{"gene":"SELPLG","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2000,"finding":"Crystal structure of P-selectin lectin-EGF domains co-complexed with the N-terminal domain of human PSGL-1 modified by tyrosine sulfation and sialyl Lewis X revealed the molecular basis of high-affinity P-selectin/PSGL-1 interaction, showing how sulfated tyrosines and glycan cooperate for binding.","method":"X-ray crystallography (crystal structure of P-selectin LE domains with PSGL-1 N-terminal peptide)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure with direct functional validation of binding interface","pmids":["11081633"],"is_preprint":false},{"year":1995,"finding":"Tyrosine sulfation of a consensus motif within the N-terminal ~20 residues of PSGL-1 is essential for P-selectin binding; mutation of N-terminal tyrosines to phenylalanine abolishes P-selectin adhesion, and sulfation inhibitors block HL-60 rolling on P-selectin.","method":"Site-directed mutagenesis, sulfation inhibitors, cell rolling assay on P-selectin-coated coverslips","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with pharmacological inhibition and functional rolling assay, replicated by subsequent structural work","pmids":["7585950"],"is_preprint":false},{"year":1998,"finding":"Dimerization of PSGL-1 through a single conserved extracellular cysteine (C320) is essential for functional recognition of P-selectin; monomeric C320A mutant fails to support rolling or binding to P-selectin chimeras despite intact surface expression.","method":"Cysteine-to-alanine mutagenesis, Western blot under native/denaturing conditions, low-shear adhesion and flow-chamber rolling assays in stable K562 transfectants","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with multiple orthogonal functional assays in same study","pmids":["9660879"],"is_preprint":false},{"year":1999,"finding":"PSGL-1 is required for P-selectin-mediated neutrophil rolling and leukocyte recruitment in early inflammation (30 min post-trauma); however, it is not required for E-selectin-mediated rolling 2 h after TNF-α stimulation, as shown in PSGL-1 gene-knockout mice.","method":"Targeted gene disruption (PSGL-1 knockout mice), intravital microscopy of cremaster venules, chemical peritonitis model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with intravital microscopy and multiple inflammatory models; replicated by antibody-blockade studies","pmids":["10601352"],"is_preprint":false},{"year":2002,"finding":"PSGL-1 associates with Syk kinase through ERM proteins (ezrin/moesin); engagement of PSGL-1 induces Syk tyrosine phosphorylation and SRE-dependent transcriptional activation. ITAM-mutated moesin or Syk dead-kinase mutant abrogates PSGL-1-induced transcription.","method":"Co-immunoprecipitation, dominant-negative overexpression, pharmacological Syk inhibition (piceatannol), SRE reporter assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus mutagenesis plus functional reporter, multiple orthogonal methods","pmids":["12387735"],"is_preprint":false},{"year":2002,"finding":"Attachment of the PSGL-1 cytoplasmic domain to the actin cytoskeleton via moesin (but not other ERM proteins) is essential for leukocyte rolling on P-selectin; cytoplasmic truncation abolishes rolling without affecting P-selectin binding or surface distribution of PSGL-1.","method":"Stable transfection with truncated PSGL-1 (ΔCyto), actin cytoskeletal toxin treatment, co-immunoprecipitation with ERM proteins, rolling assay in flow chamber","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis plus selective ERM pulldown plus functional rolling assay, replicated by subsequent studies","pmids":["12036880"],"is_preprint":false},{"year":2008,"finding":"The PSGL-1 cytoplasmic domain is dispensable for leukocyte rolling on P-selectin (when PSGL-1 surface density is matched) but is essential for Syk-dependent activation of LFA-1 (αLβ2) to convert fast rolling to slow rolling on ICAM-1.","method":"ΔCD knock-in mice expressing cytoplasmic-domain-deleted PSGL-1, O-sialoglycoprotein endopeptidase titration to match PSGL-1 density, intravital microscopy, Syk phosphorylation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with matched-density controls and biochemical signaling readout, multiple orthogonal methods","pmids":["18550846"],"is_preprint":false},{"year":2008,"finding":"E-selectin engagement of PSGL-1 activates Syk and p38 MAPK to induce slow neutrophil rolling via an ITAM-dependent pathway requiring Src-family kinase Fgr and ITAM adaptor proteins DAP12 and FcRγ, independently of Gαi-coupled receptors.","method":"Gene-deficient mice (fgr−/−, Tyrobp−/− Fcrg−/−), flow chamber rolling assay, intravital microscopy, Syk/p38 phosphorylation assay, mixed bone marrow chimeras, peritonitis model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple knockout lines with in vivo and in vitro validation; replicated by subsequent studies","pmids":["18794338"],"is_preprint":false},{"year":2010,"finding":"E-selectin engagement of either PSGL-1 or CD44 triggers slow rolling through a common lipid-raft-dependent pathway using SFKs Hck, Lyn, and Fgr; Bruton's tyrosine kinase (BTK) acts as a key intermediate between Syk and p38. PSGL-1's cytoplasmic domain is required for SFK activation during this process.","method":"Gene-deficient mice, flow chamber and intravital microscopy, lipid raft disruption, kinase inhibitors, phosphorylation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models and inhibitor experiments with in vivo confirmation","pmids":["20299514"],"is_preprint":false},{"year":2007,"finding":"Among E-selectin ligands on neutrophils, PSGL-1 plays the major role in initial leukocyte capture, ESL-1 is critical for converting initial tethers to slow rolling, and CD44 controls rolling velocity and mediates E-selectin-dependent redistribution of PSGL-1 and L-selectin to the major pole via p38 signaling.","method":"Gene-targeted and RNA-targeted loss-of-function in mice, intravital microscopy, flow chamber assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic combined gene/RNA loss-of-function across all three ligands with intravital microscopy","pmids":["17442598"],"is_preprint":false},{"year":1996,"finding":"PSGL-1 on neutrophils serves as a ligand for L-selectin, supporting L-selectin–PSGL-1-mediated neutrophil–neutrophil aggregation as the first step in homotypic aggregation.","method":"Anti-PSGL-1 Fab inhibition, simultaneous antibody blocking of L-selectin and PSGL-1 on separate cell populations, flow cytometry aggregation assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blocking experiments with two orthogonal approaches; single lab","pmids":["8839831"],"is_preprint":false},{"year":1997,"finding":"PSGL-1 is the sole P-selectin-binding glycoprotein on Th1 cells (not Th2 cells) despite similar surface expression levels; PSGL-1 on Th1 supports P-selectin binding and partially mediates their migration into cutaneous delayed-type hypersensitivity lesions.","method":"Affinity isolation with P-selectin-Ig fusion protein, flow cytometry binding assay, antibody blocking in cell adhesion assay and in vivo DTH model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — affinity isolation plus functional blocking plus in vivo migration study with defined phenotypic readout","pmids":["9053457"],"is_preprint":false},{"year":1999,"finding":"PSGL-1 engagement by P-selectin on activated platelets triggers tyrosine kinase-dependent (genistein-sensitive) phosphorylation of a 110 kDa protein and activates CD11b/CD18 (β2 integrin) on PMNs; a non-adhesion-blocking anti-PSGL-1 antibody alone triggers the same β2-integrin-dependent aggregation.","method":"Mixed-cell shear-flow aggregation assay, antibody blocking (anti-P-selectin, anti-CD11b/CD18, anti-PSGL-1), tyrosine kinase inhibitors (genistein), tyrosine phosphorylation assay, CHO-P transfectants","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple inhibitor and antibody approaches with reconstituted cell systems confirming PSGL-1 as the signaling receptor","pmids":["9920836"],"is_preprint":false},{"year":2013,"finding":"A subset of PSGL-1 molecules is constitutively associated with L-selectin on neutrophils; this PSGL-1–L-selectin complex signals through Src family kinases and ITAM adaptors to activate LFA-1, and requires the L-selectin cytoplasmic tail for signaling output.","method":"Co-immunoprecipitation of endogenous PSGL-1 and L-selectin, L-selectin cytoplasmic tail mutants, flow chamber rolling assay, intravital microscopy, SFK inhibitors","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of endogenous complex plus cytoplasmic-domain mutagenesis plus in vivo functional confirmation","pmids":["24127491"],"is_preprint":false},{"year":2007,"finding":"PSGL-1 signals through Akt/mTOR upon macrophage adherence to promote translational upregulation of ROCK-1 (but not ROCK-2) mRNA, which is required for macrophage chemotaxis and phagocytosis; PSGL-1-deficient macrophages phenocopy mTOR inhibition.","method":"PSGL-1−/− macrophages, rapamycin treatment, ribosome loading assay, ROCK-1/2 Western blot, chemotaxis and phagocytosis assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (PSGL-1 KO) plus pharmacological (rapamycin) convergence with multiple orthogonal functional readouts","pmids":["17245434"],"is_preprint":false},{"year":2016,"finding":"PSGL-1 ligation on exhausted CD8+ T cells inhibits TCR and IL-2 signaling and upregulates PD-1, leading to diminished survival upon TCR stimulation. PSGL-1-deficient mice clear chronic virus due to intrinsically improved effector T cell survival with reduced inhibitory receptor expression.","method":"PSGL-1−/− mice in chronic LCMV infection model, TCR/IL-2 signaling assays, PD-1 expression measurement, T cell survival assays, melanoma tumor model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with mechanistic signaling readouts and two disease models","pmids":["27192578"],"is_preprint":false},{"year":2023,"finding":"PSGL-1 attenuates TCR signaling upstream of PD-1 by directly restraining Zap70 phosphorylation and maintaining expression of the Zap70 inhibitor Sts-1; PSGL-1 requires co-ligation with TCR to suppress CD8+ T cell activation and drive terminal exhaustion.","method":"PSGL-1−/− mice, Zap70 phosphorylation assays, Sts-1 expression analysis, co-ligation experiments, tumor models with pharmacologic PSGL-1 blockade","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus pharmacologic blockade plus defined biochemical signaling mechanism with multiple functional readouts","pmids":["37115668"],"is_preprint":false},{"year":2019,"finding":"VISTA binds PSGL-1 selectively at acidic pH through multiple histidine residues along the rim of the VISTA extracellular domain; this interaction suppresses T cells in the tumor microenvironment and can be blocked by pH-selective antibodies.","method":"Binding assays, site-directed mutagenesis of VISTA histidines, pH-selective blocking antibodies, in vivo immune suppression assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis identifying the binding interface, pH-selective binding characterization, and in vivo functional rescue","pmids":["31645726"],"is_preprint":false},{"year":2019,"finding":"HIV-1 Vpu binds PSGL-1 and induces its ubiquitination and degradation through the ubiquitin ligase SCFβ-TrCP2; PSGL-1 (induced by IFN-γ) inhibits HIV-1 reverse transcription and blocks virion infectivity by incorporating into progeny virions.","method":"Isobaric-tag mass spectrometry proteomics, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, HIV infectivity assays, reverse transcription assay in primary CD4+ T cells","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical and virological methods with primary cell validation","pmids":["30833724"],"is_preprint":false},{"year":2020,"finding":"Virion-incorporated PSGL-1 blocks HIV-1 infectivity by preventing attachment of virions to target cells, independently of the viral glycoprotein; the extracellular N-terminal domain of PSGL-1 is necessary, and the cytoplasmic tail contributes to inhibition. Vpu (and Nef) down-regulate PSGL-1 from the cell surface to partially escape this restriction.","method":"HIV infectivity assays with PSGL-1 domain deletion mutants, particle attachment assays to CD4+ cells, Vpu/Nef expression, murine leukemia virus and influenza A virus infectivity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple domain mutants, multiple virus types, and direct attachment assays; confirmed by independent lab (PMID 32193343)","pmids":["32273392","32193343"],"is_preprint":false},{"year":2020,"finding":"Virion incorporation of PSGL-1 and CD43 inhibits HIV-1 attachment to both CD4+ target cells and fibroblastic reticular cells mediating transinfection; the full-length ectodomain of PSGL-1 is required, consistent with steric blockade of virus-cell contact.","method":"HIV-1 particle attachment assays, PSGL-1 ectodomain truncation mutants, CD4− cell transinfection assay, Gag copatching analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ectodomain mutant mapping plus transinfection assay, orthogonally confirmed by PMID 32273392","pmids":["32193343"],"is_preprint":false},{"year":2020,"finding":"PSGL-1 directly binds F-actin to restrict actin dynamics, inhibiting HIV DNA synthesis; incorporated PSGL-1 also binds gp41 and sequesters it at the plasma membrane, reducing Env incorporation into virions and impairing viral entry.","method":"F-actin co-sedimentation/binding assay, cryo-EM and super-resolution imaging of Env on virions, gp41 co-immunoprecipitation, HIV DNA synthesis assay","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays plus imaging, single lab; some mechanistic claims supported by structural imaging","pmids":["32802403"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the radixin FERM domain complexed with a PSGL-1 juxtamembrane peptide reveals that PSGL-1 binds FERM subdomain C in a beta-strand mode; non-conserved large residues (Met9, His8) compensate for the absence of the canonical Motif-1 alanine, providing structural basis for PSGL-1–ERM interaction.","method":"X-ray crystallography of radixin FERM–PSGL-1 peptide complex","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structure; single lab, but direct structural determination","pmids":["18076570"],"is_preprint":false},{"year":2004,"finding":"Human FucT-VII plays the predominant role in generating selectin-binding carbohydrate ligands on PSGL-1, while FucT-IV also contributes; core-2 O-glycans attached to Thr-57 are critical for L- and P-selectin rolling, whereas E-selectin uses additional PSGL-1 binding sites (>75% of rolling is Thr-57-independent).","method":"CHO cell transfections with FucT-IV and/or FucT-VII plus core-2 GlcNAcT, PSGL-1 Thr-57 and Thr-44 alanine mutants, rolling adhesion assays on L-, P-, and E-selectin","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic mutagenesis of glycosylation sites combined with multiple functional rolling assays","pmids":["15579466"],"is_preprint":false},{"year":2002,"finding":"For L-selectin binding, Tyr-51 at the PSGL-1 N-terminus plays a predominant role (contrasting with P-selectin where Tyr-48 is key); core-2 O-glycans on Thr-57 are critical for optimal L-selectin binding and for controlling rolling velocity.","method":"Tyr-to-Phe and Thr-to-Ala mutagenesis, CHO cell expression with core-2 GlcNAcT and FucT-VII, L-selectin binding assays, rolling adhesion assays, molecular modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional assays and structural modeling; single lab","pmids":["12403782"],"is_preprint":false},{"year":2000,"finding":"PSGL-1 is expressed on platelets at 25–100-fold lower levels than leukocytes; platelet PSGL-1 is functional and mediates platelet rolling in mesenteric venules, as shown by anti-PSGL-1 antibody blockade in intravital microscopy.","method":"P-selectin-IgG affinity purification, Western blot, anti-PSGL-1 immunopurification, flow cytometry, intravital microscopy with antibody blockade","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — affinity purification plus Western blot confirmation plus in vivo functional blockade","pmids":["10770806"],"is_preprint":false},{"year":2005,"finding":"P-selectin and its ligand PSGL-1 mediate recruitment of adult lymphoid progenitors to the thymus; PSGL-1−/− thymi contain fewer early thymic progenitors, and thymic P-selectin expression is regulated by niche occupancy, suggesting a homeostatic P-selectin/PSGL-1 thymic homing axis.","method":"Parabiosis, competitive thymus reconstitution, short-term homing assays, PSGL-1−/− mice","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo assays (parabiosis, competitive reconstitution, homing) with genetic KO","pmids":["15880112"],"is_preprint":false},{"year":1999,"finding":"PSGL-1 ligation on human CD34+ hematopoietic progenitor cells (the sole P-selectin receptor on these cells) by immobilized or soluble P-selectin, or by anti-PSGL-1 antibody, profoundly suppresses HPC proliferation stimulated by growth factors.","method":"P-selectin-IgG affinity purification to identify PSGL-1 as the sole receptor, immobilized/soluble ligand and antibody ligation, colony-forming proliferation assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor identification by affinity purification plus three independent ligation methods with functional proliferation readout","pmids":["10514015"],"is_preprint":false},{"year":2013,"finding":"Engagement of PSGL-1 and CXCR2 on rolling neutrophils cooperatively propagates signals to induce β2 integrin-dependent arrest in flow-restricted inferior vena cava. PSGL-1 signaling in this context uses Tyr-145 (not Tyr-112/128) of SLP-76 and does not require L-selectin; cooperative PSGL-1/CXCR2 signaling increases thrombus frequency and size partly by stimulating NET release.","method":"Genetically engineered mice, spinning-disk intravital microscopy, ultrasonography, IVC flow restriction model, pharmacological PSGL-1/CXCR2 blockade, NET quantification","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic and pharmacological dissection with intravital imaging and defined SLP-76 phosphosite mapping","pmids":["30068506"],"is_preprint":false},{"year":2011,"finding":"ADAM8 metalloprotease is associated with PSGL-1 through ERM proteins and proteolytically cleaves PSGL-1; ADAM8 knockdown increases PSGL-1 surface expression and enhances leukocyte rolling on P-selectin, identifying ADAM8 as a sheddase regulating PSGL-1 function.","method":"Co-immunoprecipitation via ERM proteins, ADAM8 siRNA knockdown, PSGL-1 surface expression assay, leukocyte rolling assay on P-selectin","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus siRNA knockdown plus functional rolling assay; single lab","pmids":["22229154"],"is_preprint":false},{"year":2012,"finding":"The ERM-binding sequence (EBS) of the PSGL-1 cytoplasmic tail (key residues Arg-337 and Lys-338) is required for leukocyte tethering and rolling on L-, P-, and E-selectin and for ERK activation; however, EBS is dispensable for Syk phosphorylation and E-selectin-induced slow rolling.","method":"EBS deletion and alanine-substitution mutagenesis in 32D leukocytes, rolling assays on selectins, ERK and Syk phosphorylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis distinguishing two signaling pathways downstream of PSGL-1; single lab","pmids":["22311979"],"is_preprint":false},{"year":2012,"finding":"PSGL-1 does not require dimerization or cytoskeletal anchorage to signal β2 integrin-dependent slow rolling; FRAP documented cytoskeletal restraint of WT PSGL-1, and actin depolymerization or cytoplasmic-tail mutation increasing lateral mobility did not impair slow rolling, whereas chemokine-triggered arrest remained cytoskeleton-dependent.","method":"FRAP, latrunculin B treatment, retroviral transduction of WT and mutant PSGL-1 into PSGL-1−/− macrophages, rolling/arrest assays, β2-hybrid domain swing-out assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — FRAP plus genetic reconstitution plus pharmacological actin disruption with multiple functional readouts","pmids":["22511754"],"is_preprint":false},{"year":2008,"finding":"Sorting nexin 20/SLIC-1 interacts with the PSGL-1 cytoplasmic domain and directs PSGL-1 to endosomes via its Phox homology domain; loss of the murine SLIC-1 homologue does not alter PSGL-1 signaling or neutrophil adhesion, indicating SLIC-1 is a sorting but not signaling regulator.","method":"Yeast two-hybrid screen, co-immunoprecipitation, colocalization in endosomes, murine SLIC-1 KO functional assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus colocalization plus KO; single lab","pmids":["18196517"],"is_preprint":false},{"year":2003,"finding":"Peritoneal macrophages synthesize and constitutively express P-selectin on their plasma membrane; P-selectin is rapidly internalized to lysosomes. Macrophage-macrophage interactions in flow are mediated by P-selectin on one macrophage binding PSGL-1 on another.","method":"Metabolic labeling, flow cytometry, Western blot, immunoelectron microscopy, flow-based macrophage aggregation assay with blocking antibodies","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolic labeling confirming synthesis plus functional blocking assay; single lab, two orthogonal methods","pmids":["14662752"],"is_preprint":false},{"year":2009,"finding":"Flotillin-1 and -2 co-immunoprecipitate and colocalize with PSGL-1 in resting and stimulated neutrophils, associating with PSGL-1 in actin-dependent membrane microdomains that accumulate in the uropod; PSGL-1 is not required for formation of flotillin caps.","method":"Co-immunoprecipitation, immunofluorescence colocalization, PSGL-1−/− neutrophils, differentiated HL-60 overexpression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus colocalization plus KO validation; single lab","pmids":["19404397"],"is_preprint":false},{"year":2004,"finding":"Sulfated tyrosines at the PSGL-1 N-terminus (not O-glycans or N-glycans) mediate interaction with the chemokine CCL27 (CTACK); mutation of N-terminal tyrosines to phenylalanine abolishes binding, and PSGL-1 expression on CCR10+ cells reduces chemotactic responses to CCL27.","method":"Recombinant PSGL-1-Ig binding assay with multiple chemokines, arylsulfatase/glycosidase treatment, sulfation-inhibitor synthesis, Tyr→Phe mutagenesis, CCR10+ cell chemotaxis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis plus enzymatic modification plus functional chemotaxis assay; single lab, multiple orthogonal methods","pmids":["15466853"],"is_preprint":false},{"year":2015,"finding":"The N-termini of PSGL-1 and CCR7 have overlapping binding sites for CCL19; chemical-shift mapping shows the interactions are competitive, providing a structural basis for PSGL-1's enhancement of CCL19-mediated T cell recruitment.","method":"NMR solution structure of CCL19, chemical shift perturbation mapping with PSGL-1 and CCR7 N-terminal peptides","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR structure with chemical-shift mapping; functional consequence inferred not directly tested in same paper","pmids":["26115234"],"is_preprint":false},{"year":2007,"finding":"EphB4 activation with ephrin-B2-Fc upregulates PSGL-1 expression on endothelial progenitor cells; PSGL-1 siRNA reverses both the enhanced EPC adhesion to E/P-selectin and the proangiogenic effect of EphB4 activation in a mouse hindlimb ischemia model.","method":"EphB4 siRNA, PSGL-1 siRNA, EPC adhesion assay, mouse hindlimb ischemia model, neutralizing antibodies to E/P-selectin","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — convergent siRNA knockdown of upstream receptor and PSGL-1 with in vivo model; single lab","pmids":["17510705"],"is_preprint":false},{"year":2013,"finding":"A single amino acid at EV71 capsid VP1-145 acts as a molecular switch controlling binding to PSGL-1: G or Q at VP1-145 permits binding to PSGL-1 sulfated tyrosines (mediated by conserved lysines VP1-242/244), while E at VP1-145 turns the VP1-244 lysine inward to prevent PSGL-1 binding.","method":"Site-directed mutagenesis of VP1-145, VP1-242, and VP1-244; cell binding assays on PSGL-1-expressing cells; crystal structure comparison of EV71 isolates","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of both virus and structural analysis plus functional cell binding assay","pmids":["23935488"],"is_preprint":false},{"year":2013,"finding":"EV71 entry mediated by PSGL-1 requires caveolar endocytosis (caveolin-1-dependent), whereas SCARB2-mediated entry uses clathrin-dependent endocytosis; PSGL-1 and SCARB2 thus dictate distinct endocytic routes for EV71.","method":"Specific endocytosis inhibitors, caveolin-1 siRNA, clathrin knockdown, confocal colocalization of EV71 with caveolae in Jurkat T cells and PSGL-1-L929 cells vs. RD cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological inhibitors plus siRNA knockdown in receptor-defined cell lines with confocal confirmation","pmids":["23760234"],"is_preprint":false},{"year":2016,"finding":"Soluble Siglec-5 binds PSGL-1 on leukocytes in a sialic-acid-dependent and calcium-dependent manner (sialidase treatment reduces binding by 79%); PSGL-1 and Siglec-5 are in close proximity (<40 nm) on PBMCs. Soluble Siglec-5 variants block PSGL-1-mediated leukocyte rolling on E/P-selectin in vitro and in vivo.","method":"Soluble Siglec-5 binding assay, sialidase treatment, Duolink proximity ligation assay, in vitro perfusion rolling assay, in vivo TNF-α inflammation model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity ligation plus enzymatic modification plus in vivo blocking; single lab","pmids":["27892504"],"is_preprint":false},{"year":2021,"finding":"GALNT4-catalyzed O-glycosylation of PSGL-1 is required for P-selectin-induced β2 integrin activation on monocytes and for monocyte adhesion and transmigration; GALNT4 overexpression increases PSGL-1 O-glycosylation and activates Akt/mTOR and IκBα/NFκB downstream of P-selectin/PSGL-1 engagement.","method":"VVL lectin pulldown, PSGL-1 immunoprecipitation for O-glycosylation, GALNT4 shRNA knockdown and overexpression, β2-integrin activation assay, monocyte adhesion/transmigration under flow, ApoE−/− mouse atherosclerosis model","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical O-glycosylation characterization plus gain/loss-of-function with functional and in vivo readouts; single lab","pmids":["34974060"],"is_preprint":false},{"year":2023,"finding":"P-selectin binding to PSGL-1 on tumor-associated macrophages activates the JNK/STAT1 pathway, driving transcription of complement C5 and release of C5a, which activates C5aR1 to shift TAMs toward a pro-tumor phenotype; PSGL-1 inhibition reduces CRC growth.","method":"Western blot for JNK/STAT1, dual-luciferase reporter and ChIP assay for C5 transcription, ELISA for C5a, siRNA knockdown of PSGL-1, AOM/DSS mouse CRC model, FACS","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase reporter plus siRNA plus in vivo model; single lab, multiple orthogonal methods","pmids":["37064877"],"is_preprint":false},{"year":2023,"finding":"P-selectin stimulation of neutrophils via PSGL-1 activates the Syk/Ca2+/PAD4 signaling pathway to induce NET formation; pharmacological inhibition of P-selectin (PSI-697) reduces PAD4 expression and NETs in pancreatic tissue and ameliorates acute pancreatitis in mice.","method":"Western blot for Syk phosphorylation, intracellular calcium imaging, PAD4 expression assay, flow cytometry and immunofluorescence for NETs, PSI-697 treatment in caerulein-AP mouse model","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and in vivo validation with defined signaling cascade; single lab","pmids":["37841279"],"is_preprint":false},{"year":2014,"finding":"PSGL-1 (CD162) but not CD44, when deleted by CRISPR-Cas9 from AML cell line KG1a, abolishes E-selectin-mediated chemo-resistance in vitro; absence of CD162 on AML cells delays leukemia onset, reduces BM retention, and increases chemotherapy sensitivity in vivo.","method":"CRISPR-Cas9 knockout of CD162 or CD44, in vitro E-selectin adhesion/chemo-resistance assays, preclinical murine AML model","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR knockout with parallel CD44 control plus in vitro and in vivo functional validation","pmids":["32793603"],"is_preprint":false},{"year":2014,"finding":"Basic residues in HIV-1 Gag matrix domain and a polybasic sequence in the PSGL-1 cytoplasmic tail mediate coclustering of PSGL-1 with assembling Gag at the plasma membrane, promoting virion incorporation of PSGL-1.","method":"Quantitative two-color superresolution localization microscopy, Gag matrix mutants, PSGL-1 cytoplasmic tail chimera experiments in T and HeLa cells","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — superresolution imaging plus domain-swap mutants; single lab","pmids":["25320329"],"is_preprint":false},{"year":2020,"finding":"PSGL-1 expression in virus-producing cells impairs incorporation of SARS-CoV and SARS-CoV-2 spike glycoproteins into pseudovirions and blocks pseudovirus attachment and infection of target cells, extending PSGL-1's antiviral restriction to coronaviruses.","method":"Pseudovirus infectivity assays, spike glycoprotein incorporation Western blot, PSGL-1 expression in virus-producing cells","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pseudovirus assays with biochemical confirmation; single lab","pmids":["33396594"],"is_preprint":false},{"year":2005,"finding":"PSGL-1 cross-linking induces tyrosine-phosphorylation-dependent and c-Abl-involved F-actin polymerization and redistribution in neutrophils; c-Abl relocalizes to F-actin foci, and the Abl inhibitor STI571 blocks the cytoskeletal reorganization.","method":"Anti-PSGL-1 antibody cross-linking, cytoskeletal fractionation, genistein and STI571 inhibition, F-actin immunofluorescence and redistribution assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibition with multiple inhibitors and cytoskeletal assays; single lab","pmids":["15526280"],"is_preprint":false},{"year":1998,"finding":"Characterization of O-linked oligosaccharides on PSGL-1 isolated from HL-60 cells showed that only ~4.5% of O-linked glycans (core-2 structures with sialic acid and fucose on N-acetyllactosamine) constitute the selectin-binding fraction; most O-glycans lack fucose and are insufficient for selectin binding.","method":"3H-glucosamine metabolic labeling, P-selectin/E-selectin affinity chromatography, ion-exchange/size exclusion/lectin/paper chromatography, exoglycosidase treatments, chemical modifications","journal":"Glycoconjugate journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — comprehensive biochemical glycan structural analysis; single lab","pmids":["10211703"],"is_preprint":false},{"year":2014,"finding":"PI3K is required for PSGL-1-induced β1 integrin clustering (but not for β1 integrin conformation changes or total expression), and PSGL-1-PI3K-β1 integrin signaling promotes Jurkat cell adhesion to fibronectin.","method":"PI3K inhibitors, anti-PSGL-1 antibody ligation, β1 integrin clustering assay, conformation-sensitive antibody assay, Jurkat adhesion to fibronectin","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibition only, single method, single lab","pmids":["24122451"],"is_preprint":false}],"current_model":"PSGL-1 (SELPLG/CD162) is a dimeric, sulfated, O-glycosylated mucin-like receptor that functions as the primary ligand for P-, E-, and L-selectins to mediate leukocyte tethering and rolling: its N-terminal tyrosine sulfation and core-2 sialyl Lewis X glycans cooperate (Tyr-48 for P-selectin, Tyr-51 for L-selectin) for high-affinity selectin binding, dimerization via a conserved extracellular cysteine is required for P-selectin recognition, and attachment of its cytoplasmic tail to the actin cytoskeleton via moesin/ERM proteins is essential for rolling stability; beyond adhesion, PSGL-1 engagement initiates outside-in signaling through Fgr/Hck/Lyn SFKs→DAP12/FcRγ ITAM adaptors→Syk→p38/BTK to activate LFA-1 (requiring the PSGL-1 cytoplasmic domain) for slow rolling, and a constitutive PSGL-1–L-selectin signaling complex amplifies these signals; PSGL-1 also restrains T cell function as an immune checkpoint by attenuating Zap70/TCR signaling and maintaining Sts-1 to drive T cell exhaustion, can be engaged by VISTA at acidic pH to suppress T cells in tumors, and acts as a broad-spectrum antiviral restriction factor by incorporating into virions and blocking virus-cell attachment—an activity countered by HIV-1 Vpu, which recruits SCFβ-TrCP2 to ubiquitinate and degrade PSGL-1."},"narrative":{"mechanistic_narrative":"PSGL-1 (SELPLG/CD162) is a dimeric, tyrosine-sulfated, O-glycosylated mucin-like leukocyte receptor that serves as the principal ligand for P-, E-, and L-selectins to mediate the tethering and rolling steps of leukocyte recruitment to inflamed and lymphoid tissue [PMID:11081633, PMID:10601352, PMID:15880112]. High-affinity selectin binding requires the cooperative action of N-terminal sulfated tyrosines and core-2 sialyl Lewis X glycans on the PSGL-1 N-terminus: tyrosine sulfation is essential for P-selectin adhesion, Tyr-48 versus Tyr-51 discriminate P- from L-selectin engagement, and FucT-VII-dependent core-2 O-glycans on Thr-57 are critical for L- and P-selectin rolling [PMID:11081633, PMID:7585950, PMID:12403782, PMID:15579466]. Dimerization through the extracellular cysteine C320 is required specifically for P-selectin recognition [PMID:9660879]. Coupling of the PSGL-1 cytoplasmic tail to the actin cytoskeleton via moesin/ERM proteins—through an ERM-binding sequence centered on Arg-337/Lys-338 and a β-strand interaction with the FERM C-subdomain—stabilizes rolling on selectins [PMID:12036880, PMID:18076570, PMID:22311979]. Beyond adhesion, selectin or chemokine engagement of PSGL-1 initiates outside-in signaling: it nucleates a Syk/SFK (Fgr, Hck, Lyn) → DAP12/FcRγ ITAM → BTK → p38 MAPK cascade that activates the integrin LFA-1 to convert fast rolling into slow rolling, a function that requires the PSGL-1 cytoplasmic domain, and a constitutive PSGL-1–L-selectin complex amplifies this ITAM signaling output [PMID:12387735, PMID:18550846, PMID:18794338, PMID:20299514, PMID:24127491]. PSGL-1 cooperates with CXCR2 to drive β2-integrin-dependent neutrophil arrest, NET release, and thrombosis [PMID:30068506], and downstream signaling additionally controls macrophage chemotaxis via Akt/mTOR-dependent ROCK-1 translation [PMID:17245434]. In adaptive immunity PSGL-1 functions as an inhibitory checkpoint that restrains TCR signaling by limiting Zap70 phosphorylation and maintaining the Zap70 inhibitor Sts-1, upregulating PD-1 and driving CD8+ T cell exhaustion, and it is engaged by VISTA at acidic pH to suppress T cells in the tumor microenvironment [PMID:27192578, PMID:37115668, PMID:31645726]. PSGL-1 also acts as a broad-spectrum antiviral restriction factor: incorporated into HIV-1, coronavirus, and other virions, it sterically blocks virion attachment to target cells via its ectodomain, an activity countered by HIV-1 Vpu, which recruits SCFβ-TrCP2 to ubiquitinate and degrade PSGL-1 [PMID:30833724, PMID:32273392, PMID:32193343]. Conversely, PSGL-1 serves as an entry receptor for enterovirus 71 via a VP1-145 capsid switch and caveolar endocytosis [PMID:23935488, PMID:23760234].","teleology":[{"year":1995,"claim":"Established the chemical determinant of selectin binding by showing PSGL-1's function depends on a post-translational modification rather than its peptide backbone alone.","evidence":"Tyr-to-Phe mutagenesis, sulfation inhibitors, and HL-60 rolling assays on P-selectin","pmids":["7585950"],"confidence":"High","gaps":["Did not resolve how sulfate and glycan jointly contact the lectin domain","Did not distinguish P- versus L-selectin tyrosine requirements"]},{"year":1996,"claim":"Extended PSGL-1's ligand repertoire beyond P-selectin by identifying it as an L-selectin ligand mediating neutrophil homotypic aggregation.","evidence":"Anti-PSGL-1 Fab and dual L-selectin/PSGL-1 antibody blockade in flow-cytometry aggregation assays","pmids":["8839831"],"confidence":"Medium","gaps":["Antibody blockade only, no genetic confirmation","Single lab"]},{"year":1998,"claim":"Defined dimerization as a structural prerequisite for P-selectin recognition, distinguishing it from mere surface expression.","evidence":"C320A cysteine mutagenesis with native/denaturing Western blot and rolling assays in K562 transfectants","pmids":["9660879"],"confidence":"High","gaps":["Whether dimerization is required for E- and L-selectin binding unresolved","Stoichiometry of the dimer-selectin complex not determined"]},{"year":1999,"claim":"Demonstrated in vivo that PSGL-1 is essential for P-selectin-dependent early neutrophil rolling but dispensable for late E-selectin rolling, revealing selectin-specific and temporally distinct roles.","evidence":"PSGL-1 knockout mice with intravital microscopy of cremaster venules and peritonitis models","pmids":["10601352"],"confidence":"High","gaps":["Did not identify the alternative E-selectin ligands compensating in late inflammation"]},{"year":2000,"claim":"Provided the atomic-resolution basis for how sulfated tyrosines and sialyl Lewis X cooperate at the P-selectin interface.","evidence":"X-ray crystal structure of P-selectin lectin-EGF domains bound to a modified PSGL-1 N-terminal peptide","pmids":["11081633"],"confidence":"High","gaps":["Structure of full-length dimeric PSGL-1 not solved","E- and L-selectin complexes not crystallized"]},{"year":2002,"claim":"Connected PSGL-1 adhesion to intracellular signaling by showing it recruits Syk through ERM proteins and that cytoskeletal anchorage via moesin stabilizes rolling.","evidence":"Reciprocal Co-IP, dominant-negative ITAM-mutant moesin and dead-kinase Syk, SRE reporter, and rolling assays with truncated PSGL-1","pmids":["12387735","12036880"],"confidence":"High","gaps":["The ITAM adaptors bridging Syk were not yet identified","Moesin selectivity over other ERM proteins mechanistically unexplained"]},{"year":2008,"claim":"Defined the ITAM-dependent slow-rolling pathway, identifying Fgr, DAP12, and FcRγ as the adaptors converting selectin engagement into LFA-1 activation independently of chemokine receptors.","evidence":"ΔCD knock-in and fgr/Tyrobp/Fcrg-deficient mice with density-matched rolling assays and Syk/p38 phosphorylation readouts","pmids":["18550846","18794338"],"confidence":"High","gaps":["The intermediate kinase between Syk and p38 was not yet defined","Whether the cytoplasmic-tail requirement reflects ITAM nucleation or cytoskeletal coupling left open"]},{"year":2010,"claim":"Placed BTK as the key intermediate between Syk and p38 in the shared E-selectin slow-rolling pathway used by PSGL-1 and CD44.","evidence":"Hck/Lyn/Fgr-deficient mice, lipid-raft disruption, and kinase inhibitors with intravital microscopy","pmids":["20299514"],"confidence":"High","gaps":["How lipid rafts spatially organize the cascade not fully resolved"]},{"year":2013,"claim":"Revealed a constitutive PSGL-1–L-selectin signaling complex and CXCR2 cooperativity as amplifiers driving integrin-dependent arrest and thrombosis.","evidence":"Endogenous Co-IP, L-selectin cytoplasmic mutants, SLP-76 phosphosite mapping, and IVC flow-restriction intravital models","pmids":["24127491","30068506"],"confidence":"High","gaps":["Stoichiometry and assembly trigger of the PSGL-1–L-selectin complex not defined"]},{"year":2016,"claim":"Reframed PSGL-1 as an inhibitory immune checkpoint by showing its ligation suppresses TCR/IL-2 signaling and drives CD8+ T cell exhaustion.","evidence":"PSGL-1 knockout mice in chronic LCMV and melanoma models with TCR/IL-2 signaling and survival assays","pmids":["27192578"],"confidence":"High","gaps":["The physiological ligand engaging PSGL-1 on exhausted T cells was not identified","Upstream biochemical mechanism of TCR attenuation undefined at this stage"]},{"year":2019,"claim":"Identified VISTA as a pH-selective PSGL-1 binding partner suppressing T cells in the acidic tumor microenvironment, and uncovered PSGL-1 as an antiviral restriction factor degraded by HIV-1 Vpu.","evidence":"VISTA histidine mutagenesis with pH-selective antibodies; mass-spectrometry, Co-IP, ubiquitination, and HIV infectivity assays in primary CD4+ T cells","pmids":["31645726","30833724"],"confidence":"High","gaps":["Whether VISTA is the sole inhibitory ligand for PSGL-1 unknown","Mechanistic link between checkpoint and antiviral functions unexplored"]},{"year":2023,"claim":"Resolved the proximal biochemical mechanism of PSGL-1 checkpoint activity, showing it restrains Zap70 phosphorylation and maintains Sts-1 upstream of PD-1, requiring TCR co-ligation.","evidence":"PSGL-1 knockout mice, Zap70 phosphorylation and Sts-1 expression assays, co-ligation experiments, and tumor models with PSGL-1 blockade","pmids":["37115668"],"confidence":"High","gaps":["How PSGL-1 physically couples to the proximal TCR machinery not defined","The endogenous co-ligand on tumor cells not identified"]},{"year":2020,"claim":"Established the steric mechanism of PSGL-1 antiviral restriction and its breadth across enveloped viruses.","evidence":"HIV domain-deletion infectivity and attachment assays, transinfection assays, F-actin and gp41 binding assays, and coronavirus pseudovirus assays","pmids":["32273392","32193343","32802403","33396594"],"confidence":"Medium","gaps":["Relative contribution of ectodomain steric blockade versus actin/gp41 mechanisms not quantified","Some mechanisms shown in single labs"]},{"year":null,"claim":"How PSGL-1's distinct functions—selectin adhesion, integrin-activating ITAM signaling, T-cell checkpoint inhibition, and antiviral virion incorporation—are coordinated or switched in a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying structural model links adhesion and checkpoint functions","The physiological PSGL-1 ligand driving T cell exhaustion is undefined","Regulation of PSGL-1 surface density by shedding and trafficking is incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,3,11,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,6,15,16]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[38,39]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5,22,47]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[25,33,34]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[32]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5,21,47]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,7,15,16]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[12,25,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,8,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,19,38,44]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,9,26]}],"complexes":["PSGL-1–L-selectin signaling complex"],"partners":["SELP","SELL","SELE","MSN","SYK","VSIR","SNX20","ADAM8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14242","full_name":"P-selectin glycoprotein ligand 1","aliases":["Selectin P ligand"],"length_aa":412,"mass_kda":43.2,"function":"A SLe(x)-type proteoglycan, which through high affinity, calcium-dependent interactions with E-, P- and L-selectins, mediates rapid rolling of leukocytes over vascular surfaces during the initial steps in inflammation. Critical for the initial leukocyte capture (Microbial infection) Acts as a receptor for enterovirus 71","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q14242/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SELPLG","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SELPLG","total_profiled":1310},"omim":[{"mim_id":"616627","title":"PODOCALYXIN-LIKE 2; PODXL2","url":"https://www.omim.org/entry/616627"},{"mim_id":"613281","title":"SORTING NEXIN 20; SNX20","url":"https://www.omim.org/entry/613281"},{"mim_id":"601373","title":"CHEMOKINE, CC MOTIF, RECEPTOR 5; CCR5","url":"https://www.omim.org/entry/601373"},{"mim_id":"600751","title":"SIALIC ACID-BINDING IMMUNOGLOBULIN-LIKE LECTIN 1; SIGLEC1","url":"https://www.omim.org/entry/600751"},{"mim_id":"600738","title":"SELECTIN P LIGAND; SELPLG","url":"https://www.omim.org/entry/600738"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":75.0}],"url":"https://www.proteinatlas.org/search/SELPLG"},"hgnc":{"alias_symbol":["PSGL-1","CD162"],"prev_symbol":[]},"alphafold":{"accession":"Q14242","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14242","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14242-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14242-F1-predicted_aligned_error_v6.png","plddt_mean":50.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SELPLG","jax_strain_url":"https://www.jax.org/strain/search?query=SELPLG"},"sequence":{"accession":"Q14242","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14242.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14242/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14242"}},"corpus_meta":[{"pmid":"11081633","id":"PMC_11081633","title":"Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLe(X) and PSGL-1.","date":"2000","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/11081633","citation_count":603,"is_preprint":false},{"pmid":"7585950","id":"PMC_7585950","title":"PSGL-1 recognition of P-selectin is controlled by a tyrosine sulfation consensus at the PSGL-1 amino terminus.","date":"1995","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7585950","citation_count":346,"is_preprint":false},{"pmid":"10770806","id":"PMC_10770806","title":"P-Selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo.","date":"2000","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10770806","citation_count":336,"is_preprint":false},{"pmid":"31645726","id":"PMC_31645726","title":"VISTA is an acidic pH-selective ligand for 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of P-selectin LE domains with PSGL-1 N-terminal peptide)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure with direct functional validation of binding interface\",\n      \"pmids\": [\"11081633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Tyrosine sulfation of a consensus motif within the N-terminal ~20 residues of PSGL-1 is essential for P-selectin binding; mutation of N-terminal tyrosines to phenylalanine abolishes P-selectin adhesion, and sulfation inhibitors block HL-60 rolling on P-selectin.\",\n      \"method\": \"Site-directed mutagenesis, sulfation inhibitors, cell rolling assay on P-selectin-coated coverslips\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with pharmacological inhibition and functional rolling assay, replicated by subsequent structural work\",\n      \"pmids\": [\"7585950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Dimerization of PSGL-1 through a single conserved extracellular cysteine (C320) is essential for functional recognition of P-selectin; monomeric C320A mutant fails to support rolling or binding to P-selectin chimeras despite intact surface expression.\",\n      \"method\": \"Cysteine-to-alanine mutagenesis, Western blot under native/denaturing conditions, low-shear adhesion and flow-chamber rolling assays in stable K562 transfectants\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with multiple orthogonal functional assays in same study\",\n      \"pmids\": [\"9660879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PSGL-1 is required for P-selectin-mediated neutrophil rolling and leukocyte recruitment in early inflammation (30 min post-trauma); however, it is not required for E-selectin-mediated rolling 2 h after TNF-α stimulation, as shown in PSGL-1 gene-knockout mice.\",\n      \"method\": \"Targeted gene disruption (PSGL-1 knockout mice), intravital microscopy of cremaster venules, chemical peritonitis model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with intravital microscopy and multiple inflammatory models; replicated by antibody-blockade studies\",\n      \"pmids\": [\"10601352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PSGL-1 associates with Syk kinase through ERM proteins (ezrin/moesin); engagement of PSGL-1 induces Syk tyrosine phosphorylation and SRE-dependent transcriptional activation. ITAM-mutated moesin or Syk dead-kinase mutant abrogates PSGL-1-induced transcription.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, pharmacological Syk inhibition (piceatannol), SRE reporter assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus mutagenesis plus functional reporter, multiple orthogonal methods\",\n      \"pmids\": [\"12387735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Attachment of the PSGL-1 cytoplasmic domain to the actin cytoskeleton via moesin (but not other ERM proteins) is essential for leukocyte rolling on P-selectin; cytoplasmic truncation abolishes rolling without affecting P-selectin binding or surface distribution of PSGL-1.\",\n      \"method\": \"Stable transfection with truncated PSGL-1 (ΔCyto), actin cytoskeletal toxin treatment, co-immunoprecipitation with ERM proteins, rolling assay in flow chamber\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis plus selective ERM pulldown plus functional rolling assay, replicated by subsequent studies\",\n      \"pmids\": [\"12036880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The PSGL-1 cytoplasmic domain is dispensable for leukocyte rolling on P-selectin (when PSGL-1 surface density is matched) but is essential for Syk-dependent activation of LFA-1 (αLβ2) to convert fast rolling to slow rolling on ICAM-1.\",\n      \"method\": \"ΔCD knock-in mice expressing cytoplasmic-domain-deleted PSGL-1, O-sialoglycoprotein endopeptidase titration to match PSGL-1 density, intravital microscopy, Syk phosphorylation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with matched-density controls and biochemical signaling readout, multiple orthogonal methods\",\n      \"pmids\": [\"18550846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"E-selectin engagement of PSGL-1 activates Syk and p38 MAPK to induce slow neutrophil rolling via an ITAM-dependent pathway requiring Src-family kinase Fgr and ITAM adaptor proteins DAP12 and FcRγ, independently of Gαi-coupled receptors.\",\n      \"method\": \"Gene-deficient mice (fgr−/−, Tyrobp−/− Fcrg−/−), flow chamber rolling assay, intravital microscopy, Syk/p38 phosphorylation assay, mixed bone marrow chimeras, peritonitis model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple knockout lines with in vivo and in vitro validation; replicated by subsequent studies\",\n      \"pmids\": [\"18794338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"E-selectin engagement of either PSGL-1 or CD44 triggers slow rolling through a common lipid-raft-dependent pathway using SFKs Hck, Lyn, and Fgr; Bruton's tyrosine kinase (BTK) acts as a key intermediate between Syk and p38. PSGL-1's cytoplasmic domain is required for SFK activation during this process.\",\n      \"method\": \"Gene-deficient mice, flow chamber and intravital microscopy, lipid raft disruption, kinase inhibitors, phosphorylation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models and inhibitor experiments with in vivo confirmation\",\n      \"pmids\": [\"20299514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Among E-selectin ligands on neutrophils, PSGL-1 plays the major role in initial leukocyte capture, ESL-1 is critical for converting initial tethers to slow rolling, and CD44 controls rolling velocity and mediates E-selectin-dependent redistribution of PSGL-1 and L-selectin to the major pole via p38 signaling.\",\n      \"method\": \"Gene-targeted and RNA-targeted loss-of-function in mice, intravital microscopy, flow chamber assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic combined gene/RNA loss-of-function across all three ligands with intravital microscopy\",\n      \"pmids\": [\"17442598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"PSGL-1 on neutrophils serves as a ligand for L-selectin, supporting L-selectin–PSGL-1-mediated neutrophil–neutrophil aggregation as the first step in homotypic aggregation.\",\n      \"method\": \"Anti-PSGL-1 Fab inhibition, simultaneous antibody blocking of L-selectin and PSGL-1 on separate cell populations, flow cytometry aggregation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blocking experiments with two orthogonal approaches; single lab\",\n      \"pmids\": [\"8839831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PSGL-1 is the sole P-selectin-binding glycoprotein on Th1 cells (not Th2 cells) despite similar surface expression levels; PSGL-1 on Th1 supports P-selectin binding and partially mediates their migration into cutaneous delayed-type hypersensitivity lesions.\",\n      \"method\": \"Affinity isolation with P-selectin-Ig fusion protein, flow cytometry binding assay, antibody blocking in cell adhesion assay and in vivo DTH model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — affinity isolation plus functional blocking plus in vivo migration study with defined phenotypic readout\",\n      \"pmids\": [\"9053457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PSGL-1 engagement by P-selectin on activated platelets triggers tyrosine kinase-dependent (genistein-sensitive) phosphorylation of a 110 kDa protein and activates CD11b/CD18 (β2 integrin) on PMNs; a non-adhesion-blocking anti-PSGL-1 antibody alone triggers the same β2-integrin-dependent aggregation.\",\n      \"method\": \"Mixed-cell shear-flow aggregation assay, antibody blocking (anti-P-selectin, anti-CD11b/CD18, anti-PSGL-1), tyrosine kinase inhibitors (genistein), tyrosine phosphorylation assay, CHO-P transfectants\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple inhibitor and antibody approaches with reconstituted cell systems confirming PSGL-1 as the signaling receptor\",\n      \"pmids\": [\"9920836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A subset of PSGL-1 molecules is constitutively associated with L-selectin on neutrophils; this PSGL-1–L-selectin complex signals through Src family kinases and ITAM adaptors to activate LFA-1, and requires the L-selectin cytoplasmic tail for signaling output.\",\n      \"method\": \"Co-immunoprecipitation of endogenous PSGL-1 and L-selectin, L-selectin cytoplasmic tail mutants, flow chamber rolling assay, intravital microscopy, SFK inhibitors\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of endogenous complex plus cytoplasmic-domain mutagenesis plus in vivo functional confirmation\",\n      \"pmids\": [\"24127491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PSGL-1 signals through Akt/mTOR upon macrophage adherence to promote translational upregulation of ROCK-1 (but not ROCK-2) mRNA, which is required for macrophage chemotaxis and phagocytosis; PSGL-1-deficient macrophages phenocopy mTOR inhibition.\",\n      \"method\": \"PSGL-1−/− macrophages, rapamycin treatment, ribosome loading assay, ROCK-1/2 Western blot, chemotaxis and phagocytosis assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (PSGL-1 KO) plus pharmacological (rapamycin) convergence with multiple orthogonal functional readouts\",\n      \"pmids\": [\"17245434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PSGL-1 ligation on exhausted CD8+ T cells inhibits TCR and IL-2 signaling and upregulates PD-1, leading to diminished survival upon TCR stimulation. PSGL-1-deficient mice clear chronic virus due to intrinsically improved effector T cell survival with reduced inhibitory receptor expression.\",\n      \"method\": \"PSGL-1−/− mice in chronic LCMV infection model, TCR/IL-2 signaling assays, PD-1 expression measurement, T cell survival assays, melanoma tumor model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with mechanistic signaling readouts and two disease models\",\n      \"pmids\": [\"27192578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSGL-1 attenuates TCR signaling upstream of PD-1 by directly restraining Zap70 phosphorylation and maintaining expression of the Zap70 inhibitor Sts-1; PSGL-1 requires co-ligation with TCR to suppress CD8+ T cell activation and drive terminal exhaustion.\",\n      \"method\": \"PSGL-1−/− mice, Zap70 phosphorylation assays, Sts-1 expression analysis, co-ligation experiments, tumor models with pharmacologic PSGL-1 blockade\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus pharmacologic blockade plus defined biochemical signaling mechanism with multiple functional readouts\",\n      \"pmids\": [\"37115668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VISTA binds PSGL-1 selectively at acidic pH through multiple histidine residues along the rim of the VISTA extracellular domain; this interaction suppresses T cells in the tumor microenvironment and can be blocked by pH-selective antibodies.\",\n      \"method\": \"Binding assays, site-directed mutagenesis of VISTA histidines, pH-selective blocking antibodies, in vivo immune suppression assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis identifying the binding interface, pH-selective binding characterization, and in vivo functional rescue\",\n      \"pmids\": [\"31645726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HIV-1 Vpu binds PSGL-1 and induces its ubiquitination and degradation through the ubiquitin ligase SCFβ-TrCP2; PSGL-1 (induced by IFN-γ) inhibits HIV-1 reverse transcription and blocks virion infectivity by incorporating into progeny virions.\",\n      \"method\": \"Isobaric-tag mass spectrometry proteomics, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, HIV infectivity assays, reverse transcription assay in primary CD4+ T cells\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical and virological methods with primary cell validation\",\n      \"pmids\": [\"30833724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Virion-incorporated PSGL-1 blocks HIV-1 infectivity by preventing attachment of virions to target cells, independently of the viral glycoprotein; the extracellular N-terminal domain of PSGL-1 is necessary, and the cytoplasmic tail contributes to inhibition. Vpu (and Nef) down-regulate PSGL-1 from the cell surface to partially escape this restriction.\",\n      \"method\": \"HIV infectivity assays with PSGL-1 domain deletion mutants, particle attachment assays to CD4+ cells, Vpu/Nef expression, murine leukemia virus and influenza A virus infectivity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple domain mutants, multiple virus types, and direct attachment assays; confirmed by independent lab (PMID 32193343)\",\n      \"pmids\": [\"32273392\", \"32193343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Virion incorporation of PSGL-1 and CD43 inhibits HIV-1 attachment to both CD4+ target cells and fibroblastic reticular cells mediating transinfection; the full-length ectodomain of PSGL-1 is required, consistent with steric blockade of virus-cell contact.\",\n      \"method\": \"HIV-1 particle attachment assays, PSGL-1 ectodomain truncation mutants, CD4− cell transinfection assay, Gag copatching analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ectodomain mutant mapping plus transinfection assay, orthogonally confirmed by PMID 32273392\",\n      \"pmids\": [\"32193343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSGL-1 directly binds F-actin to restrict actin dynamics, inhibiting HIV DNA synthesis; incorporated PSGL-1 also binds gp41 and sequesters it at the plasma membrane, reducing Env incorporation into virions and impairing viral entry.\",\n      \"method\": \"F-actin co-sedimentation/binding assay, cryo-EM and super-resolution imaging of Env on virions, gp41 co-immunoprecipitation, HIV DNA synthesis assay\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays plus imaging, single lab; some mechanistic claims supported by structural imaging\",\n      \"pmids\": [\"32802403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the radixin FERM domain complexed with a PSGL-1 juxtamembrane peptide reveals that PSGL-1 binds FERM subdomain C in a beta-strand mode; non-conserved large residues (Met9, His8) compensate for the absence of the canonical Motif-1 alanine, providing structural basis for PSGL-1–ERM interaction.\",\n      \"method\": \"X-ray crystallography of radixin FERM–PSGL-1 peptide complex\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structure; single lab, but direct structural determination\",\n      \"pmids\": [\"18076570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human FucT-VII plays the predominant role in generating selectin-binding carbohydrate ligands on PSGL-1, while FucT-IV also contributes; core-2 O-glycans attached to Thr-57 are critical for L- and P-selectin rolling, whereas E-selectin uses additional PSGL-1 binding sites (>75% of rolling is Thr-57-independent).\",\n      \"method\": \"CHO cell transfections with FucT-IV and/or FucT-VII plus core-2 GlcNAcT, PSGL-1 Thr-57 and Thr-44 alanine mutants, rolling adhesion assays on L-, P-, and E-selectin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic mutagenesis of glycosylation sites combined with multiple functional rolling assays\",\n      \"pmids\": [\"15579466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"For L-selectin binding, Tyr-51 at the PSGL-1 N-terminus plays a predominant role (contrasting with P-selectin where Tyr-48 is key); core-2 O-glycans on Thr-57 are critical for optimal L-selectin binding and for controlling rolling velocity.\",\n      \"method\": \"Tyr-to-Phe and Thr-to-Ala mutagenesis, CHO cell expression with core-2 GlcNAcT and FucT-VII, L-selectin binding assays, rolling adhesion assays, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional assays and structural modeling; single lab\",\n      \"pmids\": [\"12403782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PSGL-1 is expressed on platelets at 25–100-fold lower levels than leukocytes; platelet PSGL-1 is functional and mediates platelet rolling in mesenteric venules, as shown by anti-PSGL-1 antibody blockade in intravital microscopy.\",\n      \"method\": \"P-selectin-IgG affinity purification, Western blot, anti-PSGL-1 immunopurification, flow cytometry, intravital microscopy with antibody blockade\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — affinity purification plus Western blot confirmation plus in vivo functional blockade\",\n      \"pmids\": [\"10770806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"P-selectin and its ligand PSGL-1 mediate recruitment of adult lymphoid progenitors to the thymus; PSGL-1−/− thymi contain fewer early thymic progenitors, and thymic P-selectin expression is regulated by niche occupancy, suggesting a homeostatic P-selectin/PSGL-1 thymic homing axis.\",\n      \"method\": \"Parabiosis, competitive thymus reconstitution, short-term homing assays, PSGL-1−/− mice\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo assays (parabiosis, competitive reconstitution, homing) with genetic KO\",\n      \"pmids\": [\"15880112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PSGL-1 ligation on human CD34+ hematopoietic progenitor cells (the sole P-selectin receptor on these cells) by immobilized or soluble P-selectin, or by anti-PSGL-1 antibody, profoundly suppresses HPC proliferation stimulated by growth factors.\",\n      \"method\": \"P-selectin-IgG affinity purification to identify PSGL-1 as the sole receptor, immobilized/soluble ligand and antibody ligation, colony-forming proliferation assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor identification by affinity purification plus three independent ligation methods with functional proliferation readout\",\n      \"pmids\": [\"10514015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Engagement of PSGL-1 and CXCR2 on rolling neutrophils cooperatively propagates signals to induce β2 integrin-dependent arrest in flow-restricted inferior vena cava. PSGL-1 signaling in this context uses Tyr-145 (not Tyr-112/128) of SLP-76 and does not require L-selectin; cooperative PSGL-1/CXCR2 signaling increases thrombus frequency and size partly by stimulating NET release.\",\n      \"method\": \"Genetically engineered mice, spinning-disk intravital microscopy, ultrasonography, IVC flow restriction model, pharmacological PSGL-1/CXCR2 blockade, NET quantification\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic and pharmacological dissection with intravital imaging and defined SLP-76 phosphosite mapping\",\n      \"pmids\": [\"30068506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ADAM8 metalloprotease is associated with PSGL-1 through ERM proteins and proteolytically cleaves PSGL-1; ADAM8 knockdown increases PSGL-1 surface expression and enhances leukocyte rolling on P-selectin, identifying ADAM8 as a sheddase regulating PSGL-1 function.\",\n      \"method\": \"Co-immunoprecipitation via ERM proteins, ADAM8 siRNA knockdown, PSGL-1 surface expression assay, leukocyte rolling assay on P-selectin\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus siRNA knockdown plus functional rolling assay; single lab\",\n      \"pmids\": [\"22229154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The ERM-binding sequence (EBS) of the PSGL-1 cytoplasmic tail (key residues Arg-337 and Lys-338) is required for leukocyte tethering and rolling on L-, P-, and E-selectin and for ERK activation; however, EBS is dispensable for Syk phosphorylation and E-selectin-induced slow rolling.\",\n      \"method\": \"EBS deletion and alanine-substitution mutagenesis in 32D leukocytes, rolling assays on selectins, ERK and Syk phosphorylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis distinguishing two signaling pathways downstream of PSGL-1; single lab\",\n      \"pmids\": [\"22311979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PSGL-1 does not require dimerization or cytoskeletal anchorage to signal β2 integrin-dependent slow rolling; FRAP documented cytoskeletal restraint of WT PSGL-1, and actin depolymerization or cytoplasmic-tail mutation increasing lateral mobility did not impair slow rolling, whereas chemokine-triggered arrest remained cytoskeleton-dependent.\",\n      \"method\": \"FRAP, latrunculin B treatment, retroviral transduction of WT and mutant PSGL-1 into PSGL-1−/− macrophages, rolling/arrest assays, β2-hybrid domain swing-out assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — FRAP plus genetic reconstitution plus pharmacological actin disruption with multiple functional readouts\",\n      \"pmids\": [\"22511754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Sorting nexin 20/SLIC-1 interacts with the PSGL-1 cytoplasmic domain and directs PSGL-1 to endosomes via its Phox homology domain; loss of the murine SLIC-1 homologue does not alter PSGL-1 signaling or neutrophil adhesion, indicating SLIC-1 is a sorting but not signaling regulator.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, colocalization in endosomes, murine SLIC-1 KO functional assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus colocalization plus KO; single lab\",\n      \"pmids\": [\"18196517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Peritoneal macrophages synthesize and constitutively express P-selectin on their plasma membrane; P-selectin is rapidly internalized to lysosomes. Macrophage-macrophage interactions in flow are mediated by P-selectin on one macrophage binding PSGL-1 on another.\",\n      \"method\": \"Metabolic labeling, flow cytometry, Western blot, immunoelectron microscopy, flow-based macrophage aggregation assay with blocking antibodies\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolic labeling confirming synthesis plus functional blocking assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"14662752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Flotillin-1 and -2 co-immunoprecipitate and colocalize with PSGL-1 in resting and stimulated neutrophils, associating with PSGL-1 in actin-dependent membrane microdomains that accumulate in the uropod; PSGL-1 is not required for formation of flotillin caps.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, PSGL-1−/− neutrophils, differentiated HL-60 overexpression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus colocalization plus KO validation; single lab\",\n      \"pmids\": [\"19404397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sulfated tyrosines at the PSGL-1 N-terminus (not O-glycans or N-glycans) mediate interaction with the chemokine CCL27 (CTACK); mutation of N-terminal tyrosines to phenylalanine abolishes binding, and PSGL-1 expression on CCR10+ cells reduces chemotactic responses to CCL27.\",\n      \"method\": \"Recombinant PSGL-1-Ig binding assay with multiple chemokines, arylsulfatase/glycosidase treatment, sulfation-inhibitor synthesis, Tyr→Phe mutagenesis, CCR10+ cell chemotaxis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis plus enzymatic modification plus functional chemotaxis assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15466853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The N-termini of PSGL-1 and CCR7 have overlapping binding sites for CCL19; chemical-shift mapping shows the interactions are competitive, providing a structural basis for PSGL-1's enhancement of CCL19-mediated T cell recruitment.\",\n      \"method\": \"NMR solution structure of CCL19, chemical shift perturbation mapping with PSGL-1 and CCR7 N-terminal peptides\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with chemical-shift mapping; functional consequence inferred not directly tested in same paper\",\n      \"pmids\": [\"26115234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EphB4 activation with ephrin-B2-Fc upregulates PSGL-1 expression on endothelial progenitor cells; PSGL-1 siRNA reverses both the enhanced EPC adhesion to E/P-selectin and the proangiogenic effect of EphB4 activation in a mouse hindlimb ischemia model.\",\n      \"method\": \"EphB4 siRNA, PSGL-1 siRNA, EPC adhesion assay, mouse hindlimb ischemia model, neutralizing antibodies to E/P-selectin\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent siRNA knockdown of upstream receptor and PSGL-1 with in vivo model; single lab\",\n      \"pmids\": [\"17510705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A single amino acid at EV71 capsid VP1-145 acts as a molecular switch controlling binding to PSGL-1: G or Q at VP1-145 permits binding to PSGL-1 sulfated tyrosines (mediated by conserved lysines VP1-242/244), while E at VP1-145 turns the VP1-244 lysine inward to prevent PSGL-1 binding.\",\n      \"method\": \"Site-directed mutagenesis of VP1-145, VP1-242, and VP1-244; cell binding assays on PSGL-1-expressing cells; crystal structure comparison of EV71 isolates\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of both virus and structural analysis plus functional cell binding assay\",\n      \"pmids\": [\"23935488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EV71 entry mediated by PSGL-1 requires caveolar endocytosis (caveolin-1-dependent), whereas SCARB2-mediated entry uses clathrin-dependent endocytosis; PSGL-1 and SCARB2 thus dictate distinct endocytic routes for EV71.\",\n      \"method\": \"Specific endocytosis inhibitors, caveolin-1 siRNA, clathrin knockdown, confocal colocalization of EV71 with caveolae in Jurkat T cells and PSGL-1-L929 cells vs. RD cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological inhibitors plus siRNA knockdown in receptor-defined cell lines with confocal confirmation\",\n      \"pmids\": [\"23760234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Soluble Siglec-5 binds PSGL-1 on leukocytes in a sialic-acid-dependent and calcium-dependent manner (sialidase treatment reduces binding by 79%); PSGL-1 and Siglec-5 are in close proximity (<40 nm) on PBMCs. Soluble Siglec-5 variants block PSGL-1-mediated leukocyte rolling on E/P-selectin in vitro and in vivo.\",\n      \"method\": \"Soluble Siglec-5 binding assay, sialidase treatment, Duolink proximity ligation assay, in vitro perfusion rolling assay, in vivo TNF-α inflammation model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity ligation plus enzymatic modification plus in vivo blocking; single lab\",\n      \"pmids\": [\"27892504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GALNT4-catalyzed O-glycosylation of PSGL-1 is required for P-selectin-induced β2 integrin activation on monocytes and for monocyte adhesion and transmigration; GALNT4 overexpression increases PSGL-1 O-glycosylation and activates Akt/mTOR and IκBα/NFκB downstream of P-selectin/PSGL-1 engagement.\",\n      \"method\": \"VVL lectin pulldown, PSGL-1 immunoprecipitation for O-glycosylation, GALNT4 shRNA knockdown and overexpression, β2-integrin activation assay, monocyte adhesion/transmigration under flow, ApoE−/− mouse atherosclerosis model\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical O-glycosylation characterization plus gain/loss-of-function with functional and in vivo readouts; single lab\",\n      \"pmids\": [\"34974060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"P-selectin binding to PSGL-1 on tumor-associated macrophages activates the JNK/STAT1 pathway, driving transcription of complement C5 and release of C5a, which activates C5aR1 to shift TAMs toward a pro-tumor phenotype; PSGL-1 inhibition reduces CRC growth.\",\n      \"method\": \"Western blot for JNK/STAT1, dual-luciferase reporter and ChIP assay for C5 transcription, ELISA for C5a, siRNA knockdown of PSGL-1, AOM/DSS mouse CRC model, FACS\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase reporter plus siRNA plus in vivo model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37064877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"P-selectin stimulation of neutrophils via PSGL-1 activates the Syk/Ca2+/PAD4 signaling pathway to induce NET formation; pharmacological inhibition of P-selectin (PSI-697) reduces PAD4 expression and NETs in pancreatic tissue and ameliorates acute pancreatitis in mice.\",\n      \"method\": \"Western blot for Syk phosphorylation, intracellular calcium imaging, PAD4 expression assay, flow cytometry and immunofluorescence for NETs, PSI-697 treatment in caerulein-AP mouse model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and in vivo validation with defined signaling cascade; single lab\",\n      \"pmids\": [\"37841279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSGL-1 (CD162) but not CD44, when deleted by CRISPR-Cas9 from AML cell line KG1a, abolishes E-selectin-mediated chemo-resistance in vitro; absence of CD162 on AML cells delays leukemia onset, reduces BM retention, and increases chemotherapy sensitivity in vivo.\",\n      \"method\": \"CRISPR-Cas9 knockout of CD162 or CD44, in vitro E-selectin adhesion/chemo-resistance assays, preclinical murine AML model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR knockout with parallel CD44 control plus in vitro and in vivo functional validation\",\n      \"pmids\": [\"32793603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Basic residues in HIV-1 Gag matrix domain and a polybasic sequence in the PSGL-1 cytoplasmic tail mediate coclustering of PSGL-1 with assembling Gag at the plasma membrane, promoting virion incorporation of PSGL-1.\",\n      \"method\": \"Quantitative two-color superresolution localization microscopy, Gag matrix mutants, PSGL-1 cytoplasmic tail chimera experiments in T and HeLa cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — superresolution imaging plus domain-swap mutants; single lab\",\n      \"pmids\": [\"25320329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSGL-1 expression in virus-producing cells impairs incorporation of SARS-CoV and SARS-CoV-2 spike glycoproteins into pseudovirions and blocks pseudovirus attachment and infection of target cells, extending PSGL-1's antiviral restriction to coronaviruses.\",\n      \"method\": \"Pseudovirus infectivity assays, spike glycoprotein incorporation Western blot, PSGL-1 expression in virus-producing cells\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pseudovirus assays with biochemical confirmation; single lab\",\n      \"pmids\": [\"33396594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PSGL-1 cross-linking induces tyrosine-phosphorylation-dependent and c-Abl-involved F-actin polymerization and redistribution in neutrophils; c-Abl relocalizes to F-actin foci, and the Abl inhibitor STI571 blocks the cytoskeletal reorganization.\",\n      \"method\": \"Anti-PSGL-1 antibody cross-linking, cytoskeletal fractionation, genistein and STI571 inhibition, F-actin immunofluorescence and redistribution assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibition with multiple inhibitors and cytoskeletal assays; single lab\",\n      \"pmids\": [\"15526280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Characterization of O-linked oligosaccharides on PSGL-1 isolated from HL-60 cells showed that only ~4.5% of O-linked glycans (core-2 structures with sialic acid and fucose on N-acetyllactosamine) constitute the selectin-binding fraction; most O-glycans lack fucose and are insufficient for selectin binding.\",\n      \"method\": \"3H-glucosamine metabolic labeling, P-selectin/E-selectin affinity chromatography, ion-exchange/size exclusion/lectin/paper chromatography, exoglycosidase treatments, chemical modifications\",\n      \"journal\": \"Glycoconjugate journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — comprehensive biochemical glycan structural analysis; single lab\",\n      \"pmids\": [\"10211703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PI3K is required for PSGL-1-induced β1 integrin clustering (but not for β1 integrin conformation changes or total expression), and PSGL-1-PI3K-β1 integrin signaling promotes Jurkat cell adhesion to fibronectin.\",\n      \"method\": \"PI3K inhibitors, anti-PSGL-1 antibody ligation, β1 integrin clustering assay, conformation-sensitive antibody assay, Jurkat adhesion to fibronectin\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibition only, single method, single lab\",\n      \"pmids\": [\"24122451\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSGL-1 (SELPLG/CD162) is a dimeric, sulfated, O-glycosylated mucin-like receptor that functions as the primary ligand for P-, E-, and L-selectins to mediate leukocyte tethering and rolling: its N-terminal tyrosine sulfation and core-2 sialyl Lewis X glycans cooperate (Tyr-48 for P-selectin, Tyr-51 for L-selectin) for high-affinity selectin binding, dimerization via a conserved extracellular cysteine is required for P-selectin recognition, and attachment of its cytoplasmic tail to the actin cytoskeleton via moesin/ERM proteins is essential for rolling stability; beyond adhesion, PSGL-1 engagement initiates outside-in signaling through Fgr/Hck/Lyn SFKs→DAP12/FcRγ ITAM adaptors→Syk→p38/BTK to activate LFA-1 (requiring the PSGL-1 cytoplasmic domain) for slow rolling, and a constitutive PSGL-1–L-selectin signaling complex amplifies these signals; PSGL-1 also restrains T cell function as an immune checkpoint by attenuating Zap70/TCR signaling and maintaining Sts-1 to drive T cell exhaustion, can be engaged by VISTA at acidic pH to suppress T cells in tumors, and acts as a broad-spectrum antiviral restriction factor by incorporating into virions and blocking virus-cell attachment—an activity countered by HIV-1 Vpu, which recruits SCFβ-TrCP2 to ubiquitinate and degrade PSGL-1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSGL-1 (SELPLG/CD162) is a dimeric, tyrosine-sulfated, O-glycosylated mucin-like leukocyte receptor that serves as the principal ligand for P-, E-, and L-selectins to mediate the tethering and rolling steps of leukocyte recruitment to inflamed and lymphoid tissue [#0, #3, #26]. High-affinity selectin binding requires the cooperative action of N-terminal sulfated tyrosines and core-2 sialyl Lewis X glycans on the PSGL-1 N-terminus: tyrosine sulfation is essential for P-selectin adhesion, Tyr-48 versus Tyr-51 discriminate P- from L-selectin engagement, and FucT-VII-dependent core-2 O-glycans on Thr-57 are critical for L- and P-selectin rolling [#0, #1, #24, #23]. Dimerization through the extracellular cysteine C320 is required specifically for P-selectin recognition [#2]. Coupling of the PSGL-1 cytoplasmic tail to the actin cytoskeleton via moesin/ERM proteins—through an ERM-binding sequence centered on Arg-337/Lys-338 and a β-strand interaction with the FERM C-subdomain—stabilizes rolling on selectins [#5, #22, #30]. Beyond adhesion, selectin or chemokine engagement of PSGL-1 initiates outside-in signaling: it nucleates a Syk/SFK (Fgr, Hck, Lyn) → DAP12/FcRγ ITAM → BTK → p38 MAPK cascade that activates the integrin LFA-1 to convert fast rolling into slow rolling, a function that requires the PSGL-1 cytoplasmic domain, and a constitutive PSGL-1–L-selectin complex amplifies this ITAM signaling output [#4, #6, #7, #8, #13]. PSGL-1 cooperates with CXCR2 to drive β2-integrin-dependent neutrophil arrest, NET release, and thrombosis [#28], and downstream signaling additionally controls macrophage chemotaxis via Akt/mTOR-dependent ROCK-1 translation [#14]. In adaptive immunity PSGL-1 functions as an inhibitory checkpoint that restrains TCR signaling by limiting Zap70 phosphorylation and maintaining the Zap70 inhibitor Sts-1, upregulating PD-1 and driving CD8+ T cell exhaustion, and it is engaged by VISTA at acidic pH to suppress T cells in the tumor microenvironment [#15, #16, #17]. PSGL-1 also acts as a broad-spectrum antiviral restriction factor: incorporated into HIV-1, coronavirus, and other virions, it sterically blocks virion attachment to target cells via its ectodomain, an activity countered by HIV-1 Vpu, which recruits SCFβ-TrCP2 to ubiquitinate and degrade PSGL-1 [#18, #19, #20]. Conversely, PSGL-1 serves as an entry receptor for enterovirus 71 via a VP1-145 capsid switch and caveolar endocytosis [#38, #39].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the chemical determinant of selectin binding by showing PSGL-1's function depends on a post-translational modification rather than its peptide backbone alone.\",\n      \"evidence\": \"Tyr-to-Phe mutagenesis, sulfation inhibitors, and HL-60 rolling assays on P-selectin\",\n      \"pmids\": [\"7585950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how sulfate and glycan jointly contact the lectin domain\", \"Did not distinguish P- versus L-selectin tyrosine requirements\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Extended PSGL-1's ligand repertoire beyond P-selectin by identifying it as an L-selectin ligand mediating neutrophil homotypic aggregation.\",\n      \"evidence\": \"Anti-PSGL-1 Fab and dual L-selectin/PSGL-1 antibody blockade in flow-cytometry aggregation assays\",\n      \"pmids\": [\"8839831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antibody blockade only, no genetic confirmation\", \"Single lab\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined dimerization as a structural prerequisite for P-selectin recognition, distinguishing it from mere surface expression.\",\n      \"evidence\": \"C320A cysteine mutagenesis with native/denaturing Western blot and rolling assays in K562 transfectants\",\n      \"pmids\": [\"9660879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether dimerization is required for E- and L-selectin binding unresolved\", \"Stoichiometry of the dimer-selectin complex not determined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated in vivo that PSGL-1 is essential for P-selectin-dependent early neutrophil rolling but dispensable for late E-selectin rolling, revealing selectin-specific and temporally distinct roles.\",\n      \"evidence\": \"PSGL-1 knockout mice with intravital microscopy of cremaster venules and peritonitis models\",\n      \"pmids\": [\"10601352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the alternative E-selectin ligands compensating in late inflammation\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Provided the atomic-resolution basis for how sulfated tyrosines and sialyl Lewis X cooperate at the P-selectin interface.\",\n      \"evidence\": \"X-ray crystal structure of P-selectin lectin-EGF domains bound to a modified PSGL-1 N-terminal peptide\",\n      \"pmids\": [\"11081633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length dimeric PSGL-1 not solved\", \"E- and L-selectin complexes not crystallized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected PSGL-1 adhesion to intracellular signaling by showing it recruits Syk through ERM proteins and that cytoskeletal anchorage via moesin stabilizes rolling.\",\n      \"evidence\": \"Reciprocal Co-IP, dominant-negative ITAM-mutant moesin and dead-kinase Syk, SRE reporter, and rolling assays with truncated PSGL-1\",\n      \"pmids\": [\"12387735\", \"12036880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ITAM adaptors bridging Syk were not yet identified\", \"Moesin selectivity over other ERM proteins mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the ITAM-dependent slow-rolling pathway, identifying Fgr, DAP12, and FcRγ as the adaptors converting selectin engagement into LFA-1 activation independently of chemokine receptors.\",\n      \"evidence\": \"ΔCD knock-in and fgr/Tyrobp/Fcrg-deficient mice with density-matched rolling assays and Syk/p38 phosphorylation readouts\",\n      \"pmids\": [\"18550846\", \"18794338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The intermediate kinase between Syk and p38 was not yet defined\", \"Whether the cytoplasmic-tail requirement reflects ITAM nucleation or cytoskeletal coupling left open\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed BTK as the key intermediate between Syk and p38 in the shared E-selectin slow-rolling pathway used by PSGL-1 and CD44.\",\n      \"evidence\": \"Hck/Lyn/Fgr-deficient mice, lipid-raft disruption, and kinase inhibitors with intravital microscopy\",\n      \"pmids\": [\"20299514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How lipid rafts spatially organize the cascade not fully resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a constitutive PSGL-1–L-selectin signaling complex and CXCR2 cooperativity as amplifiers driving integrin-dependent arrest and thrombosis.\",\n      \"evidence\": \"Endogenous Co-IP, L-selectin cytoplasmic mutants, SLP-76 phosphosite mapping, and IVC flow-restriction intravital models\",\n      \"pmids\": [\"24127491\", \"30068506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly trigger of the PSGL-1–L-selectin complex not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reframed PSGL-1 as an inhibitory immune checkpoint by showing its ligation suppresses TCR/IL-2 signaling and drives CD8+ T cell exhaustion.\",\n      \"evidence\": \"PSGL-1 knockout mice in chronic LCMV and melanoma models with TCR/IL-2 signaling and survival assays\",\n      \"pmids\": [\"27192578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The physiological ligand engaging PSGL-1 on exhausted T cells was not identified\", \"Upstream biochemical mechanism of TCR attenuation undefined at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified VISTA as a pH-selective PSGL-1 binding partner suppressing T cells in the acidic tumor microenvironment, and uncovered PSGL-1 as an antiviral restriction factor degraded by HIV-1 Vpu.\",\n      \"evidence\": \"VISTA histidine mutagenesis with pH-selective antibodies; mass-spectrometry, Co-IP, ubiquitination, and HIV infectivity assays in primary CD4+ T cells\",\n      \"pmids\": [\"31645726\", \"30833724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VISTA is the sole inhibitory ligand for PSGL-1 unknown\", \"Mechanistic link between checkpoint and antiviral functions unexplored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the proximal biochemical mechanism of PSGL-1 checkpoint activity, showing it restrains Zap70 phosphorylation and maintains Sts-1 upstream of PD-1, requiring TCR co-ligation.\",\n      \"evidence\": \"PSGL-1 knockout mice, Zap70 phosphorylation and Sts-1 expression assays, co-ligation experiments, and tumor models with PSGL-1 blockade\",\n      \"pmids\": [\"37115668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PSGL-1 physically couples to the proximal TCR machinery not defined\", \"The endogenous co-ligand on tumor cells not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the steric mechanism of PSGL-1 antiviral restriction and its breadth across enveloped viruses.\",\n      \"evidence\": \"HIV domain-deletion infectivity and attachment assays, transinfection assays, F-actin and gp41 binding assays, and coronavirus pseudovirus assays\",\n      \"pmids\": [\"32273392\", \"32193343\", \"32802403\", \"33396594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of ectodomain steric blockade versus actin/gp41 mechanisms not quantified\", \"Some mechanisms shown in single labs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSGL-1's distinct functions—selectin adhesion, integrin-activating ITAM signaling, T-cell checkpoint inhibition, and antiviral virion incorporation—are coordinated or switched in a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying structural model links adhesion and checkpoint functions\", \"The physiological PSGL-1 ligand driving T cell exhaustion is undefined\", \"Regulation of PSGL-1 surface density by shedding and trafficking is incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3, 11, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6, 15, 16]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [38, 39]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 22, 47]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [25, 33, 34]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 21, 47]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 7, 15, 16]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [12, 25, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 8, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 19, 38, 44]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 9, 26]}\n    ],\n    \"complexes\": [\n      \"PSGL-1–L-selectin signaling complex\"\n    ],\n    \"partners\": [\n      \"SELP\",\n      \"SELL\",\n      \"SELE\",\n      \"MSN\",\n      \"SYK\",\n      \"VSIR\",\n      \"SNX20\",\n      \"ADAM8\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}