21193407"],"is_preprint":false},{"year":2010,"finding":"CD177-mediated neutrophil transmigration is influenced by the endothelial PECAM-1 S536N dimorphism: CD177+ neutrophils migrate significantly faster through HUVECs expressing the LSR allelic variant than the VNG variant; heterophilic CD177/PECAM-1 engagement suppresses PECAM-1 ITIM tyrosine phosphorylation and increases β-catenin phosphorylation, facilitating junction opening in an allele-specific manner.","method":"In vitro transendothelial migration assays through HUVECs expressing defined PECAM-1 allelic variants, rCD177-Fc engagement, phosphorylation assays for PECAM-1 ITIM and β-catenin","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined mechanistic pathway with allele-specific functional readout, single lab","pmids":["20194726"],"is_preprint":false},{"year":2012,"finding":"PR3 serine protease activity facilitates transendothelial migration specifically of NB1 (CD177)-positive neutrophils: PR3 expression and activity increase on NB1+ neutrophils following transmigration (not on NB1− neutrophils); selective serine protease inhibitors block NB1+ neutrophil diapedesis under static and flow conditions.","method":"Transendothelial migration assays through IL-1β-stimulated endothelial monolayers, blocking antibodies to PECAM-1, PR3 activity measurement after transmigration, selective serine protease inhibitors under static and flow conditions","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pharmacological inhibition plus subset-specific activity measurement, single lab","pmids":["22266279"],"is_preprint":false},{"year":2017,"finding":"CD177 ligation on CD177pos neutrophils selectively impairs their migration by immobilizing cells and causing spreading; mechanistically, CD177 ligation enhances its interaction with β2 integrins (shown by fluorescence lifetime imaging microscopy), leading to integrin-mediated phosphorylation of Src and ERK, increased surface β2 integrin expression and affinity, impaired integrin attachment internalization, and ERK-mediated attenuation of chemokine signaling.","method":"PECAM-1-independent transwell migration assay, fluorescence lifetime imaging microscopy (FLIM) for CD177–β2 integrin interaction, phosphorylation assays (Src, ERK), surface integrin expression and affinity measurements, chemokine receptor internalization assays, kinase inhibitor studies","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — FLIM imaging of protein interaction plus multiple orthogonal functional assays in one study, mechanistic pathway fully delineated","pmids":["28807980"],"is_preprint":false},{"year":2017,"finding":"Subset-restricted CD177 expression in bimodal individuals arises from monoallelic expression: CD177pos neutrophils transcribe only the maternal or paternal allele, while the other allele is silenced during neutrophil differentiation from hematopoietic stem cells that express both alleles; DNA methylation of the CD177 promoter reduces expression, demethylation causes biallelic expression, and c-Jun/c-Fos binding to the unmethylated, euchromatic promoter drives CD177 transcription in CD177pos neutrophils.","method":"Single-cell haplotype analysis, ChIP for histone marks and c-Jun/c-Fos, CpG methylation analysis, reporter assays in HeLa cells with mono- vs. biallelic expression, demethylation experiments, hematopoietic stem cell differentiation tracking","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP, reporter assays, methylation analysis, and allele tracking with multiple orthogonal methods in one study","pmids":["28559244"],"is_preprint":false},{"year":2003,"finding":"NB1-negative neutrophils in bimodal individuals contain no NB1 mRNA even after G-CSF stimulation, and this transcriptional silencing correlates with specific CD177 coding polymorphisms; three out of six identified polymorphisms are significantly associated with a small NB1-expressing neutrophil subpopulation.","method":"Immunofluorescence-based single-cell picking and FACS sorting of NB1+ vs NB1− subsets, RT-PCR for NB1 mRNA, cDNA sequencing, G-CSF stimulation experiments","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct demonstration of mRNA absence in sorted subsets plus genotype-phenotype correlation, single lab","pmids":["12623849"],"is_preprint":false},{"year":2016,"finding":"The CD177null phenotype arises when exon 7 of the CD177 gene is supplied entirely by the CD177P1 pseudogene through allelic gene conversion, introducing a stop codon; the proportion of CD177hi neutrophils in blood is heritable and correlates with CD177 reference allele homozygosity.","method":"Deep sequencing of the CD177 locus, identification of stop codon from pseudogene-derived exon 7 sequence, genotype–phenotype correlation in families and population cohorts","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deep sequencing with genotype-phenotype correlation; single study but comprehensive locus-level analysis","pmids":["27227454"],"is_preprint":false},{"year":2014,"finding":"CD177 deletion in mice reduces peripheral blood neutrophil counts and reduces neutrophil accumulation in S. aureus skin infection; CD177 deletion has no significant impact on CXCL1/KC- or fMLP-induced neutrophil migration but leads to significant neutrophil cell death, indicating a pro-survival role.","method":"CD177 genetic knockout mouse model, complete blood counts, S. aureus skin infection model with neutrophil counting, CXCL1/fMLP migration assays, cell death assays","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined infection phenotype and mechanistic distinction between migration and survival; single lab","pmids":["25359465"],"is_preprint":false},{"year":2017,"finding":"CD177+ neutrophils in IBD produce lower levels of pro-inflammatory cytokines (IFN-γ, IL-6, IL-17A) but higher levels of IL-22 and TGF-β, exhibit increased bactericidal activities (ROS, antimicrobial peptides, NETs), and protect against colitis; CD177−/− mice develop more severe DSS colitis with compromised intestinal barrier and impaired IL-22 production.","method":"Flow cytometry and immunohistochemistry in IBD patients, RNA sequencing of sorted CD177+/CD177− neutrophil subsets, cytokine/ROS/NET functional assays, DSS colitis model in CD177−/− mice","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — CD177 KO mouse plus human subset RNA-seq plus multiple functional assays; replicated across patient and mouse data","pmids":["28468761"],"is_preprint":false},{"year":2021,"finding":"CD177 is expressed on a specific Fate-1 subset of tumor-infiltrating regulatory T cells (TI Tregs) in renal clear cell carcinoma and other solid cancers; blocking CD177 reduces Treg suppressive activity in vitro, and Treg-specific deletion of Cd177 in mice leads to decreased tumor growth and reduced TI Treg frequency.","method":"Single-cell RNA sequencing of ccRCC immune cells, in vitro Treg suppression assay with CD177 blocking, conditional Treg-specific Cd177 knockout mouse tumor model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq for identification, in vitro functional assay, and conditional KO tumor model; single lab","pmids":["34599187"],"is_preprint":false},{"year":2020,"finding":"CD177 marks anterior definitive endoderm (ADE) subpopulations in human pluripotent stem cell-derived cultures; CD177+ ADE expresses and synthesizes the secreted WNT/NODAL/BMP antagonist CERBERUS1 and is specified toward pancreatic fate through non-canonical WNT signaling, whereas CD275+ ADE receives canonical WNT signaling and is specified toward liver fate; isolated CD177+ ADE differentiates more homogeneously into functional glucose-responsive β-like cells.","method":"Surface marker-based sorting of definitive endoderm subpopulations, RNA-seq and signaling pathway analysis, CERBERUS1 expression/secretion assays, in vitro pancreatic and hepatic differentiation with functional glucose-stimulated insulin secretion assays","journal":"Nature biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sorting-based subpopulation isolation with functional differentiation outcome and secreted factor identification; single lab","pmids":["32341565"],"is_preprint":false},{"year":2018,"finding":"CD177 is a functional binding partner of podoplanin (PDPN) on cancer-associated fibroblasts, identified via high-throughput surface interactome screening; CD177 acts as a functional antagonist of PDPN, recapitulating the phenotype of PDPN-deficient CAFs, and PDPN signaling involves actomyosin contractility and cell growth pathways.","method":"High-throughput PDPN cell surface interactome screen, quantitative phosphoproteomics of CAF phosphoproteome, cellular phenotype assays in PDPN-deficient and CD177-treated CAFs","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased interactome screen plus phosphoproteomics and functional cellular assays; single lab","pmids":["34879110"],"is_preprint":false},{"year":2020,"finding":"CD177 deficiency in breast cancer cells is associated with increased β-catenin/Wnt signaling; loss of CD177 leads to hyperproliferative mammary epithelium; CD177 acts as a novel regulator of mammary epithelial proliferation through modulation of the Wnt/β-catenin pathway.","method":"CD177 knockout/knockdown in breast cancer cell lines and mouse mammary gland models, β-catenin signaling pathway analysis, proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined signaling pathway readout; single lab","pmids":["32042113"],"is_preprint":false},{"year":2018,"finding":"PECAM-1 interaction with CD177 downregulates membrane PR3 (mPR3) expression on neutrophils in a dose-dependent manner; this results in attenuated PR3-ANCA-induced neutrophil degranulation and oxidative burst; the inhibitory effect on degranulation is absent in CD177-negative neutrophils, confirming CD177 dependence.","method":"ELISA and flow cytometry for mPR3 expression, DHR oxidative burst assay, degranulation ELISA, MACS-sorted CD177-negative neutrophil experiments with recombinant PECAM-1","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with CD177-negative controls confirming specificity; single lab","pmids":["30236159"],"is_preprint":false},{"year":2012,"finding":"CD177/PECAM-1 adhesive interaction supports neutrophil transendothelial migration but does not contribute to platelet–neutrophil interactions: CD177+ and CD177− neutrophils do not differ in platelet conjugate formation under static or flow conditions, whereas predominantly CD177+ neutrophils migrate preferentially across HUVEC monolayers; the PECAM-1 S536N dimorphism affects transendothelial migration but not platelet binding.","method":"Whole-blood and isolated platelet–neutrophil conjugate assays under flow and static conditions, transendothelial migration across HUVEC monolayers, comparison of PECAM-1 allelic variants","journal":"European journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comparative functional assays with defined allelic variants; negative finding for platelet interaction mechanistically informative; single lab","pmids":["22690867"],"is_preprint":false},{"year":1994,"finding":"Unstimulated NB1-positive neutrophils show reduced adherence to HUVEC monolayers compared to NB1-negative neutrophils; blocking NB1 with Fab fragments increases NB1+ neutrophil adherence to HUVEC; NB1+ neutrophils show greater chemotaxis to fMLP through nitrocellulose but not polycarbonate membranes; no differences in adhesion to extracellular matrix proteins.","method":"Adhesion assays of sorted NB1+/NB1− neutrophils to HUVEC monolayers and ECM proteins, anti-NB1 Fab fragment blocking, chemotaxis assays through nitrocellulose and polycarbonate membranes","journal":"The Journal of laboratory and clinical medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional comparison of sorted subsets with antibody blocking; single lab, but multiple functional readouts","pmids":["8301201"],"is_preprint":false},{"year":2010,"finding":"In ANCA-associated vasculitis and SLE, the percentage of CD177-expressing neutrophils is significantly increased, but primed CD177-negative neutrophils from CD177-null donors also express mPR3 and are susceptible to anti-PR3-mediated oxidative burst, indicating that a CD177-independent pathway for mPR3 membrane recruitment exists.","method":"Flow cytometry of neutrophils from ASV, SLE, RA patients and healthy controls, DHR oxidative burst assay, TNF-α priming, comparison of CD177-null donor and sorted CD177− subsets","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistically informative negative result (CD177-independent mPR3 pathway) established by functional assay in CD177-null donors; single lab","pmids":["19404956"],"is_preprint":false},{"year":2022,"finding":"CD177+ neutrophils are the main Gr-1+ population in mouse biliary atresia livers; they exhibit elevated mitochondrial ROS and form neutrophil extracellular traps (NETs) that induce apoptosis of biliary epithelial cells in co-culture; Cd177−/− mice show delayed disease onset and reduced morbidity/mortality; NET inhibitors reduce bile duct damage.","method":"scRNA-seq and Smart-Seq RNA-seq of liver Gr-1+ cells, Cd177−/− mouse BA model (rhesus rotavirus), ROS measurement, NET quantification, co-culture apoptosis assay, NET inhibitor treatment, pilot clinical study with N-acetylcysteine","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model plus scRNA-seq plus in vitro mechanistic assays plus pharmacological inhibition; multiple orthogonal methods","pmids":["35803543"],"is_preprint":false},{"year":2025,"finding":"CD177+ neutrophils in lung ischemia-reperfusion injury exhibit elevated oxidative phosphorylation and increased mitochondrial complex I activity, driving inflammation and NET formation; inhibiting complex I with IACS-010759 reduces CD177+ neutrophil activation and alleviates lung injury in mouse IRI and rat lung transplant models.","method":"scRNA-seq and spatial transcriptomics of IRI lung, mitochondrial complex I activity assays, IACS-010759 pharmacological inhibition in mouse IRI and rat transplant models, NET quantification, human lung transplant cohort AUC analysis","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (complex I → inflammation/NETs) established by pharmacological inhibition in two animal models plus transcriptomic identification; single lab","pmids":["40398393"],"is_preprint":false}],"current_model":"CD177 is a GPI-anchored, uPAR/Ly6-superfamily glycoprotein expressed on a genetically determined subset of neutrophils (and, ectopically, on tumor-infiltrating Tregs and definitive endoderm); it functions as a heterophilic counter-receptor for endothelial PECAM-1 (mediating transendothelial migration via β2 integrin/Src/ERK signaling) and as a membrane receptor for the serine protease PR3 (which it presents on the neutrophil surface via a specific hydrophobic patch, enabling Mac-1-dependent ANCA-mediated activation); CD177+ neutrophil subset restriction is controlled by monoallelic epigenetic silencing through promoter CpG methylation and c-Jun/c-Fos binding, and CD177 also modulates Wnt/β-catenin signaling in epithelial cells and has been identified as a novel ligand for podoplanin on cancer-associated fibroblasts."},"narrative":{"mechanistic_narrative":"CD177 (NB1/PRV-1) is a GPI-anchored cell-surface glycoprotein of the uPAR/CD59/Ly-6 snake-toxin superfamily, expressed on a genetically and epigenetically restricted subset of neutrophils where it governs neutrophil adhesion, transendothelial migration, and presentation of the autoantigen proteinase 3 (PR3) [PMID:11465086, PMID:17244676]. Biochemically it is a ~50 kDa N-glycosylated, GPI-linked protein with two cysteine-rich domains that is released from the membrane by PI-PLC and stored in secondary granules and secretory vesicles [PMID:1825110, PMID:2153425, PMID:10753836, PMID:12239154]. CD177 serves as a heterophilic counter-receptor for endothelial PECAM-1 (engaging PECAM-1 domain 6 in a cation-dependent manner), an interaction that supports neutrophil diapedesis and is tuned by the endothelial PECAM-1 S536N dimorphism through modulation of PECAM-1 ITIM and β-catenin phosphorylation [PMID:17580308, PMID:20194726]. It functions as the membrane receptor that presents catalytically active PR3 on the neutrophil surface via a discrete hydrophobic cluster in PR3, and assembles into a lipid-raft signaling complex with Mac-1 (CD11b/CD18) that transduces PR3-ANCA-mediated degranulation and oxidative burst [PMID:17244676, PMID:18854317, PMID:21193407]. Upon ligation, CD177 enhances its interaction with β2 integrins to drive Src/ERK signaling, increase integrin affinity, and arrest migration, while PECAM-1 engagement conversely downregulates membrane PR3 and dampens ANCA-induced activation [PMID:28807980, PMID:30236159]. Subset-restricted expression is established by monoallelic transcription enforced by promoter CpG methylation with c-Jun/c-Fos binding to the active allele, and the CD177null phenotype arises from pseudogene-derived allelic gene conversion introducing a stop codon [PMID:28559244, PMID:27227454]. Beyond neutrophils, CD177 marks immunosuppressive tumor-infiltrating Tregs, modulates Wnt/β-catenin signaling in mammary epithelium, and partners with podoplanin on cancer-associated fibroblasts [PMID:34599187, PMID:32042113, PMID:34879110]. CD177+ neutrophil subsets drive context-specific protective or pathogenic functions in colitis, biliary atresia, and lung ischemia-reperfusion injury, the latter two via mitochondrial-ROS-driven NET formation [PMID:28468761, PMID:35803543, PMID:40398393].","teleology":[{"year":1991,"claim":"Established the basic biochemical nature of the NB1 antigen, defining it as a GPI-anchored membrane glycoprotein rather than a transmembrane protein.","evidence":"PI-PLC release of surface-labeled neutrophil protein with non-denaturing gel shift and endoglycosidase digestion","pmids":["1825110","2153425"],"confidence":"High","gaps":["Protein sequence and gene identity not yet determined","Function unknown"]},{"year":2001,"claim":"Cloned the gene and placed CD177 in the uPAR/CD59/Ly-6 superfamily, defining its domain architecture and confirming surface expression in transfected cells.","evidence":"Immunoaffinity purification, MALDI-TOF MS, N-terminal sequencing, cDNA cloning, COS-7/transfection FACS (also molecular cloning of PRV-1)","pmids":["11465086","10753836","12239154"],"confidence":"High","gaps":["No ligand or receptor function identified","Reason for restricted neutrophil expression unknown"]},{"year":2007,"claim":"Identified two distinct binding functions of CD177 — as the counter-receptor for endothelial PECAM-1 and as the membrane receptor presenting PR3 — establishing its dual role in migration and autoantigen display.","evidence":"SPR, reciprocal immunoprecipitation, adhesion/transmigration assays for PECAM-1; co-IP, co-localization, GPI removal, and transfection rescue for PR3","pmids":["17580308","17244676"],"confidence":"High","gaps":["Molecular determinants of PR3 binding not yet mapped","Downstream signaling partners unknown"]},{"year":2008,"claim":"Mapped the PR3 binding determinant to a species-specific hydrophobic cluster, demonstrating molecular specificity of the CD177-PR3 interaction.","evidence":"Human-gibbon PR3 hybrid domain swaps with NB1-binding and activity assays","pmids":["18854317"],"confidence":"High","gaps":["The reciprocal CD177 binding interface not defined","Structural model absent"]},{"year":2010,"claim":"Resolved how a GPI-anchored protein transduces signals by identifying Mac-1 as the transmembrane adaptor in the CD177-PR3 raft complex that drives ANCA-mediated activation.","evidence":"Membrane complex IP with MS/MS, SPR, Mac-1-transfected adhesion assay, lipid raft fractionation, blocking-antibody degranulation/oxidative burst assays","pmids":["21193407"],"confidence":"High","gaps":["Stoichiometry of the CD177/PR3/Mac-1 complex not defined","Whether other integrins substitute in vivo unclear"]},{"year":2012,"claim":"Refined the migration mechanism by showing PR3 serine protease activity itself facilitates CD177+ neutrophil diapedesis and that the CD177/PECAM-1 axis is migration-specific, not platelet-binding.","evidence":"Transendothelial migration with serine protease inhibitors and PR3 activity measurement; platelet-neutrophil conjugate assays under flow","pmids":["22266279","22690867"],"confidence":"Medium","gaps":["Substrates cleaved by PR3 during diapedesis not identified","Single-lab functional data"]},{"year":2017,"claim":"Established the integrin-coupled signaling output of CD177 ligation and the epigenetic basis of subset restriction, explaining both how CD177 controls migration and why only some neutrophils express it.","evidence":"FLIM of CD177-β2 integrin interaction with Src/ERK phosphorylation and integrin affinity assays; single-cell haplotype analysis, ChIP for c-Jun/c-Fos and histone marks, CpG methylation and reporter assays","pmids":["28807980","28559244"],"confidence":"High","gaps":["Trigger for allele choice during differentiation unknown","Physiological ligand initiating CD177 ligation in vivo not defined"]},{"year":2016,"claim":"Defined the genetic basis of the CD177null phenotype, attributing it to pseudogene-derived gene conversion and heritable control of CD177hi neutrophil proportion.","evidence":"Deep sequencing of the CD177 locus with family and population genotype-phenotype correlation","pmids":["27227454","12623849"],"confidence":"Medium","gaps":["Mechanism of allelic gene conversion not detailed","Population frequency of conversion event unclear"]},{"year":2017,"claim":"Demonstrated context-dependent roles of CD177+ neutrophils in tissue protection and the inhibitory tuning of mPR3 by PECAM-1, linking CD177 biology to inflammatory disease.","evidence":"CD177 KO mice in DSS colitis with subset RNA-seq and functional assays; recombinant PECAM-1 mPR3 downregulation assays with CD177-negative controls (also 2014 KO survival phenotype)","pmids":["28468761","30236159","25359465"],"confidence":"High","gaps":["Molecular link between CD177 and IL-22/survival programs unclear","Whether protective vs pathogenic balance is tissue-intrinsic unknown"]},{"year":2021,"claim":"Extended CD177 function beyond neutrophils, identifying it on suppressive tumor-infiltrating Tregs, in epithelial Wnt regulation, in endoderm fate, and as a podoplanin partner on CAFs.","evidence":"scRNA-seq plus conditional Treg KO tumor model; breast cancer loss-of-function with β-catenin readout; hPSC endoderm sorting/differentiation; PDPN surface interactome screen with phosphoproteomics","pmids":["34599187","32042113","32341565","34879110"],"confidence":"Medium","gaps":["Mechanism linking GPI-anchored CD177 to intracellular Wnt/β-catenin unresolved","Direct vs indirect role in Treg suppression unclear","Single-lab findings each"]},{"year":2025,"claim":"Defined a metabolic axis in pathogenic CD177+ neutrophils, showing mitochondrial complex I activity drives NET-mediated tissue injury in biliary atresia and lung ischemia-reperfusion.","evidence":"scRNA-seq/spatial transcriptomics, complex I activity assays, NET quantification, and pharmacological complex I inhibition in mouse and rat models","pmids":["35803543","40398393"],"confidence":"Medium","gaps":["Whether CD177 itself regulates mitochondrial metabolism vs marks metabolically active cells unclear","Single-lab models"]},{"year":null,"claim":"How a GPI-anchored Ly-6 protein with no intrinsic catalytic or transmembrane domain mechanistically couples to intracellular Wnt/β-catenin and metabolic programs across diverse non-neutrophil cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CD177 or its complexes","Signal transduction in epithelial/Treg/endoderm contexts not mechanistically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[4,23]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,16]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,20]}],"complexes":["CD177/PR3/Mac-1 lipid-raft signaling complex"],"partners":["PECAM-1","PRTN3","ITGAM","ITGB2","PDPN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N6Q3","full_name":"CD177 antigen","aliases":["Human neutrophil alloantigen 2a","HNA-2a","NB1 glycoprotein","NB1 GP","Polycythemia rubra vera protein 1","PRV-1"],"length_aa":437,"mass_kda":46.4,"function":"In association with beta-2 integrin heterodimer ITGAM/CD11b and ITGB2/CD18, mediates activation of TNF primed neutrophils including degranulation and superoxide production (PubMed:21193407). In addition, by preventing beta-2 integrin internalization and attenuating chemokine signaling favors adhesion over migration (PubMed:28807980). Heterophilic interaction with PECAM1 on endothelial cells plays a role in neutrophil transendothelial migration in vitro (PubMed:17580308). However, appears to be dispensable for neutrophil recruitment caused by bacterial infection in vivo (PubMed:23461681). Acts as a receptor for the mature form of protease PRTN3 allowing its display at the cell surface of neutrophils (PubMed:17244676, PubMed:18462208). By displaying PRTN3 at the neutrophil cell surface, may play a role in enhancing endothelial cell junctional integrity and thus vascular integrity during neutrophil diapedesis (PubMed:23202369)","subcellular_location":"Cell membrane; Membrane raft; Secreted; Cytoplasmic granule membrane; Cell projection, lamellipodium","url":"https://www.uniprot.org/uniprotkb/Q8N6Q3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD177","classification":"Not Classified","n_dependent_lines":37,"n_total_lines":381,"dependency_fraction":0.09711286089238845},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD177","total_profiled":1310},"omim":[{"mim_id":"173445","title":"PLATELET-ENDOTHELIAL CELL ADHESION MOLECULE 1; PECAM1","url":"https://www.omim.org/entry/173445"},{"mim_id":"162860","title":"CD177 ANTIGEN; 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Pro-Inflammatory Environment.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33995395","citation_count":18,"is_preprint":false},{"pmid":"15384975","id":"PMC_15384975","title":"Platelet-rich plasma serotonin levels in chronic myeloproliferative disorders: evaluation of diagnostic use and comparison with the neutrophil PRV-1 assay.","date":"2004","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/15384975","citation_count":18,"is_preprint":false},{"pmid":"17256145","id":"PMC_17256145","title":"Biomarker analysis in polycythemia vera under interferon-alpha treatment: clonality, EEC, PRV-1, and JAK2 V617F.","date":"2007","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/17256145","citation_count":17,"is_preprint":false},{"pmid":"32011681","id":"PMC_32011681","title":"CD177 Enhances the Detection of Myelodysplastic Syndrome by Flow Cytometry.","date":"2020","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32011681","citation_count":16,"is_preprint":false},{"pmid":"32042113","id":"PMC_32042113","title":"Cancer cell-intrinsic function of CD177 in attenuating β-catenin signaling.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32042113","citation_count":16,"is_preprint":false},{"pmid":"15461629","id":"PMC_15461629","title":"PRV-1, erythroid colonies and platelet Mpl are unrelated to thrombosis in essential thrombocythaemia.","date":"2004","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/15461629","citation_count":16,"is_preprint":false},{"pmid":"39223577","id":"PMC_39223577","title":"Dual role of CD177 + neutrophils in inflammatory bowel disease: a review.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39223577","citation_count":15,"is_preprint":false},{"pmid":"30828823","id":"PMC_30828823","title":"The nonconservative CD177 single-nucleotide polymorphism c.1291G>A is a genetic determinant for human neutrophil antigen-2 atypical/low expression and deficiency.","date":"2019","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/30828823","citation_count":15,"is_preprint":false},{"pmid":"30236159","id":"PMC_30236159","title":"Interaction between CD177 and platelet endothelial cell adhesion molecule-1 downregulates membrane-bound proteinase-3 (PR3) expression on neutrophils and attenuates neutrophil activation induced by PR3-ANCA.","date":"2018","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30236159","citation_count":15,"is_preprint":false},{"pmid":"8488543","id":"PMC_8488543","title":"Polyclonal antibodies against the NB1-bearing 58- to 64-kDa glycoprotein of human neutrophils do not identify an NB2-bearing molecule.","date":"1993","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/8488543","citation_count":15,"is_preprint":false},{"pmid":"40398393","id":"PMC_40398393","title":"Targeting mitochondrial complex I of CD177+ neutrophils alleviates lung ischemia-reperfusion injury.","date":"2025","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40398393","citation_count":14,"is_preprint":false},{"pmid":"31509227","id":"PMC_31509227","title":"Kidney injury enhances renal G-CSF expression and modulates granulopoiesis and human neutrophil CD177 in vivo.","date":"2019","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31509227","citation_count":14,"is_preprint":false},{"pmid":"8301201","id":"PMC_8301201","title":"Neutrophil-specific antigen NB1 inhibits neutrophil-endothelial cell interactions.","date":"1994","source":"The Journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8301201","citation_count":14,"is_preprint":false},{"pmid":"32093243","id":"PMC_32093243","title":"Dissemination of Piscine orthoreovirus-1 (PRV-1) in Atlantic Salmon (Salmo salar) during the Early and Regenerating Phases of Infection.","date":"2020","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32093243","citation_count":14,"is_preprint":false},{"pmid":"16293985","id":"PMC_16293985","title":"Inhibition of thrombin-induced vascular endothelial growth factor production in human neuroblastoma (NB-1) cells by argatroban.","date":"2005","source":"Pathophysiology of haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/16293985","citation_count":14,"is_preprint":false},{"pmid":"34879110","id":"PMC_34879110","title":"The neutrophil protein CD177 is a novel PDPN receptor that regulates human cancer-associated fibroblast physiology.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34879110","citation_count":13,"is_preprint":false},{"pmid":"35710735","id":"PMC_35710735","title":"Evaluation of (rac)-, (R)-, and (S)-18F-OF-NB1 for Imaging GluN2B Subunit-Containing N-Methyl-d-Aspartate Receptors in Nonhuman Primates.","date":"2022","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35710735","citation_count":13,"is_preprint":false},{"pmid":"8342232","id":"PMC_8342232","title":"Analysis of the expression of neutrophil-specific antigen NB1: characterization of neutrophils that react with but are not agglutinated by anti-NB1.","date":"1993","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/8342232","citation_count":13,"is_preprint":false},{"pmid":"33800725","id":"PMC_33800725","title":"Piscine Orthoreovirus (PRV)-3, but Not PRV-2, Cross-Protects against PRV-1 and Heart and Skeletal Muscle Inflammation in Atlantic Salmon.","date":"2021","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/33800725","citation_count":13,"is_preprint":false},{"pmid":"26388666","id":"PMC_26388666","title":"MnSOD downregulation induced by extremely low 0.1 mGy single and fractionated X-rays and microgravity treatment in human neuroblastoma cell line, NB-1.","date":"2015","source":"Journal of clinical biochemistry and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/26388666","citation_count":13,"is_preprint":false},{"pmid":"39396046","id":"PMC_39396046","title":"Nb1.60Ti0.32W0.08O5-δ as negative electrode active material for durable and fast-charging all-solid-state Li-ion batteries.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39396046","citation_count":13,"is_preprint":false},{"pmid":"9383737","id":"PMC_9383737","title":"Synthesis and purification of NB1-palmitoyl insulin.","date":"1997","source":"Journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/9383737","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53723,"output_tokens":7305,"usd":0.135372,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16817,"output_tokens":4163,"usd":0.09408,"stage2_stop_reason":"end_turn"},"total_usd":0.229452,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"The NB1 (CD177) antigen is anchored to the neutrophil plasma membrane via a glycosyl-phosphatidylinositol (GPI) linkage, as demonstrated by release of the 58–64 kDa protein from the cell surface upon treatment with phosphatidylinositol-specific phospholipase C (PI-PLC) and shift in electrophoretic mobility under non-denaturing conditions.\",\n      \"method\": \"PI-PLC treatment of 125I-surface-labeled neutrophils, non-denaturing gel electrophoresis, endoglycosidase-F digestion\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution with PI-PLC, confirmed by multiple orthogonal methods (radiolabeling, gel mobility shift, endoglycosidase treatment), replicated by later studies\",\n      \"pmids\": [\"1825110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The NB1 (CD177) antigen resides on a 58–64 kDa surface glycoprotein that is also present in secondary (but not primary) neutrophil granules; the NB1 epitope is protein-based (not carbohydrate), requires intact tertiary structure (disulfide bonds), and is lost upon reduction.\",\n      \"method\": \"SDS-PAGE, immunoblotting with alloantisera, immunoprecipitation of 125I-labeled neutrophil membranes and granule fractions prepared by nitrogen cavitation and differential centrifugation; periodate and reduction treatments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (immunoblot, immunoprecipitation, subcellular fractionation, chemical modification) in a single focused study\",\n      \"pmids\": [\"2153425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The NB1 (CD177) glycoprotein is a ~50.6 kDa GPI-anchored glycoprotein (43 kDa after N-glycan removal) belonging to the uPAR/CD59/Ly-6 snake-toxin superfamily, with two cysteine-rich domains, three N-linked glycosylation sites, and a GPI attachment site; surface expression was confirmed in transfected COS-7 cells.\",\n      \"method\": \"Immunoaffinity chromatography, MALDI-TOF mass spectrometry, N-terminal amino acid sequencing, RACE-PCR, cDNA cloning, COS-7 transfection with flow cytometry\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — protein purification, mass spectrometry, sequencing, and functional validation in transfected cells in a single study\",\n      \"pmids\": [\"11465086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PRV-1 (CD177) encodes a GPI-anchored cell-surface receptor of 437 amino acids with two cysteine-rich uPAR/Ly6 superfamily domains; the protein is N-glycosylated, shed into cell supernatants as a soluble form, and expressed specifically on myeloid/granulocytic cells; overexpression in polycythemia vera is not due to gene rearrangement.\",\n      \"method\": \"Subtractive hybridization, Northern blot, cDNA cloning, intron-exon structure determination, FACS of stably transfected cells, immunoblotting, flow cytometry of bone marrow and peripheral blood\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — molecular cloning with full biochemical characterization in the original discovery paper, multiple orthogonal methods\",\n      \"pmids\": [\"10753836\", \"12239154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD177 (NB1) is a heterophilic counter-receptor for platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) on endothelial cells; the interaction is cation-dependent and involves PECAM-1 domain 6; blocking antibodies to CD177 or PECAM-1 domain 6 inhibit both cell adhesion and transendothelial migration of neutrophils.\",\n      \"method\": \"Flow cytometry, immunoprecipitation, surface plasmon resonance (real-time protein–protein interaction analysis), U937 cell adhesion assays with immobilized PECAM-1, transendothelial migration assays with blocking monoclonal antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — surface plasmon resonance plus reciprocal binding assays plus functional migration inhibition, replicated in subsequent studies\",\n      \"pmids\": [\"17580308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NB1 (CD177) mediates surface expression of the autoantigen proteinase 3 (PR3) on human neutrophils; PR3 and NB1 co-immunoprecipitate and co-localize on the plasma membrane; enzymatic removal of GPI anchors reduces membrane PR3 expression; transfection of NB1 into HEK293 and HL60 cells confers specific surface PR3 binding.\",\n      \"method\": \"Flow cytometry, confocal microscopy, co-immunoprecipitation, Western blot, GPI anchor removal with phospholipase, transfection of HEK293 and HL60 cells, magnetic cell sorting of NB1+/NB1− subsets, cord blood stem cell differentiation model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-IP, co-localization, GPI removal, and transfection rescue all in one study; replicated by multiple independent labs\",\n      \"pmids\": [\"17244676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD177 and membrane PR3 are co-expressed exclusively on the same neutrophil subset; their surface expression increases or decreases in parallel during cell stimulation or apoptosis; both undergo rapid internalization and recirculation (all mPR3 replaced within 30 min), and their co-expression indicates shared storage in secondary granules and secretory vesicles (not primary granules).\",\n      \"method\": \"Flow cytometry of matched CD177/mPR3 expression, stimulation and apoptosis assays, kinetic internalization experiments\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple flow cytometry readouts in one lab; no reconstitution, but consistent with co-IP data from other labs\",\n      \"pmids\": [\"17077162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A unique hydrophobic cluster in human PR3 (residues F166, W218, G219, L223 in the C-terminal half) mediates binding to the NB1 (CD177) receptor on the cell surface; the gibbon PR3 homolog, which lacks these residues, does not bind human NB1; NB1-bound PR3 retains enzymatic activity and is cleared from the surface by α1-protease inhibitor.\",\n      \"method\": \"Cloning of gibbon PR3 homolog, construction of human–gibbon PR3 hybrid proteins, NB1-binding assays, activity assays with α1-protease inhibitor\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain-swap mutagenesis plus functional binding and activity assays define the molecular determinant\",\n      \"pmids\": [\"18854317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mac-1 (CD11b/CD18) is an adaptor for NB1 (CD177)-mediated PR3-ANCA neutrophil activation: the NB1 signaling complex precipitated from plasma membranes contains Mac-1, as identified by MS/MS and immunoblotting; NB1 shows direct protein–protein interaction with CD11b and CD11a by SPR, but only Mac-1-transfected cells adhere to immobilized NB1; NB1, PR3, and Mac-1 reside in lipid rafts; CD11b blockade inhibits NB1-triggered degranulation and superoxide production.\",\n      \"method\": \"Membrane complex immunoprecipitation, MS/MS and immunoblotting identification of Mac-1, surface plasmon resonance, cell adhesion assays on transfected cells, lipid raft fractionation, confocal microscopy co-localization, functional assays (degranulation, oxidative burst) with blocking antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — SPR, MS/MS identification, transfection-based adhesion assay, and functional blocking experiments in one rigorous study\",\n      \"pmids\": [\"21193407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD177-mediated neutrophil transmigration is influenced by the endothelial PECAM-1 S536N dimorphism: CD177+ neutrophils migrate significantly faster through HUVECs expressing the LSR allelic variant than the VNG variant; heterophilic CD177/PECAM-1 engagement suppresses PECAM-1 ITIM tyrosine phosphorylation and increases β-catenin phosphorylation, facilitating junction opening in an allele-specific manner.\",\n      \"method\": \"In vitro transendothelial migration assays through HUVECs expressing defined PECAM-1 allelic variants, rCD177-Fc engagement, phosphorylation assays for PECAM-1 ITIM and β-catenin\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined mechanistic pathway with allele-specific functional readout, single lab\",\n      \"pmids\": [\"20194726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PR3 serine protease activity facilitates transendothelial migration specifically of NB1 (CD177)-positive neutrophils: PR3 expression and activity increase on NB1+ neutrophils following transmigration (not on NB1− neutrophils); selective serine protease inhibitors block NB1+ neutrophil diapedesis under static and flow conditions.\",\n      \"method\": \"Transendothelial migration assays through IL-1β-stimulated endothelial monolayers, blocking antibodies to PECAM-1, PR3 activity measurement after transmigration, selective serine protease inhibitors under static and flow conditions\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pharmacological inhibition plus subset-specific activity measurement, single lab\",\n      \"pmids\": [\"22266279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD177 ligation on CD177pos neutrophils selectively impairs their migration by immobilizing cells and causing spreading; mechanistically, CD177 ligation enhances its interaction with β2 integrins (shown by fluorescence lifetime imaging microscopy), leading to integrin-mediated phosphorylation of Src and ERK, increased surface β2 integrin expression and affinity, impaired integrin attachment internalization, and ERK-mediated attenuation of chemokine signaling.\",\n      \"method\": \"PECAM-1-independent transwell migration assay, fluorescence lifetime imaging microscopy (FLIM) for CD177–β2 integrin interaction, phosphorylation assays (Src, ERK), surface integrin expression and affinity measurements, chemokine receptor internalization assays, kinase inhibitor studies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — FLIM imaging of protein interaction plus multiple orthogonal functional assays in one study, mechanistic pathway fully delineated\",\n      \"pmids\": [\"28807980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Subset-restricted CD177 expression in bimodal individuals arises from monoallelic expression: CD177pos neutrophils transcribe only the maternal or paternal allele, while the other allele is silenced during neutrophil differentiation from hematopoietic stem cells that express both alleles; DNA methylation of the CD177 promoter reduces expression, demethylation causes biallelic expression, and c-Jun/c-Fos binding to the unmethylated, euchromatic promoter drives CD177 transcription in CD177pos neutrophils.\",\n      \"method\": \"Single-cell haplotype analysis, ChIP for histone marks and c-Jun/c-Fos, CpG methylation analysis, reporter assays in HeLa cells with mono- vs. biallelic expression, demethylation experiments, hematopoietic stem cell differentiation tracking\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP, reporter assays, methylation analysis, and allele tracking with multiple orthogonal methods in one study\",\n      \"pmids\": [\"28559244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NB1-negative neutrophils in bimodal individuals contain no NB1 mRNA even after G-CSF stimulation, and this transcriptional silencing correlates with specific CD177 coding polymorphisms; three out of six identified polymorphisms are significantly associated with a small NB1-expressing neutrophil subpopulation.\",\n      \"method\": \"Immunofluorescence-based single-cell picking and FACS sorting of NB1+ vs NB1− subsets, RT-PCR for NB1 mRNA, cDNA sequencing, G-CSF stimulation experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct demonstration of mRNA absence in sorted subsets plus genotype-phenotype correlation, single lab\",\n      \"pmids\": [\"12623849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The CD177null phenotype arises when exon 7 of the CD177 gene is supplied entirely by the CD177P1 pseudogene through allelic gene conversion, introducing a stop codon; the proportion of CD177hi neutrophils in blood is heritable and correlates with CD177 reference allele homozygosity.\",\n      \"method\": \"Deep sequencing of the CD177 locus, identification of stop codon from pseudogene-derived exon 7 sequence, genotype–phenotype correlation in families and population cohorts\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deep sequencing with genotype-phenotype correlation; single study but comprehensive locus-level analysis\",\n      \"pmids\": [\"27227454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD177 deletion in mice reduces peripheral blood neutrophil counts and reduces neutrophil accumulation in S. aureus skin infection; CD177 deletion has no significant impact on CXCL1/KC- or fMLP-induced neutrophil migration but leads to significant neutrophil cell death, indicating a pro-survival role.\",\n      \"method\": \"CD177 genetic knockout mouse model, complete blood counts, S. aureus skin infection model with neutrophil counting, CXCL1/fMLP migration assays, cell death assays\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined infection phenotype and mechanistic distinction between migration and survival; single lab\",\n      \"pmids\": [\"25359465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD177+ neutrophils in IBD produce lower levels of pro-inflammatory cytokines (IFN-γ, IL-6, IL-17A) but higher levels of IL-22 and TGF-β, exhibit increased bactericidal activities (ROS, antimicrobial peptides, NETs), and protect against colitis; CD177−/− mice develop more severe DSS colitis with compromised intestinal barrier and impaired IL-22 production.\",\n      \"method\": \"Flow cytometry and immunohistochemistry in IBD patients, RNA sequencing of sorted CD177+/CD177− neutrophil subsets, cytokine/ROS/NET functional assays, DSS colitis model in CD177−/− mice\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CD177 KO mouse plus human subset RNA-seq plus multiple functional assays; replicated across patient and mouse data\",\n      \"pmids\": [\"28468761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD177 is expressed on a specific Fate-1 subset of tumor-infiltrating regulatory T cells (TI Tregs) in renal clear cell carcinoma and other solid cancers; blocking CD177 reduces Treg suppressive activity in vitro, and Treg-specific deletion of Cd177 in mice leads to decreased tumor growth and reduced TI Treg frequency.\",\n      \"method\": \"Single-cell RNA sequencing of ccRCC immune cells, in vitro Treg suppression assay with CD177 blocking, conditional Treg-specific Cd177 knockout mouse tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq for identification, in vitro functional assay, and conditional KO tumor model; single lab\",\n      \"pmids\": [\"34599187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD177 marks anterior definitive endoderm (ADE) subpopulations in human pluripotent stem cell-derived cultures; CD177+ ADE expresses and synthesizes the secreted WNT/NODAL/BMP antagonist CERBERUS1 and is specified toward pancreatic fate through non-canonical WNT signaling, whereas CD275+ ADE receives canonical WNT signaling and is specified toward liver fate; isolated CD177+ ADE differentiates more homogeneously into functional glucose-responsive β-like cells.\",\n      \"method\": \"Surface marker-based sorting of definitive endoderm subpopulations, RNA-seq and signaling pathway analysis, CERBERUS1 expression/secretion assays, in vitro pancreatic and hepatic differentiation with functional glucose-stimulated insulin secretion assays\",\n      \"journal\": \"Nature biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sorting-based subpopulation isolation with functional differentiation outcome and secreted factor identification; single lab\",\n      \"pmids\": [\"32341565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD177 is a functional binding partner of podoplanin (PDPN) on cancer-associated fibroblasts, identified via high-throughput surface interactome screening; CD177 acts as a functional antagonist of PDPN, recapitulating the phenotype of PDPN-deficient CAFs, and PDPN signaling involves actomyosin contractility and cell growth pathways.\",\n      \"method\": \"High-throughput PDPN cell surface interactome screen, quantitative phosphoproteomics of CAF phosphoproteome, cellular phenotype assays in PDPN-deficient and CD177-treated CAFs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased interactome screen plus phosphoproteomics and functional cellular assays; single lab\",\n      \"pmids\": [\"34879110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD177 deficiency in breast cancer cells is associated with increased β-catenin/Wnt signaling; loss of CD177 leads to hyperproliferative mammary epithelium; CD177 acts as a novel regulator of mammary epithelial proliferation through modulation of the Wnt/β-catenin pathway.\",\n      \"method\": \"CD177 knockout/knockdown in breast cancer cell lines and mouse mammary gland models, β-catenin signaling pathway analysis, proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined signaling pathway readout; single lab\",\n      \"pmids\": [\"32042113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PECAM-1 interaction with CD177 downregulates membrane PR3 (mPR3) expression on neutrophils in a dose-dependent manner; this results in attenuated PR3-ANCA-induced neutrophil degranulation and oxidative burst; the inhibitory effect on degranulation is absent in CD177-negative neutrophils, confirming CD177 dependence.\",\n      \"method\": \"ELISA and flow cytometry for mPR3 expression, DHR oxidative burst assay, degranulation ELISA, MACS-sorted CD177-negative neutrophil experiments with recombinant PECAM-1\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with CD177-negative controls confirming specificity; single lab\",\n      \"pmids\": [\"30236159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD177/PECAM-1 adhesive interaction supports neutrophil transendothelial migration but does not contribute to platelet–neutrophil interactions: CD177+ and CD177− neutrophils do not differ in platelet conjugate formation under static or flow conditions, whereas predominantly CD177+ neutrophils migrate preferentially across HUVEC monolayers; the PECAM-1 S536N dimorphism affects transendothelial migration but not platelet binding.\",\n      \"method\": \"Whole-blood and isolated platelet–neutrophil conjugate assays under flow and static conditions, transendothelial migration across HUVEC monolayers, comparison of PECAM-1 allelic variants\",\n      \"journal\": \"European journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comparative functional assays with defined allelic variants; negative finding for platelet interaction mechanistically informative; single lab\",\n      \"pmids\": [\"22690867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Unstimulated NB1-positive neutrophils show reduced adherence to HUVEC monolayers compared to NB1-negative neutrophils; blocking NB1 with Fab fragments increases NB1+ neutrophil adherence to HUVEC; NB1+ neutrophils show greater chemotaxis to fMLP through nitrocellulose but not polycarbonate membranes; no differences in adhesion to extracellular matrix proteins.\",\n      \"method\": \"Adhesion assays of sorted NB1+/NB1− neutrophils to HUVEC monolayers and ECM proteins, anti-NB1 Fab fragment blocking, chemotaxis assays through nitrocellulose and polycarbonate membranes\",\n      \"journal\": \"The Journal of laboratory and clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional comparison of sorted subsets with antibody blocking; single lab, but multiple functional readouts\",\n      \"pmids\": [\"8301201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In ANCA-associated vasculitis and SLE, the percentage of CD177-expressing neutrophils is significantly increased, but primed CD177-negative neutrophils from CD177-null donors also express mPR3 and are susceptible to anti-PR3-mediated oxidative burst, indicating that a CD177-independent pathway for mPR3 membrane recruitment exists.\",\n      \"method\": \"Flow cytometry of neutrophils from ASV, SLE, RA patients and healthy controls, DHR oxidative burst assay, TNF-α priming, comparison of CD177-null donor and sorted CD177− subsets\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistically informative negative result (CD177-independent mPR3 pathway) established by functional assay in CD177-null donors; single lab\",\n      \"pmids\": [\"19404956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD177+ neutrophils are the main Gr-1+ population in mouse biliary atresia livers; they exhibit elevated mitochondrial ROS and form neutrophil extracellular traps (NETs) that induce apoptosis of biliary epithelial cells in co-culture; Cd177−/− mice show delayed disease onset and reduced morbidity/mortality; NET inhibitors reduce bile duct damage.\",\n      \"method\": \"scRNA-seq and Smart-Seq RNA-seq of liver Gr-1+ cells, Cd177−/− mouse BA model (rhesus rotavirus), ROS measurement, NET quantification, co-culture apoptosis assay, NET inhibitor treatment, pilot clinical study with N-acetylcysteine\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model plus scRNA-seq plus in vitro mechanistic assays plus pharmacological inhibition; multiple orthogonal methods\",\n      \"pmids\": [\"35803543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD177+ neutrophils in lung ischemia-reperfusion injury exhibit elevated oxidative phosphorylation and increased mitochondrial complex I activity, driving inflammation and NET formation; inhibiting complex I with IACS-010759 reduces CD177+ neutrophil activation and alleviates lung injury in mouse IRI and rat lung transplant models.\",\n      \"method\": \"scRNA-seq and spatial transcriptomics of IRI lung, mitochondrial complex I activity assays, IACS-010759 pharmacological inhibition in mouse IRI and rat transplant models, NET quantification, human lung transplant cohort AUC analysis\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (complex I → inflammation/NETs) established by pharmacological inhibition in two animal models plus transcriptomic identification; single lab\",\n      \"pmids\": [\"40398393\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD177 is a GPI-anchored, uPAR/Ly6-superfamily glycoprotein expressed on a genetically determined subset of neutrophils (and, ectopically, on tumor-infiltrating Tregs and definitive endoderm); it functions as a heterophilic counter-receptor for endothelial PECAM-1 (mediating transendothelial migration via β2 integrin/Src/ERK signaling) and as a membrane receptor for the serine protease PR3 (which it presents on the neutrophil surface via a specific hydrophobic patch, enabling Mac-1-dependent ANCA-mediated activation); CD177+ neutrophil subset restriction is controlled by monoallelic epigenetic silencing through promoter CpG methylation and c-Jun/c-Fos binding, and CD177 also modulates Wnt/β-catenin signaling in epithelial cells and has been identified as a novel ligand for podoplanin on cancer-associated fibroblasts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD177 (NB1/PRV-1) is a GPI-anchored cell-surface glycoprotein of the uPAR/CD59/Ly-6 snake-toxin superfamily, expressed on a genetically and epigenetically restricted subset of neutrophils where it governs neutrophil adhesion, transendothelial migration, and presentation of the autoantigen proteinase 3 (PR3) [#2, #5]. Biochemically it is a ~50 kDa N-glycosylated, GPI-linked protein with two cysteine-rich domains that is released from the membrane by PI-PLC and stored in secondary granules and secretory vesicles [#0, #1, #3]. CD177 serves as a heterophilic counter-receptor for endothelial PECAM-1 (engaging PECAM-1 domain 6 in a cation-dependent manner), an interaction that supports neutrophil diapedesis and is tuned by the endothelial PECAM-1 S536N dimorphism through modulation of PECAM-1 ITIM and \\u03b2-catenin phosphorylation [#4, #9]. It functions as the membrane receptor that presents catalytically active PR3 on the neutrophil surface via a discrete hydrophobic cluster in PR3, and assembles into a lipid-raft signaling complex with Mac-1 (CD11b/CD18) that transduces PR3-ANCA-mediated degranulation and oxidative burst [#5, #7, #8]. Upon ligation, CD177 enhances its interaction with \\u03b22 integrins to drive Src/ERK signaling, increase integrin affinity, and arrest migration, while PECAM-1 engagement conversely downregulates membrane PR3 and dampens ANCA-induced activation [#11, #21]. Subset-restricted expression is established by monoallelic transcription enforced by promoter CpG methylation with c-Jun/c-Fos binding to the active allele, and the CD177null phenotype arises from pseudogene-derived allelic gene conversion introducing a stop codon [#12, #14]. Beyond neutrophils, CD177 marks immunosuppressive tumor-infiltrating Tregs, modulates Wnt/\\u03b2-catenin signaling in mammary epithelium, and partners with podoplanin on cancer-associated fibroblasts [#17, #20, #19]. CD177+ neutrophil subsets drive context-specific protective or pathogenic functions in colitis, biliary atresia, and lung ischemia-reperfusion injury, the latter two via mitochondrial-ROS-driven NET formation [#16, #25, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established the basic biochemical nature of the NB1 antigen, defining it as a GPI-anchored membrane glycoprotein rather than a transmembrane protein.\",\n      \"evidence\": \"PI-PLC release of surface-labeled neutrophil protein with non-denaturing gel shift and endoglycosidase digestion\",\n      \"pmids\": [\"1825110\", \"2153425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protein sequence and gene identity not yet determined\", \"Function unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Cloned the gene and placed CD177 in the uPAR/CD59/Ly-6 superfamily, defining its domain architecture and confirming surface expression in transfected cells.\",\n      \"evidence\": \"Immunoaffinity purification, MALDI-TOF MS, N-terminal sequencing, cDNA cloning, COS-7/transfection FACS (also molecular cloning of PRV-1)\",\n      \"pmids\": [\"11465086\", \"10753836\", \"12239154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand or receptor function identified\", \"Reason for restricted neutrophil expression unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified two distinct binding functions of CD177 — as the counter-receptor for endothelial PECAM-1 and as the membrane receptor presenting PR3 — establishing its dual role in migration and autoantigen display.\",\n      \"evidence\": \"SPR, reciprocal immunoprecipitation, adhesion/transmigration assays for PECAM-1; co-IP, co-localization, GPI removal, and transfection rescue for PR3\",\n      \"pmids\": [\"17580308\", \"17244676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants of PR3 binding not yet mapped\", \"Downstream signaling partners unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the PR3 binding determinant to a species-specific hydrophobic cluster, demonstrating molecular specificity of the CD177-PR3 interaction.\",\n      \"evidence\": \"Human-gibbon PR3 hybrid domain swaps with NB1-binding and activity assays\",\n      \"pmids\": [\"18854317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The reciprocal CD177 binding interface not defined\", \"Structural model absent\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how a GPI-anchored protein transduces signals by identifying Mac-1 as the transmembrane adaptor in the CD177-PR3 raft complex that drives ANCA-mediated activation.\",\n      \"evidence\": \"Membrane complex IP with MS/MS, SPR, Mac-1-transfected adhesion assay, lipid raft fractionation, blocking-antibody degranulation/oxidative burst assays\",\n      \"pmids\": [\"21193407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the CD177/PR3/Mac-1 complex not defined\", \"Whether other integrins substitute in vivo unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Refined the migration mechanism by showing PR3 serine protease activity itself facilitates CD177+ neutrophil diapedesis and that the CD177/PECAM-1 axis is migration-specific, not platelet-binding.\",\n      \"evidence\": \"Transendothelial migration with serine protease inhibitors and PR3 activity measurement; platelet-neutrophil conjugate assays under flow\",\n      \"pmids\": [\"22266279\", \"22690867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrates cleaved by PR3 during diapedesis not identified\", \"Single-lab functional data\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the integrin-coupled signaling output of CD177 ligation and the epigenetic basis of subset restriction, explaining both how CD177 controls migration and why only some neutrophils express it.\",\n      \"evidence\": \"FLIM of CD177-\\u03b22 integrin interaction with Src/ERK phosphorylation and integrin affinity assays; single-cell haplotype analysis, ChIP for c-Jun/c-Fos and histone marks, CpG methylation and reporter assays\",\n      \"pmids\": [\"28807980\", \"28559244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for allele choice during differentiation unknown\", \"Physiological ligand initiating CD177 ligation in vivo not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the genetic basis of the CD177null phenotype, attributing it to pseudogene-derived gene conversion and heritable control of CD177hi neutrophil proportion.\",\n      \"evidence\": \"Deep sequencing of the CD177 locus with family and population genotype-phenotype correlation\",\n      \"pmids\": [\"27227454\", \"12623849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of allelic gene conversion not detailed\", \"Population frequency of conversion event unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated context-dependent roles of CD177+ neutrophils in tissue protection and the inhibitory tuning of mPR3 by PECAM-1, linking CD177 biology to inflammatory disease.\",\n      \"evidence\": \"CD177 KO mice in DSS colitis with subset RNA-seq and functional assays; recombinant PECAM-1 mPR3 downregulation assays with CD177-negative controls (also 2014 KO survival phenotype)\",\n      \"pmids\": [\"28468761\", \"30236159\", \"25359465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between CD177 and IL-22/survival programs unclear\", \"Whether protective vs pathogenic balance is tissue-intrinsic unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended CD177 function beyond neutrophils, identifying it on suppressive tumor-infiltrating Tregs, in epithelial Wnt regulation, in endoderm fate, and as a podoplanin partner on CAFs.\",\n      \"evidence\": \"scRNA-seq plus conditional Treg KO tumor model; breast cancer loss-of-function with \\u03b2-catenin readout; hPSC endoderm sorting/differentiation; PDPN surface interactome screen with phosphoproteomics\",\n      \"pmids\": [\"34599187\", \"32042113\", \"32341565\", \"34879110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GPI-anchored CD177 to intracellular Wnt/\\u03b2-catenin unresolved\", \"Direct vs indirect role in Treg suppression unclear\", \"Single-lab findings each\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a metabolic axis in pathogenic CD177+ neutrophils, showing mitochondrial complex I activity drives NET-mediated tissue injury in biliary atresia and lung ischemia-reperfusion.\",\n      \"evidence\": \"scRNA-seq/spatial transcriptomics, complex I activity assays, NET quantification, and pharmacological complex I inhibition in mouse and rat models\",\n      \"pmids\": [\"35803543\", \"40398393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CD177 itself regulates mitochondrial metabolism vs marks metabolically active cells unclear\", \"Single-lab models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a GPI-anchored Ly-6 protein with no intrinsic catalytic or transmembrane domain mechanistically couples to intracellular Wnt/\\u03b2-catenin and metabolic programs across diverse non-neutrophil cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CD177 or its complexes\", \"Signal transduction in epithelial/Treg/endoderm contexts not mechanistically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [4, 23]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 16]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 20]}\n    ],\n    \"complexes\": [\"CD177/PR3/Mac-1 lipid-raft signaling complex\"],\n    \"partners\": [\"PECAM-1\", \"PRTN3\", \"ITGAM\", \"ITGB2\", \"PDPN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}