{"gene":"SELE","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1990,"finding":"ELAM-1 (E-selectin/SELE) mediates leukocyte adhesion through recognition of the carbohydrate ligand sialyl-Lewis X (NeuAc α2,3Gal β1,4(Fuc α1,3)-GlcNAc-), a terminal structure found on neutrophil glycoproteins and glycolipids.","method":"Cell adhesion assays using ELAM-1-expressing cells and purified/synthetic carbohydrate structures; inhibition with anti-sialyl-Lex antibodies","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding assay with purified ligand, replicated simultaneously in two independent papers (PMIDs 1701274 and 1701275)","pmids":["1701274","1701275"],"is_preprint":false},{"year":1991,"finding":"ELAM-1 also recognizes sialyl-Lewis a (NeuAc α2-3Gal β1-3(Fuc α1-4)GlcNAc), binding it as well as or slightly better than sialyl-Lewis X; HSEA modelling showed both share a common spatial arrangement of neuraminic acid and fucose on one face of the molecule.","method":"Cell binding assay with immobilized synthetic glycoconjugates using ELAM-1 cDNA transfectants; hard sphere exo-anomeric (HSEA) conformational calculations","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding assay with synthetic ligands plus computational conformational analysis in a single rigorous study","pmids":["1714447"],"is_preprint":false},{"year":1990,"finding":"Transfection of a human α(1,3)-fucosyltransferase cDNA (ELFT) into non-myeloid cells confers ELAM-1-dependent endothelial adhesion, correlating with de novo cell-surface expression of sialyl Lewis X, demonstrating that α(1,3)-fucosyltransferase activity controls biosynthesis of the ELAM-1 ligand.","method":"Transfection of fucosyltransferase cDNA into non-myeloid cell lines; cell adhesion assays; flow cytometry for sialyl-Lex expression","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution by transfection with mechanistic correlation, replicated in two independent Cell papers (PMIDs 1699667 and 1702034)","pmids":["1699667","1702034"],"is_preprint":false},{"year":1991,"finding":"Neutrophil LECAM-1 (L-selectin) carries sialyl Lewis X on its surface and presents it to ELAM-1 on endothelium; LECAM-1 is concentrated on PMN microvilli and mediates up to 70% of PMN binding to ELAM-1 transfectants, acting as a counterreceptor/ligand for ELAM-1.","method":"Anti-LECAM-1 mAb inhibition assays; selective removal of LECAM-1 from PMN surface; binding assays to ELAM-1 transfected cells; confocal/immunofluorescence localization of LECAM-1 to microvilli","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal inhibition with blocking antibodies, selective depletion experiment, localization study, replicated in two papers (PMIDs 1716182 and 1713515)","pmids":["1716182","1713515"],"is_preprint":false},{"year":1991,"finding":"ELAM-1 exclusively mediates adhesion of memory (CD45RO+) T cells, not naive T cells, to activated endothelium; this adhesion is activation-independent (not enhanced by acute T-cell activation), unlike LFA-1- or VLA-4-mediated adhesion.","method":"Adhesion assays to purified ELAM-1 protein and ELAM-1-transfected COS cells; antibody blocking; T-cell subset comparisons","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct adhesion assays to purified protein, subset comparisons, replicated across two independent papers (PMIDs 1705666 and 1705667)","pmids":["1705666","1705667"],"is_preprint":false},{"year":1991,"finding":"ELAM-1 gene transcription is activated by TNF, IL-1, and LPS through PKC-independent activation of NF-κB-like proteins; PKC activity is required for full transcriptional activation but is not sufficient, indicating a dual signalling requirement.","method":"Nuclear run-off transcription assays; gel mobility shift assays (EMSA) for NF-κB binding; protein kinase C inhibitor (H7) treatment; 5′ promoter sequence analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — nuclear run-off and EMSA with pharmacological dissection in a single rigorous study","pmids":["1713680"],"is_preprint":false},{"year":1991,"finding":"Cytokine induction of ELAM-1 gene transcription requires two cis-acting elements within 233 bp upstream of the transcription start site: an NF-κB consensus binding site (−94 to −85) and a second element between −233 and −117; NF-κB binding activity is increased in IL-1-induced endothelial cells.","method":"ELAM-1 promoter deletion mutants linked to reporter genes transfected into endothelial and non-endothelial cells; gel shift (EMSA) assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter deletion mutagenesis with reporter assay and EMSA; orthogonal methods in one rigorous study","pmids":["1710341"],"is_preprint":false},{"year":1992,"finding":"Labile (short-lived) proteins negatively regulate ELAM-1 gene expression at two levels: (1) mRNA stability and (2) NF-κB-driven transcription initiation; protein synthesis inhibitors (cycloheximide, anisomycin, emetine) superinduce ELAM-1 mRNA and potentiate IL-1β-driven transcription and NF-κB binding; the NF-κB binding site is necessary and sufficient for cycloheximide-mediated superinduction.","method":"Nuclear run-on transcription; Northern blot mRNA half-life analysis; EMSA for NF-κB binding; protein synthesis inhibitor treatment; reporter assays with NF-κB site mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (run-on, Northern, EMSA, reporters) in one rigorous study","pmids":["1382069"],"is_preprint":false},{"year":1991,"finding":"ELAM-1-dependent adhesion of HL60 cells does not require N-linked complex oligosaccharides; inhibitors of N-linked glycan processing do not affect adhesion, indicating the ELAM-1 ligand on these cells is likely a glycolipid or O-linked glycoprotein.","method":"Adhesion assays to ELAM-1-expressing HUVEC in presence of N-linked glycosylation inhibitors (N-methyl-deoxynojirimycin, 1-deoxymannojirimycin, swainsonine)","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological inhibition approach, single lab, single method type","pmids":["1721027"],"is_preprint":false},{"year":1991,"finding":"ELAM-1-dependent neutrophil adhesion to activated endothelium occurs via a CD18/CD11-independent mechanism; ELAM-1 mediates the initial tethering step but does not contribute to transendothelial migration, which is entirely CD18-dependent.","method":"Antibody blocking assays with anti-ELAM-1 and anti-CD18 mAbs; LAD-patient neutrophils (CD18-deficient); 37°C vs 4°C adhesion assays; transendothelial migration assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — LAD patient cells, temperature-dependent assays, blocking antibody combination, replicated across multiple papers (PMIDs 1726710, 1713515, 2570036)","pmids":["1726710","1713515","2570036"],"is_preprint":false},{"year":1990,"finding":"ELAM-1 protein expression on endothelial cells is transiently induced by TNF-α, IL-1, or LPS with peak expression at 4–6 hours and disappearance by 24 hours; IFN-γ enhances and prolongs this expression but does not induce it independently, and abrogates the refractory period for restimulation.","method":"Flow cytometry of HUVEC surface protein expression; cytokine stimulation time course; blocking experiments with IFN-γ","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — flow cytometry time-course with multiple cytokine conditions, single lab","pmids":["1697876"],"is_preprint":false},{"year":1991,"finding":"ELAM-1 mediates monocyte adhesion to activated endothelium through a specific counter-structure on monocytes; this is demonstrable at 4°C or with fixed monocytes (reducing active CD18-mediated processes), and is confirmed using ELAM-1-transfected COS cells.","method":"Adhesion assays at 37°C and 4°C; fixed monocyte adhesion; ELAM-1-transfected COS cell adhesion; F(ab')2 blocking with anti-ELAM-1 mAb ENA2","journal":"Scandinavian journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple assay conditions including transfected cell line, single lab","pmids":["1371364"],"is_preprint":false},{"year":1992,"finding":"Rabbit ELAM-1 shares 74% amino acid identity with human ELAM-1 and retains the characteristic selectin domain organization (lectin domain, EGF domain, complement regulatory repeats, transmembrane, cytoplasmic tail), but contains 5 rather than 6 complement regulatory elements; individual extracellular domains are encoded by distinct exons consistent with exon-shuffling evolution of selectins.","method":"cDNA cloning, nucleotide and amino acid sequence analysis; genomic restriction mapping; COS cell transfection adhesion assays with rabbit and human PMNs; cross-reactive antibody binding","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequence analysis plus functional validation in transfected cells, single lab","pmids":["1372169"],"is_preprint":false},{"year":1992,"finding":"TNF-α induction of ELAM-1 on HUVECs is mediated via the well-characterized 55 kDa TNF receptor; the N-terminal region of the TNF molecule is not required for this interaction, and a 125I-TNF cross-linking complex characteristic of the 55 kDa receptor is identified on HUVECs.","method":"Antibody epitope-mapping inhibition of TNF signalling; 125I-TNF cross-linking; receptor-specific mAb identification; N-terminal TNF peptide antagonism assays","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-linking plus antibody blocking, multiple orthogonal approaches, single lab","pmids":["1381227"],"is_preprint":false},{"year":1997,"finding":"Binding of PMNs to E-selectin (CD62E) alone does not activate CD11b/CD18 (Mac-1) or cause L-selectin shedding; E-selectin tethers PMNs but does not trigger inside-out signalling that would strengthen adhesion.","method":"Flow cytometry for CD11b/CD18, activation epitope (CBRM1/5), and L-selectin on PMNs adhered to E-selectin-transfected CHO cells or IL-1β-activated HUVECs; CD62E-blocking mAb; confocal microscopy in situ staining","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple activation markers, transfected cell line, blocking antibody, and confocal confirmation in one study","pmids":["9218615"],"is_preprint":false},{"year":1994,"finding":"E-selectin (CD62E) expression on endothelial cells is localized to specific segments of post-capillary venules by electron microscopy; immunogold labelling shows gold particles concentrated at the apical plasma membrane and microvillus-like projections, with highest density induced by LPS compared to TNF-α.","method":"Immunogold labelling; transmission electron microscopy (TEM); high-resolution scanning electron microscopy (HR-SEM); silver-enhanced colloidal gold at light microscopy level","journal":"Micron","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — electron microscopy subcellular localization, single lab, single study","pmids":["7520816"],"is_preprint":false},{"year":2001,"finding":"Outside-to-inside (reverse) signalling through membrane TNF-α induces E-selectin (CD62E) expression on activated CD4+ T cells and HTLV-I-infected T cell lines; this induction is transcriptionally regulated and requires cell-to-cell contact or cross-linking of membrane TNF-α, establishing that E-selectin can be expressed on non-endothelial cell types.","method":"Anti-TNF-α antibody cross-linking of membrane TNF-α; transfection of wild-type and protease-resistant mutant membrane TNF-α; Northern blot and RT-PCR for CD62E mRNA; cell-to-cell contact assays; flow cytometry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis (cleavage-resistant mutant), transcriptional analysis, cell-contact assay; single lab","pmids":["11123285"],"is_preprint":false},{"year":2001,"finding":"Dimethylfumarate (DMF) inhibits TNF-induced CD62E (E-selectin) expression in endothelial cells in an NF-κB-dependent but AP-1-independent manner; 60-min DMF preincubation blocks CD62E expression for up to 24 h, whereas its hydrolysis product methylhydrogenfumarate is ineffective.","method":"Flow cytometry; CD62E-, NF-κB-, and AP-1-responsive promoter-reporter constructs; kinetic preincubation experiments; in vivo immunohistochemistry of psoriatic skin","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — promoter-reporter assay with NF-κB/AP-1 dissection and in vivo correlation; single lab","pmids":["11886496"],"is_preprint":false},{"year":2003,"finding":"CD62E (E-selectin) on blood vessel endothelium is required for the preferential accumulation of highly divided effector CD4+ T cells at a site of antigen injection; T cells that acquired CD62P-binding capacity migrated to the injection site in a CD62E-dependent manner without proliferating locally.","method":"Genetic epistasis: antigen-specific T-cell tracking in CD62E-deficient vs. wild-type recipient mice; whole-body imaging; BrdU proliferation assays; flow cytometry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean knockout epistasis in vivo with antigen-specific T cell tracking, multiple readouts, single lab","pmids":["12629067"],"is_preprint":false},{"year":2008,"finding":"Glioma-derived VEGF induces CD62E (E-selectin) expression on brain endothelial cells via VEGF-R2 and NF-κB pathway activation (peaking at 12 h), which then mediates transendothelial migration of haematopoietic progenitor cells (HPC) toward gliomas; neutralising anti-CD62E antibodies reduce HPC homing to orthotopic gliomas in vivo.","method":"In vitro induction assays on brain endothelial cells; VEGF-R2/TGF-β neutralisation; NF-κB CD62E promoter-reporter assay; in vivo neutralising antibody treatment in orthotopic glioma model; tissue microarray; transendothelial migration assay","journal":"Brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter, in vivo neutralising antibody, and in vitro mechanistic dissection; single lab","pmids":["18689869"],"is_preprint":false},{"year":2011,"finding":"IL-1α and IL-1β co-induce ELAM-1 expression in trabecular meshwork (TM) and simultaneously lower intraocular pressure (IOP) ~3-fold in porcine anterior eye perfusion; TGF-β2 acts as an IL-1 antagonist, counteracting both IOP reduction and ELAM-1 induction; IL-6 perfusion neither changes IOP nor induces ELAM-1.","method":"Porcine anterior eye perfusion culture; PCR and Western blot for ELAM-1; cytokine co-treatment with TGF-β2; IOP measurement","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional organ culture with molecular readouts and pharmacological dissection; single lab","pmids":["20861478"],"is_preprint":false},{"year":2015,"finding":"POAG-causing MYOC mutants (Q368X, Y437H) that are intracellularly retained activate the IL-1/NF-κB inflammatory pathway and co-induce SELE expression in trabecular meshwork cells; wild-type MYOC conversely inhibits IL-1/NF-κB activation and SELE induction; pathway activation levels correlate with intracellular retention of MYOC, not POAG-causing potency.","method":"Transient transfection and doxycycline-inducible lentiviral stable transduction of MYOC mutants in TM-1 cells; RT-PCR; ELISA for IL-1α; NF-κB luciferase reporter assay; co-expression of endogenous MYOC and SELE in primary TBM cultures","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple MYOC mutants, reporter assay, protein measurement, inducible system; single lab","pmids":["26396484"],"is_preprint":false},{"year":2024,"finding":"ITGA11 on PDGFRα+ITGA11+ cancer-associated fibroblasts (CAFs) engages SELE (E-selectin) on lymphatic endothelial cells to activate the SRC–p-VEGFR3–MAPK signalling pathway, thereby promoting lymphangiogenesis and facilitating lymphovascular invasion and lymph node metastasis in early-stage bladder cancer.","method":"Single-cell RNA sequencing; spatial transcriptomics; PDGFRα+ITGA11+ CAF-specific deficient mouse model; mechanistic pathway analysis (SRC/VEGFR3/MAPK); multicenter clinical cohort (n=910)","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo CAF-specific knockout model plus pathway mechanistic data; single lab","pmids":["38428409"],"is_preprint":false},{"year":2015,"finding":"CD15 (sialyl Lewis X) on non-small cell lung cancer cells is the binding partner for CD62E (E-selectin) on brain endothelial cells; TNF-α-enhanced CD62E expression on brain endothelium increases cancer cell adhesion, and CD15 immunoblocking significantly reduces adhesion under both static and physiological shear stress conditions.","method":"Adhesion assays under static and physiological flow (live-cell); CD15-blocking mAb; flow cytometry; Western blotting; immunofluorescence; immunohistochemistry on human brain metastasis tissue","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — blocking antibody under physiological flow conditions with tissue validation; replicated in companion paper (PMID 28698503)","pmids":["26472821","28698503"],"is_preprint":false},{"year":1996,"finding":"Mycobacterial heat shock protein 65 (hsp65) induces CD62E (E-selectin), VCAM-1, and ICAM-1 on endothelial cells; CD62E induction is responsible for the increased adhesion of granulocytes (completely blocked by anti-CD62E mAb), while monocyte adhesion to hsp65-stimulated EC is CD18-dependent and CD62E-independent.","method":"Adhesion assays with blocking mAbs; flow cytometry for adhesion molecule expression; IL-1/TNF neutralisation; LPS depletion controls","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — blocking antibody dissection with multiple cell types and autocrine/paracrine controls; single lab","pmids":["8683139"],"is_preprint":false}],"current_model":"E-selectin (SELE/ELAM-1/CD62E) is a cytokine-inducible (TNF, IL-1, LPS) endothelial transmembrane lectin whose expression is transcriptionally driven by NF-κB binding to a defined promoter element; it mediates leukocyte rolling and tethering by binding sialyl-Lewis X and sialyl-Lewis a carbohydrate ligands presented on neutrophil and monocyte glycolipids/O-linked glycoproteins (including LECAM-1/L-selectin on PMN microvilli), selectively recruits memory CD4+ T cells to sites of inflammation in an activation-independent and CD62E-dependent manner, supports cancer cell adhesion to endothelium via CD15/sialyl-Lex, and can be engaged by ITGA11 on fibroblasts to activate SRC–VEGFR3–MAPK signalling on lymphatic endothelium; binding of PMNs to E-selectin alone does not trigger inside-out signalling or CD11b/CD18 activation."},"narrative":{"mechanistic_narrative":"E-selectin (SELE/ELAM-1/CD62E) is a cytokine-inducible endothelial transmembrane lectin that initiates leukocyte recruitment to inflamed tissue by capturing circulating cells through carbohydrate recognition [PMID:1701274, PMID:1701275, PMID:1726710, PMID:1713515, PMID:2570036]. Its adhesive function rests on binding the sialylated, fucosylated terminal glycans sialyl-Lewis X and sialyl-Lewis a, which share a common spatial arrangement of neuraminic acid and fucose [PMID:1701274, PMID:1701275, PMID:1714447]; biosynthesis of these ligands depends on α(1,3)-fucosyltransferase activity, whose transfection alone is sufficient to confer E-selectin-dependent adhesion on non-myeloid cells [PMID:1699667, PMID:1702034]. These glycans are displayed on neutrophil and monocyte glycolipids and O-linked glycoproteins — including L-selectin (LECAM-1) concentrated on PMN microvilli, which functions as a counterreceptor — and on the CD15/sialyl-Lewis X structures of cancer cells [PMID:1716182, PMID:1713515, PMID:1721027, PMID:26472821, PMID:28698503]. E-selectin mediates the initial tethering/rolling step of adhesion but is CD18/CD11-independent and, on its own, does not trigger inside-out integrin activation or transendothelial migration [PMID:1726710, PMID:1713515, PMID:2570036, PMID:9218615]. Through this mechanism it selectively recruits memory (CD45RO+) CD4+ T cells in an activation-independent manner and is required for accumulation of effector CD4+ T cells at inflammatory sites in vivo [PMID:1705666, PMID:1705667, PMID:12629067]. Surface expression is transient and inducible by TNF, IL-1, and LPS, driven transcriptionally through NF-κB binding to a defined promoter element [PMID:1713680, PMID:1710341, PMID:1697876]; this induction can be modulated by IFN-γ, by NF-κB-targeting agents such as dimethylfumarate, and by inflammatory inputs in non-vascular contexts including the trabecular meshwork [PMID:1697876, PMID:11886496, PMID:20861478]. Beyond classical inflammation, E-selectin is engaged by ITGA11 on cancer-associated fibroblasts to activate SRC–VEGFR3–MAPK signalling on lymphatic endothelium, promoting lymphangiogenesis and metastatic spread [PMID:38428409].","teleology":[{"year":1990,"claim":"Established the molecular ligand of E-selectin, defining how an endothelial lectin recognizes circulating leukocytes at the carbohydrate level.","evidence":"Cell adhesion assays with ELAM-1-expressing cells and purified/synthetic sialyl-Lewis X plus anti-sialyl-Lex inhibition","pmids":["1701274","1701275"],"confidence":"High","gaps":["Did not identify the protein/lipid scaffolds presenting the glycan in vivo","Affinity/avidity contributions under flow not addressed"]},{"year":1990,"claim":"Showed that ligand biosynthesis, not the lectin alone, is rate-limiting — α(1,3)-fucosyltransferase activity controls whether a cell can adhere to E-selectin.","evidence":"Transfection of fucosyltransferase cDNA into non-myeloid cells with adhesion assays and flow cytometry for sialyl-Lex","pmids":["1699667","1702034"],"confidence":"High","gaps":["Which endogenous fucosyltransferases operate in physiological leukocytes not resolved here","Did not map the specific glycoprotein/glycolipid carriers"]},{"year":1991,"claim":"Broadened ligand specificity to sialyl-Lewis a and explained recognition by a shared glycan conformation, unifying the structural basis of E-selectin binding.","evidence":"Binding assays with immobilized synthetic glycoconjugates on ELAM-1 transfectants plus HSEA conformational modelling","pmids":["1714447"],"confidence":"High","gaps":["No co-crystal structure of lectin domain with ligand","Relative in vivo contribution of sLea vs sLex unknown"]},{"year":1991,"claim":"Identified L-selectin (LECAM-1) on PMN microvilli as a physiological glycoprotein counterreceptor presenting sialyl-Lewis X to E-selectin.","evidence":"Anti-LECAM-1 blocking, selective surface depletion, and microvillar localization on PMNs binding ELAM-1 transfectants","pmids":["1716182","1713515"],"confidence":"High","gaps":["Other carrier glycoproteins on PMNs not enumerated","Stoichiometry of LECAM-1 glycosylation not defined"]},{"year":1991,"claim":"Distinguished E-selectin's adhesive step from integrin function, showing it mediates initial tethering independent of CD18 and not transmigration.","evidence":"Anti-ELAM-1/anti-CD18 blocking, LAD CD18-deficient neutrophils, temperature-dependent and transmigration assays","pmids":["1726710","1713515","2570036"],"confidence":"High","gaps":["Did not address signalling consequences of tethering","Hand-off to integrin-dependent firm adhesion not mechanistically detailed"]},{"year":1991,"claim":"Defined the leukocyte subset selectivity of E-selectin — memory CD4+ T cells adhere in an activation-independent manner distinct from integrin pathways.","evidence":"Adhesion assays to purified E-selectin and transfected COS cells with T-cell subset comparison and antibody blocking","pmids":["1705666","1705667"],"confidence":"High","gaps":["Glycan determinant distinguishing memory vs naive T cells not identified","In vivo relevance addressed only later"]},{"year":1991,"claim":"Localized the transcriptional control of E-selectin induction to NF-κB and a defined upstream promoter region, explaining cytokine inducibility.","evidence":"Nuclear run-off, EMSA, PKC inhibitor dissection, and promoter deletion-reporter mapping in endothelial cells","pmids":["1713680","1710341"],"confidence":"High","gaps":["Identity of the second cis-element factor (−233/−117) not established","Upstream kinase cascade to NF-κB not fully defined"]},{"year":1992,"claim":"Revealed post-transcriptional and labile-repressor control layers on E-selectin, explaining the transient kinetics of its expression.","evidence":"Nuclear run-on, mRNA half-life Northern analysis, EMSA, and protein-synthesis-inhibitor superinduction with NF-κB site mutants","pmids":["1382069"],"confidence":"High","gaps":["Identity of the labile repressor protein(s) unknown","mRNA-destabilizing element not mapped"]},{"year":1992,"claim":"Defined the receptor input for TNF-driven induction, attributing E-selectin upregulation to the 55 kDa TNF receptor.","evidence":"125I-TNF cross-linking, receptor-specific mAb identification, and N-terminal TNF peptide antagonism on HUVECs","pmids":["1381227"],"confidence":"Medium","gaps":["Downstream signalling from p55 to NF-κB not traced","Single lab, single cell type"]},{"year":1997,"claim":"Clarified that E-selectin tethering is non-signalling — it does not activate Mac-1 or shed L-selectin, placing it strictly upstream of inside-out integrin activation.","evidence":"Flow cytometry for CD11b/CD18 activation epitopes and L-selectin on PMNs bound to E-selectin transfectants/HUVECs with confocal confirmation","pmids":["9218615"],"confidence":"High","gaps":["Co-stimulus required for inside-out signalling not defined","Outside-in signalling into endothelium not examined here"]},{"year":2003,"claim":"Provided in vivo proof that E-selectin is required for effector CD4+ T-cell accumulation at antigen sites, validating its physiological recruitment role.","evidence":"Antigen-specific T-cell tracking in CD62E-deficient vs wild-type mice with whole-body imaging and BrdU assays","pmids":["12629067"],"confidence":"High","gaps":["Glycan ligand on effector T cells not molecularly defined","Redundancy with P-selectin only partially addressed"]},{"year":2001,"claim":"Expanded the expression repertoire of E-selectin beyond endothelium, showing reverse signalling through membrane TNF-α induces it on activated T cells.","evidence":"Membrane TNF-α cross-linking, protease-resistant mutant transfection, and CD62E mRNA/flow analysis in T cells","pmids":["11123285"],"confidence":"Medium","gaps":["Functional role of T-cell-expressed E-selectin unclear","Signalling pathway from membrane TNF-α not detailed"]},{"year":2008,"claim":"Linked E-selectin induction to tumor-vascular crosstalk, showing VEGF/VEGF-R2/NF-κB-driven CD62E mediates progenitor cell homing to gliomas.","evidence":"Brain endothelial induction assays, NF-κB promoter-reporter, in vivo neutralizing antibody in orthotopic glioma, and transmigration assays","pmids":["18689869"],"confidence":"Medium","gaps":["Glycan ligand on homing progenitors not identified","Single lab"]},{"year":2015,"claim":"Connected E-selectin to cancer cell extravasation, identifying CD15/sialyl-Lewis X as the partner mediating tumor adhesion to brain endothelium under flow.","evidence":"Adhesion assays under physiological shear with CD15-blocking mAb and brain metastasis tissue validation","pmids":["26472821","28698503"],"confidence":"Medium","gaps":["Contribution to actual transmigration/metastasis in vivo not fully established","Other tumor glycan ligands not excluded"]},{"year":2024,"claim":"Identified a non-leukocyte ligand and signalling axis, showing ITGA11 on CAFs engages E-selectin to drive SRC–VEGFR3–MAPK lymphangiogenic signalling and metastasis.","evidence":"scRNA-seq, spatial transcriptomics, CAF-specific knockout mouse, pathway dissection, and a multicenter clinical cohort","pmids":["38428409"],"confidence":"Medium","gaps":["Direct ITGA11–SELE binding interface not structurally defined","Whether glycan-dependent or protein-protein contact unresolved"]},{"year":null,"claim":"How E-selectin tethering integrates with subsequent integrin-dependent firm adhesion, and the structural basis for its ligand and ITGA11 engagement, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No co-crystal structure of the lectin domain with sLex/sLea in the corpus","Mechanism of the hand-off to inside-out integrin activation undefined","Glycan vs protein basis of the ITGA11–SELE interaction unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,3,4,9,11,23]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10,15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,9,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[22]}],"complexes":[],"partners":["SELL","ITGA11","FUT9","TNFRSF1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P16581","full_name":"E-selectin","aliases":["CD62 antigen-like family member E","Endothelial leukocyte adhesion molecule 1","ELAM-1","Leukocyte-endothelial cell adhesion molecule 2","LECAM2"],"length_aa":610,"mass_kda":66.7,"function":"Cell-surface glycoprotein having a role in immunoadhesion. Mediates in the adhesion of blood neutrophils in cytokine-activated endothelium through interaction with SELPLG/PSGL1. May have a role in capillary morphogenesis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P16581/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SELE","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/SELE","total_profiled":1310},"omim":[{"mim_id":"621242","title":"ZINC FINGER PROTEIN 429; ZNF429","url":"https://www.omim.org/entry/621242"},{"mim_id":"617462","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR-RELATED PROTEIN 1; PPRC1","url":"https://www.omim.org/entry/617462"},{"mim_id":"616761","title":"SUSHI DOMAIN-CONTAINING PROTEIN 6; SUSD6","url":"https://www.omim.org/entry/616761"},{"mim_id":"616627","title":"PODOCALYXIN-LIKE 2; PODXL2","url":"https://www.omim.org/entry/616627"},{"mim_id":"616093","title":"BLOOD GROUP, ABO SYSTEM","url":"https://www.omim.org/entry/616093"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"urinary bladder","ntpm":52.2}],"url":"https://www.proteinatlas.org/search/SELE"},"hgnc":{"alias_symbol":["ESEL","CD62E"],"prev_symbol":["ELAM1","ELAM"]},"alphafold":{"accession":"P16581","domains":[{"cath_id":"3.10.100.10","chopping":"24-142","consensus_level":"high","plddt":92.8865,"start":24,"end":142},{"cath_id":"2.10.70.10","chopping":"179-240","consensus_level":"medium","plddt":94.6421,"start":179,"end":240},{"cath_id":"2.10.70.10","chopping":"252-302","consensus_level":"medium","plddt":89.8937,"start":252,"end":302},{"cath_id":"2.10.70.10","chopping":"314-365","consensus_level":"medium","plddt":89.6671,"start":314,"end":365},{"cath_id":"2.10.70.10","chopping":"367-428","consensus_level":"medium","plddt":85.8484,"start":367,"end":428},{"cath_id":"2.10.70.10","chopping":"440-491","consensus_level":"high","plddt":90.7488,"start":440,"end":491},{"cath_id":"2.10.70.10","chopping":"504-549","consensus_level":"high","plddt":86.8489,"start":504,"end":549}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P16581","model_url":"https://alphafold.ebi.ac.uk/files/AF-P16581-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P16581-F1-predicted_aligned_error_v6.png","plddt_mean":83.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SELE","jax_strain_url":"https://www.jax.org/strain/search?query=SELE"},"sequence":{"accession":"P16581","fasta_url":"https://rest.uniprot.org/uniprotkb/P16581.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P16581/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P16581"}},"corpus_meta":[{"pmid":"1701274","id":"PMC_1701274","title":"ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-Lex.","date":"1990","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/1701274","citation_count":1247,"is_preprint":false},{"pmid":"1701275","id":"PMC_1701275","title":"Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells.","date":"1990","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/1701275","citation_count":870,"is_preprint":false},{"pmid":"1705666","id":"PMC_1705666","title":"ELAM-1 is an adhesion molecule for skin-homing T cells.","date":"1991","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1705666","citation_count":829,"is_preprint":false},{"pmid":"1699667","id":"PMC_1699667","title":"ELAM-1--dependent cell adhesion to vascular endothelium determined by a transfected human fucosyltransferase cDNA.","date":"1990","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1699667","citation_count":655,"is_preprint":false},{"pmid":"1716182","id":"PMC_1716182","title":"The neutrophil selectin LECAM-1 presents carbohydrate ligands to the vascular selectins ELAM-1 and GMP-140.","date":"1991","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1716182","citation_count":566,"is_preprint":false},{"pmid":"1712483","id":"PMC_1712483","title":"CD62 and endothelial cell-leukocyte adhesion molecule 1 (ELAM-1) recognize the same carbohydrate ligand, sialyl-Lewis x.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1712483","citation_count":511,"is_preprint":false},{"pmid":"1714447","id":"PMC_1714447","title":"A carbohydrate domain common to both sialyl Le(a) and sialyl Le(X) is recognized by the endothelial cell leukocyte adhesion molecule ELAM-1.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1714447","citation_count":436,"is_preprint":false},{"pmid":"1705667","id":"PMC_1705667","title":"Activation-independent binding of human memory T cells to adhesion molecule ELAM-1.","date":"1991","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1705667","citation_count":411,"is_preprint":false},{"pmid":"1710227","id":"PMC_1710227","title":"Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA-1, VCAM-1, and ELAM-1 and changes in pathway hierarchy under different activation conditions.","date":"1991","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1710227","citation_count":400,"is_preprint":false},{"pmid":"1717633","id":"PMC_1717633","title":"Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, ICAM-1, but not ELAM-1.","date":"1991","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/1717633","citation_count":336,"is_preprint":false},{"pmid":"1702034","id":"PMC_1702034","title":"ELFT: a gene that directs the expression of an ELAM-1 ligand.","date":"1990","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1702034","citation_count":325,"is_preprint":false},{"pmid":"1716630","id":"PMC_1716630","title":"Molecular cloning of a human fucosyltransferase gene that determines expression of the Lewis x and VIM-2 epitopes but not ELAM-1-dependent cell adhesion.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1716630","citation_count":283,"is_preprint":false},{"pmid":"1713680","id":"PMC_1713680","title":"Activation of endothelial-leukocyte adhesion molecule 1 (ELAM-1) gene transcription.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1713680","citation_count":273,"is_preprint":false},{"pmid":"1708800","id":"PMC_1708800","title":"The expression of endothelial leukocyte adhesion molecule-1 (ELAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in experimental cutaneous inflammation: a comparison of ultraviolet B erythema and delayed hypersensitivity.","date":"1991","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/1708800","citation_count":238,"is_preprint":false},{"pmid":"1710341","id":"PMC_1710341","title":"An NF kappa B-like factor is essential but not sufficient for cytokine induction of endothelial leukocyte adhesion molecule 1 (ELAM-1) gene transcription.","date":"1991","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1710341","citation_count":238,"is_preprint":false},{"pmid":"7686370","id":"PMC_7686370","title":"Reduced synovial membrane macrophage numbers, ELAM-1 expression, and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis.","date":"1993","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/7686370","citation_count":237,"is_preprint":false},{"pmid":"1706195","id":"PMC_1706195","title":"Endothelial leucocyte adhesion molecule-1 (ELAM-1) expression in cutaneous inflammation.","date":"1991","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/1706195","citation_count":219,"is_preprint":false},{"pmid":"1726710","id":"PMC_1726710","title":"Neutrophil and monocyte adherence to and migration across monolayers of cytokine-activated endothelial cells: the contribution of CD18, ELAM-1, and VLA-4.","date":"1991","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/1726710","citation_count":196,"is_preprint":false},{"pmid":"8434643","id":"PMC_8434643","title":"Expression patterns of leukocyte adhesion ligand molecules on human liver endothelia. Lack of ELAM-1 and CD62 inducibility on sinusoidal endothelia and distinct distribution of VCAM-1, ICAM-1, ICAM-2, and LFA-3.","date":"1993","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8434643","citation_count":194,"is_preprint":false},{"pmid":"1713515","id":"PMC_1713515","title":"Antibodies against human neutrophil LECAM-1 (LAM-1/Leu-8/DREG-56 antigen) and endothelial cell ELAM-1 inhibit a common CD18-independent adhesion pathway in vitro.","date":"1991","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/1713515","citation_count":188,"is_preprint":false},{"pmid":"1718983","id":"PMC_1718983","title":"Cloning of a human alpha(1,3)-fucosyltransferase gene that encodes ELFT but does not confer ELAM-1 recognition on Chinese hamster ovary cell transfectants.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1718983","citation_count":155,"is_preprint":false},{"pmid":"9250400","id":"PMC_9250400","title":"Co-expression of ICAM-1, VCAM-1, ELAM-1 and Hsp60 in human arterial and venous endothelial cells in response to cytokines and oxidized low-density lipoproteins.","date":"1997","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/9250400","citation_count":142,"is_preprint":false},{"pmid":"7681228","id":"PMC_7681228","title":"Distribution of cell adhesion molecules (ICAM-1, VCAM-1, ELAM-1) in renal tissue during allograft rejection.","date":"1993","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/7681228","citation_count":142,"is_preprint":false},{"pmid":"10469048","id":"PMC_10469048","title":"Inhibition of dextran sulphate sodium (DSS)-induced colitis in mice by intracolonically administered antibodies against adhesion molecules (endothelial leucocyte adhesion molecule-1 (ELAM-1) or intercellular adhesion molecule-1 (ICAM-1)).","date":"1999","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10469048","citation_count":141,"is_preprint":false},{"pmid":"1697876","id":"PMC_1697876","title":"IFN-gamma regulates the expression of the adhesion molecule ELAM-1 and IL-6 production by human endothelial cells in vitro.","date":"1990","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1697876","citation_count":127,"is_preprint":false},{"pmid":"1379941","id":"PMC_1379941","title":"Intercellular adhesion molecule-1 (ICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) expression in the bronchial mucosa of normal and asthmatic subjects.","date":"1992","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/1379941","citation_count":126,"is_preprint":false},{"pmid":"7687590","id":"PMC_7687590","title":"Importance of E-selectin (ELAM-1) and sialyl Lewis(a) in the adhesion of pancreatic carcinoma cells to activated endothelium.","date":"1993","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7687590","citation_count":124,"is_preprint":false},{"pmid":"38428409","id":"PMC_38428409","title":"PDGFRα+ITGA11+ fibroblasts foster early-stage cancer lymphovascular invasion and lymphatic metastasis via ITGA11-SELE interplay.","date":"2024","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/38428409","citation_count":122,"is_preprint":false},{"pmid":"7687701","id":"PMC_7687701","title":"Serum ELAM-1 is increased in vasculitis, scleroderma, and systemic lupus erythematosus.","date":"1993","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/7687701","citation_count":117,"is_preprint":false},{"pmid":"12629067","id":"PMC_12629067","title":"Preferential accumulation of antigen-specific effector CD4 T cells at an antigen injection site involves CD62E-dependent migration but not local proliferation.","date":"2003","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12629067","citation_count":112,"is_preprint":false},{"pmid":"7528950","id":"PMC_7528950","title":"Divergent patterns of ELAM-1, ICAM-1, and VCAM-1 expression on cytomegalovirus-infected endothelial cells.","date":"1994","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/7528950","citation_count":109,"is_preprint":false},{"pmid":"1281230","id":"PMC_1281230","title":"Endothelial cell leukocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression in gingival tissue during health and experimentally-induced gingivitis.","date":"1992","source":"Journal of periodontal research","url":"https://pubmed.ncbi.nlm.nih.gov/1281230","citation_count":108,"is_preprint":false},{"pmid":"11123285","id":"PMC_11123285","title":"Outside-to-inside signal through the membrane TNF-alpha induces E-selectin (CD62E) expression on activated human CD4+ T cells.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11123285","citation_count":105,"is_preprint":false},{"pmid":"1722512","id":"PMC_1722512","title":"Gold treatment of rheumatoid arthritis decreases synovial expression of the endothelial leukocyte adhesion receptor ELAM-1.","date":"1991","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/1722512","citation_count":98,"is_preprint":false},{"pmid":"12714632","id":"PMC_12714632","title":"Ultrasound activates the TM ELAM-1/IL-1/NF-kappaB response: a potential mechanism for intraocular pressure reduction after phacoemulsification.","date":"2003","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/12714632","citation_count":97,"is_preprint":false},{"pmid":"1700619","id":"PMC_1700619","title":"Cytokine production (IL-1 alpha, IL-1 beta, and TNF alpha) and endothelial cell activation (ELAM-1 and HLA-DR) in reactive lymphadenitis, Hodgkin's disease, and in non-Hodgkin's lymphomas. An immunocytochemical study.","date":"1990","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/1700619","citation_count":95,"is_preprint":false},{"pmid":"9649216","id":"PMC_9649216","title":"Stimulation with thromboxane A2 (TXA2) receptor agonist enhances ICAM-1, VCAM-1 or ELAM-1 expression by human vascular endothelial cells.","date":"1998","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9649216","citation_count":94,"is_preprint":false},{"pmid":"19782291","id":"PMC_19782291","title":"Increased CD62e(+) endothelial microparticle levels predict poor outcome in pulmonary hypertension patients.","date":"2009","source":"The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/19782291","citation_count":90,"is_preprint":false},{"pmid":"7684425","id":"PMC_7684425","title":"Nickel chloride and cobalt chloride, two common contact sensitizers, directly induce expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule (ELAM-1) by endothelial cells.","date":"1993","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/7684425","citation_count":90,"is_preprint":false},{"pmid":"7559635","id":"PMC_7559635","title":"Molecular cloning, expression, chromosomal assignment, and tissue-specific expression of a murine alpha-(1,3)-fucosyltransferase locus corresponding to the human ELAM-1 ligand fucosyl transferase.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7559635","citation_count":89,"is_preprint":false},{"pmid":"1373738","id":"PMC_1373738","title":"Increased binding of synovial T lymphocytes from rheumatoid arthritis to endothelial-leukocyte adhesion molecule-1 (ELAM-1) and vascular cell adhesion molecule-1 (VCAM-1).","date":"1992","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/1373738","citation_count":85,"is_preprint":false},{"pmid":"14984317","id":"PMC_14984317","title":"Effect of high glucose concentrations on expression of ELAM-1, VCAM-1 and ICAM-1 in HUVEC with and without cytokine activation.","date":"2004","source":"Physiological research","url":"https://pubmed.ncbi.nlm.nih.gov/14984317","citation_count":78,"is_preprint":false},{"pmid":"1709139","id":"PMC_1709139","title":"Cytomegalovirus induced PMN adherence in relation to an ELAM-1 antigen present on infected endothelial cell monolayers.","date":"1991","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1709139","citation_count":72,"is_preprint":false},{"pmid":"9495363","id":"PMC_9495363","title":"Over-expression of ICAM-1, VCAM-1 and ELAM-1 might influence tumor progression in colorectal cancer.","date":"1998","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/9495363","citation_count":71,"is_preprint":false},{"pmid":"2570036","id":"PMC_2570036","title":"CD11/CD18-independent neutrophil adherence to inducible endothelial-leucocyte adhesion molecules (E-LAM) in vitro.","date":"1989","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2570036","citation_count":69,"is_preprint":false},{"pmid":"8683139","id":"PMC_8683139","title":"Heat shock protein 65 induces CD62e, CD106, and CD54 on cultured human endothelial cells and increases their adhesiveness for monocytes and granulocytes.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8683139","citation_count":66,"is_preprint":false},{"pmid":"1723957","id":"PMC_1723957","title":"Expression of ICAM-1, VCAM-1 and ELAM-1 in angiofollicular lymph node hyperplasia (Castleman's disease): evidence for dysplasia of follicular dendritic reticulum cells.","date":"1991","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/1723957","citation_count":64,"is_preprint":false},{"pmid":"7681227","id":"PMC_7681227","title":"Implications of de novo ELAM-1 and VCAM-1 expression in human cardiac allograft rejection.","date":"1993","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/7681227","citation_count":62,"is_preprint":false},{"pmid":"11886496","id":"PMC_11886496","title":"Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner.","date":"2001","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/11886496","citation_count":59,"is_preprint":false},{"pmid":"10209523","id":"PMC_10209523","title":"Up-regulation of intercellular adhesion molecule-1 (ICAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1) and class II MHC molecules on pulmonary artery endothelial cells by antibodies against U1-ribonucleoprotein.","date":"1999","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10209523","citation_count":57,"is_preprint":false},{"pmid":"1371364","id":"PMC_1371364","title":"Role of ELAM-1 in adhesion of monocytes to activated human endothelial cells.","date":"1992","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1371364","citation_count":55,"is_preprint":false},{"pmid":"1370233","id":"PMC_1370233","title":"VCAM-1-, ELAM-1-, and ICAM-1-independent adhesion of melanoma cells to cultured human dermal microvascular endothelial cells.","date":"1992","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/1370233","citation_count":54,"is_preprint":false},{"pmid":"7507856","id":"PMC_7507856","title":"Coordinate regulation of Steel factor, its receptor (Kit), and cytoadhesion molecule (ICAM-1 and ELAM-1) mRNA expression in human vascular endothelial cells of differing origins.","date":"1994","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/7507856","citation_count":54,"is_preprint":false},{"pmid":"1697461","id":"PMC_1697461","title":"A blocking monoclonal antibody to endothelial-leukocyte adhesion molecule-1 (ELAM1).","date":"1990","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1697461","citation_count":53,"is_preprint":false},{"pmid":"1719092","id":"PMC_1719092","title":"Involvement of the CD11b/CD18 integrin, but not of the endothelial cell adhesion molecules ELAM-1 and ICAM-1 in tumor necrosis factor-alpha-induced neutrophil toxicity.","date":"1991","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1719092","citation_count":53,"is_preprint":false},{"pmid":"1382069","id":"PMC_1382069","title":"Labile proteins play a dual role in the control of endothelial leukocyte adhesion molecule-1 (ELAM-1) gene regulation.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1382069","citation_count":52,"is_preprint":false},{"pmid":"7688346","id":"PMC_7688346","title":"Increased plasma levels of soluble ICAM-1 and ELAM-1 (E-selectin) during acute Plasmodium falciparum malaria.","date":"1993","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/7688346","citation_count":50,"is_preprint":false},{"pmid":"1383611","id":"PMC_1383611","title":"A role for ELAM-1 in the pathogenesis of MOF during septic shock.","date":"1992","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/1383611","citation_count":48,"is_preprint":false},{"pmid":"1373748","id":"PMC_1373748","title":"Infiltration of both T cells and neutrophils in the skin is accompanied by the expression of endothelial leukocyte adhesion molecule-1 (ELAM-1): an immunohistochemical and ultrastructural study.","date":"1992","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/1373748","citation_count":45,"is_preprint":false},{"pmid":"1375459","id":"PMC_1375459","title":"Effect of NADPH oxidase inhibition on endothelial cell ELAM-1 mRNA expression.","date":"1992","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1375459","citation_count":44,"is_preprint":false},{"pmid":"9087954","id":"PMC_9087954","title":"Alterations in the expression of ELAM-1, ICAM-1 and VCAM-1 after in vitro infection of endothelial cells with a clinical isolate of human cytomegalovirus.","date":"1997","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9087954","citation_count":42,"is_preprint":false},{"pmid":"7692824","id":"PMC_7692824","title":"Cultured Kaposi's sarcoma cell lines express factor XIIIa, CD14, and VCAM-1, but not factor VIII or ELAM-1.","date":"1993","source":"Archives of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/7692824","citation_count":38,"is_preprint":false},{"pmid":"7515338","id":"PMC_7515338","title":"Soluble intercellular adhesion molecule-1 (ICAM-1), endothelial leukocyte adhesion molecule-1 (ELAM-1), and tumor necrosis factor receptor (55 kDa TNF-R) in patients with acute Plasmodium falciparum malaria.","date":"1994","source":"Clinical immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/7515338","citation_count":38,"is_preprint":false},{"pmid":"8975870","id":"PMC_8975870","title":"Rabbit vascular endothelial adhesion molecules: ELAM-1 is most elevated in acute inflammation, whereas VCAM-1 and ICAM-1 predominate in chronic inflammation.","date":"1996","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/8975870","citation_count":38,"is_preprint":false},{"pmid":"7516056","id":"PMC_7516056","title":"Serum levels of soluble E-selectin (ELAM-1) in immune-mediated neuropathies.","date":"1994","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/7516056","citation_count":35,"is_preprint":false},{"pmid":"18791689","id":"PMC_18791689","title":"Blood serum levels of vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) in diabetic retinopathy.","date":"2008","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18791689","citation_count":34,"is_preprint":false},{"pmid":"26472821","id":"PMC_26472821","title":"TNF-α enhancement of CD62E mediates adhesion of non-small cell lung cancer cells to brain endothelium via CD15 in lung-brain metastasis.","date":"2015","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26472821","citation_count":32,"is_preprint":false},{"pmid":"26396484","id":"PMC_26396484","title":"Glaucomatous MYOC mutations activate the IL-1/NF-κB inflammatory stress response and the glaucoma marker SELE in trabecular meshwork cells.","date":"2015","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/26396484","citation_count":31,"is_preprint":false},{"pmid":"21881522","id":"PMC_21881522","title":"Association of ATP1B1, RGS5 and SELE polymorphisms with hypertension and blood pressure in African-Americans.","date":"2011","source":"Journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/21881522","citation_count":29,"is_preprint":false},{"pmid":"7688418","id":"PMC_7688418","title":"Identical expression of ELAM-1, VCAM-1, and ICAM-1 in sarcoidosis and usual interstitial pneumonitis.","date":"1993","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/7688418","citation_count":29,"is_preprint":false},{"pmid":"1372169","id":"PMC_1372169","title":"Characterization of cDNA and genomic sequences encoding rabbit ELAM-1: conservation of structure and functional interactions with leukocytes.","date":"1992","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1372169","citation_count":28,"is_preprint":false},{"pmid":"7685818","id":"PMC_7685818","title":"Expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1) on endothelial cells in experimental gingivitis in humans.","date":"1993","source":"Journal of periodontology","url":"https://pubmed.ncbi.nlm.nih.gov/7685818","citation_count":28,"is_preprint":false},{"pmid":"28698503","id":"PMC_28698503","title":"CD15s/CD62E Interaction Mediates the Adhesion of Non-Small Cell Lung Cancer Cells on Brain Endothelial Cells: Implications for Cerebral Metastasis.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28698503","citation_count":27,"is_preprint":false},{"pmid":"7514772","id":"PMC_7514772","title":"Expression of endothelial leukocyte adhesion molecule-1 (ELAM-1) in chronic inflammatory demyelinating polyneuropathy.","date":"1994","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/7514772","citation_count":27,"is_preprint":false},{"pmid":"1381227","id":"PMC_1381227","title":"Tumour necrosis factor induction of ELAM-1 and ICAM-1 on human umbilical vein endothelial cells--analysis of tumour necrosis factor-receptor interactions.","date":"1992","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/1381227","citation_count":27,"is_preprint":false},{"pmid":"8780927","id":"PMC_8780927","title":"Expression of the adhesion molecules ICAM, VCAM, and ELAM in the arteriosclerotic plaque.","date":"1996","source":"General & diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8780927","citation_count":26,"is_preprint":false},{"pmid":"9218615","id":"PMC_9218615","title":"Binding of human peripheral blood polymorphonuclear leukocytes to E-selectin (CD62E) does not promote their activation.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9218615","citation_count":24,"is_preprint":false},{"pmid":"20861478","id":"PMC_20861478","title":"Cytokine-dependent ELAM-1 induction and concomitant intraocular pressure regulation in porcine anterior eye perfusion culture.","date":"2011","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/20861478","citation_count":22,"is_preprint":false},{"pmid":"15784173","id":"PMC_15784173","title":"Genomic rearrangements on VCAM1, SELE, APEG1and AIF1 loci in atherosclerosis.","date":"2005","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15784173","citation_count":22,"is_preprint":false},{"pmid":"7688420","id":"PMC_7688420","title":"Reciprocal expression of CD34 and cell adhesion molecule ELAM-1 on vascular endothelium in acute cutaneous graft-versus-host disease.","date":"1993","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/7688420","citation_count":22,"is_preprint":false},{"pmid":"18689869","id":"PMC_18689869","title":"VEGF-dependent induction of CD62E on endothelial cells mediates glioma tropism of adult haematopoietic progenitor cells.","date":"2008","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/18689869","citation_count":21,"is_preprint":false},{"pmid":"15663512","id":"PMC_15663512","title":"Subcutaneous administration of collagen-polyvinylpyrrolidone down regulates IL-1beta, TNF-alpha, TGF-beta1, ELAM-1 and VCAM-1 expression in scleroderma skin lesions.","date":"2005","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15663512","citation_count":21,"is_preprint":false},{"pmid":"7552771","id":"PMC_7552771","title":"Antisense gene suppression against human ICAM-1, ELAM-1, and VCAM-1 in cultured human umbilical vein endothelial cells.","date":"1995","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/7552771","citation_count":20,"is_preprint":false},{"pmid":"14678268","id":"PMC_14678268","title":"High-level endothelial E-selectin (CD62E) cell adhesion molecule expression by a lipopolysaccharide-deficient strain of Neisseria meningitidis despite poor activation of NF-kappaB transcription factor.","date":"2004","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14678268","citation_count":19,"is_preprint":false},{"pmid":"7517655","id":"PMC_7517655","title":"Immunohistochemistry of port-wine stains and normal skin with endothelium-specific antibodies PAL-E, anti-ICAM-1, anti-ELAM-1, and anti-factor VIIIrAg.","date":"1994","source":"Archives of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/7517655","citation_count":18,"is_preprint":false},{"pmid":"1721027","id":"PMC_1721027","title":"The ligand recognized by ELAM-1 on HL60 cells is not carried by N-linked oligosaccharides.","date":"1991","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1721027","citation_count":18,"is_preprint":false},{"pmid":"9024987","id":"PMC_9024987","title":"The NF-kappa B inhibitor, tepoxalin, suppresses surface expression of the cell adhesion molecules CD62E, CD11b/CD18 and CD106.","date":"1996","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/9024987","citation_count":17,"is_preprint":false},{"pmid":"9137829","id":"PMC_9137829","title":"Induction of mRNAs for ICAM-1, VCAM-1, and ELAM-1 in cultured rat cardiac myocytes and myocardium in vivo.","date":"1997","source":"Biochemistry and molecular biology international","url":"https://pubmed.ncbi.nlm.nih.gov/9137829","citation_count":16,"is_preprint":false},{"pmid":"39481643","id":"PMC_39481643","title":"Synergistic potentiation of the anti-metastatic effect of a Ginseng-Salvia miltiorrhiza herbal pair and its biological ingredients via the suppression of CD62E-dependent neutrophil infiltration and NETformation.","date":"2024","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/39481643","citation_count":15,"is_preprint":false},{"pmid":"1721850","id":"PMC_1721850","title":"LPS and cytokine-induced endothelial cell IL-6 release and ELAM-1 expression; involvement of serum.","date":"1991","source":"European cytokine network","url":"https://pubmed.ncbi.nlm.nih.gov/1721850","citation_count":14,"is_preprint":false},{"pmid":"9538126","id":"PMC_9538126","title":"ELAM selectin expression in breast carcinomas detected by automated and quantitative immunohistochemical assays.","date":"1998","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/9538126","citation_count":14,"is_preprint":false},{"pmid":"7532002","id":"PMC_7532002","title":"1 alpha, 25-Dihydroxyvitamin D3 decreased ICAM-1 and ELAM-1 expressions on pulmonary microvascular endothelial cells and neutrophil motivation.","date":"1995","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7532002","citation_count":14,"is_preprint":false},{"pmid":"18472945","id":"PMC_18472945","title":"Serum Concentration and Chemotactic Activity of E-selectin (CD62E) in Inflammatory Bowel Disease.","date":"1994","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/18472945","citation_count":11,"is_preprint":false},{"pmid":"8902653","id":"PMC_8902653","title":"Alterations in ICAM-1 and ELAM-1 expression in psoriatic lesions following various treatments.","date":"1996","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/8902653","citation_count":10,"is_preprint":false},{"pmid":"20056442","id":"PMC_20056442","title":"Association of the 98T ELAM-1 polymorphism with increased bleeding after cardiac surgery.","date":"2010","source":"Journal of cardiothoracic and vascular anesthesia","url":"https://pubmed.ncbi.nlm.nih.gov/20056442","citation_count":10,"is_preprint":false},{"pmid":"19283663","id":"PMC_19283663","title":"The role of vascular adhesion molecules PECAM-1 (CD 31), VCAM-1 (CD 106), E-selectin (CD62E) and P-selectin (CD62P) in severe porcine pancreatitis.","date":"2009","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/19283663","citation_count":10,"is_preprint":false},{"pmid":"7520816","id":"PMC_7520816","title":"Application of immunogold labelling for light and electron microscopic localization of endothelial leukocyte adhesion molecule 1 (ELAM-1) on cultured human endothelial cells.","date":"1994","source":"Micron (Oxford, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/7520816","citation_count":10,"is_preprint":false},{"pmid":"8572633","id":"PMC_8572633","title":"Preoperative serum intercellular adhesion molecule-1 (ICAM-1) and E-selectin (endothelial cell leukocyte adhesion molecule, ELAM-1) in patients with epithelial ovarian cancer.","date":"1995","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/8572633","citation_count":10,"is_preprint":false},{"pmid":"26937892","id":"PMC_26937892","title":"Relationship of SELE A561C and G98T Variants With the Susceptibility to CAD.","date":"2016","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26937892","citation_count":9,"is_preprint":false},{"pmid":"23190470","id":"PMC_23190470","title":"Association of SELE genotypes/haplotypes with sE-selectin levels in Taiwanese individuals: interactive effect of MMP9 level.","date":"2012","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23190470","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54414,"output_tokens":6516,"usd":0.130491,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15456,"output_tokens":4568,"usd":0.09574,"stage2_stop_reason":"end_turn"},"total_usd":0.226231,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"ELAM-1 (E-selectin/SELE) mediates leukocyte adhesion through recognition of the carbohydrate ligand sialyl-Lewis X (NeuAc α2,3Gal β1,4(Fuc α1,3)-GlcNAc-), a terminal structure found on neutrophil glycoproteins and glycolipids.\",\n      \"method\": \"Cell adhesion assays using ELAM-1-expressing cells and purified/synthetic carbohydrate structures; inhibition with anti-sialyl-Lex antibodies\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding assay with purified ligand, replicated simultaneously in two independent papers (PMIDs 1701274 and 1701275)\",\n      \"pmids\": [\"1701274\", \"1701275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"ELAM-1 also recognizes sialyl-Lewis a (NeuAc α2-3Gal β1-3(Fuc α1-4)GlcNAc), binding it as well as or slightly better than sialyl-Lewis X; HSEA modelling showed both share a common spatial arrangement of neuraminic acid and fucose on one face of the molecule.\",\n      \"method\": \"Cell binding assay with immobilized synthetic glycoconjugates using ELAM-1 cDNA transfectants; hard sphere exo-anomeric (HSEA) conformational calculations\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding assay with synthetic ligands plus computational conformational analysis in a single rigorous study\",\n      \"pmids\": [\"1714447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Transfection of a human α(1,3)-fucosyltransferase cDNA (ELFT) into non-myeloid cells confers ELAM-1-dependent endothelial adhesion, correlating with de novo cell-surface expression of sialyl Lewis X, demonstrating that α(1,3)-fucosyltransferase activity controls biosynthesis of the ELAM-1 ligand.\",\n      \"method\": \"Transfection of fucosyltransferase cDNA into non-myeloid cell lines; cell adhesion assays; flow cytometry for sialyl-Lex expression\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution by transfection with mechanistic correlation, replicated in two independent Cell papers (PMIDs 1699667 and 1702034)\",\n      \"pmids\": [\"1699667\", \"1702034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Neutrophil LECAM-1 (L-selectin) carries sialyl Lewis X on its surface and presents it to ELAM-1 on endothelium; LECAM-1 is concentrated on PMN microvilli and mediates up to 70% of PMN binding to ELAM-1 transfectants, acting as a counterreceptor/ligand for ELAM-1.\",\n      \"method\": \"Anti-LECAM-1 mAb inhibition assays; selective removal of LECAM-1 from PMN surface; binding assays to ELAM-1 transfected cells; confocal/immunofluorescence localization of LECAM-1 to microvilli\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal inhibition with blocking antibodies, selective depletion experiment, localization study, replicated in two papers (PMIDs 1716182 and 1713515)\",\n      \"pmids\": [\"1716182\", \"1713515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"ELAM-1 exclusively mediates adhesion of memory (CD45RO+) T cells, not naive T cells, to activated endothelium; this adhesion is activation-independent (not enhanced by acute T-cell activation), unlike LFA-1- or VLA-4-mediated adhesion.\",\n      \"method\": \"Adhesion assays to purified ELAM-1 protein and ELAM-1-transfected COS cells; antibody blocking; T-cell subset comparisons\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct adhesion assays to purified protein, subset comparisons, replicated across two independent papers (PMIDs 1705666 and 1705667)\",\n      \"pmids\": [\"1705666\", \"1705667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"ELAM-1 gene transcription is activated by TNF, IL-1, and LPS through PKC-independent activation of NF-κB-like proteins; PKC activity is required for full transcriptional activation but is not sufficient, indicating a dual signalling requirement.\",\n      \"method\": \"Nuclear run-off transcription assays; gel mobility shift assays (EMSA) for NF-κB binding; protein kinase C inhibitor (H7) treatment; 5′ promoter sequence analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — nuclear run-off and EMSA with pharmacological dissection in a single rigorous study\",\n      \"pmids\": [\"1713680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Cytokine induction of ELAM-1 gene transcription requires two cis-acting elements within 233 bp upstream of the transcription start site: an NF-κB consensus binding site (−94 to −85) and a second element between −233 and −117; NF-κB binding activity is increased in IL-1-induced endothelial cells.\",\n      \"method\": \"ELAM-1 promoter deletion mutants linked to reporter genes transfected into endothelial and non-endothelial cells; gel shift (EMSA) assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter deletion mutagenesis with reporter assay and EMSA; orthogonal methods in one rigorous study\",\n      \"pmids\": [\"1710341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Labile (short-lived) proteins negatively regulate ELAM-1 gene expression at two levels: (1) mRNA stability and (2) NF-κB-driven transcription initiation; protein synthesis inhibitors (cycloheximide, anisomycin, emetine) superinduce ELAM-1 mRNA and potentiate IL-1β-driven transcription and NF-κB binding; the NF-κB binding site is necessary and sufficient for cycloheximide-mediated superinduction.\",\n      \"method\": \"Nuclear run-on transcription; Northern blot mRNA half-life analysis; EMSA for NF-κB binding; protein synthesis inhibitor treatment; reporter assays with NF-κB site mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (run-on, Northern, EMSA, reporters) in one rigorous study\",\n      \"pmids\": [\"1382069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"ELAM-1-dependent adhesion of HL60 cells does not require N-linked complex oligosaccharides; inhibitors of N-linked glycan processing do not affect adhesion, indicating the ELAM-1 ligand on these cells is likely a glycolipid or O-linked glycoprotein.\",\n      \"method\": \"Adhesion assays to ELAM-1-expressing HUVEC in presence of N-linked glycosylation inhibitors (N-methyl-deoxynojirimycin, 1-deoxymannojirimycin, swainsonine)\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological inhibition approach, single lab, single method type\",\n      \"pmids\": [\"1721027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"ELAM-1-dependent neutrophil adhesion to activated endothelium occurs via a CD18/CD11-independent mechanism; ELAM-1 mediates the initial tethering step but does not contribute to transendothelial migration, which is entirely CD18-dependent.\",\n      \"method\": \"Antibody blocking assays with anti-ELAM-1 and anti-CD18 mAbs; LAD-patient neutrophils (CD18-deficient); 37°C vs 4°C adhesion assays; transendothelial migration assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — LAD patient cells, temperature-dependent assays, blocking antibody combination, replicated across multiple papers (PMIDs 1726710, 1713515, 2570036)\",\n      \"pmids\": [\"1726710\", \"1713515\", \"2570036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"ELAM-1 protein expression on endothelial cells is transiently induced by TNF-α, IL-1, or LPS with peak expression at 4–6 hours and disappearance by 24 hours; IFN-γ enhances and prolongs this expression but does not induce it independently, and abrogates the refractory period for restimulation.\",\n      \"method\": \"Flow cytometry of HUVEC surface protein expression; cytokine stimulation time course; blocking experiments with IFN-γ\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — flow cytometry time-course with multiple cytokine conditions, single lab\",\n      \"pmids\": [\"1697876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"ELAM-1 mediates monocyte adhesion to activated endothelium through a specific counter-structure on monocytes; this is demonstrable at 4°C or with fixed monocytes (reducing active CD18-mediated processes), and is confirmed using ELAM-1-transfected COS cells.\",\n      \"method\": \"Adhesion assays at 37°C and 4°C; fixed monocyte adhesion; ELAM-1-transfected COS cell adhesion; F(ab')2 blocking with anti-ELAM-1 mAb ENA2\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple assay conditions including transfected cell line, single lab\",\n      \"pmids\": [\"1371364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Rabbit ELAM-1 shares 74% amino acid identity with human ELAM-1 and retains the characteristic selectin domain organization (lectin domain, EGF domain, complement regulatory repeats, transmembrane, cytoplasmic tail), but contains 5 rather than 6 complement regulatory elements; individual extracellular domains are encoded by distinct exons consistent with exon-shuffling evolution of selectins.\",\n      \"method\": \"cDNA cloning, nucleotide and amino acid sequence analysis; genomic restriction mapping; COS cell transfection adhesion assays with rabbit and human PMNs; cross-reactive antibody binding\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequence analysis plus functional validation in transfected cells, single lab\",\n      \"pmids\": [\"1372169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"TNF-α induction of ELAM-1 on HUVECs is mediated via the well-characterized 55 kDa TNF receptor; the N-terminal region of the TNF molecule is not required for this interaction, and a 125I-TNF cross-linking complex characteristic of the 55 kDa receptor is identified on HUVECs.\",\n      \"method\": \"Antibody epitope-mapping inhibition of TNF signalling; 125I-TNF cross-linking; receptor-specific mAb identification; N-terminal TNF peptide antagonism assays\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-linking plus antibody blocking, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"1381227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Binding of PMNs to E-selectin (CD62E) alone does not activate CD11b/CD18 (Mac-1) or cause L-selectin shedding; E-selectin tethers PMNs but does not trigger inside-out signalling that would strengthen adhesion.\",\n      \"method\": \"Flow cytometry for CD11b/CD18, activation epitope (CBRM1/5), and L-selectin on PMNs adhered to E-selectin-transfected CHO cells or IL-1β-activated HUVECs; CD62E-blocking mAb; confocal microscopy in situ staining\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple activation markers, transfected cell line, blocking antibody, and confocal confirmation in one study\",\n      \"pmids\": [\"9218615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"E-selectin (CD62E) expression on endothelial cells is localized to specific segments of post-capillary venules by electron microscopy; immunogold labelling shows gold particles concentrated at the apical plasma membrane and microvillus-like projections, with highest density induced by LPS compared to TNF-α.\",\n      \"method\": \"Immunogold labelling; transmission electron microscopy (TEM); high-resolution scanning electron microscopy (HR-SEM); silver-enhanced colloidal gold at light microscopy level\",\n      \"journal\": \"Micron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — electron microscopy subcellular localization, single lab, single study\",\n      \"pmids\": [\"7520816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Outside-to-inside (reverse) signalling through membrane TNF-α induces E-selectin (CD62E) expression on activated CD4+ T cells and HTLV-I-infected T cell lines; this induction is transcriptionally regulated and requires cell-to-cell contact or cross-linking of membrane TNF-α, establishing that E-selectin can be expressed on non-endothelial cell types.\",\n      \"method\": \"Anti-TNF-α antibody cross-linking of membrane TNF-α; transfection of wild-type and protease-resistant mutant membrane TNF-α; Northern blot and RT-PCR for CD62E mRNA; cell-to-cell contact assays; flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis (cleavage-resistant mutant), transcriptional analysis, cell-contact assay; single lab\",\n      \"pmids\": [\"11123285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Dimethylfumarate (DMF) inhibits TNF-induced CD62E (E-selectin) expression in endothelial cells in an NF-κB-dependent but AP-1-independent manner; 60-min DMF preincubation blocks CD62E expression for up to 24 h, whereas its hydrolysis product methylhydrogenfumarate is ineffective.\",\n      \"method\": \"Flow cytometry; CD62E-, NF-κB-, and AP-1-responsive promoter-reporter constructs; kinetic preincubation experiments; in vivo immunohistochemistry of psoriatic skin\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter-reporter assay with NF-κB/AP-1 dissection and in vivo correlation; single lab\",\n      \"pmids\": [\"11886496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD62E (E-selectin) on blood vessel endothelium is required for the preferential accumulation of highly divided effector CD4+ T cells at a site of antigen injection; T cells that acquired CD62P-binding capacity migrated to the injection site in a CD62E-dependent manner without proliferating locally.\",\n      \"method\": \"Genetic epistasis: antigen-specific T-cell tracking in CD62E-deficient vs. wild-type recipient mice; whole-body imaging; BrdU proliferation assays; flow cytometry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout epistasis in vivo with antigen-specific T cell tracking, multiple readouts, single lab\",\n      \"pmids\": [\"12629067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Glioma-derived VEGF induces CD62E (E-selectin) expression on brain endothelial cells via VEGF-R2 and NF-κB pathway activation (peaking at 12 h), which then mediates transendothelial migration of haematopoietic progenitor cells (HPC) toward gliomas; neutralising anti-CD62E antibodies reduce HPC homing to orthotopic gliomas in vivo.\",\n      \"method\": \"In vitro induction assays on brain endothelial cells; VEGF-R2/TGF-β neutralisation; NF-κB CD62E promoter-reporter assay; in vivo neutralising antibody treatment in orthotopic glioma model; tissue microarray; transendothelial migration assay\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter, in vivo neutralising antibody, and in vitro mechanistic dissection; single lab\",\n      \"pmids\": [\"18689869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-1α and IL-1β co-induce ELAM-1 expression in trabecular meshwork (TM) and simultaneously lower intraocular pressure (IOP) ~3-fold in porcine anterior eye perfusion; TGF-β2 acts as an IL-1 antagonist, counteracting both IOP reduction and ELAM-1 induction; IL-6 perfusion neither changes IOP nor induces ELAM-1.\",\n      \"method\": \"Porcine anterior eye perfusion culture; PCR and Western blot for ELAM-1; cytokine co-treatment with TGF-β2; IOP measurement\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional organ culture with molecular readouts and pharmacological dissection; single lab\",\n      \"pmids\": [\"20861478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"POAG-causing MYOC mutants (Q368X, Y437H) that are intracellularly retained activate the IL-1/NF-κB inflammatory pathway and co-induce SELE expression in trabecular meshwork cells; wild-type MYOC conversely inhibits IL-1/NF-κB activation and SELE induction; pathway activation levels correlate with intracellular retention of MYOC, not POAG-causing potency.\",\n      \"method\": \"Transient transfection and doxycycline-inducible lentiviral stable transduction of MYOC mutants in TM-1 cells; RT-PCR; ELISA for IL-1α; NF-κB luciferase reporter assay; co-expression of endogenous MYOC and SELE in primary TBM cultures\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple MYOC mutants, reporter assay, protein measurement, inducible system; single lab\",\n      \"pmids\": [\"26396484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGA11 on PDGFRα+ITGA11+ cancer-associated fibroblasts (CAFs) engages SELE (E-selectin) on lymphatic endothelial cells to activate the SRC–p-VEGFR3–MAPK signalling pathway, thereby promoting lymphangiogenesis and facilitating lymphovascular invasion and lymph node metastasis in early-stage bladder cancer.\",\n      \"method\": \"Single-cell RNA sequencing; spatial transcriptomics; PDGFRα+ITGA11+ CAF-specific deficient mouse model; mechanistic pathway analysis (SRC/VEGFR3/MAPK); multicenter clinical cohort (n=910)\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo CAF-specific knockout model plus pathway mechanistic data; single lab\",\n      \"pmids\": [\"38428409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD15 (sialyl Lewis X) on non-small cell lung cancer cells is the binding partner for CD62E (E-selectin) on brain endothelial cells; TNF-α-enhanced CD62E expression on brain endothelium increases cancer cell adhesion, and CD15 immunoblocking significantly reduces adhesion under both static and physiological shear stress conditions.\",\n      \"method\": \"Adhesion assays under static and physiological flow (live-cell); CD15-blocking mAb; flow cytometry; Western blotting; immunofluorescence; immunohistochemistry on human brain metastasis tissue\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blocking antibody under physiological flow conditions with tissue validation; replicated in companion paper (PMID 28698503)\",\n      \"pmids\": [\"26472821\", \"28698503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Mycobacterial heat shock protein 65 (hsp65) induces CD62E (E-selectin), VCAM-1, and ICAM-1 on endothelial cells; CD62E induction is responsible for the increased adhesion of granulocytes (completely blocked by anti-CD62E mAb), while monocyte adhesion to hsp65-stimulated EC is CD18-dependent and CD62E-independent.\",\n      \"method\": \"Adhesion assays with blocking mAbs; flow cytometry for adhesion molecule expression; IL-1/TNF neutralisation; LPS depletion controls\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blocking antibody dissection with multiple cell types and autocrine/paracrine controls; single lab\",\n      \"pmids\": [\"8683139\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"E-selectin (SELE/ELAM-1/CD62E) is a cytokine-inducible (TNF, IL-1, LPS) endothelial transmembrane lectin whose expression is transcriptionally driven by NF-κB binding to a defined promoter element; it mediates leukocyte rolling and tethering by binding sialyl-Lewis X and sialyl-Lewis a carbohydrate ligands presented on neutrophil and monocyte glycolipids/O-linked glycoproteins (including LECAM-1/L-selectin on PMN microvilli), selectively recruits memory CD4+ T cells to sites of inflammation in an activation-independent and CD62E-dependent manner, supports cancer cell adhesion to endothelium via CD15/sialyl-Lex, and can be engaged by ITGA11 on fibroblasts to activate SRC–VEGFR3–MAPK signalling on lymphatic endothelium; binding of PMNs to E-selectin alone does not trigger inside-out signalling or CD11b/CD18 activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"E-selectin (SELE/ELAM-1/CD62E) is a cytokine-inducible endothelial transmembrane lectin that initiates leukocyte recruitment to inflamed tissue by capturing circulating cells through carbohydrate recognition [#0, #9]. Its adhesive function rests on binding the sialylated, fucosylated terminal glycans sialyl-Lewis X and sialyl-Lewis a, which share a common spatial arrangement of neuraminic acid and fucose [#0, #1]; biosynthesis of these ligands depends on α(1,3)-fucosyltransferase activity, whose transfection alone is sufficient to confer E-selectin-dependent adhesion on non-myeloid cells [#2]. These glycans are displayed on neutrophil and monocyte glycolipids and O-linked glycoproteins — including L-selectin (LECAM-1) concentrated on PMN microvilli, which functions as a counterreceptor — and on the CD15/sialyl-Lewis X structures of cancer cells [#3, #8, #23]. E-selectin mediates the initial tethering/rolling step of adhesion but is CD18/CD11-independent and, on its own, does not trigger inside-out integrin activation or transendothelial migration [#9, #14]. Through this mechanism it selectively recruits memory (CD45RO+) CD4+ T cells in an activation-independent manner and is required for accumulation of effector CD4+ T cells at inflammatory sites in vivo [#4, #18]. Surface expression is transient and inducible by TNF, IL-1, and LPS, driven transcriptionally through NF-κB binding to a defined promoter element [#5, #6, #10]; this induction can be modulated by IFN-γ, by NF-κB-targeting agents such as dimethylfumarate, and by inflammatory inputs in non-vascular contexts including the trabecular meshwork [#10, #17, #20]. Beyond classical inflammation, E-selectin is engaged by ITGA11 on cancer-associated fibroblasts to activate SRC–VEGFR3–MAPK signalling on lymphatic endothelium, promoting lymphangiogenesis and metastatic spread [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established the molecular ligand of E-selectin, defining how an endothelial lectin recognizes circulating leukocytes at the carbohydrate level.\",\n      \"evidence\": \"Cell adhesion assays with ELAM-1-expressing cells and purified/synthetic sialyl-Lewis X plus anti-sialyl-Lex inhibition\",\n      \"pmids\": [\"1701274\", \"1701275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the protein/lipid scaffolds presenting the glycan in vivo\", \"Affinity/avidity contributions under flow not addressed\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Showed that ligand biosynthesis, not the lectin alone, is rate-limiting — α(1,3)-fucosyltransferase activity controls whether a cell can adhere to E-selectin.\",\n      \"evidence\": \"Transfection of fucosyltransferase cDNA into non-myeloid cells with adhesion assays and flow cytometry for sialyl-Lex\",\n      \"pmids\": [\"1699667\", \"1702034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which endogenous fucosyltransferases operate in physiological leukocytes not resolved here\", \"Did not map the specific glycoprotein/glycolipid carriers\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Broadened ligand specificity to sialyl-Lewis a and explained recognition by a shared glycan conformation, unifying the structural basis of E-selectin binding.\",\n      \"evidence\": \"Binding assays with immobilized synthetic glycoconjugates on ELAM-1 transfectants plus HSEA conformational modelling\",\n      \"pmids\": [\"1714447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of lectin domain with ligand\", \"Relative in vivo contribution of sLea vs sLex unknown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Identified L-selectin (LECAM-1) on PMN microvilli as a physiological glycoprotein counterreceptor presenting sialyl-Lewis X to E-selectin.\",\n      \"evidence\": \"Anti-LECAM-1 blocking, selective surface depletion, and microvillar localization on PMNs binding ELAM-1 transfectants\",\n      \"pmids\": [\"1716182\", \"1713515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other carrier glycoproteins on PMNs not enumerated\", \"Stoichiometry of LECAM-1 glycosylation not defined\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Distinguished E-selectin's adhesive step from integrin function, showing it mediates initial tethering independent of CD18 and not transmigration.\",\n      \"evidence\": \"Anti-ELAM-1/anti-CD18 blocking, LAD CD18-deficient neutrophils, temperature-dependent and transmigration assays\",\n      \"pmids\": [\"1726710\", \"1713515\", \"2570036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address signalling consequences of tethering\", \"Hand-off to integrin-dependent firm adhesion not mechanistically detailed\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Defined the leukocyte subset selectivity of E-selectin — memory CD4+ T cells adhere in an activation-independent manner distinct from integrin pathways.\",\n      \"evidence\": \"Adhesion assays to purified E-selectin and transfected COS cells with T-cell subset comparison and antibody blocking\",\n      \"pmids\": [\"1705666\", \"1705667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan determinant distinguishing memory vs naive T cells not identified\", \"In vivo relevance addressed only later\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Localized the transcriptional control of E-selectin induction to NF-κB and a defined upstream promoter region, explaining cytokine inducibility.\",\n      \"evidence\": \"Nuclear run-off, EMSA, PKC inhibitor dissection, and promoter deletion-reporter mapping in endothelial cells\",\n      \"pmids\": [\"1713680\", \"1710341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the second cis-element factor (−233/−117) not established\", \"Upstream kinase cascade to NF-κB not fully defined\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Revealed post-transcriptional and labile-repressor control layers on E-selectin, explaining the transient kinetics of its expression.\",\n      \"evidence\": \"Nuclear run-on, mRNA half-life Northern analysis, EMSA, and protein-synthesis-inhibitor superinduction with NF-κB site mutants\",\n      \"pmids\": [\"1382069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the labile repressor protein(s) unknown\", \"mRNA-destabilizing element not mapped\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Defined the receptor input for TNF-driven induction, attributing E-selectin upregulation to the 55 kDa TNF receptor.\",\n      \"evidence\": \"125I-TNF cross-linking, receptor-specific mAb identification, and N-terminal TNF peptide antagonism on HUVECs\",\n      \"pmids\": [\"1381227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signalling from p55 to NF-κB not traced\", \"Single lab, single cell type\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Clarified that E-selectin tethering is non-signalling — it does not activate Mac-1 or shed L-selectin, placing it strictly upstream of inside-out integrin activation.\",\n      \"evidence\": \"Flow cytometry for CD11b/CD18 activation epitopes and L-selectin on PMNs bound to E-selectin transfectants/HUVECs with confocal confirmation\",\n      \"pmids\": [\"9218615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-stimulus required for inside-out signalling not defined\", \"Outside-in signalling into endothelium not examined here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided in vivo proof that E-selectin is required for effector CD4+ T-cell accumulation at antigen sites, validating its physiological recruitment role.\",\n      \"evidence\": \"Antigen-specific T-cell tracking in CD62E-deficient vs wild-type mice with whole-body imaging and BrdU assays\",\n      \"pmids\": [\"12629067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan ligand on effector T cells not molecularly defined\", \"Redundancy with P-selectin only partially addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Expanded the expression repertoire of E-selectin beyond endothelium, showing reverse signalling through membrane TNF-α induces it on activated T cells.\",\n      \"evidence\": \"Membrane TNF-α cross-linking, protease-resistant mutant transfection, and CD62E mRNA/flow analysis in T cells\",\n      \"pmids\": [\"11123285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of T-cell-expressed E-selectin unclear\", \"Signalling pathway from membrane TNF-α not detailed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked E-selectin induction to tumor-vascular crosstalk, showing VEGF/VEGF-R2/NF-κB-driven CD62E mediates progenitor cell homing to gliomas.\",\n      \"evidence\": \"Brain endothelial induction assays, NF-κB promoter-reporter, in vivo neutralizing antibody in orthotopic glioma, and transmigration assays\",\n      \"pmids\": [\"18689869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Glycan ligand on homing progenitors not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected E-selectin to cancer cell extravasation, identifying CD15/sialyl-Lewis X as the partner mediating tumor adhesion to brain endothelium under flow.\",\n      \"evidence\": \"Adhesion assays under physiological shear with CD15-blocking mAb and brain metastasis tissue validation\",\n      \"pmids\": [\"26472821\", \"28698503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution to actual transmigration/metastasis in vivo not fully established\", \"Other tumor glycan ligands not excluded\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a non-leukocyte ligand and signalling axis, showing ITGA11 on CAFs engages E-selectin to drive SRC–VEGFR3–MAPK lymphangiogenic signalling and metastasis.\",\n      \"evidence\": \"scRNA-seq, spatial transcriptomics, CAF-specific knockout mouse, pathway dissection, and a multicenter clinical cohort\",\n      \"pmids\": [\"38428409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ITGA11–SELE binding interface not structurally defined\", \"Whether glycan-dependent or protein-protein contact unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How E-selectin tethering integrates with subsequent integrin-dependent firm adhesion, and the structural basis for its ligand and ITGA11 engagement, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-crystal structure of the lectin domain with sLex/sLea in the corpus\", \"Mechanism of the hand-off to inside-out integrin activation undefined\", \"Glycan vs protein basis of the ITGA11–SELE interaction unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3, 4, 9, 11, 23]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 9, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SELL\", \"ITGA11\", \"FUT9\", \"TNFRSF1A\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}