Affinage

SIGLEC15

Sialic acid-binding Ig-like lectin 15 · UniProt Q6ZMC9

Length
328 aa
Mass
35.7 kDa
Annotated
2026-06-10
81 papers in source corpus 28 papers cited in narrative 27 extracted findings
Cross-family judge faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIGLEC15 encodes a type-I transmembrane sialic acid-binding immunoglobulin-like lectin that couples recognition of sialylated glycans to ITAM-based activating signaling, functioning both as a driver of osteoclast-mediated bone resorption and as an immune-suppressive checkpoint in the tumor microenvironment (PMID:17483134, PMID:30833750). Through a transmembrane lysine residue, Siglec-15 associates constitutively with the activating adaptors DAP12 and DAP10, and engagement of its sialoglycan ligands triggers Syk recruitment and downstream activation of PI3K/Akt and Erk signaling (PMID:17483134, PMID:22451653, PMID:23677868). In osteoclasts, Siglec-15 is induced as an NFATc1 target downstream of RANK-RANKL and links this program to DAP12-dependent cytoskeletal remodeling: it drives M-CSF-induced RAP1/RAC1 activation via a p130CAS/CrkII complex required for actin-ring formation and bone resorption, and is the dominant DAP12-associated receptor in this process, with OSCAR/FcRγ able to compensate for multinucleation but not cytoskeletal organization (PMID:22451653, PMID:25460183, PMID:38849345). Siglec-15-deficient mice show mild osteopetrosis and are protected from estrogen-deficiency, arthritis-associated, and inflammatory bone loss (PMID:23677868, PMID:25460183, PMID:33020147). Genome-wide screening establishes α2-3-linked sialic acid on N-glycans as the primary glycotope and identifies LRP1, maintained at the surface by the retriever complex, as a Siglec-15 counter-receptor on osteoclast precursors (PMID:41569849). In cancer, Siglec-15 is broadly upregulated on tumor cells and myeloid cells, suppresses antigen-specific T cell responses in a manner mutually exclusive with the PD-L1/PD-1 axis, and acts on tumor-associated macrophages through DAP12-Syk-MAPK signaling to promote immunosuppressive cytokine production and M2 polarization (PMID:30833750, PMID:35077803). Structural and NMR studies define its sialic-acid binding pocket and antibody epitope and identify the integrin CD11b as a Siglec-15 ligand on T cells (PMID:37311743). Surface abundance is controlled by N-glycosylation at N172, which stabilizes the protein and is required for immune suppression, while transcription is regulated by M-CSF, IFN-γ, ETS-1/ETS-2 downstream of TGF-β, NFκB, and Arid1a/Jun/Fos-mediated chromatin remodeling (PMID:30833750, PMID:32921411, PMID:34094685, PMID:36614238, PMID:37465593, PMID:38477755).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2007 High

    Established the basic architecture and signaling potential of Siglec-15, defining it as a sialic acid-binding lectin that could engage activating ITAM adaptors rather than acting alone.

    Evidence Molecular characterization, glycan-binding assays, and co-immunoprecipitation showing two Ig-like domains, sialyl-Tn recognition, and DAP12/DAP10 association via a transmembrane lysine

    PMID:17483134

    Open questions at the time
    • Did not define downstream effectors or cellular function
    • Glycan specificity restricted to sialyl-Tn at this stage
  2. 2012 High

    Connected ligand engagement to a defined signaling output, showing the transmembrane lysine and DAP12-Syk axis convert glycan recognition into functional consequences in both immune and bone contexts.

    Evidence Co-culture with sTn-positive cancer cells plus K274A mutagenesis and Syk inhibition for TGF-β secretion (PMID 23035012); siRNA, chimeric rescue constructs, and bone resorption assays placing Siglec-15 downstream of RANKL-NFATc1 (PMID 22451653)

    PMID:22451653 PMID:23035012

    Open questions at the time
    • sTn-driven TGF-β axis later contradicted by glycan microarray data
    • Did not resolve which sialoglycan is the physiological ligand in vivo
  3. 2013 High

    Demonstrated through genetic loss-of-function that Siglec-15 is physiologically required for osteoclast development and identified PI3K/Akt and Erk as the impaired pathways, while revealing redundancy with OSCAR/FcRγ.

    Evidence Siglec-15 knockout mice, retroviral rescue, and signaling pathway analysis showing mild osteopetrosis and impaired RANKL-induced PI3K/Akt and Erk activation

    PMID:23677868

    Open questions at the time
    • Compensation by alternative ITAM pathway obscured full requirement
    • Did not pinpoint the osteoclast cytoskeletal effector machinery
  4. 2014 High

    Defined the surface-localized, antibody-targetable nature of Siglec-15 and showed receptor clustering/internalization controls signaling, validating it as a therapeutic target in bone.

    Evidence Plasma membrane localization, mAb treatment in vitro and in vivo with DXA bone density, Akt phosphorylation, and receptor internalization/lysosomal degradation assays (PMID 24446437); ovariectomy KO model dissecting cytoskeletal organization from multinucleation (PMID 25460183)

    PMID:24446437 PMID:25460183

    Open questions at the time
    • Molecular link between Siglec-15 and the actin cytoskeleton not yet identified
    • Did not resolve the in vivo ligand on bone surfaces
  5. 2019 High

    Repositioned Siglec-15 from a bone receptor to an immune checkpoint, establishing it as a T-cell-suppressive molecule operating independently of PD-L1 and regulated by M-CSF and IFN-γ.

    Evidence Genome-scale T cell activity array, knockout mice, antibody blockade, and in vitro/in vivo tumor models showing amplified anti-tumor immunity upon ablation

    PMID:30833750

    Open questions at the time
    • T-cell ligand and exact suppressive mechanism not defined at this point
    • Relationship between bone and immune functions unresolved
  6. 2019 Medium

    Extended Siglec-15 function to anti-fungal host defense, indicating its glycan-sensing role contributes to innate immune responses beyond bone and tumor settings.

    Evidence Genomic association study with PBMC cytokine profiling, HeLa stimulation, and in vivo vaginal Candida infection with Siglec15 silencing

    PMID:31189718

    Open questions at the time
    • Single lab; mechanism linking Siglec-15 to NLRP3/IL-1β not fully resolved
    • Polymorphism-function link is associative
  7. 2020 Medium

    Clarified post-translational and disease-context determinants of Siglec-15 abundance and showed osteoclast bone erosion can be uncoupled from inflammation.

    Evidence Glycosidase and inhibitor experiments showing N-glycosylation stabilizes Siglec-15 and routes it to the membrane (PMID 32921411); K/BxN arthritis KO model showing reduced bone erosion with intact inflammation (PMID 33020147)

    PMID:32921411 PMID:33020147

    Open questions at the time
    • Specific N-glycosylation site not yet mapped
    • Glucose/glycolysis link to glycosylation only correlative
  8. 2021 Medium

    Refined ligand specificity beyond sTn and uncovered a sialic-acid-dependent role in stabilizing partner glycoproteins that promote cancer cell behavior and TAM immunosuppression.

    Evidence Glycan microarray showing α2,3/α2,6 preference and negative sTn/TGF-β result (PMID 32501471); co-IP and degradation assays for CD44 (PMID 34328657) and SYK-driven TAM cytokine output in PDAC (PMID 35077803); N172 mapped as the functional glycosylation site (PMID 34094685)

    PMID:32501471 PMID:34094685 PMID:34328657 PMID:35077803

    Open questions at the time
    • Conflicting reports on sTn recognition unresolved
    • Whether CD44/EGFR stabilization is a general or cell-type-specific mechanism unclear
  9. 2023 High

    Provided structural definition of the sialic-acid binding pocket and antibody epitope and identified CD11b on T cells as a binding partner, giving a molecular basis for immune suppression.

    Evidence X-ray crystallography, co-crystallization with a blocking antibody, STD-NMR, molecular dynamics, and pulldown for CD11b

    PMID:37311743

    Open questions at the time
    • Signaling consequence of CD11b engagement on T cells not fully mapped
    • Structure of full-length receptor/DAP12 complex not determined
  10. 2023 Medium

    Mapped transcriptional and additional cell-cell mechanisms of Siglec-15-mediated immune suppression across cancer contexts, including apoptotic-body delivery and promoter regulation.

    Evidence Apoptotic-body Siglec15 binding sialylated TLR2 on CD8+ T cells (PMID 37607544); ChIP and reporter assays for ETS-1/ETS-2 downstream of TGF-β (PMID 36614238); NFκB-driven overexpression and soluble Siglec-15 in B-ALL (PMID 37465593); EGFR stabilization in thyroid carcinoma (PMID 37129515)

    PMID:36614238 PMID:37129515 PMID:37465593 PMID:37607544

    Open questions at the time
    • Multiple ligand/partner mechanisms reported by single labs without cross-validation
    • Relative contribution of soluble vs membrane Siglec-15 unclear
  11. 2024 High

    Identified the osteoclast cytoskeletal effector complex and established Siglec-15 as the dominant DAP12-associated receptor for actin-ring formation, and defined chromatin-level control of its expression.

    Evidence Single and double KO genetic epistasis with actin-ring staining and co-IP of the Siglec-15/p130CAS/CrkII complex driving RAP1/RAC1 (PMID 38849345); Arid1a conditional KO with chromatin accessibility and Jun/Fos ChIP at the promoter (PMID 38477755)

    PMID:38477755 PMID:38849345

    Open questions at the time
    • How DAP12 signaling assembles the p130CAS/CrkII complex mechanistically not detailed
    • Arid1a study from a single lab
  12. 2026 High

    Defined the physiological glycotope and counter-receptor for Siglec-15 in osteoclastogenesis, resolving longstanding ambiguity about its in vivo ligand.

    Evidence Genome-wide CRISPR knockout screen with Siglec-15 binding readout and glycan structural analysis identifying St3gal4-dependent α2-3 sialic acid on N-glycans and LRP1 (maintained by the retriever complex) as the counter-receptor, validated in KO osteoclast differentiation

    PMID:41569849

    Open questions at the time
    • Whether LRP1 is the relevant ligand in immune/tumor contexts not addressed
    • Single lab
  13. 2026 Medium

    Extended the DAP12-dependent immunosuppressive program to liver macrophages, linking Siglec-15 to an IRAK-M axis driving M2 polarization with transplant-relevant outcomes.

    Evidence Co-IP/molecular docking and siRNA epistasis for DAP12 and IRAK-M in Kupffer cell polarization, with a rat liver transplantation model

    PMID:42066581

    Open questions at the time
    • Docking-based interaction needs biochemical confirmation
    • Single lab; IRAK-M placement downstream of DAP12 not structurally validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Siglec-15 reconciles its activating DAP12-Syk signaling with reported inhibitory outputs (e.g. TIGIT/SHP-1, T-cell suppression), and which ligand-partner pairs dominate in each tissue context, remains unresolved.
  • Mechanism by which an ITAM-coupled receptor produces immunosuppression is not fully reconciled
  • Many ligand/partner interactions (CD44, EGFR, CD11b, TLR2, CA72-4) are single-lab Co-IP findings lacking cross-validation
  • No structure of the signaling-competent Siglec-15/DAP12 complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 4 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005764 lysosome 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
CD11BCD44DAP10DAP12EGFRLRP1P130CASSYK

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Siglec-15 is a type-I transmembrane protein with two Ig-like extracellular domains, a transmembrane domain containing a lysine residue, and a short cytoplasmic tail. Its extracellular domain preferentially recognizes the Neu5Acα2-6GalNAcα- (sialyl-Tn) structure. Siglec-15 associates with activating adaptor proteins DAP12 and DAP10 via its transmembrane lysine residue, implying activating signaling potential. Molecular characterization, glycan-binding assays, co-immunoprecipitation Glycobiology High 17483134
2012 Siglec-15 recognizes tumor-associated sialyl-Tn (sTn) antigen on cancer cells and signals through DAP12 via its transmembrane Lys274 to activate Syk, leading to enhanced TGF-β secretion from monocytes/macrophages. Substitution of Lys274 to Ala disrupts Siglec-15/DAP12 interaction and abolishes enhanced TGF-β production. Syk inhibitor treatment also attenuates TGF-β secretion. Co-culture model (THP-1 and H157 cells), site-directed mutagenesis (K274A), Syk inhibitor treatment, TGF-β ELISA Glycobiology High 23035012
2012 Siglec-15 is induced as an NFATc1 target gene during osteoclast differentiation and links RANK-RANKL-NFATc1 signaling to DAP12. Both sialylated glycan recognition by the V-set domain and association with DAP12 via Lys272 are required for functional osteoclast formation. Knockdown of Siglec-15 reduces multinucleated cell development, disrupts actin-ring structures, and impairs bone resorption. Siglec-15 forms complexes with Syk through DAP12 in response to vitronectin. Chimeric molecules with K272A mutation fused to the DAP12 cytoplasmic region significantly restored bone resorption, confirming that the transmembrane Lys is dispensable if DAP12 signaling is provided directly. siRNA knockdown, retroviral transduction of chimeric constructs, co-immunoprecipitation (Siglec-15/Syk via DAP12), actin-ring imaging, bone resorption assay The Journal of biological chemistry High 22451653
2013 Siglec-15 modulates RANKL-induced osteoclastogenesis through DAP12-dependent activation of PI3K/Akt and Erk pathways. Siglec-15-deficient mice exhibit mild osteopetrosis with impaired osteoclast development. RANKL-induced PI3K/Akt and Erk activation is impaired in Siglec-15-deficient cells. OSCAR/FcRγ signaling (alternative ITAM pathway) can compensate for Siglec-15 deficiency in the primary spongiosa via type II collagen ligands. Siglec-15 knockout mice, retroviral transduction with wild-type or mutant Siglec-15, signaling pathway analysis (PI3K/Akt, Erk), bone phenotype analysis, rescue with OSCAR/FcRγ ligands Journal of bone and mineral research High 23677868
2014 Siglec-15 is localized to the plasma membrane of osteoclasts where anti-Siglec-15 monoclonal antibodies inhibit osteoclast differentiation in vitro and increase bone mineral density in mice. At the molecular level, Siglec-15 interacts with DAP12 and induces Akt activation when clustered on the osteoclast surface. Monoclonal antibodies induce rapid internalization, lysosomal targeting, and degradation of Siglec-15 by inducing receptor dimerization. Plasma membrane localization assay, mAb treatment in vitro and in vivo, bone density measurement (DXA), co-immunoprecipitation (Siglec-15/DAP12), Akt phosphorylation assay, receptor internalization and lysosomal degradation assays The Journal of biological chemistry High 24446437
2014 Siglec-15 deficiency protects mice from estrogen deficiency-induced (ovariectomy) bone loss. Siglec-15-deficient osteoclasts are small, fail to spread on bone surface, and show impaired cytoskeletal organization. Siglec-15 is also required for TNF-α-induced osteoclastogenesis in vitro. The Siglec-15/DAP12 pathway is specifically important for cytoskeletal organization, while OSCAR/FcRγ signaling can rescue multinucleation but not cytoskeletal organization in Siglec-15-deficient cells. Siglec-15 knockout mice with ovariectomy model, TRAP staining, in vitro TNF-α-induced osteoclastogenesis, comparison of DAP12 vs OSCAR/FcRγ pathway rescue Bone High 25460183
2019 Siglec-15 is broadly upregulated on human cancer cells and tumor-infiltrating myeloid cells, suppresses antigen-specific T cell responses in vitro and in vivo, and its expression is mutually exclusive with B7-H1 (PD-L1). Siglec-15 expression is induced by macrophage colony-stimulating factor (M-CSF) and downregulated by IFN-γ. Genetic ablation or antibody blockade of Siglec-15 amplifies anti-tumor immunity and inhibits tumor growth in mouse models. Siglec-15 was identified using a genome-scale T cell activity array. Genome-scale T cell activity array, genetic ablation (knockout mice), antibody blockade, in vitro T cell suppression assays, in vivo tumor models Nature medicine High 30833750
2019 A SIGLEC15 gene polymorphism associated with recurrent vulvovaginal candidiasis (RVVC) leads to an altered cytokine profile after PBMC stimulation with Candida and increases IL-1B and NLRP3 expression after Candida stimulation in HeLa cells. In vivo silencing of Siglec15 at the vaginal surface of mice led to increased fungal burden and an increase in polymorphonuclear leukocytes during Candida infection, indicating Siglec-15 plays a role in anti-fungal host defense. Genomic association study integrated with in vitro cytokine profiling (PBMC stimulation), in vivo Siglec15 silencing in mouse vaginal Candida infection model, flow cytometry Science translational medicine Medium 31189718
2020 N-glycosylation of Siglec-15 stabilizes it by decreasing lysosome-dependent degradation and promotes its transportation to the cell membrane. Using glycosidase and glycosylation inhibitors, Siglec-15 was shown to be completely N-glycosylated. Glucose uptake regulates N-glycosylation of Siglec-15. Glycosidase treatment, glycosylation inhibitors, immunofluorescence for subcellular localization, protein stability assays Biochemical and biophysical research communications Medium 32921411
2020 Siglec-15 is required for bone erosion specifically in osteoclasts in an arthritis model (K/BxN serum-transfer arthritis). Siglec-15-/- mice show significant reduction in bone erosion area and osteoclast numbers but comparable inflammation and cartilage destruction to wild-type mice, placing Siglec-15 specifically in pathological osteoclast-mediated bone resorption. Siglec-15 knockout mice, K/BxN serum-transfer arthritis model, histological analysis of bone erosion, cartilage destruction, and osteoclast numbers Journal of immunology High 33020147
2021 Siglec-15 binds sialylated glycans other than sTn with higher avidity (based on glycan microarray), including α(2,3)- and α(2,6)-linked sialic acids. Using lung and breast cancer cell lines, no evidence was found for sTn recognition or enhanced TGF-β secretion following Siglec-15 co-culture with sTn-positive cells (negative result for sTn/TGF-β axis). However, antibody cross-linking of Siglec-15 activates the SYK/MAPK signaling pathway. Glycan microarray, cell line binding assays, glycan-modified cells, co-culture with sTn-positive tumor cells, TGF-β ELISA (negative), SYK/MAPK signaling (phospho-blot after mAb cross-linking) Glycobiology Medium 32501471
2021 Siglec-15 interacts with CD44, a transmembrane glycoprotein, in a sialic acid-dependent manner in hepatoma cells. CD44 is modified by α2,6-linked sialic acids on N-glycans; removal of sialic acids suppresses the Siglec-15/CD44 interaction. Siglec-15 promotes stability of CD44 by preventing its lysosomal-mediated degradation, thereby promoting hepatoma cell migration. Co-immunoprecipitation, neuraminidase treatment (sialic acid removal), lysosomal degradation assay, migration assay FEBS letters Medium 34328657
2021 In pancreatic cancer, SIGLEC15 on tumor-associated macrophages interacts with α-2,3-linked sialic acids on PDAC tumor cells to stimulate SYK phosphorylation in TAMs, which promotes immunoregulatory cytokine and chemokine production. SYK inhibitor treatment abolished M2-like TAM phenotype promotion and immunosuppressive microenvironment in vivo. Co-culture of SIGLEC15+ TAMs with PDAC cells, SYK phosphorylation assay, SYK inhibitor treatment, in vivo subcutaneous tumor model, flow cytometry Cancer letters Medium 35077803
2021 Glycosylation of Siglec-15 at N172 (N173 in mouse) is required for its immunosuppressive function. Through mass spectrometry and site mutation analysis, N172 was identified as the primary glycosylation site. Siglec-15 N172Q (glycosylation-deficient mutant) reduced tumor growth in immunocompetent C57BL/6 mice but not in nude mice, indicating N-glycosylation is required for Siglec-15-mediated immune suppression. Mass spectrometry, site-directed mutagenesis (N172Q), xenograft models in immunocompetent vs. immunodeficient mice American journal of cancer research Medium 34094685
2021 Neuraminidase (NA) influences host defense against Aspergillus fumigatus, and SIGLEC15 is upregulated in PBMCs stimulated with A. fumigatus. Silencing of SIGLEC15 decreases PBMC killing capacity of A. fumigatus, establishing a role for SIGLEC15 in anti-fungal defense. SIGLEC15 siRNA silencing in PBMCs, fungal killing assay, mouse model of pulmonary aspergillosis with oseltamivir treatment Cell reports. Medicine Medium 34095887
2022 Siglec-15 regulates M2 macrophage polarization by interacting with Glut1 to upregulate glycolysis, and this glycolytic regulation modulates cGAS/STING signaling to drive M2 phenotype. Siglec-15 knockout abolished M2 marker expression and inhibited tumor growth in a subcutaneous mouse model. NOTE: This paper was subsequently retracted (PMID:37388523). Siglec-15 knockout macrophages, co-immunoprecipitation (Siglec-15/Glut1), glycolysis assay, cGAS-STING pathway analysis — RETRACTED Oxidative medicine and cellular longevity Low 36105484 37388523
2023 Crystal structure of Siglec-15 was determined, and its binding epitope was characterized by co-crystallization with an anti-Siglec-15 blocking antibody. STD-NMR and molecular dynamics simulations revealed binding mode to α(2,3)- and α(2,6)-linked sialic acids and STn glycoform. Siglec-15 binding to T cells (which lack STn) depends on α(2,3)- and α(2,6)-linked sialoglycans. The leukocyte integrin CD11b was identified as a Siglec-15 binding partner on human T cells. X-ray crystallography, co-crystallization with blocking antibody, STD-NMR spectroscopy, molecular dynamics simulations, glycan binding assays, co-immunoprecipitation/pulldown for CD11b Nature communications High 37311743
2023 Osteoclast-derived apoptotic bodies bearing membranous Siglec15 bind sialylated Toll-like receptor 2 (TLR2) on naive CD8+ T cells, blocking downstream co-stimulatory signaling and inhibiting naive CD8+ T cell activation. Siglec15 neutralizing antibodies significantly reduced secondary breast cancer bone metastases and improved survival in mice. AB-null MRL/lpr mouse model, co-immunoprecipitation/binding assay (Siglec15 on ABs with sialylated TLR2), T cell activation assay, in vivo antibody neutralization, flow cytometry Cell reports. Medicine Medium 37607544
2023 ETS-1 and ETS-2 transcription factors bind the Siglec-15 promoter to enhance its transcription in hepatocellular carcinoma cells. TGF-β1 upregulates ETS-1 and ETS-2 and facilitates their binding to the Siglec-15 promoter via the Ras/C-Raf/MEK/ERK1/2 signaling pathway, leading to phosphorylation of ETS-1/ETS-2 and increased Siglec-15 transcription. Chromatin immunoprecipitation (ChIP), promoter-reporter assays, TGF-β1 stimulation, ERK pathway inhibition, ETS-1/ETS-2 knockdown International journal of molecular sciences Medium 36614238
2023 Siglec-15 promotes migration of thyroid carcinoma cells by binding to EGFR on cancer cells in a sialic acid-dependent manner and increasing EGFR protein stability (slowing its degradation). Pull-down assay confirmed Siglec-15/EGFR interaction; EGFR pathway inhibition blocked the pro-migratory effect. Pull-down assay (Siglec-15/EGFR interaction), cycloheximide chase assay (protein stability), wound-healing and transwell migration assays, EGFR pathway inhibitor treatment, sialic acid-dependent interaction confirmed with Siglec-15 mutant co-culture Glycobiology Medium 37129515
2023 Siglec-15 overexpression in B-ALL is driven by NFκB activation, which also increases surface localization of Siglec-15. Soluble/secreted Siglec-15 circulates at elevated levels in plasma of children with B-ALL. Genetic inhibition of Siglec-15 in a murine B-ALL model promoted immune clearance with expanded early effector CD8+ T cells and reduced immunosuppressive cytokines. NFκB pathway inhibition/activation experiments, flow cytometry for surface Siglec-15, ELISA for soluble Siglec-15 in patient plasma, genetic Siglec-15 knockdown/knockout in murine B-ALL model Cancer research communications Medium 37465593
2024 Siglec-15 activates M-CSF-induced RAP1/RAC1 cytoskeletal remodeling in osteoclasts through formation of a complex with p130CAS and CrkII. Siglec-15-deficient osteoclasts fail to form actin rings. Siglec-15/FcRγ double-deficient mice exhibit severe osteopetrosis versus mild osteopetrosis in Siglec-15-single-deficient mice. TREM-2 and CLEC5A deficient mice show normal bone phenotype, placing Siglec-15 as the dominant DAP12-associated receptor for osteoclast cytoskeletal remodeling. Knockout mice (single and double KO), bone mass analysis, actin ring staining, biochemical co-immunoprecipitation (Siglec-15/p130CAS/CrkII complex), M-CSF signaling assays (RAP1/RAC1) Bone research High 38849345
2024 The chromatin remodeling factor Arid1a cooperates with transcription factors Jun/Fos to epigenetically upregulate Siglec-15 expression in osteoclast precursors by increasing chromatin accessibility at the Siglec-15 gene promoter. Loss of Arid1a in BMDMs reprograms chromatin structure to restrict Siglec-15 expression and inhibits osteoclast differentiation. Conditional knockout of Arid1a in BMDMs, ATAC-seq or chromatin accessibility assay, ChIP for Jun/Fos at Siglec-15 promoter, osteoclast differentiation assay, ovariectomy bone loss model Journal of bone and mineral research Medium 38477755
2024 CA72-4 (a sialylated glycan antigen secreted by synovial cells) binds directly to Siglec-15 on macrophages, as confirmed by co-immunoprecipitation. This interaction activates the TIGIT/SHP-1 signaling axis in macrophages, inhibiting MSU-induced M1 polarization. Siglec-15 knockdown abolished the CA72-4-mediated activation of TIGIT/SHP-1 and its inhibitory effect on M1 polarization. Co-immunoprecipitation (CA72-4/Siglec-15), Siglec-15 siRNA knockdown, TIGIT/SHP-1 signaling assays, macrophage M1 polarization assay Autoimmunity Medium 41920724
2026 Using genome-wide knockout screening, St3gal4 (α2-3 sialyltransferase) and other enzymes in sialic acid biosynthesis and N-glycan processing are identified as contributors to Siglec-15 ligand expression, establishing that α2-3-linked sialic acid on N-glycans is the primary glycotope recognized by Siglec-15. LRP1 is identified as a Siglec-15 counter-receptor. The retriever complex (endosome-to-plasma membrane recycling) maintains LRP1 surface expression as a Siglec-15 ligand. RAW264.7 cells deficient in St3gal4, Lrp1, or Vps35l show impaired osteoclast differentiation. Genome-wide CRISPR knockout screen, Siglec-15 binding assay, glycan structural analysis, functional osteoclast differentiation assay in KO cells Cell reports High 41569849
2026 Siglec-15 promotes M2 polarization of Kupffer cells through the DAP12/IRAK-M axis. Molecular docking and in vitro experiments confirmed DAP12 and IRAK-M as downstream targets. Silencing DAP12 or IRAK-M via siRNA abolished the promoting effect of Siglec-15 on M2 KC polarization. Siglec-15 overexpression reduced acute rejection and improved survival in a rat liver transplantation model. Co-immunoprecipitation/molecular docking (Siglec-15/DAP12/IRAK-M), siRNA knockdown of DAP12 and IRAK-M, macrophage polarization assay, rat liver transplantation model Molecular immunology Medium 42066581
2022 The 3' UTR of SIGLEC15 mRNA markedly promotes mRNA degradation, reducing protein production, while the 5' UTR has a modest inhibitory effect on translation. A 43-nt stem-loop structure within the 993-1317 region of the 3' UTR has the most robust inhibitory activity in multiple cell lines. Reporter assays with 5' UTR and 3' UTR constructs, mRNA half-life measurement, shortened 3' UTR fragment analysis in four cell lines Molekuliarnaia biologiia Medium 35621101

Source papers

Stage 0 corpus · 81 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nature medicine 545 30833750
2021 Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer. Theranostics 288 33537076
2007 Siglec-15: an immune system Siglec conserved throughout vertebrate evolution. Glycobiology 161 17483134
2012 The interaction between Siglec-15 and tumor-associated sialyl-Tn antigen enhances TGF-β secretion from monocytes/macrophages through the DAP12-Syk pathway. Glycobiology 150 23035012
2020 Siglec-15 as an Emerging Target for Next-generation Cancer Immunotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research 122 32958700
2013 Siglec-15 regulates osteoclast differentiation by modulating RANKL-induced phosphatidylinositol 3-kinase/Akt and Erk pathways in association with signaling Adaptor DAP12. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 99 23677868
2012 Siglec-15 protein regulates formation of functional osteoclasts in concert with DNAX-activating protein of 12 kDa (DAP12). The Journal of biological chemistry 83 22451653
2011 Siglec-15, a member of the sialic acid-binding lectin, is a novel regulator for osteoclast differentiation. Biochemical and biophysical research communications 73 21586272
2014 Mechanism and function of monoclonal antibodies targeting siglec-15 for therapeutic inhibition of osteoclastic bone resorption. The Journal of biological chemistry 60 24446437
2019 A systems genomics approach identifies SIGLEC15 as a susceptibility factor in recurrent vulvovaginal candidiasis. Science translational medicine 52 31189718
2014 Siglec-15 is a potential therapeutic target for postmenopausal osteoporosis. Bone 49 25460183
2021 Siglec-15 recognition of sialoglycans on tumor cell lines can occur independently of sialyl Tn antigen expression. Glycobiology 43 32501471
2021 Siglec-15 Promotes Tumor Progression in Osteosarcoma via DUSP1/MAPK Pathway. Frontiers in oncology 43 34336699
2023 Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b. Nature communications 40 37311743
2022 SIGLEC15 amplifies immunosuppressive properties of tumor-associated macrophages in pancreatic cancer. Cancer letters 39 35077803
2020 LINC00973 is involved in cancer immune suppression through positive regulation of Siglec-15 in clear-cell renal cell carcinoma. Cancer science 39 32780490
2023 Osteoclast-derived apoptotic bodies inhibit naive CD8+ T cell activation via Siglec15, promoting breast cancer secondary metastasis. Cell reports. Medicine 38 37607544
2020 Integrative Analysis of Siglec-15 mRNA in Human Cancers Based on Data Mining. Journal of Cancer 34 32201516
2019 Siglec-15: An Attractive Immunotherapy Target. Cancer discovery 33 31806628
2021 Siglec-15 promotes the migration of liver cancer cells by repressing lysosomal degradation of CD44. FEBS letters 31 34328657
2020 The diverse functions of Siglec-15 in bone remodeling and antitumor responses. Pharmacological research 30 32112821
2015 Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) mediates periarticular bone loss, but not joint destruction, in murine antigen-induced arthritis. Bone 30 26027508
2021 Neuraminidase and SIGLEC15 modulate the host defense against pulmonary aspergillosis. Cell reports. Medicine 28 34095887
2022 Analysis of a novel immune checkpoint, Siglec-15, in pancreatic ductal adenocarcinoma. The journal of pathology. Clinical research 25 35083884
2021 Immunopositivity for Siglec-15 in gastric cancer and its association with clinical and pathological parameters. European journal of histochemistry : EJH 25 33666065
2023 Siglec-15 on macrophages suppress the immune microenvironment in patients with PD-L1 negative non-metastasis lung adenocarcinoma. Cancer gene therapy 24 38072971
2022 A novel immune checkpoint siglec-15 antibody inhibits LUAD by modulating mφ polarization in TME. Pharmacological research 23 35605813
2020 The significance of Siglec-15 expression in resectable non-small cell lung cancer. Neoplasma 20 32749846
2021 Glycosylation of Siglec15 promotes immunoescape and tumor growth. American journal of cancer research 19 34094685
2021 Molecular structure, expression, and the emerging role of Siglec-15 in skeletal biology and cancer. Journal of cellular physiology 19 34893976
2024 Targeting SIGLEC15 as an emerging immunotherapy for anaplastic thyroid cancer. International immunopharmacology 18 38652971
2021 High affinity monoclonal antibody targeting Siglec-15 for cancer immunotherapy. Journal of clinical and translational research 18 34988324
2022 Siglec15 Checkpoint Blockade for Simultaneous Immunochemotherapy and Osteolysis Inhibition in Lung Adenocarcinoma Spinal Metastasis via a Hollow Nanoplatform. Small (Weinheim an der Bergstrasse, Germany) 17 35751455
2023 Dynamic change in Siglec-15 expression in peritumoral macrophages confers an immunosuppressive microenvironment and poor outcome in glioma. Frontiers in immunology 16 37234161
2021 Siglec-15 Is an Immune Suppressor and Potential Target for Immunotherapy in the Pre-Metastatic Lymph Node of Colorectal Cancer. Frontiers in cell and developmental biology 16 34722496
2022 Quantitative assessment of Siglec-15 expression in lung, breast, head, and neck squamous cell carcinoma and bladder cancer. Laboratory investigation; a journal of technical methods and pathology 14 35581307
2020 N-glycosylation of Siglec-15 decreases its lysosome-dependent degradation and promotes its transportation to the cell membrane. Biochemical and biophysical research communications 14 32921411
2022 Siglec-15 Regulates the Inflammatory Response and Polarization of Tumor-Associated Macrophages in Pancreatic Cancer by Inhibiting the cGAS-STING Signaling Pathway. Oxidative medicine and cellular longevity 13 36105484
2020 Siglec-15 on Osteoclasts Is Crucial for Bone Erosion in Serum-Transfer Arthritis. Journal of immunology (Baltimore, Md. : 1950) 12 33020147
2022 Siglec15 facilitates the progression of non-small cell lung cancer and is correlated with spinal metastasis. Annals of translational medicine 11 35434017
2022 Obesity accelerates immune evasion of non-small cell lung carcinoma via TFEB-dependent upregulation of Siglec-15 and glycolytic reprogramming. Cancer letters 11 36150633
2022 Siglec-15 as a New Perspective Therapy Target in Human Giant Cell Tumor of Bone. Current oncology (Toronto, Ont.) 10 36290882
2024 Involvement of Siglec-15 in regulating RAP1/RAC signaling in cytoskeletal remodeling in osteoclasts mediated by macrophage colony-stimulating factor. Bone research 9 38849345
2023 Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy. Acta pharmaceutica Sinica. B 9 38045048
2022 Development of an immunohistochemical assay for Siglec-15. Laboratory investigation; a journal of technical methods and pathology 9 35459795
2022 Siglec-15 Silencing Inhibits Cell Proliferation and Promotes Cell Apoptosis by Inhibiting STAT1/STAT3 Signaling in Anaplastic Thyroid Carcinoma. Disease markers 9 35769818
2022 Siglec-15 as multifunctional molecule involved in osteoclast differentiation, cancer immunity and microbial infection. Progress in biophysics and molecular biology 9 36265694
2022 Significance of Siglec-15 expression in colorectal cancer: association with advanced disease stage and fewer tumor-infiltrating lymphocytes. The journal of pathology. Clinical research 9 36424637
2024 The chromatin remodeling factor Arid1a cooperates with Jun/Fos to promote osteoclastogenesis by epigenetically upregulating Siglec15 expression. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 8 38477755
2023 Transcriptional Regulation of Siglec-15 by ETS-1 and ETS-2 in Hepatocellular Carcinoma Cells. International journal of molecular sciences 8 36614238
2023 Siglec-15 Promotes Evasion of Adaptive Immunity in B-cell Acute Lymphoblastic Leukemia. Cancer research communications 8 37465593
2022 Knocking down Siglec-15 in osteosarcoma cells inhibits proliferation while promoting apoptosis and pyroptosis by targeting the Siglec-15/STAT3/Bcl-2 pathway. Advances in medical sciences 8 35398779
2025 Siglec-15 antibody-GM-CSF chimera suppresses tumor progression via reprogramming tumor-associated macrophages. Journal for immunotherapy of cancer 7 40216442
2023 Non-spatial and spatial heterogeneity revealed a suppressive immune feature of Siglec-15 in lung adenocarcinomas. Journal of translational medicine 7 37674198
2023 Enhancing the Anti-tumor Potency of a Novel Siglec-15 Antibody by Engineering its Fc-mediated Effector Functions. Journal of immunotherapy (Hagerstown, Md. : 1997) 6 37103472
2023 Siglec15 promotes the migration of thyroid carcinoma cells by enhancing the EGFR protein stability. Glycobiology 6 37129515
2022 Unveiling the molecular features, relevant immune and clinical characteristics of SIGLEC15 in thyroid cancer. Frontiers in immunology 6 36159823
2024 SIGLEC15, negatively correlated with PD-L1 in HCC, could induce CD8+ T cell apoptosis to promote immune evasion. Oncoimmunology 5 38988824
2021 A comprehensive analysis of different gene classes in pancreatic cancer: SIGLEC15 may be a promising immunotherapeutic target. Investigational new drugs 4 34515878
2024 Evasion of immunosurveillance by the upregulation of Siglec15 in bladder cancer. Journal of hematology & oncology 3 39609852
2024 Killing two birds with one stone: Siglec-15 targeting integrated bioactive glasses hydrogel for treatment of breast cancer bone metastasis. Materials today. Bio 3 39687802
2024 Siglec15 in blood system diseases: from bench to bedside. Frontiers in immunology 3 39697338
2023 Retracted: Siglec-15 Regulates the Inflammatory Response and Polarization of Tumor-Associated Macrophages in Pancreatic Cancer by Inhibiting the cGAS-STING Signaling Pathway. Oxidative medicine and cellular longevity 3 37388523
2024 Siglec-15 as a potential molecule involved in osteoclast differentiation and bone metabolism. Heliyon 2 39524871
2024 Targeting Siglec-15 mediates mitochondrial retrograde regulation of cervical cancer development. Tissue & cell 2 39756115
2025 Screening and preparation of nanobodies for SIGLEC-15 detection. Protein expression and purification 1 39880295
2025 Siglec-15 is a putative receptor for porcine epidemic diarrhea virus infection. Cellular and molecular life sciences : CMLS 1 40172660
2025 SIGLEC15 modulates the immunosuppressive microenvironment and suppresses malignant phenotypes in triple-negative breast cancer. Genes & diseases 1 41158758
2023 Core needle biopsies alter the amounts of CCR5, Siglec-15, and PD-L1 positivities in breast carcinoma. Virchows Archiv : an international journal of pathology 1 37222841
2022 [Mapping Regulatory Elements within 5' and 3' UTRs of SIGLEC15 with a Use of Reporter System]. Molekuliarnaia biologiia 1 35621101
2022 [Study on the effect and mechanisms of SIGLEC-15 on laryngeal squamous cell carcinoma]. Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery 1 35725316
2026 The Role of Siglec-15 in Tumor Immunity: Mechanisms and Therapy. Molecular cancer therapeutics 0 40833001
2026 Identification of Siglec-15 as a novel target for CAR-T cell therapy in acute myeloid leukemia. International immunopharmacology 0 41558291
2026 Comprehensive identification of the genes involved in the expression of Siglec-15 ligands on osteoclast precursors. Cell reports 0 41569849
2026 Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes. International journal of molecular medicine 0 41891952
2026 CA72-4 derived from synovial cells inhibits monosodium urate-induced macrophage M1 polarization by activating the TIGIT/SHP-1 axis through binding to Siglec-15. Autoimmunity 0 41920724
2026 Siglec-15 promotes M2 polarization of Kupffer cells via DAP12/IRAK-M axis to alleviate acute rejection in liver transplantation. Molecular immunology 0 42066581
2025 Immunochromatographic assay for rapid detection of SIGLEC15 to evaluate its therapeutic potential in cervical cancer. International journal of biological macromolecules 0 40886986
2025 Cajanin transcriptionally disrupts the Siglec15/NFATc1 signaling cascade to attenuate osteoclast fusion and bone resorption. International immunopharmacology 0 41260165
2025 Investigating the role and mechanism of methionine in different types of skeletal fluorosis based on Siglec-15 methylation. Environmental pollution (Barking, Essex : 1987) 0 41349947
2024 Siglec-15 expression in diffuse gliomas and its correlation with MRI morphologic features and apparent diffusion coefficient. Acta radiologica (Stockholm, Sweden : 1987) 0 39434541

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