{"gene":"SPN","run_date":"2026-06-10T07:46:40","timeline":{"discoveries":[{"year":1991,"finding":"CD43 binds ICAM-1 (CD54) as a ligand, demonstrated by specific binding of Daudi cells to purified immobilized CD43 and inhibition by anti-CD43 antibodies and CD43-containing liposomes; expression of human CD43 in a murine T-cell hybridoma enhanced antigen-specific T-cell activation.","method":"Cell binding assay with purified immobilized CD43, inhibition with anti-CD43 mAb and CD43-liposomes, T-cell hybridoma transfection","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay with purified protein, inhibition controls, replicated in multiple systems; foundational paper","pmids":["1683685"],"is_preprint":false},{"year":1991,"finding":"CD43-mediated T-cell activation requires its intracellular domain (which is hyperphosphorylated during activation); expression of CD43 cDNA in antigen-responsive murine T-cell hybridoma enhanced antigen-specific activation; antigen-presenting cells bind specifically to immobilized purified CD43.","method":"cDNA transfection of CD43 and cytoplasmic domain mutants into T-cell hybridoma, purified CD43 binding assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional reconstitution with domain mutants, multiple orthogonal assays in one paper","pmids":["2023632"],"is_preprint":false},{"year":1992,"finding":"CD43 expressed on opposing cells interferes with T-cell LFA-1 binding to ICAM-1; this anti-adhesive effect is dependent on sialic acid residues on CD43, as neuraminidase treatment of CD43-positive HeLa cells diminished the effect.","method":"T-lymphocyte adhesion assay to CD43-transfected HeLa cells; antibody blocking; neuraminidase treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct adhesion assay with CD43 transfectants, neuraminidase mechanistic dissection, antibody blocking controls","pmids":["1594606"],"is_preprint":false},{"year":1989,"finding":"CD43 engagement activates phospholipase C signaling pathway in T cells and monocytes: anti-CD43 mAb L10 induced phosphoinositide hydrolysis, generating diacylglycerol and inositol phosphates, PKC translocation from cytosol to membrane, and increased intracellular Ca2+; CD43 signaling proceeds independently of TCR/CD3.","method":"Phosphoinositide hydrolysis assay, PKC translocation assay, intracellular Ca2+ measurement in PBMC, T cells, monocytes, and leukemic T cell lines","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical assays demonstrating PLC pathway activation; CD3-independence confirmed in mutant cell line","pmids":["2542404"],"is_preprint":false},{"year":1995,"finding":"CD43-deficient mice show enhanced T-cell proliferation, increased homotypic adhesion, and increased ICAM-1 and fibronectin binding, demonstrating that CD43 negatively regulates T-cell activation and adhesion; CD43-knockout mice also showed augmented anti-vaccinia CTL response but increased viral load.","method":"CD43-knockout mouse generation, in vitro proliferation assays (ConA, anti-CD3, SEB, allostimulation), adhesion assays, viral infection model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal phenotypic readouts, in vitro and in vivo","pmids":["7566153"],"is_preprint":false},{"year":1995,"finding":"CD43 functions as a CD28-independent costimulatory receptor on murine T cells; expression cloning identified murine CD43 as the antigen for mAb R2/60, which synergizes with TCR engagement to induce T-cell proliferation independently of CD28.","method":"Expression cloning, T-cell proliferation assay with anti-CD43 mAb in CD28-deficient mice","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — expression cloning identification plus functional validation in CD28-deficient mice","pmids":["7790813"],"is_preprint":false},{"year":1996,"finding":"CD43 cross-linking induces association of CD43 with Fyn kinase via Fyn's SH3 domain binding to a proline-rich sequence (300ERQPAPALPPKPPKP314) in CD43's cytoplasmic tail; CD43 cross-linking also results in Fyn tyrosine phosphorylation.","method":"Co-immunoprecipitation, GST-Fyn SH3 pulldown from T-cell lysates, synthetic peptide competition assay, tyrosine phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — GST pulldown with domain mutants, peptide competition, co-IP; single lab with multiple orthogonal methods","pmids":["8910342"],"is_preprint":false},{"year":1998,"finding":"CD43 cross-linking in human T lymphocytes induces tyrosine phosphorylation of Shc and Vav, formation of a Shc/GRB2/Vav complex, enhanced Vav-SLP-76 complex formation, and ERK2 activation and nuclear translocation; CD43-mediated signals activate the MAP kinase pathway leading to IL-2 gene expression.","method":"Co-immunoprecipitation, tyrosine phosphorylation assay, luciferase reporter assay (Fos SRE), ERK2 kinase activation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple co-IP experiments, reporter assay, single lab with orthogonal biochemical methods","pmids":["9603925"],"is_preprint":false},{"year":1998,"finding":"CD43 is actively excluded from the T cell–APC contact site in an antigen-dependent manner; CD3 signaling alone can induce this exclusion. CD45 is not excluded, indicating this is a specific property of CD43.","method":"Fluorescence microscopy of T cell–APC conjugates","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging with antigen-dependence control; single lab","pmids":["9862667"],"is_preprint":false},{"year":1999,"finding":"Crosslinking CD34 or CD43 on immature hematopoietic KG1a cells activates the same signaling pathway (Lyn, Syk, and novel tyrosine-phosphorylated proteins) leading to cytoadhesion; cap formation of CD34 or CD43 colocalizes with F-actin, and cap formation is required for Syk and pp77 phosphorylation and cytoadhesion (blocked by cytochalasin D).","method":"Co-immunoprecipitation, cytochalasin D inhibition, anti-phosphotyrosine Western blot, immunofluorescence","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical signaling assays with cytoskeletal inhibitor, co-IP; single lab","pmids":["10339479"],"is_preprint":false},{"year":1996,"finding":"CD43 ligation of a hyposialylated CD43 isoform (recognized by mAb J393) on Jurkat T cells induces apoptosis via tyrosine kinase activation; herbimycin A diminished apoptosis and phosphatase inhibitor enhanced it; CD43-mediated apoptosis is potentiated by co-engagement of CD3/TCR or integrins CD18/CD29; apoptosis is associated with decreased nuclear NF-κB.","method":"Apoptosis assay, tyrosine phosphorylation assay, kinase/phosphatase inhibitor treatment, NF-κB nuclear localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection with kinase/phosphatase inhibitors, multiple apoptosis readouts; single lab","pmids":["8910360"],"is_preprint":false},{"year":2000,"finding":"CD43 ligation on normal peripheral human T cells is sufficient to induce IL-2, CD69, and CD40-L gene expression and activate NF-AT, AP-1 (c-Jun containing), and NF-κB (p65) transcription factors; this is partially inhibited by cyclosporin A (Ca2+ pathway) and staurosporine (PKC pathway).","method":"EMSA for transcription factor DNA binding, cytokine/activation marker expression assays, pharmacological inhibition","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA with multiple transcription factors, pharmacological inhibition; single lab","pmids":["10908570"],"is_preprint":false},{"year":2001,"finding":"CD43 is a T cell counterreceptor for sialoadhesin (Siglec-1) on macrophages; CD43 expressed in COS cells supports increased binding to immobilized sialoadhesin; binding is sialic acid-dependent and requires Arg97 in the sialoadhesin binding site; both core 1 and core 2 O-glycan forms of CD43 support binding.","method":"Sialoadhesin-Fc pulldown/precipitation from T-cell lysates, COS cell expression with sialoadhesin binding assay, Siglec-1 R97A mutant, CHO cells expressing defined CD43 glycoforms","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding reconstitution in COS cells, sialidase treatment, site-directed mutagenesis of receptor, multiple glycoform analysis","pmids":["11238599"],"is_preprint":false},{"year":2001,"finding":"CD43 mediates dendritic cell maturation upon cross-linking: anti-CD43 F(ab')2 (but not monovalent Fab) induced upregulation of HLA-DR, CD54, CD40, CD80, CD86, CD83, cytokine release (IL-1β, IL-6, TNF-α, IL-12, IL-10), intracellular Ca2+ rise, and tyrosine phosphorylation of a 25-kDa protein in dendritic cells.","method":"Flow cytometry for surface marker upregulation, ELISA for cytokines, Ca2+ flux assay, tyrosine phosphorylation assay; comparison of intact Ab vs F(ab')2 vs Fab","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — F(ab')2 vs Fab comparison establishes crosslinking requirement; multiple functional readouts; single lab","pmids":["10352244"],"is_preprint":false},{"year":2002,"finding":"hnRNP-K and Purα act together to repress transcriptional activity of the CD43 gene promoter during activation of K562 cells; these proteins bind single-stranded DNA sequences in the CD43 promoter; CD43 mRNA levels are dramatically downregulated during K562 activation, coinciding with promoter repression.","method":"Transcriptional reporter assay, RT-PCR for CD43 mRNA, identification of hnRNP-K and Purα as promoter-binding repressors","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus mRNA quantification, identification of specific repressors; single lab","pmids":["12411317"],"is_preprint":false},{"year":2002,"finding":"CD43 distribution on T cells is regulated by a membrane-proximal ezrin-binding site; failure to displace CD43 from the immunological synapse does not inhibit primary T cell activation, but CD43 expression at T cell–matrix contact does not negatively regulate motility while it may regulate LFA-1 de-adhesion.","method":"Fluorescence microscopy with CD43 mutants lacking ezrin-binding site, T-cell activation and motility assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CD43 mutant reconstitution in T cells with imaging; single lab","pmids":["11937524"],"is_preprint":false},{"year":2003,"finding":"CD43 recruits the ζ-chain as part of its signaling pathway in human T lymphocytes and NK cells; CD43 engagement leads to ζ-chain tyrosine phosphorylation creating docking sites for ZAP-70 and Vav; Lck is required for ζ-chain phosphorylation downstream of CD43; CD43 engagement concentrates the ζ-chain toward the bead attachment site.","method":"Co-immunoprecipitation, in vitro kinase assay, ζ-chain redistribution imaging, Lck-deficient JCaM.1 cell experiments","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, in vitro kinase assay, genetic (Lck-deficient cells) validation, imaging; multiple orthogonal methods in one study","pmids":["12902492"],"is_preprint":false},{"year":2004,"finding":"CD43 negative regulation of T-cell activation operates through an intracellular mechanism, not steric hindrance: a GPI-linked CD43 ectodomain construct failed to reverse CD43−/− T-cell hyperproliferation; an intracellular-only CD43 (small ectodomain of hCD16 fused to CD43 cytoplasmic tail) reversed hyperproliferation; exclusion of the CD43 intracellular region from the immunological synapse is required for regulation of IL-2 production.","method":"Reconstitution of CD43 mutants (GPI-linked ectodomain, intracellular-only chimera, ERM-binding mutant) in CD43−/− T cells; proliferation and IL-2 production assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — structure-function reconstitution with multiple domain mutants in KO T cells, two distinct functional readouts","pmids":["15117976"],"is_preprint":false},{"year":2005,"finding":"CD43 functions as an E-selectin ligand on activated T cells; a 130-kDa glycoform of CD43 is precipitated by E-selectin-IgG chimera from Th1 cells in a sialic acid-dependent manner; CD43-IgG chimera generated in CHO cells expressing FucT-VII and C2GnT supports E-selectin-dependent cell rolling under flow conditions.","method":"E-selectin-IgG pulldown/immunoprecipitation, O-sialoglycoprotein endopeptidase treatment, mAb 1B11 identification, CHO cell reconstitution with defined glycosyltransferases, flow chamber rolling assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of rolling with defined glycoform in flow chamber, immunoprecipitation identification, enzymatic treatment controls","pmids":["16339541"],"is_preprint":false},{"year":2005,"finding":"CD34 and CD43 act as negative regulators of mast cell adhesion; loss of CD43 and/or CD34 causes gene-dose-dependent increase in mast cell homotypic aggregation; reexpression of CD34 or CD43 reverses this phenotype; loss of these sialomucins also prevents mast cell repopulation in vivo.","method":"CD34/CD43 double-KO mouse mast cell analysis, re-expression rescue experiments, in vitro aggregation assay, in vivo reconstitution","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — rescue experiments with reexpression in KO cells, dose-dependent genetic analysis, in vivo reconstitution","pmids":["15664158"],"is_preprint":false},{"year":2006,"finding":"CD43 bearing either core 1 or core 2 O-glycans binds galectin-1 and is required for maximal T-cell susceptibility to galectin-1-induced death; galectin-1 binding clusters CD43 on the T-cell surface; loss of CD43 reduced galectin-1-induced death and galectin-1 binding by ~50%.","method":"CD43-deficient T cells, galectin-1 binding assay, galectin-1 death assay, CD43 fusion proteins with defined glycoforms (core 1 vs core 2), microscopy for CD43 clustering","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — CD43 KO comparison, defined glycoform fusion proteins, multiple orthogonal assays","pmids":["17015718"],"is_preprint":false},{"year":2007,"finding":"CD43 collaborates with PSGL-1 to mediate E-selectin-dependent T-cell migration into inflamed skin in vivo; CD43-deficient Th1 cells showed reduced E-selectin-binding activity; PSGL-1/CD43 double-deficient Th1 cells show the most profound decrease, demonstrating additive roles.","method":"CD43−/− and PSGL-1−/− mice, E-selectin binding assay, in vivo adoptive transfer migration assay to inflamed skin","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-KO genetic epistasis, in vivo migration assay with adoptive transfer, binding assay","pmids":["17277158"],"is_preprint":false},{"year":2007,"finding":"CD43 regulates T-cell trafficking through phosphorylation at Ser76 in its cytoplasmic tail; mutation of Ser76 to alanine greatly diminishes T-cell trafficking to the lymph node while leaving CD43 exclusion from the synapse and CD43-mediated regulation of T-cell proliferation intact; the CD43 extracellular domain is also required for trafficking.","method":"Tandem mass spectrometry identification of phospho-Ser76, CD43 Ser76Ala mutant reconstitution in CD43−/− T cells, lymph node trafficking assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — phosphorylation site identified by MS, confirmed by site-directed mutagenesis with functional in vivo trafficking readout","pmids":["17638845"],"is_preprint":false},{"year":2009,"finding":"Galectin-1 binds CD43 and CD45 on dendritic cells, inducing unipolar co-clustering of these receptors; galectin-1 activates Syk and PKC signaling in DCs, with phosphorylated Syk recruited to the CD43/CD45 co-cluster; Syk and PKC inhibitors abrogate galectin-1-induced DC activation, IL-6 production, MMP gene upregulation, and enhanced migration.","method":"Kinome screen, Syk phosphorylation assay, co-cluster imaging, PKC/Syk inhibitors, cytokine ELISA, migration assay, in vivo intradermal injection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinome screen plus biochemical validation, inhibitor studies, imaging of co-cluster, in vivo confirmation","pmids":["19635795"],"is_preprint":false},{"year":2009,"finding":"The CD43 ectodomain is shed from granulocytes, mast cells, and T cells (but not macrophages); after γ-secretase cleavage, the CD43 cytoplasmic tail (CD43ct) translocates to the nucleus; inhibition of nuclear translocation or γ-secretase cleavage is proapoptotic; CD43ct is modified by SUMO-1 and colocalizes with promyelocytic nuclear bodies; CD43-deficient cells show reduced PML nuclear bodies and increased sensitivity to apoptosis.","method":"CD43/CD34 transmembrane-domain chimeras, viability assays, nuclear fractionation, SUMO-1 modification assay, γ-secretase inhibitor, PML nuclear body colocalization imaging","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — chimera rescue experiments, γ-secretase inhibitor, nuclear translocation with SUMO modification; multiple orthogonal methods in single paper","pmids":["19696198"],"is_preprint":false},{"year":2011,"finding":"CD43 interaction with ERM proteins is required for CD43 phosphorylation at Ser76; mutation of Ser76 to a phosphomimetic (S76D) enhances T-cell migration and CD43 movement to the distal pole complex while blocking ERM association; protein kinase Cθ can phosphorylate CD43 at Ser76.","method":"Phospho-specific antibody, CD43 Ser76 mutants (S76A, S76D) reconstitution in CD43−/− T cells, migration assay, ERM co-immunoprecipitation, PKCθ kinase assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — phospho-specific antibody validation, mutagenesis (S76A/D), in vitro kinase assay for PKCθ, co-IP with ERM; multiple orthogonal methods","pmids":["21289089"],"is_preprint":false},{"year":2015,"finding":"CD43 is a dominant E-selectin ligand specifically in Th17 cells, functioning independently of PSGL-1; CD43-deficient Th17 cells show impaired accumulation on E-selectin under flow and impaired rolling on TNF-α-treated microvessels in vivo; CD43−/− mice are protected from EAE with impaired Th17 cell recruitment to spinal cord.","method":"Flow chamber E-selectin binding assay with PSGL-1−/−, CD43−/−, and double-KO Th17 cells; intravital microscopy; in vivo air pouch recruitment; EAE model","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double-KO epistasis, intravital microscopy, in vivo recruitment, in vitro flow assay; multiple complementary methods","pmids":["26700769"],"is_preprint":false},{"year":2020,"finding":"Virion-incorporated CD43 (and PSGL-1) inhibit HIV-1 cell-free infection and transinfection by preventing virus attachment to CD4+ cells and CD4− fibroblastic reticular cells, irrespective of Env; the inhibitory effect requires the full-length ectodomain (demonstrated for PSGL-1); CD43 and PSGL-1 cocluster with assembling HIV-1 Gag at the plasma membrane.","method":"Virion infectivity assay, virus attachment assay (CD4+ and CD4− cells), Env-deleted virus controls, full-length vs truncated PSGL-1 constructs, Gag coclustering imaging","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional reconstitution with domain mutants, multiple cell types, Env-independent controls; orthogonal infectivity and attachment assays","pmids":["32193343"],"is_preprint":false},{"year":2014,"finding":"CD43 coclusters with assembling HIV-1 Gag at the plasma membrane through polybasic motifs in the CD43 cytoplasmic tail and in the Gag matrix domain; mutation of the polybasic sequence in CD43 cytoplasmic tail reduces its coclustering with Gag; replacement of cytoplasmic tails of non-coclustering proteins with CD43/PSGL-1 tails confers coclustering.","method":"Quantitative two-color superresolution localization microscopy, Gag matrix domain basic residue mutants, chimeric transmembrane protein tail-swap constructs","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — superresolution microscopy with quantitation, domain-swap mutagenesis, mechanistic dissection of polybasic motif requirement","pmids":["25320329"],"is_preprint":false},{"year":1997,"finding":"CD43 associates with the cytoskeleton in neutrophils via F-actin; anti-CD43 crosslinking induces CD43 redistribution to caps at the uropod, dependent on the actomyosin system (blocked by cytochalasin B and butanedione monoxime); colchicine and chemotactic factor fNLP also drive CD43 redistribution to the uropod independently of mAb crosslinking, suggesting CD43 is involved in cell polarization.","method":"Triton X-100 solubility assay for cytoskeletal association, immunofluorescence, electron microscopy, cytochalasin B and BDM inhibition","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — detergent fractionation for cytoskeletal association, inhibitor studies, imaging; single lab","pmids":["9224764"],"is_preprint":false},{"year":1997,"finding":"Core 2 N-acetylglucosaminyltransferase (C2GnT) modifies CD43 O-glycans, converting the 115-kDa (core 1, S7 epitope) glycoform to the 130-kDa (core 2, 1B11 epitope) glycoform; transfection of C2GnT into EL-4 cells caused gain of 1B11 epitope and loss of S7 epitope, with ~10 kDa molecular weight increase.","method":"C2GnT transfection into EL-4 cells, flow cytometry with S7 and 1B11 antibodies, SDS-PAGE molecular weight analysis","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzyme expression showing glycoform switch; single lab, single transfection approach","pmids":["9061371"],"is_preprint":false},{"year":1999,"finding":"CD43 expression on T cells mediates T-cell homing to lymph nodes and Peyer's patches; anti-CD43 mAb L11 blocks T-cell binding to HEV in vitro and inhibits T-cell extravasation from blood into lymphoid tissues in vivo, without affecting binding to purified vascular ligands for L-selectin, α4β7, or LFA-1.","method":"HEV binding assay in vitro, in vivo lymphocyte trafficking assay, antibody blocking with selectin/integrin panel","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo trafficking assay with mechanistic controls; single lab","pmids":["9126930"],"is_preprint":false},{"year":1999,"finding":"CD43 ligation on T cells induces the CD43-Fyn interaction and mediates homotypic aggregation requiring CD43 association with cytoskeleton; the CD43 signaling pathway leading to Ca2+ mobilization and IL-2 production involves Shc, GRB2, Vav, and ERK2 activation.","method":"Referenced from 1996 and 1998 papers; reviewed in context of T-cell activation","journal":"Immunologic research","confidence":"Low","confidence_rationale":"Tier 4 / Weak — review paper, no new experimental data; citing previously established findings","pmids":["10580634"],"is_preprint":false},{"year":2003,"finding":"CD43-mediated homotypic aggregation of T lymphocytes requires Src kinases, PLCγ2, PKC, PI3K, ERK1/2, and p38; these signaling molecules regulate actin cytoskeleton remodeling after CD43 ligation; leflunomide blocks Src kinase target recruitment and actin polymerization downstream of CD43, diminishing aggregation.","method":"Pharmacological inhibitors of Src, PLCγ, PKC, PI3K, ERK, p38; F-actin staining; leflunomide treatment; homotypic aggregation assay","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic pharmacological dissection with multiple pathway inhibitors; single lab","pmids":["12972508"],"is_preprint":false},{"year":2001,"finding":"CD43-mediated apoptosis in TF-1 myeloid progenitor cells involves repression of AP-1 DNA binding activity and downregulation of 14-3-3 proteins and GM-CSF receptor β; this is followed by translocation of proapoptotic Bad to mitochondria; Daxx overexpression inhibits CD43-mediated apoptosis; co-immobilized anti-ICAM-3/CD99 partly suppress apoptosis.","method":"Immobilized anti-CD43 mAb apoptosis assay, DNA array screening, AP-1 EMSA, Bad localization assay, Daxx overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic screen with biochemical validation of AP-1 and Bad; Daxx rescue; single lab","pmids":["11773067"],"is_preprint":false},{"year":2011,"finding":"M-ficolin binds to CD43 on neutrophils in a sialic acid-dependent manner (Y271F mutant unable to bind sialic acid fails to bind neutrophils or modulate their functions); endogenous M-ficolin secreted by fMLP-activated neutrophils binds to CD43; M-ficolin binding induces cell polarization, adhesion, and homotypic aggregation, phenocopying anti-CD43 antibody crosslinking.","method":"Recombinant M-ficolin binding assay with blocking anti-CD43 mAb, Western blot of neutrophil lysate with rM-ficolin, Y271F sialic-acid-binding mutant, immunofluorescence colocalization, functional adhesion/aggregation assay","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-directed mutant of receptor, direct binding assay on Western blot, functional phenocopy with endogenous protein; multiple orthogonal methods","pmids":["22167719"],"is_preprint":false},{"year":1999,"finding":"CD43 ligation on NK cells induces secretion of RANTES, MIP-1α, and MIP-1β chemokines (blocked by tyrosine kinase inhibitor genistein); increases cytotoxic activity; and activates PYK-2 tyrosine kinase.","method":"ELISA for chemokines, cytotoxicity assay, anti-phosphotyrosine immunoprecipitation, PYK-2 kinase assay, genistein inhibition","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase identification (PYK-2), functional chemokine/cytotoxicity assays, kinase inhibitor; single lab","pmids":["10515880"],"is_preprint":false},{"year":2021,"finding":"MSC-derived ICAM-1 interacts with CD43 on activated T cells; blockade of either ICAM-1 on MSCs or CD43 on T cells reversed rapid suppression of proinflammatory cytokine (TNF-α, IFN-γ) mRNA expression; ICAM-1/CD43 interaction disrupts CD43-mediated TCR microcluster formation to limit T-cell activation, and suppresses TCR-proximal signaling and Ca2+ flux.","method":"ICAM-1 and CD43 blocking antibodies in MSC-T cell coculture; cytokine mRNA quantification; TCR microcluster imaging; Ca2+ signaling assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual antibody blockade, imaging of TCR microcluster disruption, Ca2+ signaling; single lab","pmids":["33692786"],"is_preprint":false},{"year":2008,"finding":"CD43 regulates Th2 differentiation; CD43−/− T cells show decreased calcium flux upon TCR ligation and preferentially differentiate into Th2 cells in vitro, associated with increased GATA-3 nuclear translocation; CD43−/− mice exhibit increased Th2-mediated allergic airway inflammation in vivo.","method":"CD43−/− T cells, Ca2+ flux assay, Th1/Th2 differentiation protocol, GATA-3 nuclear translocation assay, allergic airway disease model","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO T cells with mechanistic Ca2+/GATA-3 readouts and in vivo disease model; single lab","pmids":["18490738"],"is_preprint":false},{"year":2004,"finding":"CD43 expressed by cancer cell lines (PSN-1, SW1222) mediates adhesion to human peritoneal mesothelial cells (HPMC) via interaction with ICAM-1; anti-CD43 antibody significantly reduced tumor cell adhesion to HPMC; β2 integrin inhibition did not reduce this adhesion.","method":"Western blot and flow cytometry for CD43 expression, fluorometric adhesion assay with inhibitory anti-CD43 antibody vs anti-β2 integrin antibody","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct adhesion assay with CD43 antibody blockade, specificity shown by negative β2-integrin control; single lab","pmids":["15449712"],"is_preprint":false},{"year":1989,"finding":"CD43 is rapidly superphosphorylated on serine residues within minutes of phorbol ester (PMA) treatment of lymphocytes; ConA and anti-CD3 also cause CD43 superphosphorylation, albeit delayed; CD43 is constitutively superphosphorylated on serine and tyrosine in continuously growing T, B, and non-lymphoid cell lines.","method":"Metabolic radiolabeling with 32P, immunoprecipitation of CD43, SDS-PAGE","journal":"Scandinavian journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical phosphorylation assay with multiple activating stimuli; single lab","pmids":["2531463"],"is_preprint":false},{"year":1986,"finding":"gpL115 (CD43) is a heavily glycosylated transmembrane sialoglycoprotein; purification established that it is 52% carbohydrate by weight (asialo form), with major O-linked carbohydrate residues being galactose and N-acetylgalactosamine in equimolar amounts; amino acid composition shows high proline and serine/threonine content typical of mucin-like proteins.","method":"Sequential affinity chromatography purification (lentil lectin, wheat germ lectin, peanut lectin Sepharose), amino acid composition analysis, carbohydrate analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical purification and compositional analysis; foundational characterization paper","pmids":["3711098"],"is_preprint":false},{"year":2019,"finding":"CD43 functions as an E-selectin ligand on PSGL-1-deficient lymphoblasts; knockdown of CD43 on NALL-1 B-precursor ALL cells resulted in reduced rolling on E-selectin and decreased tissue engraftment in immunodeficient mice.","method":"Flow adhesion assay, E-selectin binding, RNA interference knockdown of CD43, xenograft engraftment assay in irradiated immunodeficient mice","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with both in vitro rolling and in vivo engraftment assays; single lab","pmids":["31461905"],"is_preprint":false}],"current_model":"CD43 (SPN/leukosialin) is a heavily O-glycosylated transmembrane sialomucin that functions as a multifunctional signaling and adhesion-regulatory molecule on hematopoietic cells: its large, negatively charged ectodomain provides steric/electrostatic anti-adhesive barrier function, while its cytoplasmic tail—phosphorylated at Ser76 by PKCθ and recruited to Fyn (via SH3 binding to a proline-rich sequence) and the ζ-chain—activates PLC/Ca2+, PKC, Vav/Shc/GRB2, ERK, JNK, and NF-κB/NF-AT/AP-1 pathways to positively costimulate T cells, NK cells, and dendritic cells; after ectodomain shedding, γ-secretase releases the cytoplasmic tail for nuclear translocation (as a SUMO-1-modified fragment associating with PML nuclear bodies) to promote cell survival; specific glycoforms (core 2-modified, generated by C2GnT) confer E-selectin ligand activity enabling T-cell rolling and tissue recruitment, while galectin-1 crosslinks CD43 glycoforms to induce T-cell apoptosis; on the cell surface CD43 is excluded from the immunological synapse via ERM-protein interactions and is enriched in the uropod where—with polybasic cytoplasmic tail motifs—it coclusters with HIV-1 Gag to impair virion infectivity by blocking virus-cell attachment."},"narrative":{"mechanistic_narrative":"SPN (CD43/leukosialin) is a heavily O-glycosylated transmembrane sialomucin—~52% carbohydrate by weight with mucin-like proline/serine/threonine-rich structure [PMID:3711098]—that operates on hematopoietic cells as a dual adhesion-regulatory and signaling molecule. Its large sialylated ectodomain interferes with LFA-1–ICAM-1 adhesion in a sialic acid-dependent manner [PMID:1594606], yet CD43 itself binds ICAM-1 as a counterreceptor [PMID:1683685] and serves as a ligand for sialoadhesin/Siglec-1 [PMID:11238599] and M-ficolin [PMID:22167719]. Genetic deletion establishes CD43 as a net negative regulator of T-cell activation and adhesion [PMID:7566153], and structure-function reconstitution localized this negative regulation to its cytoplasmic tail rather than steric hindrance, requiring exclusion of the intracellular region from the immunological synapse [PMID:15117976, PMID:9862667]. Beyond this restraint, CD43 cross-linking transduces CD3-independent activation signals: it engages Fyn through SH3 binding to a proline-rich cytoplasmic motif [PMID:8910342], recruits and phosphorylates the ζ-chain in an Lck-dependent manner to dock ZAP-70 and Vav [PMID:12902492], triggers PLC/Ca2+/PKC signaling [PMID:2542404], assembles Shc/GRB2/Vav complexes driving ERK activation [PMID:9603925], and induces NF-AT, AP-1, and NF-κB to costimulate IL-2 and activation-marker expression independently of CD28 [PMID:10908570, PMID:7790813]. Cytoplasmic Ser76, phosphorylated by PKCθ, governs ERM-dependent trafficking to the distal pole and lymph node homing [PMID:17638845, PMID:21289089]. Specific glycoforms tune its ligand activity: C2GnT-generated core 2 O-glycans [PMID:9061371] create E-selectin ligand activity for T-cell rolling and tissue recruitment, including a dominant role in Th17 migration [PMID:16339541, PMID:26700769], while both core 1 and core 2 forms bind galectin-1 to mediate T-cell apoptosis and dendritic-cell activation [PMID:17015718, PMID:19635795]. After ectodomain shedding, γ-secretase liberates the SUMO-1–modified cytoplasmic tail, which translocates to PML nuclear bodies to promote cell survival [PMID:19696198]. Virion-incorporated CD43 coclusters with assembling HIV-1 Gag through polybasic cytoplasmic-tail motifs and impairs virion infectivity by blocking virus attachment [PMID:25320329, PMID:32193343].","teleology":[{"year":1986,"claim":"Established the biochemical nature of CD43 as a mucin-type sialoglycoprotein, defining the structural basis for its later anti-adhesive and ligand functions.","evidence":"Sequential lectin affinity purification with amino acid and carbohydrate composition analysis","pmids":["3711098"],"confidence":"High","gaps":["Did not assign function to the glycan-rich ectodomain","No connection yet to signaling or adhesion"]},{"year":1989,"claim":"Showed CD43 is dynamically phosphorylated and couples to PLC signaling, the first evidence it is an active signaling molecule rather than a passive coat.","evidence":"32P metabolic labeling of CD43; phosphoinositide hydrolysis, PKC translocation and Ca2+ assays in T cells and monocytes with CD3-independence control","pmids":["2531463","2542404"],"confidence":"Medium","gaps":["Kinase responsible for serine phosphorylation not identified","Receptor proximal coupling to PLC not mapped"]},{"year":1991,"claim":"Defined CD43 as both an ICAM-1 counterreceptor and a costimulatory molecule whose intracellular domain is needed for T-cell activation, framing it as an adhesion-coupled signaling receptor.","evidence":"Cell binding to purified immobilized CD43 with antibody/liposome inhibition; cDNA and cytoplasmic-domain mutant transfection of T-cell hybridoma","pmids":["1683685","2023632"],"confidence":"High","gaps":["Physiological relevance versus net negative regulation unresolved","Cytoplasmic effectors unidentified"]},{"year":1992,"claim":"Demonstrated the ectodomain's anti-adhesive barrier function is sialic acid-dependent, explaining how a glycan-rich surface molecule restrains integrin-mediated adhesion.","evidence":"T-lymphocyte adhesion to CD43-transfected HeLa cells with neuraminidase treatment and antibody blocking","pmids":["1594606"],"confidence":"High","gaps":["Did not distinguish steric versus intracellular mechanisms (resolved in 2004)"]},{"year":1995,"claim":"Genetic deletion revealed CD43's dominant physiological role is negative regulation of T-cell activation and adhesion, reconciling its conflicting costimulatory and anti-adhesive activities.","evidence":"CD43-knockout mice with proliferation, adhesion, and viral infection assays; expression cloning and CD28-independent costimulation in CD28-deficient mice","pmids":["7566153","7790813"],"confidence":"High","gaps":["Mechanism of negative regulation (steric vs signaling) not yet defined","Glycoform dependence of phenotypes untested"]},{"year":1996,"claim":"Identified the Fyn-SH3/proline-rich-tail interaction and apoptotic signaling, providing the molecular link between CD43 cross-linking and downstream tyrosine kinase activation.","evidence":"GST-Fyn SH3 pulldown, peptide competition and co-IP; J393 hyposialylated-isoform apoptosis assays with kinase/phosphatase inhibitors","pmids":["8910342","8910360"],"confidence":"High","gaps":["How clustering selects activation vs apoptosis outcome unclear","Glycoform that licenses apoptosis not molecularly defined"]},{"year":1998,"claim":"Mapped the proximal-to-distal signaling cascade (Shc/GRB2/Vav, ERK) and established antigen-dependent CD43 exclusion from the synapse, connecting CD43 to MAPK-driven IL-2 expression and synapse architecture.","evidence":"Co-IP of Shc/GRB2/Vav complexes, ERK2 kinase and SRE reporter assays; fluorescence imaging of T cell–APC conjugates","pmids":["9603925","9862667"],"confidence":"High","gaps":["Functional consequence of synapse exclusion not yet tested","Link between exclusion and negative regulation unestablished"]},{"year":1999,"claim":"Extended CD43 signaling and trafficking functions across cell types—cytoskeletal capping in neutrophils, NK chemokine release via PYK-2, and lymph node homing—showing it is a general leukocyte polarization and trafficking regulator.","evidence":"Triton solubility and imaging with cytochalasin/BDM in neutrophils; chemokine ELISA and PYK-2 kinase assay in NK cells; HEV binding and in vivo trafficking with mAb L11","pmids":["9224764","10515880","9126930","10339479"],"confidence":"Medium","gaps":["Direct cytoskeletal adaptor not identified at this stage","Homing ligand on HEV not molecularly defined"]},{"year":2001,"claim":"Identified sialoadhesin (Siglec-1) as a CD43 counterreceptor and showed CD43 cross-linking matures dendritic cells, broadening its ligand repertoire and innate-immune roles.","evidence":"Sialoadhesin-Fc pulldown, COS-cell binding reconstitution with Siglec-1 R97A mutant and defined glycoforms; F(ab')2 vs Fab DC maturation assays","pmids":["11238599","10352244"],"confidence":"High","gaps":["In vivo relevance of CD43-sialoadhesin contact not established","DC signaling effectors only partly defined"]},{"year":2003,"claim":"Resolved the proximal signaling module by showing CD43 recruits and phosphorylates the ζ-chain in an Lck-dependent manner, explaining how a non-TCR receptor co-opts TCR signaling machinery.","evidence":"Co-IP, in vitro kinase assay, ζ-chain imaging and Lck-deficient JCaM.1 cells; pharmacological dissection of homotypic aggregation pathway","pmids":["12902492","12972508"],"confidence":"High","gaps":["Stoichiometry and basis of ζ-chain recruitment unresolved","How CD43 signaling integrates with TCR remains unclear"]},{"year":2004,"claim":"Showed CD43 negative regulation operates through its intracellular domain and synapse exclusion, not the ectodomain steric barrier, redefining the mechanism of its restraint on T cells.","evidence":"Reconstitution of GPI-linked ectodomain, intracellular-only chimera, and ERM-binding mutants in CD43-/- T cells with proliferation and IL-2 readouts","pmids":["15117976"],"confidence":"High","gaps":["Identity of intracellular negative effector not defined","Mechanism linking synapse exclusion to IL-2 control incomplete"]},{"year":2005,"claim":"Defined CD43 core 2 glycoforms as E-selectin ligands enabling rolling, and confirmed sialomucin anti-adhesive roles in mast cells, linking specific glycosylation to vascular recruitment.","evidence":"E-selectin-Fc pulldown and CHO reconstitution with FucT-VII/C2GnT in flow chamber; CD34/CD43 double-KO mast cell aggregation and in vivo reconstitution","pmids":["16339541","15664158"],"confidence":"High","gaps":["Relative contribution versus PSGL-1 not yet quantified","In vivo rolling not yet demonstrated"]},{"year":2006,"claim":"Established CD43 (core 1 or core 2 glycoforms) as a galectin-1 receptor mediating T-cell death, defining a glycan-dependent pro-apoptotic axis distinct from E-selectin binding.","evidence":"CD43-deficient T cells, defined-glycoform fusion proteins, galectin-1 binding/death assays and clustering microscopy","pmids":["17015718"],"confidence":"High","gaps":["Downstream death signaling from CD43 clustering not mapped"]},{"year":2007,"claim":"Mapped Ser76 phosphorylation as the trafficking-specific signal and showed CD43 collaborates additively with PSGL-1 for E-selectin-dependent skin homing, separating trafficking from synapse and proliferation functions.","evidence":"Mass-spectrometry identification of phospho-Ser76 and S76A reconstitution with lymph node trafficking; CD43-/- and PSGL-1-/- double-KO Th1 migration to inflamed skin","pmids":["17638845","17277158"],"confidence":"High","gaps":["Kinase for Ser76 not identified at this stage (resolved 2011)","Adaptor reading the phospho-tail unknown"]},{"year":2009,"claim":"Revealed regulated intramembrane proteolysis releases a SUMO-1–modified CD43 tail to PML nuclear bodies to promote survival, and showed galectin-1 co-clusters CD43/CD45 to activate DC signaling, extending CD43 function into the nucleus and innate activation.","evidence":"TMD chimeras, γ-secretase inhibitor, nuclear fractionation, SUMO-1 and PML colocalization; kinome screen with Syk/PKC inhibitors and co-cluster imaging in DCs","pmids":["19696198","19635795"],"confidence":"High","gaps":["Nuclear transcriptional targets of CD43 tail unidentified","Sheddase generating the CD43 stub not defined"]},{"year":2011,"claim":"Identified PKCθ as the Ser76 kinase and ERM association as its prerequisite, completing the trafficking signaling module that drives CD43 to the distal pole complex.","evidence":"Phospho-specific antibody, S76A/S76D reconstitution, ERM co-IP, PKCθ kinase assay, migration assays; M-ficolin sialic-acid-dependent binding and functional phenocopy on neutrophils","pmids":["21289089","22167719"],"confidence":"High","gaps":["How ERM binding gates PKCθ access to Ser76 not mechanistically resolved"]},{"year":2015,"claim":"Established CD43 as the dominant, PSGL-1-independent E-selectin ligand in Th17 cells with disease-level consequences, defining a context-specific function in autoimmune recruitment.","evidence":"Flow chamber with PSGL-1-/-, CD43-/-, double-KO Th17 cells; intravital microscopy and EAE model","pmids":["26700769"],"confidence":"High","gaps":["Glycosyltransferase basis of Th17-specific glycoform not defined","Why CD43 dominates over PSGL-1 in Th17 unexplained"]},{"year":2020,"claim":"Defined an antiviral function: virion-incorporated CD43 coclusters with HIV-1 Gag via polybasic tail motifs and blocks virus attachment, repurposing its adhesion-modulating ectodomain against infection.","evidence":"Superresolution Gag coclustering with tail-swap mutants; virion infectivity and attachment assays with Env-deleted controls and full-length vs truncated constructs","pmids":["25320329","32193343"],"confidence":"High","gaps":["Full-length ectodomain requirement shown directly for PSGL-1, inferred for CD43","Physiological impact on HIV transmission in vivo untested"]},{"year":null,"claim":"How CD43 integrates its opposing activities—negative regulation versus costimulation, survival versus apoptosis—into a single context-dependent decision, and the identity of the nuclear effectors of the released cytoplasmic tail, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model connecting glycoform, clustering state, and signaling outcome","Transcriptional program controlled by the nuclear CD43 tail unknown","Sheddase generating the substrate for γ-secretase unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,2,4,39]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,6,16,7,11]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[29,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,28,8,29]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[24]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[29,9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,11,16,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6,7,16]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,2,18,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[20,24,34]}],"complexes":[],"partners":["FYN","CD3Z","LCK","ICAM1","SIGLEC1","SELE","LGALS1","EZR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P16150","full_name":"Leukosialin","aliases":["GPL115","Galactoglycoprotein","GALGP","Leukocyte sialoglycoprotein","Sialophorin"],"length_aa":400,"mass_kda":40.3,"function":"Predominant cell surface sialoprotein of leukocytes which regulates multiple T-cell functions, including T-cell activation, proliferation, differentiation, trafficking and migration. Positively regulates T-cell trafficking to lymph-nodes via its association with ERM proteins (EZR, RDX and MSN) (By similarity). Negatively regulates Th2 cell differentiation and predisposes the differentiation of T-cells towards a Th1 lineage commitment. Promotes the expression of IFN-gamma by T-cells during T-cell receptor (TCR) activation of naive cells and induces the expression of IFN-gamma by CD4(+) T-cells and to a lesser extent by CD8(+) T-cells (PubMed:18036228). Plays a role in preparing T-cells for cytokine sensing and differentiation into effector cells by inducing the expression of cytokine receptors IFNGR and IL4R, promoting IFNGR and IL4R signaling and by mediating the clustering of IFNGR with TCR (PubMed:24328034). Acts as a major E-selectin ligand responsible for Th17 cell rolling on activated vasculature and recruitment during inflammation. Mediates Th17 cells, but not Th1 cells, adhesion to E-selectin. Acts as a T-cell counter-receptor for SIGLEC1 (By similarity) Protects cells from apoptotic signals, promoting cell survival","subcellular_location":"Nucleus; Nucleus, PML body","url":"https://www.uniprot.org/uniprotkb/P16150/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPN","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/SPN","total_profiled":1310},"omim":[{"mim_id":"616782","title":"GLUCOSAMINYL (N-ACETYL) TRANSFERASE 4; GCNT4","url":"https://www.omim.org/entry/616782"},{"mim_id":"608112","title":"TRAFFICKING PROTEIN, KINESIN-BINDING 1; TRAK1","url":"https://www.omim.org/entry/608112"},{"mim_id":"608010","title":"NPC1-LIKE INTRACELLULAR CHOLESTEROL TRANSPORTER 1; NPC1L1","url":"https://www.omim.org/entry/608010"},{"mim_id":"606230","title":"SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 3; SHANK3","url":"https://www.omim.org/entry/606230"},{"mim_id":"604999","title":"SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 1; SHANK1","url":"https://www.omim.org/entry/604999"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":67.7},{"tissue":"lung","ntpm":26.6},{"tissue":"lymphoid tissue","ntpm":47.6}],"url":"https://www.proteinatlas.org/search/SPN"},"hgnc":{"alias_symbol":["LSN","CD43","GPL115","LEU-22"],"prev_symbol":[]},"alphafold":{"accession":"P16150","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P16150","model_url":"https://alphafold.ebi.ac.uk/files/AF-P16150-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P16150-F1-predicted_aligned_error_v6.png","plddt_mean":53.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPN","jax_strain_url":"https://www.jax.org/strain/search?query=SPN"},"sequence":{"accession":"P16150","fasta_url":"https://rest.uniprot.org/uniprotkb/P16150.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P16150/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P16150"}},"corpus_meta":[{"pmid":"16757688","id":"PMC_16757688","title":"Leukosialin (CD43) defines hematopoietic progenitors in human embryonic stem cell differentiation cultures.","date":"2006","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16757688","citation_count":281,"is_preprint":false},{"pmid":"1683685","id":"PMC_1683685","title":"CD43, a molecule defective in Wiskott-Aldrich syndrome, binds ICAM-1.","date":"1991","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1683685","citation_count":270,"is_preprint":false},{"pmid":"11432837","id":"PMC_11432837","title":"Spt16-Pob3 and the HMG protein Nhp6 combine to form the nucleosome-binding factor SPN.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11432837","citation_count":214,"is_preprint":false},{"pmid":"7566153","id":"PMC_7566153","title":"Negative regulation of T-cell adhesion and activation by CD43.","date":"1995","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/7566153","citation_count":177,"is_preprint":false},{"pmid":"1594606","id":"PMC_1594606","title":"CD43 interferes with T-lymphocyte adhesion.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1594606","citation_count":161,"is_preprint":false},{"pmid":"2023632","id":"PMC_2023632","title":"Enhancement of T-cell activation by the CD43 molecule whose expression is defective in Wiskott-Aldrich syndrome.","date":"1991","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2023632","citation_count":131,"is_preprint":false},{"pmid":"7790813","id":"PMC_7790813","title":"CD43 is a murine T cell costimulatory receptor that functions independently of CD28.","date":"1995","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7790813","citation_count":121,"is_preprint":false},{"pmid":"7989752","id":"PMC_7989752","title":"CD43 (S7) expression identifies peripheral B cell subsets.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7989752","citation_count":113,"is_preprint":false},{"pmid":"11238599","id":"PMC_11238599","title":"Cutting edge: CD43 functions as a T cell counterreceptor for the macrophage adhesion receptor sialoadhesin (Siglec-1).","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11238599","citation_count":112,"is_preprint":false},{"pmid":"24689054","id":"PMC_24689054","title":"Aberrant glycosylation as biomarker for cancer: focus on CD43.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/24689054","citation_count":107,"is_preprint":false},{"pmid":"10191768","id":"PMC_10191768","title":"Frequency of CD43 expression in non-Hodgkin lymphoma. 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expression of human CD43 in a murine T-cell hybridoma enhanced antigen-specific T-cell activation.\",\n      \"method\": \"Cell binding assay with purified immobilized CD43, inhibition with anti-CD43 mAb and CD43-liposomes, T-cell hybridoma transfection\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay with purified protein, inhibition controls, replicated in multiple systems; foundational paper\",\n      \"pmids\": [\"1683685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD43-mediated T-cell activation requires its intracellular domain (which is hyperphosphorylated during activation); expression of CD43 cDNA in antigen-responsive murine T-cell hybridoma enhanced antigen-specific activation; antigen-presenting cells bind specifically to immobilized purified CD43.\",\n      \"method\": \"cDNA transfection of CD43 and cytoplasmic domain mutants into T-cell hybridoma, purified CD43 binding assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional reconstitution with domain mutants, multiple orthogonal assays in one paper\",\n      \"pmids\": [\"2023632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CD43 expressed on opposing cells interferes with T-cell LFA-1 binding to ICAM-1; this anti-adhesive effect is dependent on sialic acid residues on CD43, as neuraminidase treatment of CD43-positive HeLa cells diminished the effect.\",\n      \"method\": \"T-lymphocyte adhesion assay to CD43-transfected HeLa cells; antibody blocking; neuraminidase treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct adhesion assay with CD43 transfectants, neuraminidase mechanistic dissection, antibody blocking controls\",\n      \"pmids\": [\"1594606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD43 engagement activates phospholipase C signaling pathway in T cells and monocytes: anti-CD43 mAb L10 induced phosphoinositide hydrolysis, generating diacylglycerol and inositol phosphates, PKC translocation from cytosol to membrane, and increased intracellular Ca2+; CD43 signaling proceeds independently of TCR/CD3.\",\n      \"method\": \"Phosphoinositide hydrolysis assay, PKC translocation assay, intracellular Ca2+ measurement in PBMC, T cells, monocytes, and leukemic T cell lines\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical assays demonstrating PLC pathway activation; CD3-independence confirmed in mutant cell line\",\n      \"pmids\": [\"2542404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD43-deficient mice show enhanced T-cell proliferation, increased homotypic adhesion, and increased ICAM-1 and fibronectin binding, demonstrating that CD43 negatively regulates T-cell activation and adhesion; CD43-knockout mice also showed augmented anti-vaccinia CTL response but increased viral load.\",\n      \"method\": \"CD43-knockout mouse generation, in vitro proliferation assays (ConA, anti-CD3, SEB, allostimulation), adhesion assays, viral infection model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal phenotypic readouts, in vitro and in vivo\",\n      \"pmids\": [\"7566153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD43 functions as a CD28-independent costimulatory receptor on murine T cells; expression cloning identified murine CD43 as the antigen for mAb R2/60, which synergizes with TCR engagement to induce T-cell proliferation independently of CD28.\",\n      \"method\": \"Expression cloning, T-cell proliferation assay with anti-CD43 mAb in CD28-deficient mice\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — expression cloning identification plus functional validation in CD28-deficient mice\",\n      \"pmids\": [\"7790813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD43 cross-linking induces association of CD43 with Fyn kinase via Fyn's SH3 domain binding to a proline-rich sequence (300ERQPAPALPPKPPKP314) in CD43's cytoplasmic tail; CD43 cross-linking also results in Fyn tyrosine phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, GST-Fyn SH3 pulldown from T-cell lysates, synthetic peptide competition assay, tyrosine phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — GST pulldown with domain mutants, peptide competition, co-IP; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"8910342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD43 cross-linking in human T lymphocytes induces tyrosine phosphorylation of Shc and Vav, formation of a Shc/GRB2/Vav complex, enhanced Vav-SLP-76 complex formation, and ERK2 activation and nuclear translocation; CD43-mediated signals activate the MAP kinase pathway leading to IL-2 gene expression.\",\n      \"method\": \"Co-immunoprecipitation, tyrosine phosphorylation assay, luciferase reporter assay (Fos SRE), ERK2 kinase activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple co-IP experiments, reporter assay, single lab with orthogonal biochemical methods\",\n      \"pmids\": [\"9603925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD43 is actively excluded from the T cell–APC contact site in an antigen-dependent manner; CD3 signaling alone can induce this exclusion. CD45 is not excluded, indicating this is a specific property of CD43.\",\n      \"method\": \"Fluorescence microscopy of T cell–APC conjugates\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging with antigen-dependence control; single lab\",\n      \"pmids\": [\"9862667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Crosslinking CD34 or CD43 on immature hematopoietic KG1a cells activates the same signaling pathway (Lyn, Syk, and novel tyrosine-phosphorylated proteins) leading to cytoadhesion; cap formation of CD34 or CD43 colocalizes with F-actin, and cap formation is required for Syk and pp77 phosphorylation and cytoadhesion (blocked by cytochalasin D).\",\n      \"method\": \"Co-immunoprecipitation, cytochalasin D inhibition, anti-phosphotyrosine Western blot, immunofluorescence\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical signaling assays with cytoskeletal inhibitor, co-IP; single lab\",\n      \"pmids\": [\"10339479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD43 ligation of a hyposialylated CD43 isoform (recognized by mAb J393) on Jurkat T cells induces apoptosis via tyrosine kinase activation; herbimycin A diminished apoptosis and phosphatase inhibitor enhanced it; CD43-mediated apoptosis is potentiated by co-engagement of CD3/TCR or integrins CD18/CD29; apoptosis is associated with decreased nuclear NF-κB.\",\n      \"method\": \"Apoptosis assay, tyrosine phosphorylation assay, kinase/phosphatase inhibitor treatment, NF-κB nuclear localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection with kinase/phosphatase inhibitors, multiple apoptosis readouts; single lab\",\n      \"pmids\": [\"8910360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD43 ligation on normal peripheral human T cells is sufficient to induce IL-2, CD69, and CD40-L gene expression and activate NF-AT, AP-1 (c-Jun containing), and NF-κB (p65) transcription factors; this is partially inhibited by cyclosporin A (Ca2+ pathway) and staurosporine (PKC pathway).\",\n      \"method\": \"EMSA for transcription factor DNA binding, cytokine/activation marker expression assays, pharmacological inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA with multiple transcription factors, pharmacological inhibition; single lab\",\n      \"pmids\": [\"10908570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD43 is a T cell counterreceptor for sialoadhesin (Siglec-1) on macrophages; CD43 expressed in COS cells supports increased binding to immobilized sialoadhesin; binding is sialic acid-dependent and requires Arg97 in the sialoadhesin binding site; both core 1 and core 2 O-glycan forms of CD43 support binding.\",\n      \"method\": \"Sialoadhesin-Fc pulldown/precipitation from T-cell lysates, COS cell expression with sialoadhesin binding assay, Siglec-1 R97A mutant, CHO cells expressing defined CD43 glycoforms\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding reconstitution in COS cells, sialidase treatment, site-directed mutagenesis of receptor, multiple glycoform analysis\",\n      \"pmids\": [\"11238599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD43 mediates dendritic cell maturation upon cross-linking: anti-CD43 F(ab')2 (but not monovalent Fab) induced upregulation of HLA-DR, CD54, CD40, CD80, CD86, CD83, cytokine release (IL-1β, IL-6, TNF-α, IL-12, IL-10), intracellular Ca2+ rise, and tyrosine phosphorylation of a 25-kDa protein in dendritic cells.\",\n      \"method\": \"Flow cytometry for surface marker upregulation, ELISA for cytokines, Ca2+ flux assay, tyrosine phosphorylation assay; comparison of intact Ab vs F(ab')2 vs Fab\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — F(ab')2 vs Fab comparison establishes crosslinking requirement; multiple functional readouts; single lab\",\n      \"pmids\": [\"10352244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"hnRNP-K and Purα act together to repress transcriptional activity of the CD43 gene promoter during activation of K562 cells; these proteins bind single-stranded DNA sequences in the CD43 promoter; CD43 mRNA levels are dramatically downregulated during K562 activation, coinciding with promoter repression.\",\n      \"method\": \"Transcriptional reporter assay, RT-PCR for CD43 mRNA, identification of hnRNP-K and Purα as promoter-binding repressors\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus mRNA quantification, identification of specific repressors; single lab\",\n      \"pmids\": [\"12411317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD43 distribution on T cells is regulated by a membrane-proximal ezrin-binding site; failure to displace CD43 from the immunological synapse does not inhibit primary T cell activation, but CD43 expression at T cell–matrix contact does not negatively regulate motility while it may regulate LFA-1 de-adhesion.\",\n      \"method\": \"Fluorescence microscopy with CD43 mutants lacking ezrin-binding site, T-cell activation and motility assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CD43 mutant reconstitution in T cells with imaging; single lab\",\n      \"pmids\": [\"11937524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD43 recruits the ζ-chain as part of its signaling pathway in human T lymphocytes and NK cells; CD43 engagement leads to ζ-chain tyrosine phosphorylation creating docking sites for ZAP-70 and Vav; Lck is required for ζ-chain phosphorylation downstream of CD43; CD43 engagement concentrates the ζ-chain toward the bead attachment site.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, ζ-chain redistribution imaging, Lck-deficient JCaM.1 cell experiments\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, in vitro kinase assay, genetic (Lck-deficient cells) validation, imaging; multiple orthogonal methods in one study\",\n      \"pmids\": [\"12902492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD43 negative regulation of T-cell activation operates through an intracellular mechanism, not steric hindrance: a GPI-linked CD43 ectodomain construct failed to reverse CD43−/− T-cell hyperproliferation; an intracellular-only CD43 (small ectodomain of hCD16 fused to CD43 cytoplasmic tail) reversed hyperproliferation; exclusion of the CD43 intracellular region from the immunological synapse is required for regulation of IL-2 production.\",\n      \"method\": \"Reconstitution of CD43 mutants (GPI-linked ectodomain, intracellular-only chimera, ERM-binding mutant) in CD43−/− T cells; proliferation and IL-2 production assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — structure-function reconstitution with multiple domain mutants in KO T cells, two distinct functional readouts\",\n      \"pmids\": [\"15117976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD43 functions as an E-selectin ligand on activated T cells; a 130-kDa glycoform of CD43 is precipitated by E-selectin-IgG chimera from Th1 cells in a sialic acid-dependent manner; CD43-IgG chimera generated in CHO cells expressing FucT-VII and C2GnT supports E-selectin-dependent cell rolling under flow conditions.\",\n      \"method\": \"E-selectin-IgG pulldown/immunoprecipitation, O-sialoglycoprotein endopeptidase treatment, mAb 1B11 identification, CHO cell reconstitution with defined glycosyltransferases, flow chamber rolling assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of rolling with defined glycoform in flow chamber, immunoprecipitation identification, enzymatic treatment controls\",\n      \"pmids\": [\"16339541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD34 and CD43 act as negative regulators of mast cell adhesion; loss of CD43 and/or CD34 causes gene-dose-dependent increase in mast cell homotypic aggregation; reexpression of CD34 or CD43 reverses this phenotype; loss of these sialomucins also prevents mast cell repopulation in vivo.\",\n      \"method\": \"CD34/CD43 double-KO mouse mast cell analysis, re-expression rescue experiments, in vitro aggregation assay, in vivo reconstitution\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rescue experiments with reexpression in KO cells, dose-dependent genetic analysis, in vivo reconstitution\",\n      \"pmids\": [\"15664158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD43 bearing either core 1 or core 2 O-glycans binds galectin-1 and is required for maximal T-cell susceptibility to galectin-1-induced death; galectin-1 binding clusters CD43 on the T-cell surface; loss of CD43 reduced galectin-1-induced death and galectin-1 binding by ~50%.\",\n      \"method\": \"CD43-deficient T cells, galectin-1 binding assay, galectin-1 death assay, CD43 fusion proteins with defined glycoforms (core 1 vs core 2), microscopy for CD43 clustering\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CD43 KO comparison, defined glycoform fusion proteins, multiple orthogonal assays\",\n      \"pmids\": [\"17015718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD43 collaborates with PSGL-1 to mediate E-selectin-dependent T-cell migration into inflamed skin in vivo; CD43-deficient Th1 cells showed reduced E-selectin-binding activity; PSGL-1/CD43 double-deficient Th1 cells show the most profound decrease, demonstrating additive roles.\",\n      \"method\": \"CD43−/− and PSGL-1−/− mice, E-selectin binding assay, in vivo adoptive transfer migration assay to inflamed skin\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-KO genetic epistasis, in vivo migration assay with adoptive transfer, binding assay\",\n      \"pmids\": [\"17277158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD43 regulates T-cell trafficking through phosphorylation at Ser76 in its cytoplasmic tail; mutation of Ser76 to alanine greatly diminishes T-cell trafficking to the lymph node while leaving CD43 exclusion from the synapse and CD43-mediated regulation of T-cell proliferation intact; the CD43 extracellular domain is also required for trafficking.\",\n      \"method\": \"Tandem mass spectrometry identification of phospho-Ser76, CD43 Ser76Ala mutant reconstitution in CD43−/− T cells, lymph node trafficking assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phosphorylation site identified by MS, confirmed by site-directed mutagenesis with functional in vivo trafficking readout\",\n      \"pmids\": [\"17638845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Galectin-1 binds CD43 and CD45 on dendritic cells, inducing unipolar co-clustering of these receptors; galectin-1 activates Syk and PKC signaling in DCs, with phosphorylated Syk recruited to the CD43/CD45 co-cluster; Syk and PKC inhibitors abrogate galectin-1-induced DC activation, IL-6 production, MMP gene upregulation, and enhanced migration.\",\n      \"method\": \"Kinome screen, Syk phosphorylation assay, co-cluster imaging, PKC/Syk inhibitors, cytokine ELISA, migration assay, in vivo intradermal injection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinome screen plus biochemical validation, inhibitor studies, imaging of co-cluster, in vivo confirmation\",\n      \"pmids\": [\"19635795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The CD43 ectodomain is shed from granulocytes, mast cells, and T cells (but not macrophages); after γ-secretase cleavage, the CD43 cytoplasmic tail (CD43ct) translocates to the nucleus; inhibition of nuclear translocation or γ-secretase cleavage is proapoptotic; CD43ct is modified by SUMO-1 and colocalizes with promyelocytic nuclear bodies; CD43-deficient cells show reduced PML nuclear bodies and increased sensitivity to apoptosis.\",\n      \"method\": \"CD43/CD34 transmembrane-domain chimeras, viability assays, nuclear fractionation, SUMO-1 modification assay, γ-secretase inhibitor, PML nuclear body colocalization imaging\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chimera rescue experiments, γ-secretase inhibitor, nuclear translocation with SUMO modification; multiple orthogonal methods in single paper\",\n      \"pmids\": [\"19696198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD43 interaction with ERM proteins is required for CD43 phosphorylation at Ser76; mutation of Ser76 to a phosphomimetic (S76D) enhances T-cell migration and CD43 movement to the distal pole complex while blocking ERM association; protein kinase Cθ can phosphorylate CD43 at Ser76.\",\n      \"method\": \"Phospho-specific antibody, CD43 Ser76 mutants (S76A, S76D) reconstitution in CD43−/− T cells, migration assay, ERM co-immunoprecipitation, PKCθ kinase assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phospho-specific antibody validation, mutagenesis (S76A/D), in vitro kinase assay for PKCθ, co-IP with ERM; multiple orthogonal methods\",\n      \"pmids\": [\"21289089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD43 is a dominant E-selectin ligand specifically in Th17 cells, functioning independently of PSGL-1; CD43-deficient Th17 cells show impaired accumulation on E-selectin under flow and impaired rolling on TNF-α-treated microvessels in vivo; CD43−/− mice are protected from EAE with impaired Th17 cell recruitment to spinal cord.\",\n      \"method\": \"Flow chamber E-selectin binding assay with PSGL-1−/−, CD43−/−, and double-KO Th17 cells; intravital microscopy; in vivo air pouch recruitment; EAE model\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double-KO epistasis, intravital microscopy, in vivo recruitment, in vitro flow assay; multiple complementary methods\",\n      \"pmids\": [\"26700769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Virion-incorporated CD43 (and PSGL-1) inhibit HIV-1 cell-free infection and transinfection by preventing virus attachment to CD4+ cells and CD4− fibroblastic reticular cells, irrespective of Env; the inhibitory effect requires the full-length ectodomain (demonstrated for PSGL-1); CD43 and PSGL-1 cocluster with assembling HIV-1 Gag at the plasma membrane.\",\n      \"method\": \"Virion infectivity assay, virus attachment assay (CD4+ and CD4− cells), Env-deleted virus controls, full-length vs truncated PSGL-1 constructs, Gag coclustering imaging\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional reconstitution with domain mutants, multiple cell types, Env-independent controls; orthogonal infectivity and attachment assays\",\n      \"pmids\": [\"32193343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD43 coclusters with assembling HIV-1 Gag at the plasma membrane through polybasic motifs in the CD43 cytoplasmic tail and in the Gag matrix domain; mutation of the polybasic sequence in CD43 cytoplasmic tail reduces its coclustering with Gag; replacement of cytoplasmic tails of non-coclustering proteins with CD43/PSGL-1 tails confers coclustering.\",\n      \"method\": \"Quantitative two-color superresolution localization microscopy, Gag matrix domain basic residue mutants, chimeric transmembrane protein tail-swap constructs\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — superresolution microscopy with quantitation, domain-swap mutagenesis, mechanistic dissection of polybasic motif requirement\",\n      \"pmids\": [\"25320329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD43 associates with the cytoskeleton in neutrophils via F-actin; anti-CD43 crosslinking induces CD43 redistribution to caps at the uropod, dependent on the actomyosin system (blocked by cytochalasin B and butanedione monoxime); colchicine and chemotactic factor fNLP also drive CD43 redistribution to the uropod independently of mAb crosslinking, suggesting CD43 is involved in cell polarization.\",\n      \"method\": \"Triton X-100 solubility assay for cytoskeletal association, immunofluorescence, electron microscopy, cytochalasin B and BDM inhibition\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — detergent fractionation for cytoskeletal association, inhibitor studies, imaging; single lab\",\n      \"pmids\": [\"9224764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Core 2 N-acetylglucosaminyltransferase (C2GnT) modifies CD43 O-glycans, converting the 115-kDa (core 1, S7 epitope) glycoform to the 130-kDa (core 2, 1B11 epitope) glycoform; transfection of C2GnT into EL-4 cells caused gain of 1B11 epitope and loss of S7 epitope, with ~10 kDa molecular weight increase.\",\n      \"method\": \"C2GnT transfection into EL-4 cells, flow cytometry with S7 and 1B11 antibodies, SDS-PAGE molecular weight analysis\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzyme expression showing glycoform switch; single lab, single transfection approach\",\n      \"pmids\": [\"9061371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD43 expression on T cells mediates T-cell homing to lymph nodes and Peyer's patches; anti-CD43 mAb L11 blocks T-cell binding to HEV in vitro and inhibits T-cell extravasation from blood into lymphoid tissues in vivo, without affecting binding to purified vascular ligands for L-selectin, α4β7, or LFA-1.\",\n      \"method\": \"HEV binding assay in vitro, in vivo lymphocyte trafficking assay, antibody blocking with selectin/integrin panel\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo trafficking assay with mechanistic controls; single lab\",\n      \"pmids\": [\"9126930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD43 ligation on T cells induces the CD43-Fyn interaction and mediates homotypic aggregation requiring CD43 association with cytoskeleton; the CD43 signaling pathway leading to Ca2+ mobilization and IL-2 production involves Shc, GRB2, Vav, and ERK2 activation.\",\n      \"method\": \"Referenced from 1996 and 1998 papers; reviewed in context of T-cell activation\",\n      \"journal\": \"Immunologic research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — review paper, no new experimental data; citing previously established findings\",\n      \"pmids\": [\"10580634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD43-mediated homotypic aggregation of T lymphocytes requires Src kinases, PLCγ2, PKC, PI3K, ERK1/2, and p38; these signaling molecules regulate actin cytoskeleton remodeling after CD43 ligation; leflunomide blocks Src kinase target recruitment and actin polymerization downstream of CD43, diminishing aggregation.\",\n      \"method\": \"Pharmacological inhibitors of Src, PLCγ, PKC, PI3K, ERK, p38; F-actin staining; leflunomide treatment; homotypic aggregation assay\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic pharmacological dissection with multiple pathway inhibitors; single lab\",\n      \"pmids\": [\"12972508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD43-mediated apoptosis in TF-1 myeloid progenitor cells involves repression of AP-1 DNA binding activity and downregulation of 14-3-3 proteins and GM-CSF receptor β; this is followed by translocation of proapoptotic Bad to mitochondria; Daxx overexpression inhibits CD43-mediated apoptosis; co-immobilized anti-ICAM-3/CD99 partly suppress apoptosis.\",\n      \"method\": \"Immobilized anti-CD43 mAb apoptosis assay, DNA array screening, AP-1 EMSA, Bad localization assay, Daxx overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic screen with biochemical validation of AP-1 and Bad; Daxx rescue; single lab\",\n      \"pmids\": [\"11773067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"M-ficolin binds to CD43 on neutrophils in a sialic acid-dependent manner (Y271F mutant unable to bind sialic acid fails to bind neutrophils or modulate their functions); endogenous M-ficolin secreted by fMLP-activated neutrophils binds to CD43; M-ficolin binding induces cell polarization, adhesion, and homotypic aggregation, phenocopying anti-CD43 antibody crosslinking.\",\n      \"method\": \"Recombinant M-ficolin binding assay with blocking anti-CD43 mAb, Western blot of neutrophil lysate with rM-ficolin, Y271F sialic-acid-binding mutant, immunofluorescence colocalization, functional adhesion/aggregation assay\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-directed mutant of receptor, direct binding assay on Western blot, functional phenocopy with endogenous protein; multiple orthogonal methods\",\n      \"pmids\": [\"22167719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD43 ligation on NK cells induces secretion of RANTES, MIP-1α, and MIP-1β chemokines (blocked by tyrosine kinase inhibitor genistein); increases cytotoxic activity; and activates PYK-2 tyrosine kinase.\",\n      \"method\": \"ELISA for chemokines, cytotoxicity assay, anti-phosphotyrosine immunoprecipitation, PYK-2 kinase assay, genistein inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase identification (PYK-2), functional chemokine/cytotoxicity assays, kinase inhibitor; single lab\",\n      \"pmids\": [\"10515880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MSC-derived ICAM-1 interacts with CD43 on activated T cells; blockade of either ICAM-1 on MSCs or CD43 on T cells reversed rapid suppression of proinflammatory cytokine (TNF-α, IFN-γ) mRNA expression; ICAM-1/CD43 interaction disrupts CD43-mediated TCR microcluster formation to limit T-cell activation, and suppresses TCR-proximal signaling and Ca2+ flux.\",\n      \"method\": \"ICAM-1 and CD43 blocking antibodies in MSC-T cell coculture; cytokine mRNA quantification; TCR microcluster imaging; Ca2+ signaling assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual antibody blockade, imaging of TCR microcluster disruption, Ca2+ signaling; single lab\",\n      \"pmids\": [\"33692786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD43 regulates Th2 differentiation; CD43−/− T cells show decreased calcium flux upon TCR ligation and preferentially differentiate into Th2 cells in vitro, associated with increased GATA-3 nuclear translocation; CD43−/− mice exhibit increased Th2-mediated allergic airway inflammation in vivo.\",\n      \"method\": \"CD43−/− T cells, Ca2+ flux assay, Th1/Th2 differentiation protocol, GATA-3 nuclear translocation assay, allergic airway disease model\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO T cells with mechanistic Ca2+/GATA-3 readouts and in vivo disease model; single lab\",\n      \"pmids\": [\"18490738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD43 expressed by cancer cell lines (PSN-1, SW1222) mediates adhesion to human peritoneal mesothelial cells (HPMC) via interaction with ICAM-1; anti-CD43 antibody significantly reduced tumor cell adhesion to HPMC; β2 integrin inhibition did not reduce this adhesion.\",\n      \"method\": \"Western blot and flow cytometry for CD43 expression, fluorometric adhesion assay with inhibitory anti-CD43 antibody vs anti-β2 integrin antibody\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct adhesion assay with CD43 antibody blockade, specificity shown by negative β2-integrin control; single lab\",\n      \"pmids\": [\"15449712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD43 is rapidly superphosphorylated on serine residues within minutes of phorbol ester (PMA) treatment of lymphocytes; ConA and anti-CD3 also cause CD43 superphosphorylation, albeit delayed; CD43 is constitutively superphosphorylated on serine and tyrosine in continuously growing T, B, and non-lymphoid cell lines.\",\n      \"method\": \"Metabolic radiolabeling with 32P, immunoprecipitation of CD43, SDS-PAGE\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical phosphorylation assay with multiple activating stimuli; single lab\",\n      \"pmids\": [\"2531463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"gpL115 (CD43) is a heavily glycosylated transmembrane sialoglycoprotein; purification established that it is 52% carbohydrate by weight (asialo form), with major O-linked carbohydrate residues being galactose and N-acetylgalactosamine in equimolar amounts; amino acid composition shows high proline and serine/threonine content typical of mucin-like proteins.\",\n      \"method\": \"Sequential affinity chromatography purification (lentil lectin, wheat germ lectin, peanut lectin Sepharose), amino acid composition analysis, carbohydrate analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical purification and compositional analysis; foundational characterization paper\",\n      \"pmids\": [\"3711098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD43 functions as an E-selectin ligand on PSGL-1-deficient lymphoblasts; knockdown of CD43 on NALL-1 B-precursor ALL cells resulted in reduced rolling on E-selectin and decreased tissue engraftment in immunodeficient mice.\",\n      \"method\": \"Flow adhesion assay, E-selectin binding, RNA interference knockdown of CD43, xenograft engraftment assay in irradiated immunodeficient mice\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with both in vitro rolling and in vivo engraftment assays; single lab\",\n      \"pmids\": [\"31461905\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD43 (SPN/leukosialin) is a heavily O-glycosylated transmembrane sialomucin that functions as a multifunctional signaling and adhesion-regulatory molecule on hematopoietic cells: its large, negatively charged ectodomain provides steric/electrostatic anti-adhesive barrier function, while its cytoplasmic tail—phosphorylated at Ser76 by PKCθ and recruited to Fyn (via SH3 binding to a proline-rich sequence) and the ζ-chain—activates PLC/Ca2+, PKC, Vav/Shc/GRB2, ERK, JNK, and NF-κB/NF-AT/AP-1 pathways to positively costimulate T cells, NK cells, and dendritic cells; after ectodomain shedding, γ-secretase releases the cytoplasmic tail for nuclear translocation (as a SUMO-1-modified fragment associating with PML nuclear bodies) to promote cell survival; specific glycoforms (core 2-modified, generated by C2GnT) confer E-selectin ligand activity enabling T-cell rolling and tissue recruitment, while galectin-1 crosslinks CD43 glycoforms to induce T-cell apoptosis; on the cell surface CD43 is excluded from the immunological synapse via ERM-protein interactions and is enriched in the uropod where—with polybasic cytoplasmic tail motifs—it coclusters with HIV-1 Gag to impair virion infectivity by blocking virus-cell attachment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPN (CD43/leukosialin) is a heavily O-glycosylated transmembrane sialomucin\\u2014~52% carbohydrate by weight with mucin-like proline/serine/threonine-rich structure [#41]\\u2014that operates on hematopoietic cells as a dual adhesion-regulatory and signaling molecule. Its large sialylated ectodomain interferes with LFA-1\\u2013ICAM-1 adhesion in a sialic acid-dependent manner [#2], yet CD43 itself binds ICAM-1 as a counterreceptor [#0] and serves as a ligand for sialoadhesin/Siglec-1 [#12] and M-ficolin [#35]. Genetic deletion establishes CD43 as a net negative regulator of T-cell activation and adhesion [#4], and structure-function reconstitution localized this negative regulation to its cytoplasmic tail rather than steric hindrance, requiring exclusion of the intracellular region from the immunological synapse [#17, #8]. Beyond this restraint, CD43 cross-linking transduces CD3-independent activation signals: it engages Fyn through SH3 binding to a proline-rich cytoplasmic motif [#6], recruits and phosphorylates the \\u03b6-chain in an Lck-dependent manner to dock ZAP-70 and Vav [#16], triggers PLC/Ca2+/PKC signaling [#3], assembles Shc/GRB2/Vav complexes driving ERK activation [#7], and induces NF-AT, AP-1, and NF-\\u03baB to costimulate IL-2 and activation-marker expression independently of CD28 [#11, #5]. Cytoplasmic Ser76, phosphorylated by PKC\\u03b8, governs ERM-dependent trafficking to the distal pole and lymph node homing [#22, #25]. Specific glycoforms tune its ligand activity: C2GnT-generated core 2 O-glycans [#30] create E-selectin ligand activity for T-cell rolling and tissue recruitment, including a dominant role in Th17 migration [#18, #26], while both core 1 and core 2 forms bind galectin-1 to mediate T-cell apoptosis and dendritic-cell activation [#20, #23]. After ectodomain shedding, \\u03b3-secretase liberates the SUMO-1\\u2013modified cytoplasmic tail, which translocates to PML nuclear bodies to promote cell survival [#24]. Virion-incorporated CD43 coclusters with assembling HIV-1 Gag through polybasic cytoplasmic-tail motifs and impairs virion infectivity by blocking virus attachment [#28, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Established the biochemical nature of CD43 as a mucin-type sialoglycoprotein, defining the structural basis for its later anti-adhesive and ligand functions.\",\n      \"evidence\": \"Sequential lectin affinity purification with amino acid and carbohydrate composition analysis\",\n      \"pmids\": [\"3711098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not assign function to the glycan-rich ectodomain\", \"No connection yet to signaling or adhesion\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Showed CD43 is dynamically phosphorylated and couples to PLC signaling, the first evidence it is an active signaling molecule rather than a passive coat.\",\n      \"evidence\": \"32P metabolic labeling of CD43; phosphoinositide hydrolysis, PKC translocation and Ca2+ assays in T cells and monocytes with CD3-independence control\",\n      \"pmids\": [\"2531463\", \"2542404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for serine phosphorylation not identified\", \"Receptor proximal coupling to PLC not mapped\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Defined CD43 as both an ICAM-1 counterreceptor and a costimulatory molecule whose intracellular domain is needed for T-cell activation, framing it as an adhesion-coupled signaling receptor.\",\n      \"evidence\": \"Cell binding to purified immobilized CD43 with antibody/liposome inhibition; cDNA and cytoplasmic-domain mutant transfection of T-cell hybridoma\",\n      \"pmids\": [\"1683685\", \"2023632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance versus net negative regulation unresolved\", \"Cytoplasmic effectors unidentified\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Demonstrated the ectodomain's anti-adhesive barrier function is sialic acid-dependent, explaining how a glycan-rich surface molecule restrains integrin-mediated adhesion.\",\n      \"evidence\": \"T-lymphocyte adhesion to CD43-transfected HeLa cells with neuraminidase treatment and antibody blocking\",\n      \"pmids\": [\"1594606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish steric versus intracellular mechanisms (resolved in 2004)\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Genetic deletion revealed CD43's dominant physiological role is negative regulation of T-cell activation and adhesion, reconciling its conflicting costimulatory and anti-adhesive activities.\",\n      \"evidence\": \"CD43-knockout mice with proliferation, adhesion, and viral infection assays; expression cloning and CD28-independent costimulation in CD28-deficient mice\",\n      \"pmids\": [\"7566153\", \"7790813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of negative regulation (steric vs signaling) not yet defined\", \"Glycoform dependence of phenotypes untested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified the Fyn-SH3/proline-rich-tail interaction and apoptotic signaling, providing the molecular link between CD43 cross-linking and downstream tyrosine kinase activation.\",\n      \"evidence\": \"GST-Fyn SH3 pulldown, peptide competition and co-IP; J393 hyposialylated-isoform apoptosis assays with kinase/phosphatase inhibitors\",\n      \"pmids\": [\"8910342\", \"8910360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How clustering selects activation vs apoptosis outcome unclear\", \"Glycoform that licenses apoptosis not molecularly defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapped the proximal-to-distal signaling cascade (Shc/GRB2/Vav, ERK) and established antigen-dependent CD43 exclusion from the synapse, connecting CD43 to MAPK-driven IL-2 expression and synapse architecture.\",\n      \"evidence\": \"Co-IP of Shc/GRB2/Vav complexes, ERK2 kinase and SRE reporter assays; fluorescence imaging of T cell\\u2013APC conjugates\",\n      \"pmids\": [\"9603925\", \"9862667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of synapse exclusion not yet tested\", \"Link between exclusion and negative regulation unestablished\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Extended CD43 signaling and trafficking functions across cell types\\u2014cytoskeletal capping in neutrophils, NK chemokine release via PYK-2, and lymph node homing\\u2014showing it is a general leukocyte polarization and trafficking regulator.\",\n      \"evidence\": \"Triton solubility and imaging with cytochalasin/BDM in neutrophils; chemokine ELISA and PYK-2 kinase assay in NK cells; HEV binding and in vivo trafficking with mAb L11\",\n      \"pmids\": [\"9224764\", \"10515880\", \"9126930\", \"10339479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cytoskeletal adaptor not identified at this stage\", \"Homing ligand on HEV not molecularly defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified sialoadhesin (Siglec-1) as a CD43 counterreceptor and showed CD43 cross-linking matures dendritic cells, broadening its ligand repertoire and innate-immune roles.\",\n      \"evidence\": \"Sialoadhesin-Fc pulldown, COS-cell binding reconstitution with Siglec-1 R97A mutant and defined glycoforms; F(ab')2 vs Fab DC maturation assays\",\n      \"pmids\": [\"11238599\", \"10352244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of CD43-sialoadhesin contact not established\", \"DC signaling effectors only partly defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the proximal signaling module by showing CD43 recruits and phosphorylates the \\u03b6-chain in an Lck-dependent manner, explaining how a non-TCR receptor co-opts TCR signaling machinery.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, \\u03b6-chain imaging and Lck-deficient JCaM.1 cells; pharmacological dissection of homotypic aggregation pathway\",\n      \"pmids\": [\"12902492\", \"12972508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and basis of \\u03b6-chain recruitment unresolved\", \"How CD43 signaling integrates with TCR remains unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed CD43 negative regulation operates through its intracellular domain and synapse exclusion, not the ectodomain steric barrier, redefining the mechanism of its restraint on T cells.\",\n      \"evidence\": \"Reconstitution of GPI-linked ectodomain, intracellular-only chimera, and ERM-binding mutants in CD43-/- T cells with proliferation and IL-2 readouts\",\n      \"pmids\": [\"15117976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of intracellular negative effector not defined\", \"Mechanism linking synapse exclusion to IL-2 control incomplete\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined CD43 core 2 glycoforms as E-selectin ligands enabling rolling, and confirmed sialomucin anti-adhesive roles in mast cells, linking specific glycosylation to vascular recruitment.\",\n      \"evidence\": \"E-selectin-Fc pulldown and CHO reconstitution with FucT-VII/C2GnT in flow chamber; CD34/CD43 double-KO mast cell aggregation and in vivo reconstitution\",\n      \"pmids\": [\"16339541\", \"15664158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution versus PSGL-1 not yet quantified\", \"In vivo rolling not yet demonstrated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established CD43 (core 1 or core 2 glycoforms) as a galectin-1 receptor mediating T-cell death, defining a glycan-dependent pro-apoptotic axis distinct from E-selectin binding.\",\n      \"evidence\": \"CD43-deficient T cells, defined-glycoform fusion proteins, galectin-1 binding/death assays and clustering microscopy\",\n      \"pmids\": [\"17015718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream death signaling from CD43 clustering not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped Ser76 phosphorylation as the trafficking-specific signal and showed CD43 collaborates additively with PSGL-1 for E-selectin-dependent skin homing, separating trafficking from synapse and proliferation functions.\",\n      \"evidence\": \"Mass-spectrometry identification of phospho-Ser76 and S76A reconstitution with lymph node trafficking; CD43-/- and PSGL-1-/- double-KO Th1 migration to inflamed skin\",\n      \"pmids\": [\"17638845\", \"17277158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase for Ser76 not identified at this stage (resolved 2011)\", \"Adaptor reading the phospho-tail unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed regulated intramembrane proteolysis releases a SUMO-1\\u2013modified CD43 tail to PML nuclear bodies to promote survival, and showed galectin-1 co-clusters CD43/CD45 to activate DC signaling, extending CD43 function into the nucleus and innate activation.\",\n      \"evidence\": \"TMD chimeras, \\u03b3-secretase inhibitor, nuclear fractionation, SUMO-1 and PML colocalization; kinome screen with Syk/PKC inhibitors and co-cluster imaging in DCs\",\n      \"pmids\": [\"19696198\", \"19635795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear transcriptional targets of CD43 tail unidentified\", \"Sheddase generating the CD43 stub not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified PKC\\u03b8 as the Ser76 kinase and ERM association as its prerequisite, completing the trafficking signaling module that drives CD43 to the distal pole complex.\",\n      \"evidence\": \"Phospho-specific antibody, S76A/S76D reconstitution, ERM co-IP, PKC\\u03b8 kinase assay, migration assays; M-ficolin sialic-acid-dependent binding and functional phenocopy on neutrophils\",\n      \"pmids\": [\"21289089\", \"22167719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ERM binding gates PKC\\u03b8 access to Ser76 not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established CD43 as the dominant, PSGL-1-independent E-selectin ligand in Th17 cells with disease-level consequences, defining a context-specific function in autoimmune recruitment.\",\n      \"evidence\": \"Flow chamber with PSGL-1-/-, CD43-/-, double-KO Th17 cells; intravital microscopy and EAE model\",\n      \"pmids\": [\"26700769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycosyltransferase basis of Th17-specific glycoform not defined\", \"Why CD43 dominates over PSGL-1 in Th17 unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined an antiviral function: virion-incorporated CD43 coclusters with HIV-1 Gag via polybasic tail motifs and blocks virus attachment, repurposing its adhesion-modulating ectodomain against infection.\",\n      \"evidence\": \"Superresolution Gag coclustering with tail-swap mutants; virion infectivity and attachment assays with Env-deleted controls and full-length vs truncated constructs\",\n      \"pmids\": [\"25320329\", \"32193343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length ectodomain requirement shown directly for PSGL-1, inferred for CD43\", \"Physiological impact on HIV transmission in vivo untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD43 integrates its opposing activities\\u2014negative regulation versus costimulation, survival versus apoptosis\\u2014into a single context-dependent decision, and the identity of the nuclear effectors of the released cytoplasmic tail, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model connecting glycoform, clustering state, and signaling outcome\", \"Transcriptional program controlled by the nuclear CD43 tail unknown\", \"Sheddase generating the substrate for \\u03b3-secretase unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 2, 4, 39]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 6, 16, 7, 11]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [29, 9]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 28, 8, 29]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [29, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 11, 16, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6, 7, 16]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 2, 18, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [20, 24, 34]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FYN\", \"CD3Z\", \"LCK\", \"ICAM1\", \"SIGLEC1\", \"SELE\", \"LGALS1\", \"EZR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}