{"gene":"SELL","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1989,"finding":"L-selectin (LAM-1/SELL) is a cell surface glycoprotein with a multi-domain architecture: an amino-terminal lectin-like domain, an EGF-like domain, and two short consensus repeat units homologous to C3/C4 binding proteins; its amino acid sequence is 77% homologous to the mouse lymphocyte homing receptor MEL-14, establishing it as the human orthologue involved in lymphocyte adhesion.","method":"cDNA cloning, sequence analysis, chromosomal localization","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — primary structural characterization by cDNA cloning with sequence homology analysis, foundational paper replicated across multiple subsequent studies","pmids":["2473156"],"is_preprint":false},{"year":1989,"finding":"The human Leu-8 antigen (L-selectin/SELL) is the human homologue of the murine MEL-14 lymph node homing receptor and can adopt both conventional transmembrane and phospholipid-anchored forms.","method":"cDNA cloning, functional expression, antigen identity comparison","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct molecular identification with functional validation, independently confirmed by multiple labs","pmids":["2509939"],"is_preprint":false},{"year":1990,"finding":"The LYAM-1 gene encoding L-selectin spans >30 kb, is composed of at least 10 exons: exon IV encodes the lectin-like domain, exon V the EGF-like domain, exons VI–VII the short consensus repeats, exon VIII the transmembrane region, and exons IX–X the cytoplasmic tail. A single major protein product is expressed by both lymphocytes and neutrophils; no evidence for phosphatidylinositol-anchored isoforms was found in either cell type.","method":"Genomic DNA cloning, exon mapping, primer extension, sequencing of neutrophil and lymphocyte cDNA, PNH patient analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct genomic characterization with multiple orthogonal methods (sequencing, primer extension, PNH controls)","pmids":["1692315"],"is_preprint":false},{"year":1990,"finding":"L-selectin (LAM-1) mediates lymphocyte binding to peripheral lymph node high endothelial venules (HEV); PMA-induced loss of LAM-1 from the lymphocyte surface correlates with loss of HEV-binding ability, establishing LAM-1 surface expression as necessary for lymphocyte homing.","method":"Anti-LAM-1 monoclonal antibody blocking of HEV binding; flow cytometry of surface expression after PMA stimulation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional blocking antibody experiments replicated across multiple labs in concurrent papers","pmids":["1688580"],"is_preprint":false},{"year":1991,"finding":"LAM-1 (L-selectin/SELL) mediates approximately 50% of the initial attachment of both lymphocytes and neutrophils to TNF-activated endothelium under nonstatic (rotating) conditions at 4°C and is required for optimal neutrophil transendothelial migration. Adhesion requires an inducible, neuraminidase-sensitive carbohydrate-containing ligand on activated endothelium, induced by LPS, TNF-α, and IL-1β.","method":"In vitro adhesion assay with anti-LAM-1 blocking antibodies under rotating and static conditions; videomicroscopic transmigration assay; neuraminidase treatment of endothelial cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays (adhesion, transmigration, enzyme treatment) with blocking antibody controls, replicated across labs","pmids":["1717567"],"is_preprint":false},{"year":1991,"finding":"Leukocyte activation by lineage-specific stimuli dramatically increases the affinity of L-selectin (LAM-1) for its carbohydrate-based ligand PPME (phosphomannan monoester core polysaccharide), directly influencing leukocyte migration. This activation-dependent increase in affinity was distinct for lymphocytes and neutrophils.","method":"PPME binding assay on activated vs. resting lymphocytes and neutrophils; HEV binding assay with physiological stimuli","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct ligand-binding assay with functional HEV-binding readout, published in Nature with clear mechanistic interpretation","pmids":["1705015"],"is_preprint":false},{"year":1991,"finding":"The lectin domain of LAM-1 is necessary and sufficient for carbohydrate (PPME/fucoidin) binding. The EGF domain contains an epitope (LAM1-1) that, when engaged by antibody, enhances carbohydrate binding, suggesting cooperativity between the lectin and EGF domains. The LAM1-3 blocking epitope maps to the lectin domain and overlaps the carbohydrate-binding site; the LAM1-6 epitope is also in the lectin domain but does not affect carbohydrate binding.","method":"Chimeric selectin construction (LAM-1/PADGEM domain swaps), PPME/fucoidin binding assays, mAb epitope mapping, lymphocyte-HEV adhesion blocking","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain mapping by chimeric protein reconstitution combined with functional carbohydrate-binding and adhesion assays","pmids":["1712791"],"is_preprint":false},{"year":1991,"finding":"L-selectin (LAM-1) is shed from the cell surface upon leukocyte activation by a proteolytic cleavage mechanism; shedding is decreased by protein kinase C (PKC) inhibitors, implicating PKC signaling in regulation of shedding. Soluble LAM-1 appears in culture medium concurrent with loss from the cell surface.","method":"Flow cytometry of surface LAM-1 after PMA stimulation; detection of soluble LAM-1 in culture supernatants; PKC inhibitor experiments","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical detection of shed protein with pharmacological inhibitor evidence, replicated across normal and malignant cells","pmids":["1709244"],"is_preprint":false},{"year":1990,"finding":"Neutrophil L-selectin (Leu-8) has a higher and more variable molecular weight (70–120 kDa) compared to lymphocyte Leu-8 (70 kDa), consistent with differential glycosylation. During neutrophil activation, L-selectin is released from the membrane (not internalized), indicating proteolytic shedding as the mechanism of surface loss. Neutrophil L-selectin has a conventional transmembrane anchor (not PI-linked), as demonstrated by normal expression in a PNH patient.","method":"SDS-PAGE/immunoblotting, 125I-antibody tracking during activation, PI-PLC treatment, PNH patient analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical characterization by multiple orthogonal methods (SDS-PAGE, radiolabeling, enzyme treatment, genetic disease control)","pmids":["1701670"],"is_preprint":false},{"year":1991,"finding":"L-selectin on neutrophils (LECAM-1) and ELAM-1 on endothelium operate in the same CD18-independent adhesion pathway; anti-LECAM-1 inhibits neutrophil binding to ELAM-1-transfected L cells, suggesting LECAM-1 and ELAM-1 can function as a receptor–counterreceptor pair.","method":"Blocking antibody adhesion assays, ELAM-1-transfected L-cell adhesion assay, anti-ELAM-1 and anti-LECAM-1 combination inhibition","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transfected cell line adhesion assay with blocking antibodies from one lab; receptor-counterreceptor interpretation is functional but indirect","pmids":["1713515"],"is_preprint":false},{"year":1992,"finding":"L-selectin (LAM-1) on neutrophils, monocytes, and lymphocytes mediates initial attachment to TNF-activated kidney glomerular endothelial cells through a neuraminidase-sensitive, mannose-6-phosphate-inhibitable ligand whose induction requires RNA and protein synthesis, establishing that glomerular endothelium expresses an inducible L-selectin ligand analogous to those on HEV and large vessel endothelium.","method":"Anti-LAM-1 antibody blocking assay, L-selectin-cDNA-transfected pre-B cell adhesion assay, neuraminidase/inhibitor treatment, RNA/protein synthesis inhibitor experiments","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — transfected cell line adhesion assay plus multiple pharmacological dissections with functional blocking antibody, multiple orthogonal approaches","pmids":["1382103"],"is_preprint":false},{"year":1992,"finding":"L-selectin (Leu-8) physically associates with the TCR/CD3 complex on human T cells: co-immunoprecipitation under mild detergent conditions co-purifies the TCR α, β, γ, δ, ε, and ζ chains with Leu-8, and on average ~18% of the TCR/CD3 complex associates with Leu-8. Cross-linking Leu-8 with OKT3 markedly augments T cell proliferation, indicating functional cooperativity.","method":"Co-immunoprecipitation with surface radioiodination, 1D and 2D diagonal SDS-PAGE, immunoblotting with anti-zeta peptide antibody, T cell proliferation assay with immobilized antibodies","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with multiple biochemical validation steps but single lab; functional readout supports physical association","pmids":["1371790"],"is_preprint":false},{"year":1991,"finding":"Cross-linking L-selectin (Leu-8) on B cells with immobilized anti-Leu-8 antibody directly inhibits immunoglobulin differentiation/secretion (IgM and IgG) without affecting B cell proliferation, IL-2R expression, or c-myc mRNA levels, demonstrating that L-selectin transduces a selective differentiation-inhibitory signal in B cells.","method":"Anti-Leu-8 antibody cross-linking, B cell Ig secretion assay (ELISA), proliferation assay, mRNA analysis, cytokine rescue experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional signaling assay with multiple controls ruling out indirect mechanisms, single lab","pmids":["1701799"],"is_preprint":false},{"year":1985,"finding":"L-selectin (Leu-8) down-regulation during lymphocyte activation with PMA occurs rapidly; CD4+,Leu-8+ T cells mediate suppression of pokeweed mitogen-induced immunoglobulin synthesis, establishing a functional role for the Leu-8+ subset in immunoregulation.","method":"Flow cytometry of surface Leu-8 after stimulation; functional suppression assay of PWM-induced Ig synthesis with CD4+ T cell subsets","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional lymphocyte subset assay with direct surface phenotype-function correlation, single lab but replicated in subsequent papers","pmids":["3156924"],"is_preprint":false},{"year":1990,"finding":"Rapid down-regulation of L-selectin (Leu-8/TQ1) surface expression by PMA is mediated via protein kinase C (blocked by H7, a PKC inhibitor), while calcium ionophore-induced down-regulation is PKC-independent. NK cell Leu-8 expression is sensitive to PMA but not to calcium ionophore A23187, revealing cell-type-specific regulation.","method":"Flow cytometry after stimulation with PMA, calcium ionophore, PKC inhibitor (H7); comparison across T, B, and NK cells","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection with PKC inhibitor, multiple cell types, single lab","pmids":["1702752"],"is_preprint":false},{"year":1991,"finding":"Supernatants from activated CD4+,Leu-8+ T cells suppress B cell Ig production without affecting B cell proliferation; the suppressive activity is protease-sensitive and elutes by HPLC at ~44 kDa and ~12 kDa, indicating that L-selectin-bearing T cells secrete soluble immunosuppressive factors.","method":"Supernatant transfer experiments, protease treatment, HPLC fractionation, B cell Ig secretion and proliferation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation of secreted factors with functional readout, single lab, two orthogonal methods","pmids":["1711071"],"is_preprint":false},{"year":1991,"finding":"L-selectin functional domains are evolutionarily conserved: anti-LAM-1 mAbs that block lymphocyte binding to HEV in humans also block this function in rhesus monkey and dog, and PPME-binding activity correlates with antibody reactivity across multiple mammalian species.","method":"Species cross-reactivity of mAb panel; PPME binding assay across species; HEV adhesion blocking in primate and dog","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-species functional analysis with well-characterized mAb panel, single lab","pmids":["1713609"],"is_preprint":false},{"year":1985,"finding":"Treatment of B cells with anti-IgM plus B cell growth factor induces loss of Leu-8 (L-selectin) expression, and only Leu-8− B cells contain antibody-forming cell precursors in response to PWM plus T cells, linking Leu-8 down-regulation to antigen-driven B cell differentiation.","method":"Functional assays (PWM-stimulated PFC), surface phenotyping, in vitro activation with anti-IgM/BCGF","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional B cell differentiation assay correlated with surface phenotype, single lab","pmids":["3920308"],"is_preprint":false},{"year":1992,"finding":"Complement activation during hemodialysis with cellulosic membranes causes a ~2-fold decrease in L-selectin (LAM-1) surface expression on granulocytes concurrent with a ~4-fold increase in MAC-1 (CD11b/CD18) expression; granulocytes with high MAC-1 / low LAM-1 expression have significantly decreased adherence to endothelial cell monolayers, linking LAM-1 shedding to altered leukocyte adhesive function.","method":"Flow cytometry of granulocyte surface receptors; endothelial cell adherence assay; randomized crossover clinical study","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional adhesion readout correlated with receptor down-regulation in a controlled crossover study","pmids":["1372668"],"is_preprint":false},{"year":1991,"finding":"Lamina propria lymphocytes (LPL) are Leu-8 (L-selectin)-negative; LPL lack Leu-8 mRNA and do not re-express Leu-8 after in vitro culture or PMA treatment, indicating they are derived from circulating Leu-8-negative lymphocytes rather than representing recently activated Leu-8-positive cells. Leu-8-negative peripheral blood and LPL lymphocytes show partial methylation of an MspI site near the Leu-8 gene, consistent with prior but not current transcriptional activity.","method":"Northern blot for Leu-8 mRNA, flow cytometry, in vitro culture/re-expression experiments, Southern blot/methylation analysis","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal molecular methods (mRNA, methylation, surface expression) in single lab establishing tissue-specific regulation","pmids":["2044931"],"is_preprint":false},{"year":2026,"finding":"In a rat model of chronic thromboembolic pulmonary hypertension, the Sell (L-selectin)–Podxl (podocalyxin) ligand–receptor pair mediates immune cell–endothelial cell interactions specifically in diseased animals; L-selectin promotes neutrophil adhesion and dysfunction in both pulmonary arterial and microvascular endothelial cells, and knockdown of PODXL reverses these effects.","method":"Single-cell RNA sequencing, immunofluorescence, PODXL knockdown cell-based experiments, rat CTEPH model","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ligand-receptor pair identified by scRNA-seq with functional validation by knockdown, single lab, model organism","pmids":["41568451"],"is_preprint":false}],"current_model":"L-selectin (SELL/CD62L) is a transmembrane lectin-family adhesion molecule whose lectin domain directly binds carbohydrate ligands (including sialylated, sulfated structures mimicked by PPME/fucoidin) on inducible endothelial counter-receptors, mediating initial tethering of lymphocytes to peripheral lymph node HEV and of neutrophils/monocytes to activated vascular and glomerular endothelium; the EGF domain cooperatively modulates ligand-binding affinity; leukocyte activation triggers PKC-dependent proteolytic shedding of L-selectin from the cell surface, rapidly reducing adhesive capacity; beyond adhesion, L-selectin physically associates with the TCR/CD3 complex and transduces signals that suppress B cell immunoglobulin differentiation and enhance T cell activation, while CD4+,Leu-8+ T cells secrete protease-sensitive soluble factors (~44 and ~12 kDa) that selectively inhibit B cell Ig production without affecting proliferation."},"narrative":{"mechanistic_narrative":"L-selectin (SELL/CD62L/LAM-1/Leu-8) is a leukocyte transmembrane adhesion glycoprotein that mediates the initial tethering of circulating lymphocytes, neutrophils, and monocytes to inducible endothelial ligands and thereby governs leukocyte homing and recruitment [PMID:2473156, PMID:1688580, PMID:1382103]. The protein is built from an N-terminal lectin-like domain, an EGF-like domain, and two short consensus repeats homologous to complement-binding proteins, and is the human orthologue of the murine MEL-14 homing receptor [PMID:2473156]. The lectin domain is necessary and sufficient for binding sialylated, sulfated carbohydrate ligands (mimicked by PPME and fucoidin), while antibody engagement of the EGF domain enhances this binding, indicating cooperativity between the two domains [PMID:1712791]. Functionally, L-selectin mediates roughly half of the initial leukocyte attachment to TNF-activated endothelium and is required for optimal neutrophil transendothelial migration, recognizing an inducible, neuraminidase-sensitive carbohydrate ligand whose expression is driven by LPS, TNF-α, and IL-1β on both large-vessel and glomerular endothelium [PMID:1717567, PMID:1382103]; it can pair with endothelial ELAM-1 as a counter-receptor [PMID:1713515]. Leukocyte activation rapidly increases L-selectin's affinity for ligand and then triggers PKC-dependent proteolytic shedding of the molecule from the cell surface, releasing soluble L-selectin and reducing adhesive capacity [PMID:1705015, PMID:1709244, PMID:1702752]. Beyond adhesion, L-selectin physically associates with the TCR/CD3 complex and acts as a signaling receptor: cross-linking augments T cell proliferation but transduces a selective inhibitory signal that blocks B cell immunoglobulin differentiation without affecting proliferation [PMID:1371790, PMID:1701799]. In a rat model of chronic thromboembolic pulmonary hypertension, L-selectin pairs with endothelial podocalyxin (PODXL) to drive disease-specific neutrophil–endothelial adhesion [PMID:41568451].","teleology":[{"year":1989,"claim":"Establishing the molecular identity and domain architecture of human L-selectin defined it as a multi-domain lectin adhesion receptor and the human counterpart of the murine MEL-14 homing receptor.","evidence":"cDNA cloning, sequence/homology analysis and functional expression","pmids":["2473156","2509939"],"confidence":"High","gaps":["Did not resolve which carbohydrate structures the lectin domain recognizes","Conflicting early claims about PI-anchored versus transmembrane forms"]},{"year":1990,"claim":"Genomic mapping assigned each functional domain to discrete exons and resolved the isoform question, showing a single major transmembrane product in both lymphocytes and neutrophils.","evidence":"Genomic cloning, exon mapping, primer extension, and PNH patient controls","pmids":["1692315","1701670"],"confidence":"High","gaps":["Glycosylation differences between neutrophil and lymphocyte forms not mechanistically explained","Did not identify the protease responsible for shedding"]},{"year":1990,"claim":"Linking surface L-selectin expression to HEV-binding capacity established that the receptor is required for lymphocyte homing and that activation-induced loss disables adhesion.","evidence":"Anti-LAM-1 blocking antibodies and flow cytometry after PMA stimulation","pmids":["1688580"],"confidence":"High","gaps":["Mechanism of PMA-induced surface loss not yet defined","Endothelial ligand not molecularly identified"]},{"year":1991,"claim":"Mapping the carbohydrate-binding function to the lectin domain and demonstrating EGF-domain cooperativity defined the structural basis of ligand recognition.","evidence":"Chimeric selectin domain swaps, PPME/fucoidin binding assays, and mAb epitope mapping","pmids":["1712791"],"confidence":"High","gaps":["Physiological endothelial ligand structure not defined","Molecular basis of lectin–EGF cooperativity unresolved"]},{"year":1991,"claim":"Showing that leukocyte activation raises L-selectin ligand affinity revealed an inside-out regulatory layer controlling adhesive strength independent of expression level.","evidence":"PPME binding assays on activated versus resting lymphocytes and neutrophils with HEV-binding readout","pmids":["1705015"],"confidence":"High","gaps":["Signaling pathway converting activation into affinity change not defined","Distinct lymphocyte/neutrophil mechanisms not resolved"]},{"year":1991,"claim":"Demonstrating that activation triggers PKC-dependent proteolytic shedding established the mechanism by which leukocytes rapidly downregulate adhesion and generate soluble L-selectin.","evidence":"Flow cytometry, soluble L-selectin detection in supernatants, and PKC inhibitor (H7) experiments across cell types","pmids":["1709244","1702752"],"confidence":"High","gaps":["Identity of the sheddase protease not determined","PKC-independent calcium-ionophore pathway mechanism unknown"]},{"year":1991,"claim":"Identifying inducible endothelial ligands and the L-selectin–ELAM-1 counter-receptor relationship placed the molecule in a CD18-independent neutrophil adhesion pathway.","evidence":"Blocking antibody adhesion assays and ELAM-1-transfected L-cell adhesion experiments","pmids":["1713515"],"confidence":"Medium","gaps":["Receptor-counterreceptor interpretation is indirect from one lab","Direct biochemical L-selectin–ELAM-1 binding not shown"]},{"year":1992,"claim":"Extending ligand recognition to TNF-activated glomerular endothelium showed L-selectin engages inducible, sialylated, mannose-6-phosphate-inhibitable ligands across multiple endothelial beds.","evidence":"Anti-LAM-1 blocking, L-selectin-cDNA-transfected pre-B cell adhesion, neuraminidase/inhibitor and RNA/protein synthesis inhibitor treatments","pmids":["1382103"],"confidence":"High","gaps":["Molecular identity of the glomerular endothelial ligand not defined","In vivo relevance to renal inflammation not tested"]},{"year":1992,"claim":"Discovery that L-selectin physically associates with the TCR/CD3 complex and modulates T cell proliferation revealed a signaling role beyond adhesion.","evidence":"Co-immunoprecipitation with surface radioiodination, 2D diagonal SDS-PAGE, and T cell proliferation assays","pmids":["1371790"],"confidence":"Medium","gaps":["Single-lab co-IP without reciprocal independent validation","Downstream signaling pathway not mapped"]},{"year":1991,"claim":"Defining an L-selectin-transduced, differentiation-selective inhibitory signal in B cells, together with secretion of soluble suppressive factors by Leu-8+ T cells, established a immunoregulatory function for the molecule.","evidence":"Anti-Leu-8 cross-linking with B cell Ig secretion/proliferation/mRNA assays; supernatant transfer, protease treatment, and HPLC fractionation","pmids":["1701799","1711071","3156924","3920308"],"confidence":"Medium","gaps":["Molecular identities of the ~44 and ~12 kDa soluble factors not determined","Signaling intermediates downstream of L-selectin cross-linking unknown"]},{"year":1992,"claim":"Correlating L-selectin shedding with reduced leukocyte adhesion in hemodialysis-induced complement activation provided in vivo confirmation that shedding alters adhesive function.","evidence":"Flow cytometry of granulocyte receptors and endothelial adherence assays in a randomized crossover clinical study","pmids":["1372668"],"confidence":"Medium","gaps":["Did not separate L-selectin loss from concurrent MAC-1 upregulation as the cause","Mechanism of complement-triggered shedding not defined"]},{"year":2026,"claim":"Identification of the L-selectin–podocalyxin ligand pair in pulmonary hypertension extended L-selectin adhesion biology into disease-specific neutrophil–endothelial interactions and a candidate intervention point.","evidence":"Single-cell RNA sequencing, immunofluorescence, and PODXL knockdown in a rat CTEPH model","pmids":["41568451"],"confidence":"Medium","gaps":["Direct L-selectin–PODXL binding not biochemically demonstrated","Findings limited to a rat model"]},{"year":null,"claim":"The molecular identity of the physiological inducible endothelial carbohydrate ligands and the identity of the activation-regulated sheddase remain unresolved.","evidence":"No discovery in the timeline isolates the native HEV/glomerular ligand or the responsible protease","pmids":[],"confidence":"Low","gaps":["Native endothelial ligand structures not defined","Sheddase enzyme not identified","Signaling pathway linking the cytoplasmic tail to function not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,4,9,10,20]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[11,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,3,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4,10,12]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,9,20]}],"complexes":["TCR/CD3 complex"],"partners":["CD3","ELAM-1","PODXL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14151","full_name":"L-selectin","aliases":["CD62 antigen-like family member L","Leukocyte adhesion molecule 1","LAM-1","Leukocyte surface antigen Leu-8","Leukocyte-endothelial cell adhesion molecule 1","LECAM1","Lymph node homing receptor","TQ1","gp90-MEL"],"length_aa":372,"mass_kda":42.2,"function":"Calcium-dependent lectin that mediates cell adhesion by binding to glycoproteins on neighboring cells (PubMed:12403782, PubMed:28011641, PubMed:28489325). Mediates the adherence of lymphocytes to endothelial cells of high endothelial venules in peripheral lymph nodes. Promotes initial tethering and rolling of leukocytes in endothelia (PubMed:12403782, PubMed:28011641)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P14151/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SELL","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/SELL","total_profiled":1310},"omim":[{"mim_id":"620073","title":"NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND SKELETAL AND BRAIN ABNORMALITIES; NEDDFSB","url":"https://www.omim.org/entry/620073"},{"mim_id":"617873","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 35; COXPD35","url":"https://www.omim.org/entry/617873"},{"mim_id":"617840","title":"tRNA ISOPENTENYLTRANSFERASE 1; TRIT1","url":"https://www.omim.org/entry/617840"},{"mim_id":"616627","title":"PODOCALYXIN-LIKE 2; PODXL2","url":"https://www.omim.org/entry/616627"},{"mim_id":"614388","title":"ENCEPHALOPATHY DUE TO DEFECTIVE MITOCHONDRIAL AND PEROXISOMAL FISSION 1; EMPF1","url":"https://www.omim.org/entry/614388"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":142.1},{"tissue":"lymphoid tissue","ntpm":216.7}],"url":"https://www.proteinatlas.org/search/SELL"},"hgnc":{"alias_symbol":["LSEL","LAM1","LAM-1","hLHRc","Leu-8","Lyam-1","PLNHR","CD62L"],"prev_symbol":["LYAM1","LNHR"]},"alphafold":{"accession":"P14151","domains":[{"cath_id":"3.10.100.10","chopping":"41-158","consensus_level":"high","plddt":94.9506,"start":41,"end":158},{"cath_id":"2.10.70.10","chopping":"207-257","consensus_level":"high","plddt":97.66,"start":207,"end":257},{"cath_id":"2.10.70.10","chopping":"269-323","consensus_level":"high","plddt":93.3829,"start":269,"end":323}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14151","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14151-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14151-F1-predicted_aligned_error_v6.png","plddt_mean":85.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SELL","jax_strain_url":"https://www.jax.org/strain/search?query=SELL"},"sequence":{"accession":"P14151","fasta_url":"https://rest.uniprot.org/uniprotkb/P14151.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14151/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14151"}},"corpus_meta":[{"pmid":"1717567","id":"PMC_1717567","title":"Leukocyte adhesion molecule-1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion.","date":"1991","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1717567","citation_count":384,"is_preprint":false},{"pmid":"2473156","id":"PMC_2473156","title":"Isolation and chromosomal localization of cDNAs encoding a novel human lymphocyte cell surface molecule, LAM-1. Homology with the mouse lymphocyte homing receptor and other human adhesion proteins.","date":"1989","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2473156","citation_count":334,"is_preprint":false},{"pmid":"2509939","id":"PMC_2509939","title":"Leu-8/TQ1 is the human equivalent of the Mel-14 lymph node homing receptor.","date":"1989","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2509939","citation_count":292,"is_preprint":false},{"pmid":"1705015","id":"PMC_1705015","title":"Regulation of leukocyte migration by activation of the leukocyte adhesion molecule-1 (LAM-1) selectin.","date":"1991","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1705015","citation_count":289,"is_preprint":false},{"pmid":"1688580","id":"PMC_1688580","title":"Expression of the human leukocyte adhesion molecule, LAM1. 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Epidemiology].","date":"2006","source":"Fogorvosi szemle","url":"https://pubmed.ncbi.nlm.nih.gov/17016924","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46999,"output_tokens":5324,"usd":0.110428,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13824,"output_tokens":3955,"usd":0.083998,"stage2_stop_reason":"end_turn"},"total_usd":0.194426,"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\": 1989,\n      \"finding\": \"L-selectin (LAM-1/SELL) is a cell surface glycoprotein with a multi-domain architecture: an amino-terminal lectin-like domain, an EGF-like domain, and two short consensus repeat units homologous to C3/C4 binding proteins; its amino acid sequence is 77% homologous to the mouse lymphocyte homing receptor MEL-14, establishing it as the human orthologue involved in lymphocyte adhesion.\",\n      \"method\": \"cDNA cloning, sequence analysis, chromosomal localization\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — primary structural characterization by cDNA cloning with sequence homology analysis, foundational paper replicated across multiple subsequent studies\",\n      \"pmids\": [\"2473156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"The human Leu-8 antigen (L-selectin/SELL) is the human homologue of the murine MEL-14 lymph node homing receptor and can adopt both conventional transmembrane and phospholipid-anchored forms.\",\n      \"method\": \"cDNA cloning, functional expression, antigen identity comparison\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct molecular identification with functional validation, independently confirmed by multiple labs\",\n      \"pmids\": [\"2509939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The LYAM-1 gene encoding L-selectin spans >30 kb, is composed of at least 10 exons: exon IV encodes the lectin-like domain, exon V the EGF-like domain, exons VI–VII the short consensus repeats, exon VIII the transmembrane region, and exons IX–X the cytoplasmic tail. A single major protein product is expressed by both lymphocytes and neutrophils; no evidence for phosphatidylinositol-anchored isoforms was found in either cell type.\",\n      \"method\": \"Genomic DNA cloning, exon mapping, primer extension, sequencing of neutrophil and lymphocyte cDNA, PNH patient analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct genomic characterization with multiple orthogonal methods (sequencing, primer extension, PNH controls)\",\n      \"pmids\": [\"1692315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"L-selectin (LAM-1) mediates lymphocyte binding to peripheral lymph node high endothelial venules (HEV); PMA-induced loss of LAM-1 from the lymphocyte surface correlates with loss of HEV-binding ability, establishing LAM-1 surface expression as necessary for lymphocyte homing.\",\n      \"method\": \"Anti-LAM-1 monoclonal antibody blocking of HEV binding; flow cytometry of surface expression after PMA stimulation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional blocking antibody experiments replicated across multiple labs in concurrent papers\",\n      \"pmids\": [\"1688580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"LAM-1 (L-selectin/SELL) mediates approximately 50% of the initial attachment of both lymphocytes and neutrophils to TNF-activated endothelium under nonstatic (rotating) conditions at 4°C and is required for optimal neutrophil transendothelial migration. Adhesion requires an inducible, neuraminidase-sensitive carbohydrate-containing ligand on activated endothelium, induced by LPS, TNF-α, and IL-1β.\",\n      \"method\": \"In vitro adhesion assay with anti-LAM-1 blocking antibodies under rotating and static conditions; videomicroscopic transmigration assay; neuraminidase treatment of endothelial cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays (adhesion, transmigration, enzyme treatment) with blocking antibody controls, replicated across labs\",\n      \"pmids\": [\"1717567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Leukocyte activation by lineage-specific stimuli dramatically increases the affinity of L-selectin (LAM-1) for its carbohydrate-based ligand PPME (phosphomannan monoester core polysaccharide), directly influencing leukocyte migration. This activation-dependent increase in affinity was distinct for lymphocytes and neutrophils.\",\n      \"method\": \"PPME binding assay on activated vs. resting lymphocytes and neutrophils; HEV binding assay with physiological stimuli\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct ligand-binding assay with functional HEV-binding readout, published in Nature with clear mechanistic interpretation\",\n      \"pmids\": [\"1705015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The lectin domain of LAM-1 is necessary and sufficient for carbohydrate (PPME/fucoidin) binding. The EGF domain contains an epitope (LAM1-1) that, when engaged by antibody, enhances carbohydrate binding, suggesting cooperativity between the lectin and EGF domains. The LAM1-3 blocking epitope maps to the lectin domain and overlaps the carbohydrate-binding site; the LAM1-6 epitope is also in the lectin domain but does not affect carbohydrate binding.\",\n      \"method\": \"Chimeric selectin construction (LAM-1/PADGEM domain swaps), PPME/fucoidin binding assays, mAb epitope mapping, lymphocyte-HEV adhesion blocking\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain mapping by chimeric protein reconstitution combined with functional carbohydrate-binding and adhesion assays\",\n      \"pmids\": [\"1712791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"L-selectin (LAM-1) is shed from the cell surface upon leukocyte activation by a proteolytic cleavage mechanism; shedding is decreased by protein kinase C (PKC) inhibitors, implicating PKC signaling in regulation of shedding. Soluble LAM-1 appears in culture medium concurrent with loss from the cell surface.\",\n      \"method\": \"Flow cytometry of surface LAM-1 after PMA stimulation; detection of soluble LAM-1 in culture supernatants; PKC inhibitor experiments\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical detection of shed protein with pharmacological inhibitor evidence, replicated across normal and malignant cells\",\n      \"pmids\": [\"1709244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Neutrophil L-selectin (Leu-8) has a higher and more variable molecular weight (70–120 kDa) compared to lymphocyte Leu-8 (70 kDa), consistent with differential glycosylation. During neutrophil activation, L-selectin is released from the membrane (not internalized), indicating proteolytic shedding as the mechanism of surface loss. Neutrophil L-selectin has a conventional transmembrane anchor (not PI-linked), as demonstrated by normal expression in a PNH patient.\",\n      \"method\": \"SDS-PAGE/immunoblotting, 125I-antibody tracking during activation, PI-PLC treatment, PNH patient analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical characterization by multiple orthogonal methods (SDS-PAGE, radiolabeling, enzyme treatment, genetic disease control)\",\n      \"pmids\": [\"1701670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"L-selectin on neutrophils (LECAM-1) and ELAM-1 on endothelium operate in the same CD18-independent adhesion pathway; anti-LECAM-1 inhibits neutrophil binding to ELAM-1-transfected L cells, suggesting LECAM-1 and ELAM-1 can function as a receptor–counterreceptor pair.\",\n      \"method\": \"Blocking antibody adhesion assays, ELAM-1-transfected L-cell adhesion assay, anti-ELAM-1 and anti-LECAM-1 combination inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transfected cell line adhesion assay with blocking antibodies from one lab; receptor-counterreceptor interpretation is functional but indirect\",\n      \"pmids\": [\"1713515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"L-selectin (LAM-1) on neutrophils, monocytes, and lymphocytes mediates initial attachment to TNF-activated kidney glomerular endothelial cells through a neuraminidase-sensitive, mannose-6-phosphate-inhibitable ligand whose induction requires RNA and protein synthesis, establishing that glomerular endothelium expresses an inducible L-selectin ligand analogous to those on HEV and large vessel endothelium.\",\n      \"method\": \"Anti-LAM-1 antibody blocking assay, L-selectin-cDNA-transfected pre-B cell adhesion assay, neuraminidase/inhibitor treatment, RNA/protein synthesis inhibitor experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transfected cell line adhesion assay plus multiple pharmacological dissections with functional blocking antibody, multiple orthogonal approaches\",\n      \"pmids\": [\"1382103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"L-selectin (Leu-8) physically associates with the TCR/CD3 complex on human T cells: co-immunoprecipitation under mild detergent conditions co-purifies the TCR α, β, γ, δ, ε, and ζ chains with Leu-8, and on average ~18% of the TCR/CD3 complex associates with Leu-8. Cross-linking Leu-8 with OKT3 markedly augments T cell proliferation, indicating functional cooperativity.\",\n      \"method\": \"Co-immunoprecipitation with surface radioiodination, 1D and 2D diagonal SDS-PAGE, immunoblotting with anti-zeta peptide antibody, T cell proliferation assay with immobilized antibodies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with multiple biochemical validation steps but single lab; functional readout supports physical association\",\n      \"pmids\": [\"1371790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Cross-linking L-selectin (Leu-8) on B cells with immobilized anti-Leu-8 antibody directly inhibits immunoglobulin differentiation/secretion (IgM and IgG) without affecting B cell proliferation, IL-2R expression, or c-myc mRNA levels, demonstrating that L-selectin transduces a selective differentiation-inhibitory signal in B cells.\",\n      \"method\": \"Anti-Leu-8 antibody cross-linking, B cell Ig secretion assay (ELISA), proliferation assay, mRNA analysis, cytokine rescue experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional signaling assay with multiple controls ruling out indirect mechanisms, single lab\",\n      \"pmids\": [\"1701799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"L-selectin (Leu-8) down-regulation during lymphocyte activation with PMA occurs rapidly; CD4+,Leu-8+ T cells mediate suppression of pokeweed mitogen-induced immunoglobulin synthesis, establishing a functional role for the Leu-8+ subset in immunoregulation.\",\n      \"method\": \"Flow cytometry of surface Leu-8 after stimulation; functional suppression assay of PWM-induced Ig synthesis with CD4+ T cell subsets\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional lymphocyte subset assay with direct surface phenotype-function correlation, single lab but replicated in subsequent papers\",\n      \"pmids\": [\"3156924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Rapid down-regulation of L-selectin (Leu-8/TQ1) surface expression by PMA is mediated via protein kinase C (blocked by H7, a PKC inhibitor), while calcium ionophore-induced down-regulation is PKC-independent. NK cell Leu-8 expression is sensitive to PMA but not to calcium ionophore A23187, revealing cell-type-specific regulation.\",\n      \"method\": \"Flow cytometry after stimulation with PMA, calcium ionophore, PKC inhibitor (H7); comparison across T, B, and NK cells\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection with PKC inhibitor, multiple cell types, single lab\",\n      \"pmids\": [\"1702752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Supernatants from activated CD4+,Leu-8+ T cells suppress B cell Ig production without affecting B cell proliferation; the suppressive activity is protease-sensitive and elutes by HPLC at ~44 kDa and ~12 kDa, indicating that L-selectin-bearing T cells secrete soluble immunosuppressive factors.\",\n      \"method\": \"Supernatant transfer experiments, protease treatment, HPLC fractionation, B cell Ig secretion and proliferation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation of secreted factors with functional readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"1711071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"L-selectin functional domains are evolutionarily conserved: anti-LAM-1 mAbs that block lymphocyte binding to HEV in humans also block this function in rhesus monkey and dog, and PPME-binding activity correlates with antibody reactivity across multiple mammalian species.\",\n      \"method\": \"Species cross-reactivity of mAb panel; PPME binding assay across species; HEV adhesion blocking in primate and dog\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-species functional analysis with well-characterized mAb panel, single lab\",\n      \"pmids\": [\"1713609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Treatment of B cells with anti-IgM plus B cell growth factor induces loss of Leu-8 (L-selectin) expression, and only Leu-8− B cells contain antibody-forming cell precursors in response to PWM plus T cells, linking Leu-8 down-regulation to antigen-driven B cell differentiation.\",\n      \"method\": \"Functional assays (PWM-stimulated PFC), surface phenotyping, in vitro activation with anti-IgM/BCGF\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional B cell differentiation assay correlated with surface phenotype, single lab\",\n      \"pmids\": [\"3920308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Complement activation during hemodialysis with cellulosic membranes causes a ~2-fold decrease in L-selectin (LAM-1) surface expression on granulocytes concurrent with a ~4-fold increase in MAC-1 (CD11b/CD18) expression; granulocytes with high MAC-1 / low LAM-1 expression have significantly decreased adherence to endothelial cell monolayers, linking LAM-1 shedding to altered leukocyte adhesive function.\",\n      \"method\": \"Flow cytometry of granulocyte surface receptors; endothelial cell adherence assay; randomized crossover clinical study\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional adhesion readout correlated with receptor down-regulation in a controlled crossover study\",\n      \"pmids\": [\"1372668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Lamina propria lymphocytes (LPL) are Leu-8 (L-selectin)-negative; LPL lack Leu-8 mRNA and do not re-express Leu-8 after in vitro culture or PMA treatment, indicating they are derived from circulating Leu-8-negative lymphocytes rather than representing recently activated Leu-8-positive cells. Leu-8-negative peripheral blood and LPL lymphocytes show partial methylation of an MspI site near the Leu-8 gene, consistent with prior but not current transcriptional activity.\",\n      \"method\": \"Northern blot for Leu-8 mRNA, flow cytometry, in vitro culture/re-expression experiments, Southern blot/methylation analysis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal molecular methods (mRNA, methylation, surface expression) in single lab establishing tissue-specific regulation\",\n      \"pmids\": [\"2044931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In a rat model of chronic thromboembolic pulmonary hypertension, the Sell (L-selectin)–Podxl (podocalyxin) ligand–receptor pair mediates immune cell–endothelial cell interactions specifically in diseased animals; L-selectin promotes neutrophil adhesion and dysfunction in both pulmonary arterial and microvascular endothelial cells, and knockdown of PODXL reverses these effects.\",\n      \"method\": \"Single-cell RNA sequencing, immunofluorescence, PODXL knockdown cell-based experiments, rat CTEPH model\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ligand-receptor pair identified by scRNA-seq with functional validation by knockdown, single lab, model organism\",\n      \"pmids\": [\"41568451\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"L-selectin (SELL/CD62L) is a transmembrane lectin-family adhesion molecule whose lectin domain directly binds carbohydrate ligands (including sialylated, sulfated structures mimicked by PPME/fucoidin) on inducible endothelial counter-receptors, mediating initial tethering of lymphocytes to peripheral lymph node HEV and of neutrophils/monocytes to activated vascular and glomerular endothelium; the EGF domain cooperatively modulates ligand-binding affinity; leukocyte activation triggers PKC-dependent proteolytic shedding of L-selectin from the cell surface, rapidly reducing adhesive capacity; beyond adhesion, L-selectin physically associates with the TCR/CD3 complex and transduces signals that suppress B cell immunoglobulin differentiation and enhance T cell activation, while CD4+,Leu-8+ T cells secrete protease-sensitive soluble factors (~44 and ~12 kDa) that selectively inhibit B cell Ig production without affecting proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"L-selectin (SELL/CD62L/LAM-1/Leu-8) is a leukocyte transmembrane adhesion glycoprotein that mediates the initial tethering of circulating lymphocytes, neutrophils, and monocytes to inducible endothelial ligands and thereby governs leukocyte homing and recruitment [#0, #3, #10]. The protein is built from an N-terminal lectin-like domain, an EGF-like domain, and two short consensus repeats homologous to complement-binding proteins, and is the human orthologue of the murine MEL-14 homing receptor [#0]. The lectin domain is necessary and sufficient for binding sialylated, sulfated carbohydrate ligands (mimicked by PPME and fucoidin), while antibody engagement of the EGF domain enhances this binding, indicating cooperativity between the two domains [#6]. Functionally, L-selectin mediates roughly half of the initial leukocyte attachment to TNF-activated endothelium and is required for optimal neutrophil transendothelial migration, recognizing an inducible, neuraminidase-sensitive carbohydrate ligand whose expression is driven by LPS, TNF-\\u03b1, and IL-1\\u03b2 on both large-vessel and glomerular endothelium [#4, #10]; it can pair with endothelial ELAM-1 as a counter-receptor [#9]. Leukocyte activation rapidly increases L-selectin's affinity for ligand and then triggers PKC-dependent proteolytic shedding of the molecule from the cell surface, releasing soluble L-selectin and reducing adhesive capacity [#5, #7, #14]. Beyond adhesion, L-selectin physically associates with the TCR/CD3 complex and acts as a signaling receptor: cross-linking augments T cell proliferation but transduces a selective inhibitory signal that blocks B cell immunoglobulin differentiation without affecting proliferation [#11, #12]. In a rat model of chronic thromboembolic pulmonary hypertension, L-selectin pairs with endothelial podocalyxin (PODXL) to drive disease-specific neutrophil\\u2013endothelial adhesion [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing the molecular identity and domain architecture of human L-selectin defined it as a multi-domain lectin adhesion receptor and the human counterpart of the murine MEL-14 homing receptor.\",\n      \"evidence\": \"cDNA cloning, sequence/homology analysis and functional expression\",\n      \"pmids\": [\"2473156\", \"2509939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which carbohydrate structures the lectin domain recognizes\", \"Conflicting early claims about PI-anchored versus transmembrane forms\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Genomic mapping assigned each functional domain to discrete exons and resolved the isoform question, showing a single major transmembrane product in both lymphocytes and neutrophils.\",\n      \"evidence\": \"Genomic cloning, exon mapping, primer extension, and PNH patient controls\",\n      \"pmids\": [\"1692315\", \"1701670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycosylation differences between neutrophil and lymphocyte forms not mechanistically explained\", \"Did not identify the protease responsible for shedding\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Linking surface L-selectin expression to HEV-binding capacity established that the receptor is required for lymphocyte homing and that activation-induced loss disables adhesion.\",\n      \"evidence\": \"Anti-LAM-1 blocking antibodies and flow cytometry after PMA stimulation\",\n      \"pmids\": [\"1688580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PMA-induced surface loss not yet defined\", \"Endothelial ligand not molecularly identified\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Mapping the carbohydrate-binding function to the lectin domain and demonstrating EGF-domain cooperativity defined the structural basis of ligand recognition.\",\n      \"evidence\": \"Chimeric selectin domain swaps, PPME/fucoidin binding assays, and mAb epitope mapping\",\n      \"pmids\": [\"1712791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological endothelial ligand structure not defined\", \"Molecular basis of lectin\\u2013EGF cooperativity unresolved\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Showing that leukocyte activation raises L-selectin ligand affinity revealed an inside-out regulatory layer controlling adhesive strength independent of expression level.\",\n      \"evidence\": \"PPME binding assays on activated versus resting lymphocytes and neutrophils with HEV-binding readout\",\n      \"pmids\": [\"1705015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway converting activation into affinity change not defined\", \"Distinct lymphocyte/neutrophil mechanisms not resolved\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Demonstrating that activation triggers PKC-dependent proteolytic shedding established the mechanism by which leukocytes rapidly downregulate adhesion and generate soluble L-selectin.\",\n      \"evidence\": \"Flow cytometry, soluble L-selectin detection in supernatants, and PKC inhibitor (H7) experiments across cell types\",\n      \"pmids\": [\"1709244\", \"1702752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the sheddase protease not determined\", \"PKC-independent calcium-ionophore pathway mechanism unknown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Identifying inducible endothelial ligands and the L-selectin\\u2013ELAM-1 counter-receptor relationship placed the molecule in a CD18-independent neutrophil adhesion pathway.\",\n      \"evidence\": \"Blocking antibody adhesion assays and ELAM-1-transfected L-cell adhesion experiments\",\n      \"pmids\": [\"1713515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-counterreceptor interpretation is indirect from one lab\", \"Direct biochemical L-selectin\\u2013ELAM-1 binding not shown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Extending ligand recognition to TNF-activated glomerular endothelium showed L-selectin engages inducible, sialylated, mannose-6-phosphate-inhibitable ligands across multiple endothelial beds.\",\n      \"evidence\": \"Anti-LAM-1 blocking, L-selectin-cDNA-transfected pre-B cell adhesion, neuraminidase/inhibitor and RNA/protein synthesis inhibitor treatments\",\n      \"pmids\": [\"1382103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the glomerular endothelial ligand not defined\", \"In vivo relevance to renal inflammation not tested\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Discovery that L-selectin physically associates with the TCR/CD3 complex and modulates T cell proliferation revealed a signaling role beyond adhesion.\",\n      \"evidence\": \"Co-immunoprecipitation with surface radioiodination, 2D diagonal SDS-PAGE, and T cell proliferation assays\",\n      \"pmids\": [\"1371790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab co-IP without reciprocal independent validation\", \"Downstream signaling pathway not mapped\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Defining an L-selectin-transduced, differentiation-selective inhibitory signal in B cells, together with secretion of soluble suppressive factors by Leu-8+ T cells, established a immunoregulatory function for the molecule.\",\n      \"evidence\": \"Anti-Leu-8 cross-linking with B cell Ig secretion/proliferation/mRNA assays; supernatant transfer, protease treatment, and HPLC fractionation\",\n      \"pmids\": [\"1701799\", \"1711071\", \"3156924\", \"3920308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular identities of the ~44 and ~12 kDa soluble factors not determined\", \"Signaling intermediates downstream of L-selectin cross-linking unknown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Correlating L-selectin shedding with reduced leukocyte adhesion in hemodialysis-induced complement activation provided in vivo confirmation that shedding alters adhesive function.\",\n      \"evidence\": \"Flow cytometry of granulocyte receptors and endothelial adherence assays in a randomized crossover clinical study\",\n      \"pmids\": [\"1372668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not separate L-selectin loss from concurrent MAC-1 upregulation as the cause\", \"Mechanism of complement-triggered shedding not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of the L-selectin\\u2013podocalyxin ligand pair in pulmonary hypertension extended L-selectin adhesion biology into disease-specific neutrophil\\u2013endothelial interactions and a candidate intervention point.\",\n      \"evidence\": \"Single-cell RNA sequencing, immunofluorescence, and PODXL knockdown in a rat CTEPH model\",\n      \"pmids\": [\"41568451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct L-selectin\\u2013PODXL binding not biochemically demonstrated\", \"Findings limited to a rat model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of the physiological inducible endothelial carbohydrate ligands and the identity of the activation-regulated sheddase remain unresolved.\",\n      \"evidence\": \"No discovery in the timeline isolates the native HEV/glomerular ligand or the responsible protease\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Native endothelial ligand structures not defined\", \"Sheddase enzyme not identified\", \"Signaling pathway linking the cytoplasmic tail to function not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 4, 9, 10, 20]},\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4, 10, 12]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 9, 20]}\n    ],\n    \"complexes\": [\"TCR/CD3 complex\"],\n    \"partners\": [\"CD3\", \"ELAM-1\", \"PODXL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}