{"gene":"CD177","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2007,"finding":"CD177 (NB1) was identified as a heterophilic binding partner of PECAM-1 (CD31) on endothelial cells. Flow cytometry, immunoprecipitation, and surface plasmon resonance confirmed a cation-dependent, specific interaction between CD177 and PECAM-1 domain 6. Monoclonal antibodies against CD177 and PECAM-1 domain 6 inhibited adhesion of CD177-expressing U937 cells to immobilized PECAM-1 and blocked transendothelial migration of human neutrophils.","method":"Flow cytometry, immunoprecipitation, surface plasmon resonance, antibody blocking of transendothelial migration","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, SPR, functional migration assay) in single study, foundational discovery","pmids":["17580308"],"is_preprint":false},{"year":2007,"finding":"NB1 (CD177) mediates surface expression of proteinase 3 (PR3) on human neutrophils. PR3 and NB1 co-immunoprecipitated and co-localized on the neutrophil plasma membrane. Transfection of NB1 into HEK293 and HL60 cells resulted in specific PR3 surface binding. Enzymatic removal of GPI anchors decreased mPR3 expression, and mPR3 was absent in a paroxysmal nocturnal hemoglobinuria patient lacking GPI-anchored proteins.","method":"Co-immunoprecipitation, confocal microscopy, flow cytometry, GPI anchor removal, cell transfection","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, transfection, GPI-anchor enzymatic removal), replicated in patient cells and cell lines","pmids":["17244676"],"is_preprint":false},{"year":2010,"finding":"Mac-1 (CD11b/CD18) was identified as a transmembrane adaptor for NB1 (CD177) signaling. MS/MS analysis of NB1 signaling complexes precipitated from plasma membranes identified Mac-1 as the key component. Direct protein-protein interaction between NB1 and CD11b/CD11a was confirmed by surface plasmon resonance, but only Mac-1-transfected cells adhered to immobilized NB1. NB1, PR3, and Mac-1 co-localized in lipid rafts. Blocking CD11b inhibited PR3-ANCA-induced neutrophil degranulation and superoxide production.","method":"MS/MS proteomics, immunoprecipitation, surface plasmon resonance, transfection adhesion assay, confocal microscopy, lipid raft fractionation, blocking antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution/SPR plus MS/MS plus functional blocking, multiple orthogonal methods in one study","pmids":["21193407"],"is_preprint":false},{"year":2017,"finding":"CD177 modulates neutrophil migration through β2 integrin-dependent signaling. CD177 ligation enhanced its interaction with β2 integrins (revealed by fluorescence lifetime imaging microscopy), leading to integrin-mediated phosphorylation of Src and ERK. This caused increased surface β2 integrin expression and affinity, impaired integrin attachment internalization, and ERK-mediated attenuation of chemokine signaling, collectively impairing neutrophil migration.","method":"Fluorescence lifetime imaging microscopy (FLIM), phosphorylation assays, transwell migration, flow cytometry, signaling inhibitors","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (FLIM, phosphoproteomics, functional migration assays) with rigorous mechanistic follow-up","pmids":["28807980"],"is_preprint":false},{"year":2008,"finding":"A hydrophobic cluster unique to human PR3 (residues F166, W218, G219, L223) mediates its binding to the NB1 receptor on the neutrophil surface. Gibbon PR3, which lacks these residues, did not bind human NB1. A human-gibbon hybrid PR3 lacking the C-terminal human residues also failed to bind NB1. NB1-bound PR3 remained enzymatically active and was cleared from the surface by alpha-1-protease inhibitor.","method":"Cloning and expression of gibbon PR3 ortholog, human-gibbon hybrid protein construction, NB1 binding assay, functional enzymatic assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — structure-function mutagenesis using natural and chimeric proteins with direct binding readout","pmids":["18854317"],"is_preprint":false},{"year":2010,"finding":"CD177-positive neutrophils migrate significantly faster through endothelial cells expressing the LSR allelic variant of PECAM-1 compared to VNG variant. Engagement of PECAM-1 by rCD177-Fc suppressed ITIM tyrosine phosphorylation and increased β-catenin phosphorylation in an allele-specific manner, suggesting that CD177/PECAM-1 heterophilic interaction modulates endothelial junctional integrity to facilitate neutrophil transmigration.","method":"In vitro transendothelial migration assay, PECAM-1 ITIM phosphorylation measurement, β-catenin phosphorylation, recombinant CD177-Fc protein","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — functional migration assay with defined molecular mechanism and allele-specific controls","pmids":["20194726"],"is_preprint":false},{"year":2012,"finding":"Proteinase 3 (PR3) activity contributes to transendothelial migration selectively in NB1 (CD177)-positive neutrophils. PR3 expression and activity were significantly increased on NB1-positive neutrophils following transmigration. Using selective serine protease inhibitors, PR3 activity was shown to facilitate transmigration of NB1-positive neutrophils under both static and flow conditions, while NB1-negative neutrophils showed no increase in PR3.","method":"In vitro transendothelial migration under static and flow conditions, selective serine protease inhibitors, flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — functional assay with pharmacological inhibitors under multiple conditions establishing causal role","pmids":["22266279"],"is_preprint":false},{"year":2006,"finding":"CD177 and membrane PR3 are expressed on the same neutrophil subset; their surface expression increases and decreases in parallel during cell stimulation or spontaneous apoptosis. Rapid internalization and recirculation of both mPR3 and CD177 occur together (all mPR3 replaced within 30 min), indicating they share the same intracellular storage compartment: secondary granules and secretory vesicles.","method":"Flow cytometry, cell stimulation assays, apoptosis assays, subcellular fractionation inference","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-expression and co-internalization data, single lab but multiple conditions","pmids":["17077162"],"is_preprint":false},{"year":2001,"finding":"CD177 (NB1) was biochemically characterized as a 437-amino-acid GPI-anchored glycoprotein with two cysteine-rich domains homologous to the uPAR/Ly6/CD59/snake toxin superfamily, three N-linked glycosylation sites, and a GPI attachment site. COS-7 cells transfected with NB1 cDNA expressed immunoreactive NB1 glycoprotein, confirming the protein-coding sequence.","method":"MALDI-TOF mass spectrometry, N-terminal sequencing, RACE PCR, cDNA cloning, COS-7 transfection","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — molecular cloning with mass spectrometry and reconstitution in transfected cells","pmids":["11465086"],"is_preprint":false},{"year":2002,"finding":"PRV-1 (CD177) protein is N-glycosylated and GPI-anchored, confirmed biochemically. Multiple PRV-1 transcripts arise from alternative polyadenylation and encode the same protein. Soluble CD177 is shed from the cell surface and can be detected in cell supernatants. Stably transfected cells expressing PRV-1 are recognized by anti-NB1/CD177 antibodies, confirming PRV-1 and NB1 are products of the same gene.","method":"Northern blot, biochemical deglycosylation, PI-PLC treatment, flow cytometry, FACS analysis of transfected cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical characterization with multiple methods confirming GPI anchor and glycosylation","pmids":["12239154"],"is_preprint":false},{"year":1991,"finding":"The NB1 antigen (CD177) is anchored to the neutrophil plasma membrane via a glycosyl-phosphatidylinositol (GPI) linkage. Treatment with PI-PLC specifically released the 58–64 kDa NB1-bearing protein from the cell surface. Removal of N-linked carbohydrates with endoglycosidase-F reduced the apparent molecular weight to ~45 kDa.","method":"PI-PLC treatment, 125I surface labeling, non-denaturing gel electrophoresis, endoglycosidase-F treatment","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical demonstration of GPI anchor by enzymatic release","pmids":["1825110"],"is_preprint":false},{"year":1990,"finding":"The NB1 antigen resides on a 58–64 kDa surface glycoprotein also present in secondary granules but not primary granules of neutrophils. The NB1 epitope is not a carbohydrate but likely resides in the tertiary structure of the protein backbone, as periodate treatment had no effect but reduction abolished antibody recognition.","method":"SDS-PAGE immunoblotting, immunoprecipitation with 125I-labeled neutrophils, differential centrifugation fractionation, periodate treatment, reduction","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical fractionation and epitope characterization with multiple antisera","pmids":["2153425"],"is_preprint":false},{"year":2017,"finding":"CD177 expression in neutrophils is controlled by epigenetic mechanisms including a novel monoallelic expression pattern. In bimodal individuals, CD177pos neutrophils transcribe either the maternal or paternal CD177 allele exclusively. ChIP and reporter assays showed that CpG methylation of the CD177 promoter reduces transcription, while demethylation causes biallelic expression. c-Jun and c-Fos bound the CD177 promoter in CD177pos neutrophils (which have a euchromatic, unmethylated promoter) but not CD177neg neutrophils.","method":"ChIP, reporter assays (HeLa cells), haplotype analysis, bisulfite sequencing, transcription factor transfection","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP plus reporter assays plus functional demethylation experiments; multiple orthogonal approaches","pmids":["28559244"],"is_preprint":false},{"year":2003,"finding":"CD177-negative neutrophils within bimodal individuals lack NB1 mRNA, and this absence persists even after G-CSF administration. Three CD177 cDNA polymorphisms were significantly associated with a small CD177-expressing neutrophil subpopulation, indicating a genetic basis for subset-restricted expression.","method":"Single-cell picking, FACS sorting, RT-PCR, cDNA sequencing, G-CSF stimulation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — single-cell mRNA analysis with genetic polymorphism association, multiple controls","pmids":["12623849"],"is_preprint":false},{"year":2014,"finding":"CD177 knockout mice show decreased neutrophil counts in peripheral blood and reduced neutrophil accumulation in skin infected with Staphylococcus aureus. CD177 deletion had no significant impact on CXCL1/KC- or fMLP-induced migration in vitro but led to significant neutrophil cell death, indicating CD177 supports neutrophil survival rather than chemotaxis per se.","method":"Genetic knockout mouse model, skin infection model with S. aureus, in vitro migration assays, flow cytometry","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with specific in vivo and in vitro phenotypic readouts separating survival from migration functions","pmids":["25359465"],"is_preprint":false},{"year":2021,"finding":"CD177 expressed on tumor-infiltrating regulatory T cells (TI Tregs) modulates their suppressive activity. Blocking CD177 reduced the suppressive activity of Tregs in vitro, while Treg-specific deletion of Cd177 in mice led to decreased tumor growth and reduced TI Treg frequency, establishing a functional role for CD177 in TI Treg-mediated immunosuppression.","method":"scRNA-seq, in vitro Treg suppression assay with CD177 blocking, conditional Treg-specific Cd177 knockout mice, tumor growth assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with functional in vitro suppression assay and in vivo tumor model","pmids":["34599187"],"is_preprint":false},{"year":2020,"finding":"CD177 marks anterior definitive endoderm (ADE) specified toward pancreatic fate. CD177+ ADE expresses and synthesizes the secreted WNT/NODAL/BMP antagonist CERBERUS1 and shows inverse canonical vs. noncanonical WNT signaling compared to CD275+ (hepatic) ADE. Isolated CD177+ ADE differentiates more homogeneously into pancreatic progenitors and more functional glucose-responsive β-like cells.","method":"Flow cytometry sorting, scRNA-seq, differentiation assays from human pluripotent stem cells, glucose stimulation assay","journal":"Nature biotechnology","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional differentiation assay with molecular pathway characterization, single lab","pmids":["32341565"],"is_preprint":false},{"year":2020,"finding":"CD177 deficiency in cancer cells is associated with increased β-catenin/Wnt signaling. Loss of CD177 leads to hyperproliferative mammary epithelium. CD177 was identified as a novel regulator of mammary epithelial proliferation acting via modulation of the Wnt/β-catenin signaling pathway.","method":"CD177 loss-of-function (KO/KD), proliferation assays, β-catenin signaling reporters and immunoblot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional KO with signaling pathway readout, single lab","pmids":["32042113"],"is_preprint":false},{"year":2021,"finding":"CD177 was identified as a novel receptor for podoplanin (PDPN) on cancer-associated fibroblasts. High-throughput interactome screening identified the CD177-PDPN interaction. CD177 acts as a functional antagonist of PDPN, recapitulating the phenotype of PDPN-deficient CAFs including effects on cell signaling, growth, and actomyosin contractility.","method":"High-throughput receptor-ligand screening, quantitative phosphoproteomics, cellular functional assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 — unbiased interactome screening with phosphoproteomics and functional validation, single lab","pmids":["34879110"],"is_preprint":false},{"year":2018,"finding":"PECAM-1 interaction with CD177 downregulates membrane PR3 (mPR3) expression on neutrophils in a dose-dependent manner and attenuates PR3-ANCA-induced neutrophil degranulation and respiratory burst. This effect was CD177-dependent: in CD177-negative neutrophils, PECAM-1 did not significantly change degranulation induced by PR3-ANCA.","method":"ELISA, flow cytometry, DHR oxidative burst assay, MACS sorting of CD177-negative neutrophils, degranulation assay","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional neutrophil activation assays with CD177-negative controls, single lab","pmids":["30236159"],"is_preprint":false},{"year":2017,"finding":"CD177+ neutrophils in IBD produce lower levels of proinflammatory cytokines (IFN-γ, IL-6, IL-17A) but higher levels of IL-22 and TGF-β, and exhibit increased bactericidal activities (ROS, antimicrobial peptides, NETs) compared to CD177- neutrophils. CD177-/- mice developed more severe DSS colitis with compromised intestinal barrier, impaired antibacterial immunity, and decreased IL-22 production.","method":"Flow cytometry, RNA sequencing, CD177-/- mouse DSS colitis model, cytokine quantification, bactericidal assays","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — genetic KO mouse model with specific mechanistic readouts plus human patient cell characterization","pmids":["28468761"],"is_preprint":false},{"year":2022,"finding":"CD177+ cells produce neutrophil extracellular traps (NETs) that promote biliary atresia (BA) pathogenesis. Cd177-/- mice exhibited delayed BA onset and reduced morbidity/mortality. CD177+ cells from BA mice had high mitochondrial content, elevated ROS, and increased NET formation; NETs induced apoptosis of biliary epithelial cells in co-culture.","method":"Cd177-/- mouse model, Smart-Seq RNA-seq, co-culture apoptosis assay, ROS measurement, NET inhibitor studies","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO mouse with defined in vitro mechanistic readout (NET-induced apoptosis) and NET inhibitor confirmation","pmids":["35803543"],"is_preprint":false},{"year":2012,"finding":"CD177 interaction with PECAM-1 supports preferential transendothelial migration of CD177-positive neutrophils, but CD177/PECAM-1 interaction does not mediate platelet-neutrophil interactions; CD177-positive and CD177-negative neutrophils formed platelet conjugates equally under static and flow conditions.","method":"Whole blood platelet-neutrophil conjugate assay, flow chamber adhesion assay, HUVEC migration assay","journal":"European journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional assays under static and flow conditions dissecting specificity of CD177 interactions","pmids":["22690867"],"is_preprint":false},{"year":1994,"finding":"NB1 antigen (CD177) inhibits neutrophil-endothelial cell interactions. Unstimulated NB1-positive neutrophils adhered less to HUVEC monolayers than NB1-negative neutrophils. Incubation with anti-NB1 Fab fragments increased CD177+ neutrophil adherence to HUVEC, suggesting NB1 normally suppresses adhesion to endothelium. NB1-positive neutrophils showed greater chemotaxis to FMLP through nitrocellulose.","method":"HUVEC adhesion assay, Fab fragment blocking, chemotaxis assay","journal":"The Journal of laboratory and clinical medicine","confidence":"Medium","confidence_rationale":"Tier 3 — functional adhesion and chemotaxis assays, single lab, foundational functional data","pmids":["8301201"],"is_preprint":false}],"current_model":"CD177 is a GPI-anchored neutrophil surface glycoprotein (member of the uPAR/Ly6/CD59 superfamily) that functions as a heterophilic ligand for endothelial PECAM-1, mediating neutrophil transendothelial migration via a β2 integrin (Mac-1/CD11b)-dependent signaling complex that activates Src and ERK; it also serves as the membrane receptor and presenter for proteinase 3 (PR3), enabling PR3-ANCA-mediated neutrophil activation, and its subset-restricted expression is controlled by monoallelic epigenetic silencing through CpG methylation and AP-1 (c-Jun/c-Fos) transcription factor binding during neutrophil differentiation."},"narrative":{"teleology":[{"year":1990,"claim":"Establishing the molecular identity of CD177 resolved that the NB1 neutrophil alloantigen is a 58–64 kDa surface glycoprotein stored in secondary granules, with a conformational (non-carbohydrate) epitope.","evidence":"SDS-PAGE immunoblotting, immunoprecipitation with 125I-labeled neutrophils, differential centrifugation fractionation of granule subsets","pmids":["2153425"],"confidence":"High","gaps":["Primary structure unknown","Membrane anchoring mechanism not yet determined","Function of NB1 entirely unknown"]},{"year":1991,"claim":"Demonstrating that NB1 is GPI-anchored established its mode of membrane attachment and explained its absence in PNH patients lacking GPI-linked proteins.","evidence":"PI-PLC enzymatic release of 125I-surface-labeled NB1 from neutrophils, endoglycosidase-F deglycosylation","pmids":["1825110"],"confidence":"High","gaps":["Gene identity and sequence unknown","No known ligand or function"]},{"year":1994,"claim":"Functional studies first indicated that NB1 modulates neutrophil-endothelial interactions, with NB1-positive neutrophils showing reduced basal adhesion to endothelium but enhanced chemotaxis.","evidence":"HUVEC adhesion assay and Fab fragment blocking of NB1, chemotaxis through nitrocellulose","pmids":["8301201"],"confidence":"Medium","gaps":["Endothelial ligand for NB1 unknown","Mechanism of adhesion modulation unclear","Single lab observation"]},{"year":2001,"claim":"Molecular cloning of CD177 revealed it as a 437-amino-acid member of the uPAR/Ly6/CD59 superfamily with two cysteine-rich domains and three N-glycosylation sites, providing the sequence foundation for all subsequent mechanistic work.","evidence":"MALDI-TOF MS, N-terminal sequencing, RACE PCR, cDNA cloning and expression in COS-7 cells","pmids":["11465086"],"confidence":"High","gaps":["Physiological ligand and function still unknown","Basis for bimodal expression pattern not explained"]},{"year":2003,"claim":"Demonstrating that CD177-negative neutrophils lack NB1 mRNA and that cDNA polymorphisms correlate with small CD177+ subsets established that bimodal expression is transcriptionally regulated with a genetic component.","evidence":"Single-cell FACS sorting followed by RT-PCR, cDNA polymorphism analysis, G-CSF stimulation","pmids":["12623849"],"confidence":"High","gaps":["Epigenetic vs. purely genetic mechanism undetermined","Promoter regulation unexplored"]},{"year":2007,"claim":"Two simultaneous discoveries identified CD177's two key molecular partners: PECAM-1 as its heterophilic endothelial ligand mediating transendothelial migration, and PR3 as its surface-presented cargo, linking CD177 to both neutrophil trafficking and ANCA-mediated activation.","evidence":"Co-IP, SPR, antibody blocking of transmigration for PECAM-1 interaction; co-IP, confocal co-localization, transfection binding, and GPI removal for PR3 interaction","pmids":["17580308","17244676"],"confidence":"High","gaps":["Transmembrane signaling mechanism unknown (CD177 is GPI-anchored)","Structural basis of CD177-PECAM-1 and CD177-PR3 interfaces unresolved","In vivo relevance of each interaction not tested"]},{"year":2008,"claim":"Mapping the PR3 binding interface to a species-specific hydrophobic cluster (F166/W218/G219/L223) defined the structural determinants for CD177-PR3 interaction and showed that surface-bound PR3 retains enzymatic activity.","evidence":"Human-gibbon PR3 chimeric proteins and binding assays to NB1-expressing cells","pmids":["18854317"],"confidence":"High","gaps":["Reciprocal mapping of the CD177 binding surface for PR3 not done","No crystal structure of the complex"]},{"year":2010,"claim":"Identification of Mac-1 (CD11b/CD18) as the transmembrane signaling adaptor for GPI-anchored CD177 resolved how CD177 transduces signals, and showing allele-specific modulation of PECAM-1 ITIM phosphorylation and β-catenin phosphorylation explained how CD177 regulates endothelial junctional integrity during transmigration.","evidence":"MS/MS proteomics of NB1 signaling complexes, SPR for direct interaction, lipid raft co-localization, CD11b blocking of PR3-ANCA responses; transendothelial migration with PECAM-1 allelic variants and phosphorylation assays","pmids":["21193407","20194726"],"confidence":"High","gaps":["Structural basis of CD177-Mac-1 interaction unknown","In vivo validation of allele-specific migration not performed"]},{"year":2012,"claim":"Demonstrating that PR3 enzymatic activity selectively enhances transmigration of CD177-positive neutrophils, and that CD177-PECAM-1 interaction does not mediate platelet-neutrophil conjugation, refined the specificity of CD177's functional roles to endothelial transmigration.","evidence":"Transendothelial migration with selective serine protease inhibitors under static and flow conditions; platelet-neutrophil conjugate assays","pmids":["22266279","22690867"],"confidence":"High","gaps":["PR3 substrates at the endothelial junction not identified","Relative contributions of CD177-PECAM-1 binding versus PR3 proteolysis to transmigration not quantified"]},{"year":2017,"claim":"Three key advances in 2017 completed the signaling model: CD177 ligation enhances β2 integrin interaction via FLIM, activates Src/ERK to paradoxically impair migration through integrin internalization defects; epigenetic control was shown to involve monoallelic CpG methylation and AP-1 binding; and CD177+ neutrophils were demonstrated to be anti-inflammatory in IBD with IL-22 production and barrier-protective functions.","evidence":"FLIM, phosphorylation/signaling inhibitor assays; ChIP, bisulfite sequencing, reporter assays; CD177−/− mouse DSS colitis model with cytokine profiling and RNA-seq","pmids":["28807980","28559244","28468761"],"confidence":"High","gaps":["How Src/ERK activation simultaneously promotes transmigration yet impairs chemokine-directed migration is not fully reconciled","Whether monoallelic expression is stochastic or deterministic during granulopoiesis is unclear","Mechanism linking CD177 to IL-22 production not defined"]},{"year":2018,"claim":"Establishing that PECAM-1 engagement of CD177 downregulates membrane PR3 and attenuates PR3-ANCA-induced activation revealed a negative feedback loop that may limit ANCA vasculitis pathology in CD177-positive neutrophils.","evidence":"Dose-dependent PR3 downregulation by recombinant PECAM-1, degranulation and oxidative burst assays with MACS-sorted CD177-negative controls","pmids":["30236159"],"confidence":"Medium","gaps":["In vivo relevance in ANCA vasculitis not tested","Mechanism of PECAM-1-induced PR3 internalization not defined","Single lab observation"]},{"year":2020,"claim":"Discovery that CD177 marks anterior definitive endoderm fated toward pancreas and that CD177 deficiency increases β-catenin/Wnt signaling in mammary epithelium extended CD177 function beyond neutrophils to developmental and tumor-suppressive contexts.","evidence":"hPSC differentiation with FACS sorting and scRNA-seq; CD177 KO/KD with Wnt signaling reporters in mammary cells","pmids":["32341565","32042113"],"confidence":"Medium","gaps":["Mechanism by which CD177 inhibits Wnt/β-catenin signaling is unknown","Whether CD177's developmental role is cell-autonomous or paracrine is unclear","Single lab for each observation"]},{"year":2021,"claim":"CD177 was found to function on tumor-infiltrating Tregs to sustain immunosuppression and was identified as a novel receptor for podoplanin on cancer-associated fibroblasts, broadening CD177's role to immune regulation in the tumor microenvironment.","evidence":"Treg-specific Cd177 conditional KO mice with tumor growth assays and in vitro suppression; high-throughput receptor-ligand screening with phosphoproteomics for PDPN interaction","pmids":["34599187","34879110"],"confidence":"Medium","gaps":["Signaling downstream of CD177 in Tregs is uncharacterized","CD177-PDPN interaction awaits independent replication","Whether CD177 on Tregs engages PECAM-1 or PDPN in vivo is unknown"]},{"year":2022,"claim":"Demonstrating that CD177+ neutrophils produce NETs that cause biliary epithelial apoptosis in biliary atresia, with amelioration in Cd177−/− mice, established CD177 as a pathogenic driver through NET-mediated tissue injury.","evidence":"Cd177−/− mouse BA model, Smart-Seq RNA-seq, co-culture apoptosis assay, NET inhibitor studies","pmids":["35803543"],"confidence":"High","gaps":["Whether CD177 directly promotes NET formation or acts indirectly through survival/ROS is unclear","Human genetic validation in biliary atresia patients not provided"]},{"year":null,"claim":"No atomic-resolution structure of CD177 or its complexes with PECAM-1, PR3, Mac-1, or podoplanin exists, and the mechanism by which this GPI-anchored protein modulates intracellular Wnt/β-catenin signaling and Treg suppressive function remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of CD177 or any CD177-ligand complex","Mechanism of CD177-mediated Wnt pathway inhibition unknown","How CD177 regulates Treg suppressive function at the molecular level is unexplored","Whether neutrophil and non-neutrophil functions share common signaling mechanisms is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,5,6,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[17,18,19]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,8,10,11]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7,11]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,6,14,20,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,17,18]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,5,22]}],"complexes":["CD177–Mac-1 (CD11b/CD18) lipid raft signaling complex","CD177–PR3 surface complex"],"partners":["PECAM1","PRTN3","ITGAM","PDPN","JUN","FOS"],"other_free_text":[]},"mechanistic_narrative":"CD177 is a GPI-anchored neutrophil surface glycoprotein of the uPAR/Ly6/CD59 superfamily that orchestrates neutrophil transendothelial migration, activation, and survival through engagement of endothelial PECAM-1 and presentation of proteinase 3 (PR3) at the cell surface. CD177 binds PECAM-1 domain 6 in a cation-dependent manner to facilitate neutrophil transmigration, simultaneously signaling through a β2 integrin (Mac-1/CD11b) complex that activates Src and ERK pathways [PMID:17580308, PMID:21193407, PMID:28807980]. CD177 serves as the obligate membrane receptor for PR3, enabling PR3-ANCA-mediated neutrophil degranulation and respiratory burst, while PECAM-1 engagement downregulates membrane PR3 to attenuate this activation [PMID:17244676, PMID:30236159]. Subset-restricted bimodal expression on neutrophils is governed by monoallelic epigenetic silencing through CpG methylation and AP-1 (c-Jun/c-Fos) transcription factor binding, and CD177 deficiency in mice causes increased neutrophil death, exacerbated colitis with impaired barrier function, and altered NET-dependent tissue injury [PMID:28559244, PMID:25359465, PMID:28468761, PMID:35803543]."},"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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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39223577","citation_count":15,"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":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":"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":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":"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 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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":"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},{"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 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/39396046","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53026,"output_tokens":5994,"usd":0.124494},"stage2":{"model":"claude-opus-4-6","input_tokens":9624,"output_tokens":3730,"usd":0.212055},"total_usd":0.336549,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"CD177 (NB1) was identified as a heterophilic binding partner of PECAM-1 (CD31) on endothelial cells. Flow cytometry, immunoprecipitation, and surface plasmon resonance confirmed a cation-dependent, specific interaction between CD177 and PECAM-1 domain 6. Monoclonal antibodies against CD177 and PECAM-1 domain 6 inhibited adhesion of CD177-expressing U937 cells to immobilized PECAM-1 and blocked transendothelial migration of human neutrophils.\",\n      \"method\": \"Flow cytometry, immunoprecipitation, surface plasmon resonance, antibody blocking of transendothelial migration\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, SPR, functional migration assay) in single study, foundational discovery\",\n      \"pmids\": [\"17580308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NB1 (CD177) mediates surface expression of proteinase 3 (PR3) on human neutrophils. PR3 and NB1 co-immunoprecipitated and co-localized on the neutrophil plasma membrane. Transfection of NB1 into HEK293 and HL60 cells resulted in specific PR3 surface binding. Enzymatic removal of GPI anchors decreased mPR3 expression, and mPR3 was absent in a paroxysmal nocturnal hemoglobinuria patient lacking GPI-anchored proteins.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, flow cytometry, GPI anchor removal, cell transfection\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, transfection, GPI-anchor enzymatic removal), replicated in patient cells and cell lines\",\n      \"pmids\": [\"17244676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mac-1 (CD11b/CD18) was identified as a transmembrane adaptor for NB1 (CD177) signaling. MS/MS analysis of NB1 signaling complexes precipitated from plasma membranes identified Mac-1 as the key component. Direct protein-protein interaction between NB1 and CD11b/CD11a was confirmed by surface plasmon resonance, but only Mac-1-transfected cells adhered to immobilized NB1. NB1, PR3, and Mac-1 co-localized in lipid rafts. Blocking CD11b inhibited PR3-ANCA-induced neutrophil degranulation and superoxide production.\",\n      \"method\": \"MS/MS proteomics, immunoprecipitation, surface plasmon resonance, transfection adhesion assay, confocal microscopy, lipid raft fractionation, blocking antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution/SPR plus MS/MS plus functional blocking, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21193407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD177 modulates neutrophil migration through β2 integrin-dependent signaling. CD177 ligation enhanced its interaction with β2 integrins (revealed by fluorescence lifetime imaging microscopy), leading to integrin-mediated phosphorylation of Src and ERK. This caused increased surface β2 integrin expression and affinity, impaired integrin attachment internalization, and ERK-mediated attenuation of chemokine signaling, collectively impairing neutrophil migration.\",\n      \"method\": \"Fluorescence lifetime imaging microscopy (FLIM), phosphorylation assays, transwell migration, flow cytometry, signaling inhibitors\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (FLIM, phosphoproteomics, functional migration assays) with rigorous mechanistic follow-up\",\n      \"pmids\": [\"28807980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A hydrophobic cluster unique to human PR3 (residues F166, W218, G219, L223) mediates its binding to the NB1 receptor on the neutrophil surface. Gibbon PR3, which lacks these residues, did not bind human NB1. A human-gibbon hybrid PR3 lacking the C-terminal human residues also failed to bind NB1. NB1-bound PR3 remained enzymatically active and was cleared from the surface by alpha-1-protease inhibitor.\",\n      \"method\": \"Cloning and expression of gibbon PR3 ortholog, human-gibbon hybrid protein construction, NB1 binding assay, functional enzymatic assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-function mutagenesis using natural and chimeric proteins with direct binding readout\",\n      \"pmids\": [\"18854317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD177-positive neutrophils migrate significantly faster through endothelial cells expressing the LSR allelic variant of PECAM-1 compared to VNG variant. Engagement of PECAM-1 by rCD177-Fc suppressed ITIM tyrosine phosphorylation and increased β-catenin phosphorylation in an allele-specific manner, suggesting that CD177/PECAM-1 heterophilic interaction modulates endothelial junctional integrity to facilitate neutrophil transmigration.\",\n      \"method\": \"In vitro transendothelial migration assay, PECAM-1 ITIM phosphorylation measurement, β-catenin phosphorylation, recombinant CD177-Fc protein\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional migration assay with defined molecular mechanism and allele-specific controls\",\n      \"pmids\": [\"20194726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Proteinase 3 (PR3) activity contributes to transendothelial migration selectively in NB1 (CD177)-positive neutrophils. PR3 expression and activity were significantly increased on NB1-positive neutrophils following transmigration. Using selective serine protease inhibitors, PR3 activity was shown to facilitate transmigration of NB1-positive neutrophils under both static and flow conditions, while NB1-negative neutrophils showed no increase in PR3.\",\n      \"method\": \"In vitro transendothelial migration under static and flow conditions, selective serine protease inhibitors, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional assay with pharmacological inhibitors under multiple conditions establishing causal role\",\n      \"pmids\": [\"22266279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD177 and membrane PR3 are expressed on the same neutrophil subset; their surface expression increases and decreases in parallel during cell stimulation or spontaneous apoptosis. Rapid internalization and recirculation of both mPR3 and CD177 occur together (all mPR3 replaced within 30 min), indicating they share the same intracellular storage compartment: secondary granules and secretory vesicles.\",\n      \"method\": \"Flow cytometry, cell stimulation assays, apoptosis assays, subcellular fractionation inference\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-expression and co-internalization data, single lab but multiple conditions\",\n      \"pmids\": [\"17077162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD177 (NB1) was biochemically characterized as a 437-amino-acid GPI-anchored glycoprotein with two cysteine-rich domains homologous to the uPAR/Ly6/CD59/snake toxin superfamily, three N-linked glycosylation sites, and a GPI attachment site. COS-7 cells transfected with NB1 cDNA expressed immunoreactive NB1 glycoprotein, confirming the protein-coding sequence.\",\n      \"method\": \"MALDI-TOF mass spectrometry, N-terminal sequencing, RACE PCR, cDNA cloning, COS-7 transfection\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — molecular cloning with mass spectrometry and reconstitution in transfected cells\",\n      \"pmids\": [\"11465086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PRV-1 (CD177) protein is N-glycosylated and GPI-anchored, confirmed biochemically. Multiple PRV-1 transcripts arise from alternative polyadenylation and encode the same protein. Soluble CD177 is shed from the cell surface and can be detected in cell supernatants. Stably transfected cells expressing PRV-1 are recognized by anti-NB1/CD177 antibodies, confirming PRV-1 and NB1 are products of the same gene.\",\n      \"method\": \"Northern blot, biochemical deglycosylation, PI-PLC treatment, flow cytometry, FACS analysis of transfected cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical characterization with multiple methods confirming GPI anchor and glycosylation\",\n      \"pmids\": [\"12239154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The NB1 antigen (CD177) is anchored to the neutrophil plasma membrane via a glycosyl-phosphatidylinositol (GPI) linkage. Treatment with PI-PLC specifically released the 58–64 kDa NB1-bearing protein from the cell surface. Removal of N-linked carbohydrates with endoglycosidase-F reduced the apparent molecular weight to ~45 kDa.\",\n      \"method\": \"PI-PLC treatment, 125I surface labeling, non-denaturing gel electrophoresis, endoglycosidase-F treatment\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical demonstration of GPI anchor by enzymatic release\",\n      \"pmids\": [\"1825110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The NB1 antigen resides on a 58–64 kDa surface glycoprotein also present in secondary granules but not primary granules of neutrophils. The NB1 epitope is not a carbohydrate but likely resides in the tertiary structure of the protein backbone, as periodate treatment had no effect but reduction abolished antibody recognition.\",\n      \"method\": \"SDS-PAGE immunoblotting, immunoprecipitation with 125I-labeled neutrophils, differential centrifugation fractionation, periodate treatment, reduction\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical fractionation and epitope characterization with multiple antisera\",\n      \"pmids\": [\"2153425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD177 expression in neutrophils is controlled by epigenetic mechanisms including a novel monoallelic expression pattern. In bimodal individuals, CD177pos neutrophils transcribe either the maternal or paternal CD177 allele exclusively. ChIP and reporter assays showed that CpG methylation of the CD177 promoter reduces transcription, while demethylation causes biallelic expression. c-Jun and c-Fos bound the CD177 promoter in CD177pos neutrophils (which have a euchromatic, unmethylated promoter) but not CD177neg neutrophils.\",\n      \"method\": \"ChIP, reporter assays (HeLa cells), haplotype analysis, bisulfite sequencing, transcription factor transfection\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP plus reporter assays plus functional demethylation experiments; multiple orthogonal approaches\",\n      \"pmids\": [\"28559244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD177-negative neutrophils within bimodal individuals lack NB1 mRNA, and this absence persists even after G-CSF administration. Three CD177 cDNA polymorphisms were significantly associated with a small CD177-expressing neutrophil subpopulation, indicating a genetic basis for subset-restricted expression.\",\n      \"method\": \"Single-cell picking, FACS sorting, RT-PCR, cDNA sequencing, G-CSF stimulation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — single-cell mRNA analysis with genetic polymorphism association, multiple controls\",\n      \"pmids\": [\"12623849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD177 knockout mice show decreased neutrophil counts in peripheral blood and reduced neutrophil accumulation in skin infected with Staphylococcus aureus. CD177 deletion had no significant impact on CXCL1/KC- or fMLP-induced migration in vitro but led to significant neutrophil cell death, indicating CD177 supports neutrophil survival rather than chemotaxis per se.\",\n      \"method\": \"Genetic knockout mouse model, skin infection model with S. aureus, in vitro migration assays, flow cytometry\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific in vivo and in vitro phenotypic readouts separating survival from migration functions\",\n      \"pmids\": [\"25359465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD177 expressed on tumor-infiltrating regulatory T cells (TI Tregs) modulates their suppressive activity. Blocking CD177 reduced the suppressive activity of Tregs in vitro, while Treg-specific deletion of Cd177 in mice led to decreased tumor growth and reduced TI Treg frequency, establishing a functional role for CD177 in TI Treg-mediated immunosuppression.\",\n      \"method\": \"scRNA-seq, in vitro Treg suppression assay with CD177 blocking, conditional Treg-specific Cd177 knockout mice, tumor growth assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with functional in vitro suppression assay and in vivo tumor model\",\n      \"pmids\": [\"34599187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD177 marks anterior definitive endoderm (ADE) specified toward pancreatic fate. CD177+ ADE expresses and synthesizes the secreted WNT/NODAL/BMP antagonist CERBERUS1 and shows inverse canonical vs. noncanonical WNT signaling compared to CD275+ (hepatic) ADE. Isolated CD177+ ADE differentiates more homogeneously into pancreatic progenitors and more functional glucose-responsive β-like cells.\",\n      \"method\": \"Flow cytometry sorting, scRNA-seq, differentiation assays from human pluripotent stem cells, glucose stimulation assay\",\n      \"journal\": \"Nature biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional differentiation assay with molecular pathway characterization, single lab\",\n      \"pmids\": [\"32341565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD177 deficiency in cancer cells is associated with increased β-catenin/Wnt signaling. Loss of CD177 leads to hyperproliferative mammary epithelium. CD177 was identified as a novel regulator of mammary epithelial proliferation acting via modulation of the Wnt/β-catenin signaling pathway.\",\n      \"method\": \"CD177 loss-of-function (KO/KD), proliferation assays, β-catenin signaling reporters and immunoblot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional KO with signaling pathway readout, single lab\",\n      \"pmids\": [\"32042113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD177 was identified as a novel receptor for podoplanin (PDPN) on cancer-associated fibroblasts. High-throughput interactome screening identified the CD177-PDPN interaction. CD177 acts as a functional antagonist of PDPN, recapitulating the phenotype of PDPN-deficient CAFs including effects on cell signaling, growth, and actomyosin contractility.\",\n      \"method\": \"High-throughput receptor-ligand screening, quantitative phosphoproteomics, cellular functional assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — unbiased interactome screening with phosphoproteomics and functional validation, single lab\",\n      \"pmids\": [\"34879110\"],\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 and attenuates PR3-ANCA-induced neutrophil degranulation and respiratory burst. This effect was CD177-dependent: in CD177-negative neutrophils, PECAM-1 did not significantly change degranulation induced by PR3-ANCA.\",\n      \"method\": \"ELISA, flow cytometry, DHR oxidative burst assay, MACS sorting of CD177-negative neutrophils, degranulation assay\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional neutrophil activation assays with CD177-negative controls, single lab\",\n      \"pmids\": [\"30236159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD177+ neutrophils in IBD produce lower levels of proinflammatory cytokines (IFN-γ, IL-6, IL-17A) but higher levels of IL-22 and TGF-β, and exhibit increased bactericidal activities (ROS, antimicrobial peptides, NETs) compared to CD177- neutrophils. CD177-/- mice developed more severe DSS colitis with compromised intestinal barrier, impaired antibacterial immunity, and decreased IL-22 production.\",\n      \"method\": \"Flow cytometry, RNA sequencing, CD177-/- mouse DSS colitis model, cytokine quantification, bactericidal assays\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO mouse model with specific mechanistic readouts plus human patient cell characterization\",\n      \"pmids\": [\"28468761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD177+ cells produce neutrophil extracellular traps (NETs) that promote biliary atresia (BA) pathogenesis. Cd177-/- mice exhibited delayed BA onset and reduced morbidity/mortality. CD177+ cells from BA mice had high mitochondrial content, elevated ROS, and increased NET formation; NETs induced apoptosis of biliary epithelial cells in co-culture.\",\n      \"method\": \"Cd177-/- mouse model, Smart-Seq RNA-seq, co-culture apoptosis assay, ROS measurement, NET inhibitor studies\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO mouse with defined in vitro mechanistic readout (NET-induced apoptosis) and NET inhibitor confirmation\",\n      \"pmids\": [\"35803543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD177 interaction with PECAM-1 supports preferential transendothelial migration of CD177-positive neutrophils, but CD177/PECAM-1 interaction does not mediate platelet-neutrophil interactions; CD177-positive and CD177-negative neutrophils formed platelet conjugates equally under static and flow conditions.\",\n      \"method\": \"Whole blood platelet-neutrophil conjugate assay, flow chamber adhesion assay, HUVEC migration assay\",\n      \"journal\": \"European journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional assays under static and flow conditions dissecting specificity of CD177 interactions\",\n      \"pmids\": [\"22690867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"NB1 antigen (CD177) inhibits neutrophil-endothelial cell interactions. Unstimulated NB1-positive neutrophils adhered less to HUVEC monolayers than NB1-negative neutrophils. Incubation with anti-NB1 Fab fragments increased CD177+ neutrophil adherence to HUVEC, suggesting NB1 normally suppresses adhesion to endothelium. NB1-positive neutrophils showed greater chemotaxis to FMLP through nitrocellulose.\",\n      \"method\": \"HUVEC adhesion assay, Fab fragment blocking, chemotaxis assay\",\n      \"journal\": \"The Journal of laboratory and clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional adhesion and chemotaxis assays, single lab, foundational functional data\",\n      \"pmids\": [\"8301201\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD177 is a GPI-anchored neutrophil surface glycoprotein (member of the uPAR/Ly6/CD59 superfamily) that functions as a heterophilic ligand for endothelial PECAM-1, mediating neutrophil transendothelial migration via a β2 integrin (Mac-1/CD11b)-dependent signaling complex that activates Src and ERK; it also serves as the membrane receptor and presenter for proteinase 3 (PR3), enabling PR3-ANCA-mediated neutrophil activation, and its subset-restricted expression is controlled by monoallelic epigenetic silencing through CpG methylation and AP-1 (c-Jun/c-Fos) transcription factor binding during neutrophil differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD177 is a GPI-anchored neutrophil surface glycoprotein of the uPAR/Ly6/CD59 superfamily that orchestrates neutrophil transendothelial migration, activation, and survival through engagement of endothelial PECAM-1 and presentation of proteinase 3 (PR3) at the cell surface. CD177 binds PECAM-1 domain 6 in a cation-dependent manner to facilitate neutrophil transmigration, simultaneously signaling through a β2 integrin (Mac-1/CD11b) complex that activates Src and ERK pathways [PMID:17580308, PMID:21193407, PMID:28807980]. CD177 serves as the obligate membrane receptor for PR3, enabling PR3-ANCA-mediated neutrophil degranulation and respiratory burst, while PECAM-1 engagement downregulates membrane PR3 to attenuate this activation [PMID:17244676, PMID:30236159]. Subset-restricted bimodal expression on neutrophils is governed by monoallelic epigenetic silencing through CpG methylation and AP-1 (c-Jun/c-Fos) transcription factor binding, and CD177 deficiency in mice causes increased neutrophil death, exacerbated colitis with impaired barrier function, and altered NET-dependent tissue injury [PMID:28559244, PMID:25359465, PMID:28468761, PMID:35803543].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing the molecular identity of CD177 resolved that the NB1 neutrophil alloantigen is a 58–64 kDa surface glycoprotein stored in secondary granules, with a conformational (non-carbohydrate) epitope.\",\n      \"evidence\": \"SDS-PAGE immunoblotting, immunoprecipitation with 125I-labeled neutrophils, differential centrifugation fractionation of granule subsets\",\n      \"pmids\": [\"2153425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Primary structure unknown\", \"Membrane anchoring mechanism not yet determined\", \"Function of NB1 entirely unknown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Demonstrating that NB1 is GPI-anchored established its mode of membrane attachment and explained its absence in PNH patients lacking GPI-linked proteins.\",\n      \"evidence\": \"PI-PLC enzymatic release of 125I-surface-labeled NB1 from neutrophils, endoglycosidase-F deglycosylation\",\n      \"pmids\": [\"1825110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Gene identity and sequence unknown\", \"No known ligand or function\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Functional studies first indicated that NB1 modulates neutrophil-endothelial interactions, with NB1-positive neutrophils showing reduced basal adhesion to endothelium but enhanced chemotaxis.\",\n      \"evidence\": \"HUVEC adhesion assay and Fab fragment blocking of NB1, chemotaxis through nitrocellulose\",\n      \"pmids\": [\"8301201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endothelial ligand for NB1 unknown\", \"Mechanism of adhesion modulation unclear\", \"Single lab observation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Molecular cloning of CD177 revealed it as a 437-amino-acid member of the uPAR/Ly6/CD59 superfamily with two cysteine-rich domains and three N-glycosylation sites, providing the sequence foundation for all subsequent mechanistic work.\",\n      \"evidence\": \"MALDI-TOF MS, N-terminal sequencing, RACE PCR, cDNA cloning and expression in COS-7 cells\",\n      \"pmids\": [\"11465086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological ligand and function still unknown\", \"Basis for bimodal expression pattern not explained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that CD177-negative neutrophils lack NB1 mRNA and that cDNA polymorphisms correlate with small CD177+ subsets established that bimodal expression is transcriptionally regulated with a genetic component.\",\n      \"evidence\": \"Single-cell FACS sorting followed by RT-PCR, cDNA polymorphism analysis, G-CSF stimulation\",\n      \"pmids\": [\"12623849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epigenetic vs. purely genetic mechanism undetermined\", \"Promoter regulation unexplored\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Two simultaneous discoveries identified CD177's two key molecular partners: PECAM-1 as its heterophilic endothelial ligand mediating transendothelial migration, and PR3 as its surface-presented cargo, linking CD177 to both neutrophil trafficking and ANCA-mediated activation.\",\n      \"evidence\": \"Co-IP, SPR, antibody blocking of transmigration for PECAM-1 interaction; co-IP, confocal co-localization, transfection binding, and GPI removal for PR3 interaction\",\n      \"pmids\": [\"17580308\", \"17244676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transmembrane signaling mechanism unknown (CD177 is GPI-anchored)\", \"Structural basis of CD177-PECAM-1 and CD177-PR3 interfaces unresolved\", \"In vivo relevance of each interaction not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping the PR3 binding interface to a species-specific hydrophobic cluster (F166/W218/G219/L223) defined the structural determinants for CD177-PR3 interaction and showed that surface-bound PR3 retains enzymatic activity.\",\n      \"evidence\": \"Human-gibbon PR3 chimeric proteins and binding assays to NB1-expressing cells\",\n      \"pmids\": [\"18854317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reciprocal mapping of the CD177 binding surface for PR3 not done\", \"No crystal structure of the complex\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of Mac-1 (CD11b/CD18) as the transmembrane signaling adaptor for GPI-anchored CD177 resolved how CD177 transduces signals, and showing allele-specific modulation of PECAM-1 ITIM phosphorylation and β-catenin phosphorylation explained how CD177 regulates endothelial junctional integrity during transmigration.\",\n      \"evidence\": \"MS/MS proteomics of NB1 signaling complexes, SPR for direct interaction, lipid raft co-localization, CD11b blocking of PR3-ANCA responses; transendothelial migration with PECAM-1 allelic variants and phosphorylation assays\",\n      \"pmids\": [\"21193407\", \"20194726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CD177-Mac-1 interaction unknown\", \"In vivo validation of allele-specific migration not performed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that PR3 enzymatic activity selectively enhances transmigration of CD177-positive neutrophils, and that CD177-PECAM-1 interaction does not mediate platelet-neutrophil conjugation, refined the specificity of CD177's functional roles to endothelial transmigration.\",\n      \"evidence\": \"Transendothelial migration with selective serine protease inhibitors under static and flow conditions; platelet-neutrophil conjugate assays\",\n      \"pmids\": [\"22266279\", \"22690867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PR3 substrates at the endothelial junction not identified\", \"Relative contributions of CD177-PECAM-1 binding versus PR3 proteolysis to transmigration not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Three key advances in 2017 completed the signaling model: CD177 ligation enhances β2 integrin interaction via FLIM, activates Src/ERK to paradoxically impair migration through integrin internalization defects; epigenetic control was shown to involve monoallelic CpG methylation and AP-1 binding; and CD177+ neutrophils were demonstrated to be anti-inflammatory in IBD with IL-22 production and barrier-protective functions.\",\n      \"evidence\": \"FLIM, phosphorylation/signaling inhibitor assays; ChIP, bisulfite sequencing, reporter assays; CD177−/− mouse DSS colitis model with cytokine profiling and RNA-seq\",\n      \"pmids\": [\"28807980\", \"28559244\", \"28468761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Src/ERK activation simultaneously promotes transmigration yet impairs chemokine-directed migration is not fully reconciled\", \"Whether monoallelic expression is stochastic or deterministic during granulopoiesis is unclear\", \"Mechanism linking CD177 to IL-22 production not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing that PECAM-1 engagement of CD177 downregulates membrane PR3 and attenuates PR3-ANCA-induced activation revealed a negative feedback loop that may limit ANCA vasculitis pathology in CD177-positive neutrophils.\",\n      \"evidence\": \"Dose-dependent PR3 downregulation by recombinant PECAM-1, degranulation and oxidative burst assays with MACS-sorted CD177-negative controls\",\n      \"pmids\": [\"30236159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance in ANCA vasculitis not tested\", \"Mechanism of PECAM-1-induced PR3 internalization not defined\", \"Single lab observation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that CD177 marks anterior definitive endoderm fated toward pancreas and that CD177 deficiency increases β-catenin/Wnt signaling in mammary epithelium extended CD177 function beyond neutrophils to developmental and tumor-suppressive contexts.\",\n      \"evidence\": \"hPSC differentiation with FACS sorting and scRNA-seq; CD177 KO/KD with Wnt signaling reporters in mammary cells\",\n      \"pmids\": [\"32341565\", \"32042113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CD177 inhibits Wnt/β-catenin signaling is unknown\", \"Whether CD177's developmental role is cell-autonomous or paracrine is unclear\", \"Single lab for each observation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CD177 was found to function on tumor-infiltrating Tregs to sustain immunosuppression and was identified as a novel receptor for podoplanin on cancer-associated fibroblasts, broadening CD177's role to immune regulation in the tumor microenvironment.\",\n      \"evidence\": \"Treg-specific Cd177 conditional KO mice with tumor growth assays and in vitro suppression; high-throughput receptor-ligand screening with phosphoproteomics for PDPN interaction\",\n      \"pmids\": [\"34599187\", \"34879110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling downstream of CD177 in Tregs is uncharacterized\", \"CD177-PDPN interaction awaits independent replication\", \"Whether CD177 on Tregs engages PECAM-1 or PDPN in vivo is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that CD177+ neutrophils produce NETs that cause biliary epithelial apoptosis in biliary atresia, with amelioration in Cd177−/− mice, established CD177 as a pathogenic driver through NET-mediated tissue injury.\",\n      \"evidence\": \"Cd177−/− mouse BA model, Smart-Seq RNA-seq, co-culture apoptosis assay, NET inhibitor studies\",\n      \"pmids\": [\"35803543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD177 directly promotes NET formation or acts indirectly through survival/ROS is unclear\", \"Human genetic validation in biliary atresia patients not provided\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No atomic-resolution structure of CD177 or its complexes with PECAM-1, PR3, Mac-1, or podoplanin exists, and the mechanism by which this GPI-anchored protein modulates intracellular Wnt/β-catenin signaling and Treg suppressive function remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of CD177 or any CD177-ligand complex\", \"Mechanism of CD177-mediated Wnt pathway inhibition unknown\", \"How CD177 regulates Treg suppressive function at the molecular level is unexplored\", \"Whether neutrophil and non-neutrophil functions share common signaling mechanisms is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 5, 6, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [17, 18, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 8, 10, 11]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 6, 14, 20, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 17, 18]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 5, 22]}\n    ],\n    \"complexes\": [\n      \"CD177–Mac-1 (CD11b/CD18) lipid raft signaling complex\",\n      \"CD177–PR3 surface complex\"\n    ],\n    \"partners\": [\n      \"PECAM1\",\n      \"PRTN3\",\n      \"ITGAM\",\n      \"PDPN\",\n      \"JUN\",\n      \"FOS\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}