{"gene":"SIGLEC10","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2001,"finding":"Siglec-10 is a sialic acid-binding inhibitory receptor containing five extracellular Ig-like domains and a cytoplasmic tail with ITIM signaling motifs; the expressed protein mediates sialic acid-dependent binding to human erythrocytes and soluble sialoglycoconjugates, and is detected on eosinophils, monocytes, and NK-like cells.","method":"cDNA cloning, expression in COS-7 cells, binding assays with erythrocytes and sialoglycoconjugates, flow cytometry with specific antibodies","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (expression, binding assay, flow cytometry) in founding characterization paper, independently replicated by two other groups same year (PMIDs 11733002, 11358961)","pmids":["11284738"],"is_preprint":false},{"year":2001,"finding":"The cytoplasmic ITIM tyrosines Y597 and Y667 of Siglec-10 are the principal phosphorylation sites; SHP-1 interacts with Y667 and SHP-2 interacts with Y667 and an additional tyrosine, indicating inhibitory signaling analogous to CD33.","method":"In vitro kinase assay with wild-type and Y→F mutant cytoplasmic domain constructs; cell extract co-precipitation","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis plus cell-extract interaction data, single lab but multiple orthogonal methods","pmids":["11733002"],"is_preprint":false},{"year":2001,"finding":"Siglec-10 expressed on COS-7 cells binds human red blood cells and soluble sialoglycoconjugates in a sialic acid-dependent manner, consistent with its V-set domain mediating lectin activity.","method":"Transfection of COS-7 cells with Siglec-10 cDNA; erythrocyte binding assay; inhibition with sialic acid","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding assay with sialic acid-dependent inhibition, replicated across multiple labs same year","pmids":["11358961"],"is_preprint":false},{"year":2002,"finding":"SHP-1 recruitment to the Siglec-10 cytoplasmic tail requires tyrosine phosphorylation and is mediated specifically through ITIM tyrosine Y609 and the N-terminal SH2 domain of SHP-1; Siglec-10 does not bind SAP/SH2D1A, distinguishing the CD150-like motif as a docking site for other mediators.","method":"Yeast three-hybrid cloning of splice variant; Western blot; ITIM mutational analysis (Y→F substitutions); SH2-domain pulldown","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus direct binding assay in single lab with multiple orthogonal methods","pmids":["12163025"],"is_preprint":false},{"year":2009,"finding":"CD24 associates with the DAMPs HMGB1, HSP70, and HSP90, negatively regulates their stimulatory activity, and inhibits NF-κB activation; this occurs through CD24 association with Siglec-10 (in humans) or Siglec-G (in mice), selectively suppressing danger- but not pathogen-associated molecular pattern-triggered innate immune responses.","method":"CD24-deficient mouse model; co-immunoprecipitation; NF-κB reporter assays; genetic epistasis (CD24-KO × DAMP challenge vs. PAMP challenge)","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotypic readout, Co-IP of complex, epistasis analysis, replicated across danger vs. pathogen stimuli","pmids":["19264983"],"is_preprint":false},{"year":2009,"finding":"Siglec-10 functions as a leukocyte ligand for endothelial VAP-1 (SSAO enzyme); binding was identified by phage display and confirmed by adhesion assays and molecular modeling; interaction leads to increased hydrogen peroxide production, indicating Siglec-10 serves as a VAP-1 substrate.","method":"Phage display screening; cell adhesion assays; molecular modeling; hydrogen peroxide production assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phage display identification confirmed by independent adhesion assays and enzymatic read-out, single lab","pmids":["19861682"],"is_preprint":false},{"year":2013,"finding":"Soluble CD52, released from activated T cells by phospholipase C cleavage, binds to Siglec-10 on T cells and impairs phosphorylation of TCR-associated kinases Lck and Zap70, thereby suppressing T cell activation.","method":"Co-immunoprecipitation; phosphorylation assays (Lck, Zap70); soluble CD52 binding to Siglec-10 on T cells; phospholipase C treatment","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, kinase phosphorylation assay, functional suppression readout, single lab with multiple orthogonal methods","pmids":["23685786"],"is_preprint":false},{"year":2014,"finding":"Pseudaminic acid residues on Campylobacter jejuni flagellin (FlaA) bind to Siglec-10 on dendritic cells; Siglec-10 overexpression in cells infected with C. jejuni increases IL-10 expression in a p38 MAPK-dependent manner, establishing a novel anti-inflammatory flagellin–host receptor axis.","method":"C. jejuni isogenic flagellin mutants; Siglec-10 overexpression in cell lines; IL-10 ELISA; p38 inhibitor experiments; direct binding assay with purified flagellum","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic mutants, overexpression, pharmacological inhibition, single lab","pmids":["24823621"],"is_preprint":false},{"year":2018,"finding":"CD52-mediated T cell suppression via Siglec-10 requires HMGB1 as a bridging molecule: CD52-Fc binds specifically to the proinflammatory Box B domain of HMGB1, which promotes engagement of the CD52 N-linked glycan (α-2,3 sialic acid linked to galactose) with Siglec-10; this triggers Siglec-10 tyrosine phosphorylation, SHP1 recruitment to the Siglec-10 ITIM, and physical association of the complex with the TCR.","method":"Co-immunoprecipitation (Siglec-10/HMGB1/SHP1/TCR complex); domain-mapping with Box A vs. Box B HMGB1 constructs; anti-HMGB1 antibody blocking; Siglec-10 phosphorylation assay; glycan-binding specificity (EDTA, α-2,3 sialic acid)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain-mapping mutagenesis equivalent, phosphorylation assay, multiple orthogonal blocking experiments, builds on prior PMID:23685786","pmids":["29997173"],"is_preprint":false},{"year":2019,"finding":"CD24 acts as an anti-phagocytic 'don't eat me' signal on tumor cells by engaging Siglec-10 on tumor-associated macrophages; genetic ablation of either CD24 or Siglec-10, or antibody blockade of their interaction, robustly augments macrophage phagocytosis of CD24-expressing human tumors and reduces tumor growth in vivo.","method":"Genetic ablation (CRISPR KO of CD24 or Siglec-10); monoclonal antibody blockade; phagocytosis assay; in vivo xenograft tumor models; macrophage depletion","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO of both receptor and ligand, antibody blockade, in vivo tumor model, macrophage depletion, multiple orthogonal methods","pmids":["31367043"],"is_preprint":false},{"year":2016,"finding":"Placental CD24 interacts with Siglec-10 via terminal sialic acid glycan residues in an EDTA-sensitive manner; CD24 does not interact with Siglec-3 or Siglec-5, establishing selectivity of the CD24–Siglec-10 interaction; co-localization of CD24 and Siglec-10 was observed in first-trimester decidual cells at the fetal–maternal interface.","method":"Affinity purification of placental CD24; ELISA-based binding assay with recombinant Siglecs; EDTA inhibition; immunohistochemistry and immunofluorescence co-localization","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with specificity controls (Siglec-3, -5), EDTA inhibition, single lab","pmids":["28012129"],"is_preprint":false},{"year":2017,"finding":"Porcine Siglec-10 functions as an alternative receptor for PRRSV entry; Siglec-10 expression in CD163-transfected PK15 cells significantly enhances PRRSV infection and production, and Siglec-10 mediates endocytosis of the virus.","method":"Transfection of PK15 cells with porcine Siglec-10 + CD163; virus infection and production assays (TCID50); endocytosis assay","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in transfected cells, endocytosis assay, single lab","pmids":["28742001"],"is_preprint":false},{"year":2020,"finding":"The R47Q substitution (but not A108V alone) in the ligand-binding V-set domain of Siglec-10 impairs ganglioside binding, as shown by recombinant protein binding assays; homology modeling revealed marked alteration in the ligand-binding site at position 47.","method":"Recombinant Siglec-10 protein with R47Q and A108V variants; ganglioside binding assay; homology modeling of ligand-binding site","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — recombinant protein binding assay with defined point mutant, single lab, structural modeling corroborating","pmids":["33223341"],"is_preprint":false},{"year":2020,"finding":"Siglec-10 molecular recognition of sialoglycans was characterized by combined NMR spectroscopy (STD-NMR), computational modeling, and biophysical approaches; Siglec-10 binds α2,3- and α2,6-linked sialoglycans with defined epitope-mapping and conformational features, providing the first structural insights into its glycan recognition mechanism.","method":"STD-NMR; computational (MD simulations, docking); biophysical binding assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biophysical/structural approaches, but no crystal structure and single lab","pmids":["32629603"],"is_preprint":false},{"year":2023,"finding":"SIGLEC10 in macrophages suppresses CD8+ T cell proliferation and function via the Akt/P38/Erk signaling pathway; SIGLEC10 blockade promotes CD8+ T cell effector function in ex vivo and in vivo models.","method":"In vitro co-culture of SIGLEC10+ macrophages with CD8+ T cells; signaling pathway inhibitors; ex vivo tumor models; in vivo blockade","journal":"Cancer immunology, immunotherapy : CII","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional co-culture assays with signaling readouts, ex vivo and in vivo validation, single lab","pmids":["37432407"],"is_preprint":false},{"year":2024,"finding":"Bacterial pseudaminic acid (Pse) on exopolysaccharide engages Siglec-10 on macrophages via the 7-N-acetyl group of Pse, stimulating IL-10 secretion that suppresses phagocytosis; blockade of Pse–Siglec-10 interaction with Pse-binding protein reverses this effect.","method":"Pse-Siglec-10 binding assay; IL-10 ELISA; phagocytosis assay; blocking with Pse-binding protein","journal":"Chemical communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay, functional IL-10 and phagocytosis readouts, ligand-blocking reversal, single lab","pmids":["38372418"],"is_preprint":false},{"year":2024,"finding":"Siglec-10 on dendritic cells in cervical cancer senses aberrant sialylated structures on tumor cells, inducing transformation of conventional DCs into immunotolerant phenotypes; Siglec-10+ DCs suppress adaptive T cells via galectin-9 signaling; Siglec-10 blockade restores DC-mediated tumoricidal responses.","method":"Single-cell RNA sequencing; patient-derived tumor fragment platform; Siglec-10 blockade assays; T cell activation readouts","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq, ex vivo tumor fragment functional blockade, single lab","pmids":["39209455"],"is_preprint":false},{"year":2024,"finding":"CLL cells suppress CAR T cell function via surface expression of Siglec-10 ligands CD24 and CD52; blocking CD24 and/or CD52 markedly reduces CAR T cell dysfunction upon co-culture, and CD40 activation of CLL cells downregulates these ligands via an SRC kinase-dependent pathway.","method":"Co-culture of CLL cells with CAR T cells; CD40 stimulation; SRC kinase inhibitor (dasatinib); antibody blockade of CD24/CD52; transcriptome profiling","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional co-culture assay, pharmacological inhibition, antibody blockade, transcriptomic validation, single lab","pmids":["39042920"],"is_preprint":false},{"year":2025,"finding":"PU.1 transcription factor in macrophages directly targets and transcriptionally activates Siglec-10 expression (demonstrated by luciferase and ChIP assays), suppressing macrophage phagocytosis; PU.1 knockdown in macrophages increases phagocytic activity and inhibits glioma growth in vivo.","method":"Luciferase reporter assay; chromatin immunoprecipitation (ChIP); PU.1 knockdown; phagocytosis assay; in vivo glioma model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct transcriptional regulation, functional KD with phenotypic readout, single lab","pmids":["41115355"],"is_preprint":false},{"year":2026,"finding":"Crystal structures of Siglec-10 bound to α2,3- and α2,6-sialyllactose reveal that domain 1 (D1) engages sialylated ligands via a non-conserved, selectivity-determining CC' loop; Siglec-10 homodimerization is mediated by a hydrophobic domain 2 (D2) interface, and mutation of the D2 interface ablates cellular binding equivalently to mutations in the CC' loop and glycan-binding site.","method":"X-ray crystallography (Siglec-10/sialyllactose complex); mutagenesis of D2 dimerization interface and CC' loop; cell-based binding assays; CD24 KO binding experiments","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis of multiple sites, cell-based binding validation, and CD24-KO negative control establishing broader ligand profile","pmids":["41747717"],"is_preprint":false},{"year":2026,"finding":"Integrin α3β1 (composed of ITGA3 and ITGB1) on pancreatic ductal adenocarcinoma (PDAC) cells is a sialylated glycoprotein ligand for Siglec-10 on tumor-associated macrophages; this interaction suppresses macrophage-mediated phagocytosis; antibody blockade of Siglec-10 enhances phagocytosis in vitro and reduces tumor growth in xenograft and human Siglec-10 transgenic mouse models.","method":"Ligand identification (glycoproteomic/interaction approach); co-culture phagocytosis assay; monoclonal antibody blockade; PDAC xenograft with human macrophages; human Siglec-10 transgenic mouse model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — identified novel ligand, functional phagocytosis assay with blockade, two independent in vivo models, multiple orthogonal approaches","pmids":["41182080"],"is_preprint":false},{"year":2025,"finding":"Crystal structure of the Siglec-10 extracellular domain in complex with α2-6 sialyllactose identified two key arginine residues (R119 and R127) in the binding site that interact with the sialic acid carboxyl group; STD-NMR confirmed R119 is essential for sialoglycan binding in solution, while R127 is dispensable in solution but required for cellular recognition on primary human T cells and engineered monocytic lines; super-resolution microscopy revealed glycan-independent Siglec-10 dimerization on human monocytes; proximity labeling/MS identified additional sialylated glycoproteins as Siglec-10 ligands on T cells beyond CD24.","method":"X-ray crystallography; STD-NMR; point mutagenesis (R119A, R127A); cell-based binding assays on primary T cells and monocytes; super-resolution microscopy; proximity labeling + mass spectrometry","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus NMR plus mutagenesis plus cell-based validation plus proximity proteomics, multiple orthogonal methods in single preprint study","pmids":[],"is_preprint":true},{"year":2024,"finding":"Soluble CD52 immunosuppressive function via Siglec-10 requires hyper-sialylated glycans; the N-linked glycan at N3 with α-2,3-linked sialic acid is essential for Siglec-10 binding; molecular dynamics simulations defined specific interactions between CD52 glycans and the Box B domain of HMGB1 that stabilize the CD52/HMGB1 complex required for Siglec-10 engagement.","method":"High-resolution mass spectrometry of CD52 glycopeptides; molecular dynamics simulation of CD52/HMGB1/Siglec-10 ternary complex; glycan characterization","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — detailed glycan MS characterization plus MD simulation, but preprint and primarily computational/structural without new functional cellular assay","pmids":[],"is_preprint":true}],"current_model":"Siglec-10 is a sialic acid-binding inhibitory receptor expressed on innate and adaptive immune cells that engages sialylated ligands (including CD24, CD52/HMGB1, integrin α3β1, bacterial pseudaminic acid, and VAP-1) through a CC'-loop-dependent V-set domain and homodimerizes via a domain 2 hydrophobic interface; upon ligand engagement its ITIM tyrosines (principally Y609/Y667) are phosphorylated, recruiting SHP-1 (via its N-terminal SH2 domain) and SHP-2 to suppress downstream kinase signaling (Lck, Zap70, Akt/p38/Erk), thereby inhibiting phagocytosis by macrophages, suppressing T cell activation, dampening danger-associated molecular pattern (DAMP)-triggered NF-κB responses, and facilitating immune evasion by tumors; the transcription factor PU.1 directly drives Siglec-10 expression in macrophages, and PRRSV exploits Siglec-10 as an endocytic entry receptor."},"narrative":{"mechanistic_narrative":"Siglec-10 is a sialic acid-binding inhibitory receptor of the immune system that couples recognition of sialylated ligands on host and tumor cells to suppression of phagocytic, T cell, and innate inflammatory responses [PMID:11284738, PMID:31367043]. Its membrane-distal V-set domain mediates calcium-dependent lectin activity toward both α2,3- and α2,6-linked sialoglycans, with crystallographic and NMR analyses localizing recognition to a non-conserved, selectivity-determining CC' loop and to binding-site arginines (R119, R127) that contact the sialic acid carboxyl group, while a hydrophobic domain 2 interface drives glycan-independent homodimerization required for cellular ligand engagement [PMID:41747717, PMID:32629603]. Upon ligand binding, the cytoplasmic ITIM tyrosines are phosphorylated and recruit the phosphatases SHP-1 (via its N-terminal SH2 domain) and SHP-2, transducing the inhibitory signal in a manner analogous to other CD33-related Siglecs [PMID:11733002, PMID:12163025]. Through these signals Siglec-10 enforces immune tolerance across multiple contexts: the receptor binds CD24 to deliver an anti-phagocytic 'don't eat me' signal that lets tumors evade macrophages [PMID:31367043], cooperates with HMGB1 to suppress DAMP-triggered NF-κB responses [PMID:19264983], and engages soluble CD52 (bridged by HMGB1) to block TCR-proximal Lck and Zap70 phosphorylation and dampen T cell activation [PMID:23685786, PMID:29997173]. Additional sialylated ligands including integrin α3β1, endothelial VAP-1, and microbial pseudaminic acid extend this inhibitory axis to tumor-associated macrophages, leukocyte adhesion, and anti-inflammatory responses to bacterial flagellin [PMID:41182080, PMID:19861682, PMID:24823621, PMID:38372418]. Siglec-10 expression in macrophages is directly activated by the transcription factor PU.1, and the receptor is co-opted as an endocytic entry receptor by PRRSV [PMID:41115355, PMID:28742001].","teleology":[{"year":2001,"claim":"Established the founding identity of Siglec-10 as a sialic acid-binding inhibitory receptor, answering what kind of molecule it is and where it acts.","evidence":"cDNA cloning and expression in COS-7 cells with erythrocyte/sialoglycoconjugate binding assays and flow cytometry, replicated across labs","pmids":["11284738","11358961"],"confidence":"High","gaps":["Structural basis of glycan recognition not defined","Physiological ligands and signaling consequences unknown"]},{"year":2001,"claim":"Defined the intracellular signaling logic by mapping the ITIM tyrosines and showing they recruit the inhibitory phosphatases SHP-1 and SHP-2.","evidence":"In vitro kinase assays with Y→F cytoplasmic mutants and cell-extract co-precipitation; SH2-domain pulldown mapping SHP-1 to a specific ITIM tyrosine","pmids":["11733002","12163025"],"confidence":"High","gaps":["Tyrosine numbering conventions differ across studies","Cellular signaling outputs downstream of phosphatase recruitment not yet established"]},{"year":2009,"claim":"Connected Siglec-10 to selective suppression of danger-signal immunity, showing it partners with CD24 to dampen DAMP- but not PAMP-triggered NF-κB responses.","evidence":"CD24-deficient mouse model, co-immunoprecipitation of CD24 with Siglec-10/Siglec-G, NF-κB reporter and danger-vs-pathogen epistasis","pmids":["19264983"],"confidence":"High","gaps":["Precise glycan epitope on CD24 not defined here","Direct phosphatase engagement in this pathway not measured"]},{"year":2009,"claim":"Extended Siglec-10's ligand repertoire to the endothelial enzyme VAP-1, implicating it in leukocyte adhesion and oxidative signaling.","evidence":"Phage display screening, adhesion assays, molecular modeling, and hydrogen peroxide production readout","pmids":["19861682"],"confidence":"Medium","gaps":["Single lab without structural confirmation of the interface","Physiological relevance in vivo not established"]},{"year":2013,"claim":"Identified soluble CD52 as a Siglec-10 ligand that suppresses T cell activation, linking the receptor to TCR-proximal kinase inhibition.","evidence":"Co-IP, Lck/Zap70 phosphorylation assays, and phospholipase C-mediated CD52 release with binding to Siglec-10 on T cells","pmids":["23685786"],"confidence":"High","gaps":["Mechanism bridging CD52 to Siglec-10 not yet resolved","Single-lab functional data"]},{"year":2014,"claim":"Demonstrated that microbial sialic-acid mimics (pseudaminic acid on C. jejuni flagellin) exploit Siglec-10 to drive anti-inflammatory IL-10, revealing pathogen subversion of the receptor.","evidence":"Isogenic flagellin mutants, Siglec-10 overexpression, IL-10 ELISA, and p38 inhibitor experiments with purified flagellum binding","pmids":["24823621"],"confidence":"Medium","gaps":["Relies on overexpression rather than endogenous receptor","ITIM/phosphatase requirement not tested"]},{"year":2016,"claim":"Established selectivity and tissue context of the CD24–Siglec-10 interaction at the fetal-maternal interface.","evidence":"Affinity-purified placental CD24, ELISA binding to recombinant Siglecs with Siglec-3/-5 negative controls, EDTA inhibition, and co-localization imaging","pmids":["28012129"],"confidence":"Medium","gaps":["Functional consequence at the decidua not tested","Single lab"]},{"year":2018,"claim":"Resolved the CD52 suppression mechanism by showing HMGB1 bridges CD52 glycan to Siglec-10, triggering ITIM phosphorylation, SHP-1 recruitment, and TCR association.","evidence":"Reciprocal Co-IP of the Siglec-10/HMGB1/SHP1/TCR complex, HMGB1 Box A vs Box B domain mapping, antibody blocking, and α2,3-sialic-acid glycan specificity","pmids":["29997173"],"confidence":"High","gaps":["In vivo relevance of the ternary complex not shown","Single lab"]},{"year":2019,"claim":"Defined CD24–Siglec-10 as a macrophage 'don't eat me' checkpoint exploited by tumors, establishing therapeutic blockade as a strategy.","evidence":"CRISPR KO of CD24 and Siglec-10, antibody blockade, phagocytosis assays, in vivo xenografts and macrophage depletion","pmids":["31367043"],"confidence":"High","gaps":["Phosphatase-dependence of the anti-phagocytic signal not directly tested here","Range of tumor-cell glycan ligands not enumerated"]},{"year":2020,"claim":"Provided the first structural/biophysical models of Siglec-10 glycan recognition and showed a V-set point mutation (R47Q) impairs ligand binding.","evidence":"STD-NMR, MD simulations and docking for α2,3/α2,6 sialoglycans; recombinant R47Q and A108V variant binding assays with homology modeling","pmids":["32629603","33223341"],"confidence":"Medium","gaps":["No crystal structure at this stage","Functional consequences of variants in primary cells not tested"]},{"year":2023,"claim":"Linked macrophage Siglec-10 to suppression of CD8+ T cell function via Akt/p38/Erk signaling, broadening its role in the tumor microenvironment.","evidence":"Macrophage–CD8 T cell co-culture, signaling inhibitors, ex vivo and in vivo blockade","pmids":["37432407"],"confidence":"Medium","gaps":["Receptor-intrinsic signaling steps not dissected","Single lab"]},{"year":2024,"claim":"Expanded the ligand and disease repertoire to dendritic-cell tolerance (galectin-9), CLL CAR-T suppression (CD24/CD52), and macrophage pseudaminic-acid sensing driving IL-10 and phagocytosis blockade.","evidence":"scRNA-seq and tumor-fragment blockade in cervical cancer; CLL/CAR-T co-culture with CD40 stimulation and SRC inhibition; Pse–Siglec-10 binding, IL-10 ELISA and phagocytosis assays with ligand blockade","pmids":["39209455","39042920","38372418"],"confidence":"Medium","gaps":["Mechanistic coupling of these ligands to ITIM signaling not directly shown","Each finding from a single lab"]},{"year":2025,"claim":"Identified PU.1 as a direct transcriptional driver of macrophage Siglec-10, explaining how its expression is established and linking it to phagocytic control of glioma.","evidence":"Luciferase reporter and ChIP assays, PU.1 knockdown, phagocytosis assays, in vivo glioma model","pmids":["41115355"],"confidence":"Medium","gaps":["Other transcriptional regulators not assessed","Single lab"]},{"year":2026,"claim":"Delivered the crystallographic basis of ligand selectivity and dimerization, showing the CC' loop determines glycan selectivity and a D2 hydrophobic interface mediates homodimerization essential for cellular binding.","evidence":"X-ray structures of Siglec-10/sialyllactose complexes with mutagenesis of the CC' loop, glycan site, and D2 interface, plus cell-based and CD24-KO binding validation","pmids":["41747717"],"confidence":"High","gaps":["How dimerization is regulated on the cell surface in physiological signaling not fully defined"]},{"year":2026,"claim":"Identified integrin α3β1 as a sialylated tumor-cell ligand engaging macrophage Siglec-10 to block phagocytosis in PDAC, validated in humanized models.","evidence":"Glycoproteomic ligand identification, co-culture phagocytosis assays, antibody blockade, PDAC xenografts and human Siglec-10 transgenic mice","pmids":["41182080"],"confidence":"High","gaps":["Relative contribution of integrin α3β1 vs CD24 in different tumors not ranked","Downstream phosphatase signaling not dissected here"]},{"year":2025,"claim":"Refined the structural binding mechanism, defining arginines R119/R127 with distinct solution vs cellular roles, demonstrating glycan-independent dimerization on monocytes, and identifying additional T-cell sialoglycoprotein ligands beyond CD24.","evidence":"X-ray crystallography with α2,6-sialyllactose, STD-NMR, R119A/R127A mutagenesis, cell binding on primary T cells and monocytes, super-resolution microscopy, and proximity-labeling MS (preprint)","pmids":[],"confidence":"High","gaps":["Preprint not yet peer-reviewed","Identity and function of the newly mapped T-cell ligands not yet characterized"]},{"year":null,"claim":"How the multiple ligand engagements, surface dimerization state, and ITIM/SHP signaling are quantitatively integrated to set inhibitory thresholds across distinct cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking ligand identity to differential phosphatase output","Cell-type-specific signaling logic not mapped","In vivo hierarchy of competing ligands unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,8]}],"complexes":[],"partners":["CD24","CD52","HMGB1","SHP-1","SHP-2","VAP-1","ITGA3","ITGB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96LC7","full_name":"Sialic acid-binding Ig-like lectin 10","aliases":["Siglec-like protein 2"],"length_aa":697,"mass_kda":76.6,"function":"Putative adhesion molecule that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,3- or alpha-2,6-linked sialic acid (By similarity). The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface. In the immune response, seems to act as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules (PubMed:11284738, PubMed:12163025). Involved in negative regulation of B-cell antigen receptor signaling. The inhibition of B cell activation is dependent on PTPN6/SHP-1 (By similarity). In association with CD24 may be involved in the selective suppression of the immune response to danger-associated molecular patterns (DAMPs) such as HMGB1, HSP70 and HSP90 (By similarity). In association with CD24 may regulate the immune repsonse of natural killer (NK) cells (PubMed:25450598). Plays a role in the control of autoimmunity (By similarity). During initiation of adaptive immune responses by CD8-alpha(+) dendritic cells inhibits cross-presentation by impairing the formation of MHC class I-peptide complexes. The function seems to implicate recruitment of PTPN6/SHP-1, which dephosphorylates NCF1 of the NADPH oxidase complex consequently promoting phagosomal acidification (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q96LC7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIGLEC10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SIGLEC10","total_profiled":1310},"omim":[{"mim_id":"606091","title":"SIALIC ACID-BINDING IMMUNOGLOBULIN-LIKE LECTIN 10; SIGLEC10","url":"https://www.omim.org/entry/606091"},{"mim_id":"600074","title":"CD24 ANTIGEN; CD24","url":"https://www.omim.org/entry/600074"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid 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acid-binding inhibitory receptor containing five extracellular Ig-like domains and a cytoplasmic tail with ITIM signaling motifs; the expressed protein mediates sialic acid-dependent binding to human erythrocytes and soluble sialoglycoconjugates, and is detected on eosinophils, monocytes, and NK-like cells.\",\n      \"method\": \"cDNA cloning, expression in COS-7 cells, binding assays with erythrocytes and sialoglycoconjugates, flow cytometry with specific antibodies\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (expression, binding assay, flow cytometry) in founding characterization paper, independently replicated by two other groups same year (PMIDs 11733002, 11358961)\",\n      \"pmids\": [\"11284738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The cytoplasmic ITIM tyrosines Y597 and Y667 of Siglec-10 are the principal phosphorylation sites; SHP-1 interacts with Y667 and SHP-2 interacts with Y667 and an additional tyrosine, indicating inhibitory signaling analogous to CD33.\",\n      \"method\": \"In vitro kinase assay with wild-type and Y→F mutant cytoplasmic domain constructs; cell extract co-precipitation\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis plus cell-extract interaction data, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11733002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Siglec-10 expressed on COS-7 cells binds human red blood cells and soluble sialoglycoconjugates in a sialic acid-dependent manner, consistent with its V-set domain mediating lectin activity.\",\n      \"method\": \"Transfection of COS-7 cells with Siglec-10 cDNA; erythrocyte binding assay; inhibition with sialic acid\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding assay with sialic acid-dependent inhibition, replicated across multiple labs same year\",\n      \"pmids\": [\"11358961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SHP-1 recruitment to the Siglec-10 cytoplasmic tail requires tyrosine phosphorylation and is mediated specifically through ITIM tyrosine Y609 and the N-terminal SH2 domain of SHP-1; Siglec-10 does not bind SAP/SH2D1A, distinguishing the CD150-like motif as a docking site for other mediators.\",\n      \"method\": \"Yeast three-hybrid cloning of splice variant; Western blot; ITIM mutational analysis (Y→F substitutions); SH2-domain pulldown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus direct binding assay in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12163025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD24 associates with the DAMPs HMGB1, HSP70, and HSP90, negatively regulates their stimulatory activity, and inhibits NF-κB activation; this occurs through CD24 association with Siglec-10 (in humans) or Siglec-G (in mice), selectively suppressing danger- but not pathogen-associated molecular pattern-triggered innate immune responses.\",\n      \"method\": \"CD24-deficient mouse model; co-immunoprecipitation; NF-κB reporter assays; genetic epistasis (CD24-KO × DAMP challenge vs. PAMP challenge)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotypic readout, Co-IP of complex, epistasis analysis, replicated across danger vs. pathogen stimuli\",\n      \"pmids\": [\"19264983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Siglec-10 functions as a leukocyte ligand for endothelial VAP-1 (SSAO enzyme); binding was identified by phage display and confirmed by adhesion assays and molecular modeling; interaction leads to increased hydrogen peroxide production, indicating Siglec-10 serves as a VAP-1 substrate.\",\n      \"method\": \"Phage display screening; cell adhesion assays; molecular modeling; hydrogen peroxide production assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phage display identification confirmed by independent adhesion assays and enzymatic read-out, single lab\",\n      \"pmids\": [\"19861682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Soluble CD52, released from activated T cells by phospholipase C cleavage, binds to Siglec-10 on T cells and impairs phosphorylation of TCR-associated kinases Lck and Zap70, thereby suppressing T cell activation.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assays (Lck, Zap70); soluble CD52 binding to Siglec-10 on T cells; phospholipase C treatment\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, kinase phosphorylation assay, functional suppression readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23685786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pseudaminic acid residues on Campylobacter jejuni flagellin (FlaA) bind to Siglec-10 on dendritic cells; Siglec-10 overexpression in cells infected with C. jejuni increases IL-10 expression in a p38 MAPK-dependent manner, establishing a novel anti-inflammatory flagellin–host receptor axis.\",\n      \"method\": \"C. jejuni isogenic flagellin mutants; Siglec-10 overexpression in cell lines; IL-10 ELISA; p38 inhibitor experiments; direct binding assay with purified flagellum\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic mutants, overexpression, pharmacological inhibition, single lab\",\n      \"pmids\": [\"24823621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD52-mediated T cell suppression via Siglec-10 requires HMGB1 as a bridging molecule: CD52-Fc binds specifically to the proinflammatory Box B domain of HMGB1, which promotes engagement of the CD52 N-linked glycan (α-2,3 sialic acid linked to galactose) with Siglec-10; this triggers Siglec-10 tyrosine phosphorylation, SHP1 recruitment to the Siglec-10 ITIM, and physical association of the complex with the TCR.\",\n      \"method\": \"Co-immunoprecipitation (Siglec-10/HMGB1/SHP1/TCR complex); domain-mapping with Box A vs. Box B HMGB1 constructs; anti-HMGB1 antibody blocking; Siglec-10 phosphorylation assay; glycan-binding specificity (EDTA, α-2,3 sialic acid)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain-mapping mutagenesis equivalent, phosphorylation assay, multiple orthogonal blocking experiments, builds on prior PMID:23685786\",\n      \"pmids\": [\"29997173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD24 acts as an anti-phagocytic 'don't eat me' signal on tumor cells by engaging Siglec-10 on tumor-associated macrophages; genetic ablation of either CD24 or Siglec-10, or antibody blockade of their interaction, robustly augments macrophage phagocytosis of CD24-expressing human tumors and reduces tumor growth in vivo.\",\n      \"method\": \"Genetic ablation (CRISPR KO of CD24 or Siglec-10); monoclonal antibody blockade; phagocytosis assay; in vivo xenograft tumor models; macrophage depletion\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO of both receptor and ligand, antibody blockade, in vivo tumor model, macrophage depletion, multiple orthogonal methods\",\n      \"pmids\": [\"31367043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Placental CD24 interacts with Siglec-10 via terminal sialic acid glycan residues in an EDTA-sensitive manner; CD24 does not interact with Siglec-3 or Siglec-5, establishing selectivity of the CD24–Siglec-10 interaction; co-localization of CD24 and Siglec-10 was observed in first-trimester decidual cells at the fetal–maternal interface.\",\n      \"method\": \"Affinity purification of placental CD24; ELISA-based binding assay with recombinant Siglecs; EDTA inhibition; immunohistochemistry and immunofluorescence co-localization\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with specificity controls (Siglec-3, -5), EDTA inhibition, single lab\",\n      \"pmids\": [\"28012129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Porcine Siglec-10 functions as an alternative receptor for PRRSV entry; Siglec-10 expression in CD163-transfected PK15 cells significantly enhances PRRSV infection and production, and Siglec-10 mediates endocytosis of the virus.\",\n      \"method\": \"Transfection of PK15 cells with porcine Siglec-10 + CD163; virus infection and production assays (TCID50); endocytosis assay\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in transfected cells, endocytosis assay, single lab\",\n      \"pmids\": [\"28742001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The R47Q substitution (but not A108V alone) in the ligand-binding V-set domain of Siglec-10 impairs ganglioside binding, as shown by recombinant protein binding assays; homology modeling revealed marked alteration in the ligand-binding site at position 47.\",\n      \"method\": \"Recombinant Siglec-10 protein with R47Q and A108V variants; ganglioside binding assay; homology modeling of ligand-binding site\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — recombinant protein binding assay with defined point mutant, single lab, structural modeling corroborating\",\n      \"pmids\": [\"33223341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Siglec-10 molecular recognition of sialoglycans was characterized by combined NMR spectroscopy (STD-NMR), computational modeling, and biophysical approaches; Siglec-10 binds α2,3- and α2,6-linked sialoglycans with defined epitope-mapping and conformational features, providing the first structural insights into its glycan recognition mechanism.\",\n      \"method\": \"STD-NMR; computational (MD simulations, docking); biophysical binding assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biophysical/structural approaches, but no crystal structure and single lab\",\n      \"pmids\": [\"32629603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIGLEC10 in macrophages suppresses CD8+ T cell proliferation and function via the Akt/P38/Erk signaling pathway; SIGLEC10 blockade promotes CD8+ T cell effector function in ex vivo and in vivo models.\",\n      \"method\": \"In vitro co-culture of SIGLEC10+ macrophages with CD8+ T cells; signaling pathway inhibitors; ex vivo tumor models; in vivo blockade\",\n      \"journal\": \"Cancer immunology, immunotherapy : CII\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional co-culture assays with signaling readouts, ex vivo and in vivo validation, single lab\",\n      \"pmids\": [\"37432407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Bacterial pseudaminic acid (Pse) on exopolysaccharide engages Siglec-10 on macrophages via the 7-N-acetyl group of Pse, stimulating IL-10 secretion that suppresses phagocytosis; blockade of Pse–Siglec-10 interaction with Pse-binding protein reverses this effect.\",\n      \"method\": \"Pse-Siglec-10 binding assay; IL-10 ELISA; phagocytosis assay; blocking with Pse-binding protein\",\n      \"journal\": \"Chemical communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay, functional IL-10 and phagocytosis readouts, ligand-blocking reversal, single lab\",\n      \"pmids\": [\"38372418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Siglec-10 on dendritic cells in cervical cancer senses aberrant sialylated structures on tumor cells, inducing transformation of conventional DCs into immunotolerant phenotypes; Siglec-10+ DCs suppress adaptive T cells via galectin-9 signaling; Siglec-10 blockade restores DC-mediated tumoricidal responses.\",\n      \"method\": \"Single-cell RNA sequencing; patient-derived tumor fragment platform; Siglec-10 blockade assays; T cell activation readouts\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq, ex vivo tumor fragment functional blockade, single lab\",\n      \"pmids\": [\"39209455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CLL cells suppress CAR T cell function via surface expression of Siglec-10 ligands CD24 and CD52; blocking CD24 and/or CD52 markedly reduces CAR T cell dysfunction upon co-culture, and CD40 activation of CLL cells downregulates these ligands via an SRC kinase-dependent pathway.\",\n      \"method\": \"Co-culture of CLL cells with CAR T cells; CD40 stimulation; SRC kinase inhibitor (dasatinib); antibody blockade of CD24/CD52; transcriptome profiling\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional co-culture assay, pharmacological inhibition, antibody blockade, transcriptomic validation, single lab\",\n      \"pmids\": [\"39042920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PU.1 transcription factor in macrophages directly targets and transcriptionally activates Siglec-10 expression (demonstrated by luciferase and ChIP assays), suppressing macrophage phagocytosis; PU.1 knockdown in macrophages increases phagocytic activity and inhibits glioma growth in vivo.\",\n      \"method\": \"Luciferase reporter assay; chromatin immunoprecipitation (ChIP); PU.1 knockdown; phagocytosis assay; in vivo glioma model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct transcriptional regulation, functional KD with phenotypic readout, single lab\",\n      \"pmids\": [\"41115355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Crystal structures of Siglec-10 bound to α2,3- and α2,6-sialyllactose reveal that domain 1 (D1) engages sialylated ligands via a non-conserved, selectivity-determining CC' loop; Siglec-10 homodimerization is mediated by a hydrophobic domain 2 (D2) interface, and mutation of the D2 interface ablates cellular binding equivalently to mutations in the CC' loop and glycan-binding site.\",\n      \"method\": \"X-ray crystallography (Siglec-10/sialyllactose complex); mutagenesis of D2 dimerization interface and CC' loop; cell-based binding assays; CD24 KO binding experiments\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis of multiple sites, cell-based binding validation, and CD24-KO negative control establishing broader ligand profile\",\n      \"pmids\": [\"41747717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Integrin α3β1 (composed of ITGA3 and ITGB1) on pancreatic ductal adenocarcinoma (PDAC) cells is a sialylated glycoprotein ligand for Siglec-10 on tumor-associated macrophages; this interaction suppresses macrophage-mediated phagocytosis; antibody blockade of Siglec-10 enhances phagocytosis in vitro and reduces tumor growth in xenograft and human Siglec-10 transgenic mouse models.\",\n      \"method\": \"Ligand identification (glycoproteomic/interaction approach); co-culture phagocytosis assay; monoclonal antibody blockade; PDAC xenograft with human macrophages; human Siglec-10 transgenic mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identified novel ligand, functional phagocytosis assay with blockade, two independent in vivo models, multiple orthogonal approaches\",\n      \"pmids\": [\"41182080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structure of the Siglec-10 extracellular domain in complex with α2-6 sialyllactose identified two key arginine residues (R119 and R127) in the binding site that interact with the sialic acid carboxyl group; STD-NMR confirmed R119 is essential for sialoglycan binding in solution, while R127 is dispensable in solution but required for cellular recognition on primary human T cells and engineered monocytic lines; super-resolution microscopy revealed glycan-independent Siglec-10 dimerization on human monocytes; proximity labeling/MS identified additional sialylated glycoproteins as Siglec-10 ligands on T cells beyond CD24.\",\n      \"method\": \"X-ray crystallography; STD-NMR; point mutagenesis (R119A, R127A); cell-based binding assays on primary T cells and monocytes; super-resolution microscopy; proximity labeling + mass spectrometry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus NMR plus mutagenesis plus cell-based validation plus proximity proteomics, multiple orthogonal methods in single preprint study\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Soluble CD52 immunosuppressive function via Siglec-10 requires hyper-sialylated glycans; the N-linked glycan at N3 with α-2,3-linked sialic acid is essential for Siglec-10 binding; molecular dynamics simulations defined specific interactions between CD52 glycans and the Box B domain of HMGB1 that stabilize the CD52/HMGB1 complex required for Siglec-10 engagement.\",\n      \"method\": \"High-resolution mass spectrometry of CD52 glycopeptides; molecular dynamics simulation of CD52/HMGB1/Siglec-10 ternary complex; glycan characterization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — detailed glycan MS characterization plus MD simulation, but preprint and primarily computational/structural without new functional cellular assay\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"Siglec-10 is a sialic acid-binding inhibitory receptor expressed on innate and adaptive immune cells that engages sialylated ligands (including CD24, CD52/HMGB1, integrin α3β1, bacterial pseudaminic acid, and VAP-1) through a CC'-loop-dependent V-set domain and homodimerizes via a domain 2 hydrophobic interface; upon ligand engagement its ITIM tyrosines (principally Y609/Y667) are phosphorylated, recruiting SHP-1 (via its N-terminal SH2 domain) and SHP-2 to suppress downstream kinase signaling (Lck, Zap70, Akt/p38/Erk), thereby inhibiting phagocytosis by macrophages, suppressing T cell activation, dampening danger-associated molecular pattern (DAMP)-triggered NF-κB responses, and facilitating immune evasion by tumors; the transcription factor PU.1 directly drives Siglec-10 expression in macrophages, and PRRSV exploits Siglec-10 as an endocytic entry receptor.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Siglec-10 is a sialic acid-binding inhibitory receptor of the immune system that couples recognition of sialylated ligands on host and tumor cells to suppression of phagocytic, T cell, and innate inflammatory responses [#0, #9]. Its membrane-distal V-set domain mediates calcium-dependent lectin activity toward both α2,3- and α2,6-linked sialoglycans, with crystallographic and NMR analyses localizing recognition to a non-conserved, selectivity-determining CC' loop and to binding-site arginines (R119, R127) that contact the sialic acid carboxyl group, while a hydrophobic domain 2 interface drives glycan-independent homodimerization required for cellular ligand engagement [#19, #21, #13]. Upon ligand binding, the cytoplasmic ITIM tyrosines are phosphorylated and recruit the phosphatases SHP-1 (via its N-terminal SH2 domain) and SHP-2, transducing the inhibitory signal in a manner analogous to other CD33-related Siglecs [#1, #3]. Through these signals Siglec-10 enforces immune tolerance across multiple contexts: the receptor binds CD24 to deliver an anti-phagocytic 'don't eat me' signal that lets tumors evade macrophages [#9], cooperates with HMGB1 to suppress DAMP-triggered NF-κB responses [#4], and engages soluble CD52 (bridged by HMGB1) to block TCR-proximal Lck and Zap70 phosphorylation and dampen T cell activation [#6, #8]. Additional sialylated ligands including integrin α3β1, endothelial VAP-1, and microbial pseudaminic acid extend this inhibitory axis to tumor-associated macrophages, leukocyte adhesion, and anti-inflammatory responses to bacterial flagellin [#20, #5, #7, #15]. Siglec-10 expression in macrophages is directly activated by the transcription factor PU.1, and the receptor is co-opted as an endocytic entry receptor by PRRSV [#18, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the founding identity of Siglec-10 as a sialic acid-binding inhibitory receptor, answering what kind of molecule it is and where it acts.\",\n      \"evidence\": \"cDNA cloning and expression in COS-7 cells with erythrocyte/sialoglycoconjugate binding assays and flow cytometry, replicated across labs\",\n      \"pmids\": [\"11284738\", \"11358961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of glycan recognition not defined\", \"Physiological ligands and signaling consequences unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the intracellular signaling logic by mapping the ITIM tyrosines and showing they recruit the inhibitory phosphatases SHP-1 and SHP-2.\",\n      \"evidence\": \"In vitro kinase assays with Y→F cytoplasmic mutants and cell-extract co-precipitation; SH2-domain pulldown mapping SHP-1 to a specific ITIM tyrosine\",\n      \"pmids\": [\"11733002\", \"12163025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tyrosine numbering conventions differ across studies\", \"Cellular signaling outputs downstream of phosphatase recruitment not yet established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected Siglec-10 to selective suppression of danger-signal immunity, showing it partners with CD24 to dampen DAMP- but not PAMP-triggered NF-κB responses.\",\n      \"evidence\": \"CD24-deficient mouse model, co-immunoprecipitation of CD24 with Siglec-10/Siglec-G, NF-κB reporter and danger-vs-pathogen epistasis\",\n      \"pmids\": [\"19264983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise glycan epitope on CD24 not defined here\", \"Direct phosphatase engagement in this pathway not measured\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended Siglec-10's ligand repertoire to the endothelial enzyme VAP-1, implicating it in leukocyte adhesion and oxidative signaling.\",\n      \"evidence\": \"Phage display screening, adhesion assays, molecular modeling, and hydrogen peroxide production readout\",\n      \"pmids\": [\"19861682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without structural confirmation of the interface\", \"Physiological relevance in vivo not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified soluble CD52 as a Siglec-10 ligand that suppresses T cell activation, linking the receptor to TCR-proximal kinase inhibition.\",\n      \"evidence\": \"Co-IP, Lck/Zap70 phosphorylation assays, and phospholipase C-mediated CD52 release with binding to Siglec-10 on T cells\",\n      \"pmids\": [\"23685786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism bridging CD52 to Siglec-10 not yet resolved\", \"Single-lab functional data\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that microbial sialic-acid mimics (pseudaminic acid on C. jejuni flagellin) exploit Siglec-10 to drive anti-inflammatory IL-10, revealing pathogen subversion of the receptor.\",\n      \"evidence\": \"Isogenic flagellin mutants, Siglec-10 overexpression, IL-10 ELISA, and p38 inhibitor experiments with purified flagellum binding\",\n      \"pmids\": [\"24823621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relies on overexpression rather than endogenous receptor\", \"ITIM/phosphatase requirement not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established selectivity and tissue context of the CD24–Siglec-10 interaction at the fetal-maternal interface.\",\n      \"evidence\": \"Affinity-purified placental CD24, ELISA binding to recombinant Siglecs with Siglec-3/-5 negative controls, EDTA inhibition, and co-localization imaging\",\n      \"pmids\": [\"28012129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence at the decidua not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the CD52 suppression mechanism by showing HMGB1 bridges CD52 glycan to Siglec-10, triggering ITIM phosphorylation, SHP-1 recruitment, and TCR association.\",\n      \"evidence\": \"Reciprocal Co-IP of the Siglec-10/HMGB1/SHP1/TCR complex, HMGB1 Box A vs Box B domain mapping, antibody blocking, and α2,3-sialic-acid glycan specificity\",\n      \"pmids\": [\"29997173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the ternary complex not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined CD24–Siglec-10 as a macrophage 'don't eat me' checkpoint exploited by tumors, establishing therapeutic blockade as a strategy.\",\n      \"evidence\": \"CRISPR KO of CD24 and Siglec-10, antibody blockade, phagocytosis assays, in vivo xenografts and macrophage depletion\",\n      \"pmids\": [\"31367043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase-dependence of the anti-phagocytic signal not directly tested here\", \"Range of tumor-cell glycan ligands not enumerated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the first structural/biophysical models of Siglec-10 glycan recognition and showed a V-set point mutation (R47Q) impairs ligand binding.\",\n      \"evidence\": \"STD-NMR, MD simulations and docking for α2,3/α2,6 sialoglycans; recombinant R47Q and A108V variant binding assays with homology modeling\",\n      \"pmids\": [\"32629603\", \"33223341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal structure at this stage\", \"Functional consequences of variants in primary cells not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked macrophage Siglec-10 to suppression of CD8+ T cell function via Akt/p38/Erk signaling, broadening its role in the tumor microenvironment.\",\n      \"evidence\": \"Macrophage–CD8 T cell co-culture, signaling inhibitors, ex vivo and in vivo blockade\",\n      \"pmids\": [\"37432407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-intrinsic signaling steps not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the ligand and disease repertoire to dendritic-cell tolerance (galectin-9), CLL CAR-T suppression (CD24/CD52), and macrophage pseudaminic-acid sensing driving IL-10 and phagocytosis blockade.\",\n      \"evidence\": \"scRNA-seq and tumor-fragment blockade in cervical cancer; CLL/CAR-T co-culture with CD40 stimulation and SRC inhibition; Pse–Siglec-10 binding, IL-10 ELISA and phagocytosis assays with ligand blockade\",\n      \"pmids\": [\"39209455\", \"39042920\", \"38372418\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic coupling of these ligands to ITIM signaling not directly shown\", \"Each finding from a single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified PU.1 as a direct transcriptional driver of macrophage Siglec-10, explaining how its expression is established and linking it to phagocytic control of glioma.\",\n      \"evidence\": \"Luciferase reporter and ChIP assays, PU.1 knockdown, phagocytosis assays, in vivo glioma model\",\n      \"pmids\": [\"41115355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other transcriptional regulators not assessed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Delivered the crystallographic basis of ligand selectivity and dimerization, showing the CC' loop determines glycan selectivity and a D2 hydrophobic interface mediates homodimerization essential for cellular binding.\",\n      \"evidence\": \"X-ray structures of Siglec-10/sialyllactose complexes with mutagenesis of the CC' loop, glycan site, and D2 interface, plus cell-based and CD24-KO binding validation\",\n      \"pmids\": [\"41747717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dimerization is regulated on the cell surface in physiological signaling not fully defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified integrin α3β1 as a sialylated tumor-cell ligand engaging macrophage Siglec-10 to block phagocytosis in PDAC, validated in humanized models.\",\n      \"evidence\": \"Glycoproteomic ligand identification, co-culture phagocytosis assays, antibody blockade, PDAC xenografts and human Siglec-10 transgenic mice\",\n      \"pmids\": [\"41182080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of integrin α3β1 vs CD24 in different tumors not ranked\", \"Downstream phosphatase signaling not dissected here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined the structural binding mechanism, defining arginines R119/R127 with distinct solution vs cellular roles, demonstrating glycan-independent dimerization on monocytes, and identifying additional T-cell sialoglycoprotein ligands beyond CD24.\",\n      \"evidence\": \"X-ray crystallography with α2,6-sialyllactose, STD-NMR, R119A/R127A mutagenesis, cell binding on primary T cells and monocytes, super-resolution microscopy, and proximity-labeling MS (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Identity and function of the newly mapped T-cell ligands not yet characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple ligand engagements, surface dimerization state, and ITIM/SHP signaling are quantitatively integrated to set inhibitory thresholds across distinct cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking ligand identity to differential phosphatase output\", \"Cell-type-specific signaling logic not mapped\", \"In vivo hierarchy of competing ligands unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD24\", \"CD52\", \"HMGB1\", \"SHP-1\", \"SHP-2\", \"VAP-1\", \"ITGA3\", \"ITGB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}