{"gene":"SIGLEC10","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2001,"finding":"Siglec-10 is a type I transmembrane protein with five extracellular Ig-like domains and a cytoplasmic tail containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs); it mediates sialic acid-dependent binding to human erythrocytes and soluble sialoglycoconjugates, establishing it as an inhibitory lectin receptor.","method":"cDNA cloning, binding assays with erythrocytes and sialoglycoconjugates, flow cytometry","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 — original characterization with multiple orthogonal methods; replicated by two independent groups in same year","pmids":["11284738","11733002","11358961"],"is_preprint":false},{"year":2001,"finding":"The ITIM tyrosines Y597 and Y667 in the Siglec-10 cytoplasmic tail are phosphorylated by tyrosine kinases; SHP-1 interacts with Y667 and SHP-2 interacts with Y667 and at least one additional tyrosine, establishing Siglec-10 as an inhibitory receptor that recruits SHP phosphatases.","method":"In vitro kinase assay with wild-type and Y→F mutant cytoplasmic domain constructs; cell extract pulldown assays","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis, confirmed by cell-based pulldown","pmids":["11733002"],"is_preprint":false},{"year":2002,"finding":"Siglec-10 recruits SHP-1 to its cytoplasmic tail in a tyrosine phosphorylation-dependent manner; mutational analysis identified ITIM Y609 of Siglec-10 and the N-terminal SH2 domain of SHP-1 as critical for this interaction. 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, site-directed mutagenesis of ITIM tyrosines","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis plus biochemical confirmation; consistent with prior ITIM phosphorylation data","pmids":["12163025"],"is_preprint":false},{"year":2009,"finding":"CD24 associates with the DAMPs HMGB1, HSP70, and HSP90 and negatively regulates their stimulatory activity; CD24 interaction with Siglec-10 (Siglec-G in mice) inhibits NF-κB activation and selectively suppresses danger-associated (but not pathogen-associated) innate immune responses.","method":"Co-immunoprecipitation, CD24-deficient mouse models, NF-κB reporter assays, genetic epistasis (CD24/Siglec-G double knockout)","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus genetic epistasis in vivo; highly cited foundational study","pmids":["19264983"],"is_preprint":false},{"year":2009,"finding":"Siglec-10 on leukocytes binds VAP-1 (vascular adhesion protein-1) on inflamed endothelium, identified by phage display; this interaction was verified by adhesion assays and molecular modeling. Siglec-10 serves as a substrate for VAP-1's amine oxidase activity, leading to increased hydrogen peroxide production, implicating the Siglec-10–VAP-1 axis in lymphocyte adhesion and modulation of the inflammatory microenvironment.","method":"Phage display screening, adhesion assays, molecular modeling, hydrogen peroxide production assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (phage display, adhesion assay, enzymatic assay) in a single study","pmids":["19861682"],"is_preprint":false},{"year":2013,"finding":"Soluble CD52 released by phospholipase C from CD52hi T cells binds Siglec-10 on T cells and impairs phosphorylation of TCR-associated kinases Lck and ZAP-70, thereby suppressing T cell activation. This defines a ligand-receptor mechanism of T cell regulation distinct from Foxp3+ Tregs.","method":"Binding assay (soluble CD52-Siglec-10), phosphokinase assays (Lck, ZAP-70), T cell suppression assays, adoptive transfer in NOD mice","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including binding, signaling readouts, and in vivo transfer; replicated across human and mouse","pmids":["23685786"],"is_preprint":false},{"year":2014,"finding":"Campylobacter jejuni flagella bearing pseudaminic acid residues bind Siglec-10 on dendritic cells; overexpression of Siglec-10 in cells infected with C. jejuni increased IL-10 production in a p38 MAPK-dependent manner, defining a novel flagellin-Siglec-10 immune modulatory axis.","method":"C. jejuni isogenic mutant analysis, Siglec-10 overexpression in cells, p38 inhibitor experiments, flow cytometry","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2-3 — overexpression plus isogenic mutant bacteria, but single-lab study","pmids":["24823621"],"is_preprint":false},{"year":2016,"finding":"Placental CD24 interacts with Siglec-10 via terminal sialic acid glycan residues in an EDTA-sensitive manner; CD24 did not interact with Siglec-3 or Siglec-5, establishing specificity. Co-localization of CD24 and Siglec-10 was observed at the fetal-maternal interface, suggesting a role in immune tolerance during pregnancy.","method":"Affinity purification of placental CD24, ELISA binding assays, EDTA inhibition, immunohistochemistry, immunofluorescence co-localization","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct binding assay with specificity controls; localization study linked to functional context","pmids":["28012129"],"is_preprint":false},{"year":2017,"finding":"Porcine Siglec-10 functions as an alternative receptor for PRRSV; Siglec-10-expressing cells showed significantly enhanced PRRSV infection in a CD163-dependent manner, and Siglec-10 was demonstrated to mediate endocytosis of PRRSV, establishing its role in viral entry.","method":"Transfection of Siglec-10 into PK15-CD163 cells, virus infection assays, TCID50 measurement, endocytosis assays","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function cell line with multiple functional readouts; porcine ortholog of human Siglec-10","pmids":["28742001"],"is_preprint":false},{"year":2018,"finding":"Soluble CD52 binds specifically to the proinflammatory Box B domain of HMGB1; this CD52-HMGB1 complex then promotes binding of the CD52 N-linked glycan (α-2,3 sialic acid linked to galactose) to Siglec-10. This triggers tyrosine phosphorylation of Siglec-10, recruitment of SHP1 phosphatase to Siglec-10's ITIM, and interaction of Siglec-10 with the TCR, suppressing T cell function.","method":"CD52-Fc binding assays to Siglec-10 and HMGB1 domains, anti-HMGB1 antibody blockade, co-immunoprecipitation (CD52-HMGB1-Siglec-10-SHP1-TCR complex), tyrosine phosphorylation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (binding domain mapping, complex Co-IP, phosphorylation assay); mechanistically extends prior findings","pmids":["29997173"],"is_preprint":false},{"year":2019,"finding":"Tumor-expressed CD24 engages Siglec-10 on tumor-associated macrophages to promote immune evasion; genetic ablation or antibody blockade of either CD24 or Siglec-10 robustly augments macrophage phagocytosis of human tumors expressing CD24. In vivo, CD24 or Siglec-10 blockade resulted in macrophage-dependent reduction of tumor growth.","method":"Genetic ablation (CRISPR knockout of CD24 or Siglec-10), monoclonal antibody blockade, phagocytosis assays, in vivo xenograft mouse models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO plus antibody blockade plus in vivo validation; highly cited foundational study","pmids":["31367043"],"is_preprint":false},{"year":2020,"finding":"Structural and biophysical analysis of Siglec-10 interactions with naturally occurring sialoglycans provided the first molecular insights into ligand recognition; spectroscopic (NMR), computational, and biophysical approaches defined glycan epitope mapping and 3D complex conformations of Siglec-10 with sialoglycans.","method":"NMR spectroscopy, computational modeling, biophysical binding assays (STD-NMR, molecular dynamics)","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 1 — NMR and computational structural characterization, but no crystal structure or mutagenesis in this study","pmids":["32629603"],"is_preprint":false},{"year":2020,"finding":"A GBS-associated rare variant encoding R47Q substitution in the ligand-binding domain of Siglec-10 impairs binding to gangliosides; homology modeling showed marked alteration of the ligand-binding site, indicating that Siglec-10 suppresses antibody production to gangliosides and defects in its function predispose to Guillain-Barré syndrome.","method":"Recombinant Siglec-10 protein binding assays, rare variant analysis, homology modeling of ligand-binding site","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2-3 — recombinant protein binding assay with disease-associated mutant plus structural modeling; single study","pmids":["33223341"],"is_preprint":false},{"year":2023,"finding":"PU.1 transcription factor directly targets and drives Siglec-10 expression in macrophages; PU.1 knockdown reduces Siglec-10 levels, enhances macrophage phagocytosis, and inhibits glioma tumor formation in vivo, establishing a PU.1–Siglec-10 axis in macrophage immune checkpoint regulation.","method":"PU.1 knockdown (RNA-seq, qRT-PCR, Western blot), luciferase assay, chromatin immunoprecipitation (ChIP), flow cytometry, in vivo tumor models","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase confirm direct transcriptional targeting; loss-of-function with defined phenotypic readout","pmids":["41115355"],"is_preprint":false},{"year":2024,"finding":"Bacterial pseudaminic acid (Pse) on pathogen exopolysaccharide engages Siglec-10 on macrophages via the 7-N-acetyl group of Pse; this interaction stimulates macrophages to secrete IL-10 and suppresses phagocytosis against bacteria.","method":"Carbohydrate-receptor binding assay (identifying critical 7-N-acetyl group), IL-10 secretion assay, phagocytosis assay, blocking experiment with Pse-binding protein","journal":"Chemical communications","confidence":"Medium","confidence_rationale":"Tier 2 — defined molecular determinant of binding with functional (cytokine secretion, phagocytosis) readouts","pmids":["38372418"],"is_preprint":false},{"year":2024,"finding":"CLL cells suppress CAR T-cell function via CD24 and CD52 — Siglec-10 ligands — expressed on their surface; CD40 stimulation of CLL cells downregulated CD24 and CD52 (prevented by the SRC kinase inhibitor dasatinib), and blocking CD24 and/or CD52 markedly reduced CAR T-cell dysfunction in coculture, demonstrating that CLL-T cell interaction through Siglec-10 ligands mediates T-cell suppression.","method":"Co-culture assays, CD40 stimulation, SRC kinase inhibitor (dasatinib) experiments, transcriptome profiling, CD24/CD52 blocking antibodies, flow cytometry","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods with pharmacologic and antibody inhibition; defined mechanistic pathway","pmids":["39042920"],"is_preprint":false},{"year":2025,"finding":"Integrin α3β1 (composed of ITGA3 and ITGB1) on PDAC cells is a sialylated glycoprotein ligand for Siglec-10 on tumor-associated macrophages; the Siglec-10–α3β1 interaction suppresses macrophage phagocytosis, and disruption with monoclonal antibodies restores phagocytosis, reduces PDAC tumor growth in xenograft and Siglec-10 transgenic mouse models.","method":"Ligand identification, Co-IP/pulldown, monoclonal antibody blockade, phagocytosis assays, PDAC xenograft and transgenic mouse models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — identification of novel ligand with in vitro and in vivo validation across multiple models","pmids":["41182080"],"is_preprint":false},{"year":2026,"finding":"Crystal structures of Siglec-10 bound to sialyllactose (SL) ligands revealed that domain 1 (D1) engages SL using a non-conserved, selectivity-determining CC' loop; Siglec-10 binds α2,3- and α2,6-linked SL with similar affinities. Homodimerization of Siglec-10 is mediated by a hydrophobic domain 2 (D2) interface, and mutation of this interface ablates cellular binding similarly to mutations in the glycan-binding site. Knockout of CD24 did not affect binding to breast cancer cells, indicating Siglec-10 has a broader glycoprotein recognition profile.","method":"X-ray crystallography, mutagenesis of CC' loop and D2 interface, cellular binding assays, CD24 knockout","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis validation and cellular functional assays in one study","pmids":["41747717"],"is_preprint":false},{"year":2025,"finding":"X-ray crystallography of Siglec-10 identified two arginine residues in the binding site (canonical R119 and non-canonical R127) that interact with the carboxyl group of sialic acid; STD-NMR confirmed R119 is essential for binding sialoglycans in solution, while cell-based assays showed both R119 and R127 are critical for cellular glycocalyx recognition. CD24 was ruled out as a principal Siglec-10 ligand on T cells and breast cancer cells, despite high CD24 expression.","method":"X-ray crystallography, STD-NMR, site-directed mutagenesis (R119A, R127A), cell-based binding assays with primary human T cells and engineered monocytic lines","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — crystal structure plus NMR plus mutagenesis; preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.06.10.658867"],"is_preprint":true},{"year":2024,"finding":"Molecular dynamics simulations defined atomistic interactions between CD52 glycans, HMGB1 Box B domain, and Siglec-10; O-glycosylation of CD52 was localized to T8, and terminal α-2,3-linked sialic acids on the N-linked glycan were confirmed essential for Siglec-10 binding and T-cell suppression.","method":"High-resolution mass spectrometry (glycopeptide/released glycan characterization), molecular dynamics simulation, O-glycosylation site mapping","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 — MS glycan characterization plus MD simulation; preprint not yet peer-reviewed but mechanistically detailed","pmids":["bio_10.1101_2024.10.24.620132"],"is_preprint":true}],"current_model":"Siglec-10 is an inhibitory transmembrane lectin receptor that recognizes sialylated glycans (via a CC' loop in domain 1 and key arginine residues) and signals through ITIM tyrosine phosphorylation to recruit SHP-1/SHP-2 phosphatases, suppressing immune cell activation; it engages multiple ligands including CD24, soluble CD52 (bridged via HMGB1), VAP-1 on endothelium, integrin α3β1 on tumor cells, and bacterial pseudaminic acid, thereby broadly dampening innate and adaptive immune responses and enabling tumor immune evasion through macrophage phagocytosis inhibition."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing Siglec-10 as an inhibitory sialic acid–binding receptor resolved its molecular identity: cDNA cloning revealed a type I transmembrane protein with five Ig-like domains and cytoplasmic ITIMs that bind sialic acid–bearing ligands, while biochemical analysis showed that ITIM tyrosines Y597/Y667 are phosphorylated and recruit SHP-1 and SHP-2 phosphatases.","evidence":"cDNA cloning, erythrocyte/sialoglycoconjugate binding assays, in vitro kinase assays with Y→F mutants, and cell-extract pulldowns across three independent studies","pmids":["11284738","11733002","11358961"],"confidence":"High","gaps":["No endogenous physiological ligand identified","Downstream signaling consequences in primary immune cells not yet tested","Three-dimensional structure unknown"]},{"year":2002,"claim":"Fine-mapping of the SHP-1 docking site to ITIM Y609 and the N-terminal SH2 domain of SHP-1 refined the signaling model and showed that Siglec-10 does not engage SAP/SH2D1A, distinguishing its signaling from SLAM-family receptors.","evidence":"Yeast three-hybrid cloning, site-directed mutagenesis of ITIM tyrosines, Western blot","pmids":["12163025"],"confidence":"High","gaps":["Physiological context of SHP-1 recruitment (which cell types, which stimuli) not defined","Relative contributions of Y597, Y609, Y667 to signaling in intact cells unresolved"]},{"year":2009,"claim":"Identification of two physiological ligands—CD24 and VAP-1—placed Siglec-10 in distinct immunological contexts: CD24 bridges DAMPs (HMGB1, HSP70, HSP90) to Siglec-10/Siglec-G to selectively suppress danger-associated NF-κB activation, while VAP-1 on inflamed endothelium engages Siglec-10 on leukocytes to modulate adhesion and hydrogen peroxide production.","evidence":"Co-IP plus Siglec-G-KO/CD24-KO genetic epistasis in mice and NF-κB reporter assays (CD24); phage display, adhesion assays, and enzymatic H₂O₂ assays (VAP-1)","pmids":["19264983","19861682"],"confidence":"High","gaps":["Sialic acid dependence of CD24–Siglec-10 binding not formally demonstrated in this study","In vivo consequence of VAP-1–Siglec-10 axis on leukocyte trafficking not assessed"]},{"year":2013,"claim":"Discovery that soluble CD52 released from CD52hi T cells suppresses T cell activation by engaging Siglec-10 and inhibiting Lck/ZAP-70 phosphorylation established a non-Treg mechanism of T cell regulation.","evidence":"Binding assays, phosphokinase assays, T cell suppression assays, adoptive transfer in NOD mice","pmids":["23685786"],"confidence":"High","gaps":["Whether CD52–Siglec-10 interaction is sialic acid–dependent was not molecularly defined","Contribution of HMGB1 bridging to this interaction was not explored until later"]},{"year":2018,"claim":"Mechanistic dissection of the CD52–HMGB1–Siglec-10 signaling complex showed that CD52's α2,3-sialylated N-glycan binds Siglec-10 only after CD52 engages HMGB1's Box B domain, triggering ITIM phosphorylation, SHP-1 recruitment, and Siglec-10 association with the TCR to suppress T cell function.","evidence":"CD52-Fc domain-mapping binding assays, anti-HMGB1 blockade, Co-IP of the quaternary complex (CD52–HMGB1–Siglec-10–SHP-1–TCR), tyrosine phosphorylation assay","pmids":["29997173"],"confidence":"High","gaps":["Structural basis of HMGB1-facilitated glycan presentation to Siglec-10 unknown","Stoichiometry of the multiprotein complex not determined"]},{"year":2019,"claim":"Demonstrating that tumor-expressed CD24 exploits Siglec-10 on macrophages as a 'don't-eat-me' signal to evade phagocytosis established Siglec-10 as an innate immune checkpoint in cancer, with therapeutic blockade reducing tumor growth in vivo.","evidence":"CRISPR knockout of CD24 or Siglec-10, monoclonal antibody blockade, phagocytosis assays, xenograft mouse models","pmids":["31367043"],"confidence":"High","gaps":["Whether the anti-phagocytic effect requires SHP-1/SHP-2 signaling specifically was not tested","Relative importance of CD24 vs. other sialylated ligands on tumor cells not delineated"]},{"year":2014,"claim":"Bacterial pseudaminic acid on Campylobacter jejuni flagella was identified as a microbial ligand for Siglec-10, revealing that pathogens can co-opt inhibitory Siglec signaling to induce IL-10 via p38 MAPK and dampen dendritic cell responses; subsequent work mapped the critical 7-N-acetyl group on pseudaminic acid and showed suppression of macrophage phagocytosis.","evidence":"Isogenic bacterial mutants, Siglec-10 overexpression, p38 inhibitor experiments (2014); carbohydrate-receptor binding assays identifying 7-N-acetyl group, IL-10 secretion and phagocytosis assays (2024)","pmids":["24823621","38372418"],"confidence":"Medium","gaps":["Pseudaminic acid–Siglec-10 structural complex not determined","In vivo relevance of this axis during natural infection not established"]},{"year":2023,"claim":"Identification of PU.1 as a direct transcriptional activator of SIGLEC10 in macrophages defined a regulatory mechanism controlling checkpoint expression; PU.1 knockdown reduced Siglec-10 levels, enhanced phagocytosis, and inhibited glioma growth in vivo.","evidence":"ChIP, luciferase reporter assay, PU.1 knockdown with RNA-seq/qRT-PCR/Western blot, in vivo tumor models","pmids":["41115355"],"confidence":"Medium","gaps":["Whether PU.1 is the sole or dominant transcriptional regulator of Siglec-10 is not established","Post-transcriptional regulation of Siglec-10 surface expression unexplored"]},{"year":2025,"claim":"Identification of integrin α3β1 as a sialylated glycoprotein ligand for Siglec-10 on pancreatic cancer cells expanded the don't-eat-me ligand repertoire beyond CD24; antibody blockade of this interaction restored macrophage phagocytosis and reduced PDAC tumor growth across xenograft and transgenic models.","evidence":"Ligand identification, Co-IP/pulldown, monoclonal antibody blockade, phagocytosis assays, PDAC xenograft and Siglec-10 transgenic mouse models","pmids":["41182080"],"confidence":"High","gaps":["Specific sialoglycan structures on α3β1 that engage Siglec-10 not identified","Whether α3β1-mediated immune evasion operates in cancer types beyond PDAC is untested"]},{"year":2026,"claim":"Crystal structures of Siglec-10 revealed how domain 1's CC' loop confers ligand selectivity for both α2,3- and α2,6-sialylated glycans, identified dual arginine residues (R119, R127) in the binding site, and showed that D2-mediated homodimerization is functionally required for cellular glycan recognition; CD24 knockout did not abolish binding to breast cancer cells, indicating a broader glycoprotein ligand repertoire.","evidence":"X-ray crystallography, STD-NMR, mutagenesis of CC' loop and D2 interface, cellular binding assays, CD24 knockout","pmids":["41747717"],"confidence":"High","gaps":["Structural basis of Siglec-10 interaction with specific glycoprotein ligands (e.g., integrin α3β1, CD52–HMGB1 complex) not captured","Functional significance of homodimerization for ITIM signaling not tested","Identity of the dominant non-CD24 sialylated ligands on breast cancer cells remains unknown"]},{"year":null,"claim":"Outstanding questions include the structural basis of Siglec-10 engagement with intact glycoprotein ligands (CD24, CD52–HMGB1, α3β1), the relative contribution of individual ITIM tyrosines to SHP-1/SHP-2 recruitment in primary immune cells, how homodimerization couples to intracellular signaling, and whether therapeutic disruption of specific ligand–Siglec-10 pairs can achieve tumor-selective immune activation without systemic autoimmunity.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal structure of Siglec-10 with any glycoprotein ligand","In vivo functional consequences of D2 dimerization interface mutations unknown","Therapeutic window for Siglec-10 blockade vs. autoimmune risk not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,11,17,18]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,5,10,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,10,16,17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,5,9,10,14,15,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,5,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,13,16]}],"complexes":[],"partners":["SHP-1","SHP-2","CD24","CD52","HMGB1","VAP-1","ITGA3","ITGB1"],"other_free_text":[]},"mechanistic_narrative":"Siglec-10 is an inhibitory sialic acid–binding immunoglobulin-like lectin that broadly dampens innate and adaptive immune responses by transducing inhibitory signals through cytoplasmic ITIM-mediated recruitment of SHP-1 and SHP-2 phosphatases. Its N-terminal domain 1 recognizes α2,3- and α2,6-sialylated glycans through a selectivity-determining CC' loop and dual arginine residues (R119, R127), while domain 2 mediates functionally required homodimerization [PMID:41747717, PMID:11284738]. Engagement of diverse sialylated ligands—including CD24 (which bridges DAMPs such as HMGB1 to suppress NF-κB signaling), soluble CD52 (which inhibits TCR-proximal Lck/ZAP-70 phosphorylation), integrin α3β1 on tumor cells, and bacterial pseudaminic acid—triggers ITIM phosphorylation and SHP-1 recruitment, suppressing macrophage phagocytosis, T cell activation, and proinflammatory cytokine production [PMID:19264983, PMID:23685786, PMID:29997173, PMID:41182080, PMID:38372418]. Tumor-expressed CD24 and integrin α3β1 exploit this checkpoint to evade macrophage-mediated clearance, and genetic ablation or antibody blockade of the CD24–Siglec-10 or α3β1–Siglec-10 axis restores phagocytosis and reduces tumor growth in vivo [PMID:31367043, PMID:41182080]."},"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 tissue","ntpm":45.5}],"url":"https://www.proteinatlas.org/search/SIGLEC10"},"hgnc":{"alias_symbol":["SIGLEC-10","SLG2","PRO940","MGC126774"],"prev_symbol":[]},"alphafold":{"accession":"Q96LC7","domains":[{"cath_id":"2.60.40.10","chopping":"23-141","consensus_level":"high","plddt":91.3987,"start":23,"end":141},{"cath_id":"2.60.40.10","chopping":"148-233","consensus_level":"medium","plddt":86.1074,"start":148,"end":233},{"cath_id":"2.60.40.10","chopping":"237-342","consensus_level":"medium","plddt":84.4739,"start":237,"end":342},{"cath_id":"2.60.40.10","chopping":"344-443","consensus_level":"medium","plddt":84.6522,"start":344,"end":443},{"cath_id":"2.60.40.10","chopping":"446-536","consensus_level":"medium","plddt":80.2022,"start":446,"end":536}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96LC7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96LC7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96LC7-F1-predicted_aligned_error_v6.png","plddt_mean":73.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIGLEC10","jax_strain_url":"https://www.jax.org/strain/search?query=SIGLEC10"},"sequence":{"accession":"Q96LC7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96LC7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96LC7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96LC7"}},"corpus_meta":[{"pmid":"31367043","id":"PMC_31367043","title":"CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31367043","citation_count":1084,"is_preprint":false},{"pmid":"19264983","id":"PMC_19264983","title":"CD24 and Siglec-10 selectively repress tissue damage-induced immune responses.","date":"2009","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19264983","citation_count":666,"is_preprint":false},{"pmid":"23685786","id":"PMC_23685786","title":"T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor Siglec-10.","date":"2013","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23685786","citation_count":162,"is_preprint":false},{"pmid":"11284738","id":"PMC_11284738","title":"Identification, characterization and leucocyte expression of Siglec-10, a novel human sialic acid-binding receptor.","date":"2001","source":"The Biochemical 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a cytoplasmic tail containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs); it mediates sialic acid-dependent binding to human erythrocytes and soluble sialoglycoconjugates, establishing it as an inhibitory lectin receptor.\",\n      \"method\": \"cDNA cloning, binding assays with erythrocytes and sialoglycoconjugates, flow cytometry\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original characterization with multiple orthogonal methods; replicated by two independent groups in same year\",\n      \"pmids\": [\"11284738\", \"11733002\", \"11358961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The ITIM tyrosines Y597 and Y667 in the Siglec-10 cytoplasmic tail are phosphorylated by tyrosine kinases; SHP-1 interacts with Y667 and SHP-2 interacts with Y667 and at least one additional tyrosine, establishing Siglec-10 as an inhibitory receptor that recruits SHP phosphatases.\",\n      \"method\": \"In vitro kinase assay with wild-type and Y→F mutant cytoplasmic domain constructs; cell extract pulldown assays\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis, confirmed by cell-based pulldown\",\n      \"pmids\": [\"11733002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Siglec-10 recruits SHP-1 to its cytoplasmic tail in a tyrosine phosphorylation-dependent manner; mutational analysis identified ITIM Y609 of Siglec-10 and the N-terminal SH2 domain of SHP-1 as critical for this interaction. 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, site-directed mutagenesis of ITIM tyrosines\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis plus biochemical confirmation; consistent with prior ITIM phosphorylation data\",\n      \"pmids\": [\"12163025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD24 associates with the DAMPs HMGB1, HSP70, and HSP90 and negatively regulates their stimulatory activity; CD24 interaction with Siglec-10 (Siglec-G in mice) inhibits NF-κB activation and selectively suppresses danger-associated (but not pathogen-associated) innate immune responses.\",\n      \"method\": \"Co-immunoprecipitation, CD24-deficient mouse models, NF-κB reporter assays, genetic epistasis (CD24/Siglec-G double knockout)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus genetic epistasis in vivo; highly cited foundational study\",\n      \"pmids\": [\"19264983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Siglec-10 on leukocytes binds VAP-1 (vascular adhesion protein-1) on inflamed endothelium, identified by phage display; this interaction was verified by adhesion assays and molecular modeling. Siglec-10 serves as a substrate for VAP-1's amine oxidase activity, leading to increased hydrogen peroxide production, implicating the Siglec-10–VAP-1 axis in lymphocyte adhesion and modulation of the inflammatory microenvironment.\",\n      \"method\": \"Phage display screening, adhesion assays, molecular modeling, hydrogen peroxide production assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (phage display, adhesion assay, enzymatic assay) in a single study\",\n      \"pmids\": [\"19861682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Soluble CD52 released by phospholipase C from CD52hi T cells binds Siglec-10 on T cells and impairs phosphorylation of TCR-associated kinases Lck and ZAP-70, thereby suppressing T cell activation. This defines a ligand-receptor mechanism of T cell regulation distinct from Foxp3+ Tregs.\",\n      \"method\": \"Binding assay (soluble CD52-Siglec-10), phosphokinase assays (Lck, ZAP-70), T cell suppression assays, adoptive transfer in NOD mice\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including binding, signaling readouts, and in vivo transfer; replicated across human and mouse\",\n      \"pmids\": [\"23685786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Campylobacter jejuni flagella bearing pseudaminic acid residues bind Siglec-10 on dendritic cells; overexpression of Siglec-10 in cells infected with C. jejuni increased IL-10 production in a p38 MAPK-dependent manner, defining a novel flagellin-Siglec-10 immune modulatory axis.\",\n      \"method\": \"C. jejuni isogenic mutant analysis, Siglec-10 overexpression in cells, p38 inhibitor experiments, flow cytometry\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — overexpression plus isogenic mutant bacteria, but single-lab study\",\n      \"pmids\": [\"24823621\"],\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 did not interact with Siglec-3 or Siglec-5, establishing specificity. Co-localization of CD24 and Siglec-10 was observed at the fetal-maternal interface, suggesting a role in immune tolerance during pregnancy.\",\n      \"method\": \"Affinity purification of placental CD24, ELISA binding assays, EDTA inhibition, immunohistochemistry, immunofluorescence co-localization\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct binding assay with specificity controls; localization study linked to functional context\",\n      \"pmids\": [\"28012129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Porcine Siglec-10 functions as an alternative receptor for PRRSV; Siglec-10-expressing cells showed significantly enhanced PRRSV infection in a CD163-dependent manner, and Siglec-10 was demonstrated to mediate endocytosis of PRRSV, establishing its role in viral entry.\",\n      \"method\": \"Transfection of Siglec-10 into PK15-CD163 cells, virus infection assays, TCID50 measurement, endocytosis assays\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function cell line with multiple functional readouts; porcine ortholog of human Siglec-10\",\n      \"pmids\": [\"28742001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Soluble CD52 binds specifically to the proinflammatory Box B domain of HMGB1; this CD52-HMGB1 complex then promotes binding of the CD52 N-linked glycan (α-2,3 sialic acid linked to galactose) to Siglec-10. This triggers tyrosine phosphorylation of Siglec-10, recruitment of SHP1 phosphatase to Siglec-10's ITIM, and interaction of Siglec-10 with the TCR, suppressing T cell function.\",\n      \"method\": \"CD52-Fc binding assays to Siglec-10 and HMGB1 domains, anti-HMGB1 antibody blockade, co-immunoprecipitation (CD52-HMGB1-Siglec-10-SHP1-TCR complex), tyrosine phosphorylation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (binding domain mapping, complex Co-IP, phosphorylation assay); mechanistically extends prior findings\",\n      \"pmids\": [\"29997173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tumor-expressed CD24 engages Siglec-10 on tumor-associated macrophages to promote immune evasion; genetic ablation or antibody blockade of either CD24 or Siglec-10 robustly augments macrophage phagocytosis of human tumors expressing CD24. In vivo, CD24 or Siglec-10 blockade resulted in macrophage-dependent reduction of tumor growth.\",\n      \"method\": \"Genetic ablation (CRISPR knockout of CD24 or Siglec-10), monoclonal antibody blockade, phagocytosis assays, in vivo xenograft mouse models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO plus antibody blockade plus in vivo validation; highly cited foundational study\",\n      \"pmids\": [\"31367043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Structural and biophysical analysis of Siglec-10 interactions with naturally occurring sialoglycans provided the first molecular insights into ligand recognition; spectroscopic (NMR), computational, and biophysical approaches defined glycan epitope mapping and 3D complex conformations of Siglec-10 with sialoglycans.\",\n      \"method\": \"NMR spectroscopy, computational modeling, biophysical binding assays (STD-NMR, molecular dynamics)\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR and computational structural characterization, but no crystal structure or mutagenesis in this study\",\n      \"pmids\": [\"32629603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A GBS-associated rare variant encoding R47Q substitution in the ligand-binding domain of Siglec-10 impairs binding to gangliosides; homology modeling showed marked alteration of the ligand-binding site, indicating that Siglec-10 suppresses antibody production to gangliosides and defects in its function predispose to Guillain-Barré syndrome.\",\n      \"method\": \"Recombinant Siglec-10 protein binding assays, rare variant analysis, homology modeling of ligand-binding site\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — recombinant protein binding assay with disease-associated mutant plus structural modeling; single study\",\n      \"pmids\": [\"33223341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PU.1 transcription factor directly targets and drives Siglec-10 expression in macrophages; PU.1 knockdown reduces Siglec-10 levels, enhances macrophage phagocytosis, and inhibits glioma tumor formation in vivo, establishing a PU.1–Siglec-10 axis in macrophage immune checkpoint regulation.\",\n      \"method\": \"PU.1 knockdown (RNA-seq, qRT-PCR, Western blot), luciferase assay, chromatin immunoprecipitation (ChIP), flow cytometry, in vivo tumor models\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase confirm direct transcriptional targeting; loss-of-function with defined phenotypic readout\",\n      \"pmids\": [\"41115355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Bacterial pseudaminic acid (Pse) on pathogen exopolysaccharide engages Siglec-10 on macrophages via the 7-N-acetyl group of Pse; this interaction stimulates macrophages to secrete IL-10 and suppresses phagocytosis against bacteria.\",\n      \"method\": \"Carbohydrate-receptor binding assay (identifying critical 7-N-acetyl group), IL-10 secretion assay, phagocytosis assay, blocking experiment with Pse-binding protein\",\n      \"journal\": \"Chemical communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined molecular determinant of binding with functional (cytokine secretion, phagocytosis) readouts\",\n      \"pmids\": [\"38372418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CLL cells suppress CAR T-cell function via CD24 and CD52 — Siglec-10 ligands — expressed on their surface; CD40 stimulation of CLL cells downregulated CD24 and CD52 (prevented by the SRC kinase inhibitor dasatinib), and blocking CD24 and/or CD52 markedly reduced CAR T-cell dysfunction in coculture, demonstrating that CLL-T cell interaction through Siglec-10 ligands mediates T-cell suppression.\",\n      \"method\": \"Co-culture assays, CD40 stimulation, SRC kinase inhibitor (dasatinib) experiments, transcriptome profiling, CD24/CD52 blocking antibodies, flow cytometry\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with pharmacologic and antibody inhibition; defined mechanistic pathway\",\n      \"pmids\": [\"39042920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Integrin α3β1 (composed of ITGA3 and ITGB1) on PDAC cells is a sialylated glycoprotein ligand for Siglec-10 on tumor-associated macrophages; the Siglec-10–α3β1 interaction suppresses macrophage phagocytosis, and disruption with monoclonal antibodies restores phagocytosis, reduces PDAC tumor growth in xenograft and Siglec-10 transgenic mouse models.\",\n      \"method\": \"Ligand identification, Co-IP/pulldown, monoclonal antibody blockade, phagocytosis assays, PDAC xenograft and transgenic mouse models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — identification of novel ligand with in vitro and in vivo validation across multiple models\",\n      \"pmids\": [\"41182080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Crystal structures of Siglec-10 bound to sialyllactose (SL) ligands revealed that domain 1 (D1) engages SL using a non-conserved, selectivity-determining CC' loop; Siglec-10 binds α2,3- and α2,6-linked SL with similar affinities. Homodimerization of Siglec-10 is mediated by a hydrophobic domain 2 (D2) interface, and mutation of this interface ablates cellular binding similarly to mutations in the glycan-binding site. Knockout of CD24 did not affect binding to breast cancer cells, indicating Siglec-10 has a broader glycoprotein recognition profile.\",\n      \"method\": \"X-ray crystallography, mutagenesis of CC' loop and D2 interface, cellular binding assays, CD24 knockout\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis validation and cellular functional assays in one study\",\n      \"pmids\": [\"41747717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"X-ray crystallography of Siglec-10 identified two arginine residues in the binding site (canonical R119 and non-canonical R127) that interact with the carboxyl group of sialic acid; STD-NMR confirmed R119 is essential for binding sialoglycans in solution, while cell-based assays showed both R119 and R127 are critical for cellular glycocalyx recognition. CD24 was ruled out as a principal Siglec-10 ligand on T cells and breast cancer cells, despite high CD24 expression.\",\n      \"method\": \"X-ray crystallography, STD-NMR, site-directed mutagenesis (R119A, R127A), cell-based binding assays with primary human T cells and engineered monocytic lines\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus NMR plus mutagenesis; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.10.658867\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Molecular dynamics simulations defined atomistic interactions between CD52 glycans, HMGB1 Box B domain, and Siglec-10; O-glycosylation of CD52 was localized to T8, and terminal α-2,3-linked sialic acids on the N-linked glycan were confirmed essential for Siglec-10 binding and T-cell suppression.\",\n      \"method\": \"High-resolution mass spectrometry (glycopeptide/released glycan characterization), molecular dynamics simulation, O-glycosylation site mapping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — MS glycan characterization plus MD simulation; preprint not yet peer-reviewed but mechanistically detailed\",\n      \"pmids\": [\"bio_10.1101_2024.10.24.620132\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"Siglec-10 is an inhibitory transmembrane lectin receptor that recognizes sialylated glycans (via a CC' loop in domain 1 and key arginine residues) and signals through ITIM tyrosine phosphorylation to recruit SHP-1/SHP-2 phosphatases, suppressing immune cell activation; it engages multiple ligands including CD24, soluble CD52 (bridged via HMGB1), VAP-1 on endothelium, integrin α3β1 on tumor cells, and bacterial pseudaminic acid, thereby broadly dampening innate and adaptive immune responses and enabling tumor immune evasion through macrophage phagocytosis inhibition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Siglec-10 is an inhibitory sialic acid–binding immunoglobulin-like lectin that broadly dampens innate and adaptive immune responses by transducing inhibitory signals through cytoplasmic ITIM-mediated recruitment of SHP-1 and SHP-2 phosphatases. Its N-terminal domain 1 recognizes α2,3- and α2,6-sialylated glycans through a selectivity-determining CC' loop and dual arginine residues (R119, R127), while domain 2 mediates functionally required homodimerization [PMID:41747717, PMID:11284738]. Engagement of diverse sialylated ligands—including CD24 (which bridges DAMPs such as HMGB1 to suppress NF-κB signaling), soluble CD52 (which inhibits TCR-proximal Lck/ZAP-70 phosphorylation), integrin α3β1 on tumor cells, and bacterial pseudaminic acid—triggers ITIM phosphorylation and SHP-1 recruitment, suppressing macrophage phagocytosis, T cell activation, and proinflammatory cytokine production [PMID:19264983, PMID:23685786, PMID:29997173, PMID:41182080, PMID:38372418]. Tumor-expressed CD24 and integrin α3β1 exploit this checkpoint to evade macrophage-mediated clearance, and genetic ablation or antibody blockade of the CD24–Siglec-10 or α3β1–Siglec-10 axis restores phagocytosis and reduces tumor growth in vivo [PMID:31367043, PMID:41182080].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing Siglec-10 as an inhibitory sialic acid–binding receptor resolved its molecular identity: cDNA cloning revealed a type I transmembrane protein with five Ig-like domains and cytoplasmic ITIMs that bind sialic acid–bearing ligands, while biochemical analysis showed that ITIM tyrosines Y597/Y667 are phosphorylated and recruit SHP-1 and SHP-2 phosphatases.\",\n      \"evidence\": \"cDNA cloning, erythrocyte/sialoglycoconjugate binding assays, in vitro kinase assays with Y→F mutants, and cell-extract pulldowns across three independent studies\",\n      \"pmids\": [\"11284738\", \"11733002\", \"11358961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No endogenous physiological ligand identified\",\n        \"Downstream signaling consequences in primary immune cells not yet tested\",\n        \"Three-dimensional structure unknown\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Fine-mapping of the SHP-1 docking site to ITIM Y609 and the N-terminal SH2 domain of SHP-1 refined the signaling model and showed that Siglec-10 does not engage SAP/SH2D1A, distinguishing its signaling from SLAM-family receptors.\",\n      \"evidence\": \"Yeast three-hybrid cloning, site-directed mutagenesis of ITIM tyrosines, Western blot\",\n      \"pmids\": [\"12163025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological context of SHP-1 recruitment (which cell types, which stimuli) not defined\",\n        \"Relative contributions of Y597, Y609, Y667 to signaling in intact cells unresolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of two physiological ligands—CD24 and VAP-1—placed Siglec-10 in distinct immunological contexts: CD24 bridges DAMPs (HMGB1, HSP70, HSP90) to Siglec-10/Siglec-G to selectively suppress danger-associated NF-κB activation, while VAP-1 on inflamed endothelium engages Siglec-10 on leukocytes to modulate adhesion and hydrogen peroxide production.\",\n      \"evidence\": \"Co-IP plus Siglec-G-KO/CD24-KO genetic epistasis in mice and NF-κB reporter assays (CD24); phage display, adhesion assays, and enzymatic H₂O₂ assays (VAP-1)\",\n      \"pmids\": [\"19264983\", \"19861682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Sialic acid dependence of CD24–Siglec-10 binding not formally demonstrated in this study\",\n        \"In vivo consequence of VAP-1–Siglec-10 axis on leukocyte trafficking not assessed\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that soluble CD52 released from CD52hi T cells suppresses T cell activation by engaging Siglec-10 and inhibiting Lck/ZAP-70 phosphorylation established a non-Treg mechanism of T cell regulation.\",\n      \"evidence\": \"Binding assays, phosphokinase assays, T cell suppression assays, adoptive transfer in NOD mice\",\n      \"pmids\": [\"23685786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CD52–Siglec-10 interaction is sialic acid–dependent was not molecularly defined\",\n        \"Contribution of HMGB1 bridging to this interaction was not explored until later\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mechanistic dissection of the CD52–HMGB1–Siglec-10 signaling complex showed that CD52's α2,3-sialylated N-glycan binds Siglec-10 only after CD52 engages HMGB1's Box B domain, triggering ITIM phosphorylation, SHP-1 recruitment, and Siglec-10 association with the TCR to suppress T cell function.\",\n      \"evidence\": \"CD52-Fc domain-mapping binding assays, anti-HMGB1 blockade, Co-IP of the quaternary complex (CD52–HMGB1–Siglec-10–SHP-1–TCR), tyrosine phosphorylation assay\",\n      \"pmids\": [\"29997173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of HMGB1-facilitated glycan presentation to Siglec-10 unknown\",\n        \"Stoichiometry of the multiprotein complex not determined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that tumor-expressed CD24 exploits Siglec-10 on macrophages as a 'don't-eat-me' signal to evade phagocytosis established Siglec-10 as an innate immune checkpoint in cancer, with therapeutic blockade reducing tumor growth in vivo.\",\n      \"evidence\": \"CRISPR knockout of CD24 or Siglec-10, monoclonal antibody blockade, phagocytosis assays, xenograft mouse models\",\n      \"pmids\": [\"31367043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the anti-phagocytic effect requires SHP-1/SHP-2 signaling specifically was not tested\",\n        \"Relative importance of CD24 vs. other sialylated ligands on tumor cells not delineated\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Bacterial pseudaminic acid on Campylobacter jejuni flagella was identified as a microbial ligand for Siglec-10, revealing that pathogens can co-opt inhibitory Siglec signaling to induce IL-10 via p38 MAPK and dampen dendritic cell responses; subsequent work mapped the critical 7-N-acetyl group on pseudaminic acid and showed suppression of macrophage phagocytosis.\",\n      \"evidence\": \"Isogenic bacterial mutants, Siglec-10 overexpression, p38 inhibitor experiments (2014); carbohydrate-receptor binding assays identifying 7-N-acetyl group, IL-10 secretion and phagocytosis assays (2024)\",\n      \"pmids\": [\"24823621\", \"38372418\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Pseudaminic acid–Siglec-10 structural complex not determined\",\n        \"In vivo relevance of this axis during natural infection not established\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of PU.1 as a direct transcriptional activator of SIGLEC10 in macrophages defined a regulatory mechanism controlling checkpoint expression; PU.1 knockdown reduced Siglec-10 levels, enhanced phagocytosis, and inhibited glioma growth in vivo.\",\n      \"evidence\": \"ChIP, luciferase reporter assay, PU.1 knockdown with RNA-seq/qRT-PCR/Western blot, in vivo tumor models\",\n      \"pmids\": [\"41115355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PU.1 is the sole or dominant transcriptional regulator of Siglec-10 is not established\",\n        \"Post-transcriptional regulation of Siglec-10 surface expression unexplored\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of integrin α3β1 as a sialylated glycoprotein ligand for Siglec-10 on pancreatic cancer cells expanded the don't-eat-me ligand repertoire beyond CD24; antibody blockade of this interaction restored macrophage phagocytosis and reduced PDAC tumor growth across xenograft and transgenic models.\",\n      \"evidence\": \"Ligand identification, Co-IP/pulldown, monoclonal antibody blockade, phagocytosis assays, PDAC xenograft and Siglec-10 transgenic mouse models\",\n      \"pmids\": [\"41182080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific sialoglycan structures on α3β1 that engage Siglec-10 not identified\",\n        \"Whether α3β1-mediated immune evasion operates in cancer types beyond PDAC is untested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Crystal structures of Siglec-10 revealed how domain 1's CC' loop confers ligand selectivity for both α2,3- and α2,6-sialylated glycans, identified dual arginine residues (R119, R127) in the binding site, and showed that D2-mediated homodimerization is functionally required for cellular glycan recognition; CD24 knockout did not abolish binding to breast cancer cells, indicating a broader glycoprotein ligand repertoire.\",\n      \"evidence\": \"X-ray crystallography, STD-NMR, mutagenesis of CC' loop and D2 interface, cellular binding assays, CD24 knockout\",\n      \"pmids\": [\"41747717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of Siglec-10 interaction with specific glycoprotein ligands (e.g., integrin α3β1, CD52–HMGB1 complex) not captured\",\n        \"Functional significance of homodimerization for ITIM signaling not tested\",\n        \"Identity of the dominant non-CD24 sialylated ligands on breast cancer cells remains unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Outstanding questions include the structural basis of Siglec-10 engagement with intact glycoprotein ligands (CD24, CD52–HMGB1, α3β1), the relative contribution of individual ITIM tyrosines to SHP-1/SHP-2 recruitment in primary immune cells, how homodimerization couples to intracellular signaling, and whether therapeutic disruption of specific ligand–Siglec-10 pairs can achieve tumor-selective immune activation without systemic autoimmunity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No co-crystal structure of Siglec-10 with any glycoprotein ligand\",\n        \"In vivo functional consequences of D2 dimerization interface mutations unknown\",\n        \"Therapeutic window for Siglec-10 blockade vs. autoimmune risk not defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 11, 17, 18]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 5, 10, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 10, 16, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 5, 9, 10, 14, 15, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 5, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 13, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SHP-1\",\n      \"SHP-2\",\n      \"CD24\",\n      \"CD52\",\n      \"HMGB1\",\n      \"VAP-1\",\n      \"ITGA3\",\n      \"ITGB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}