Affinage

IGSF11

Immunoglobulin superfamily member 11 · UniProt Q5DX21

Length
431 aa
Mass
46.1 kDa
Annotated
2026-06-10
29 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IGSF11 (BT-IgSF/VSIG3) is a type I transmembrane immunoglobulin-superfamily cell adhesion molecule that engages in Ca2+/Mg2+-independent homophilic adhesion, a function that resides entirely in its extracellular region and is independent of the cytoplasmic tail or β1 integrin (PMID:15795899). Through this homophilic activity it organizes tissue-specific cell–cell contacts: it determines layer-specific synaptic connectivity of cortical chandelier interneurons, where loss disrupts and ectopic expression induces target-layer synapses (PMID:34261648), and it is required cell-autonomously in pigment cell lineages for adult patterning (PMID:22916035). At excitatory synapses IGSF11 forms a tripartite complex with the scaffold PSD-95 and AMPA receptors, requiring PSD-95 binding for synaptic localization and stabilizing surface AMPARs to sustain AMPAR-mediated transmission and hippocampal LTP (PMID:26595655). The same C-terminal PSD-95-binding module drives osteoclast differentiation (PMID:32047704), where IGSF11 activates Src-family kinases (c-Src, Fyn, Hck) that tyrosine-phosphorylate and inhibit pyruvate kinase M2, linking adhesion signaling to a metabolic switch required for bone resorption (PMID:36928396). In the testis IGSF11 localizes to the Sertoli-cell blood–testis barrier and is required for its functional integrity, proper connexin43 localization, and spermatocyte development (PMID:29123028, PMID:34491997), and in the brain it maintains astrocyte connexin43 levels and gap-junction coupling by limiting lysosomal connexin43 degradation (PMID:38388443). Independently of its adhesive role, the IGSF11 extracellular domain, whose crystal structure has been solved, binds the inhibitory checkpoint ligand VISTA to suppress T-cell proliferation and cytokine production, defining an immune checkpoint axis (PMID:30220083, PMID:33841409).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 High

    Established the founding molecular activity of IGSF11 as a cell adhesion molecule and defined the structural basis of that activity.

    Evidence Overexpression cell aggregation assays in two cell lines with antibody and inducible-expression controls

    PMID:15795899

    Open questions at the time
    • Did not identify physiological tissues where homophilic adhesion operates
    • Cytoplasmic signaling consequences of adhesion not addressed
  2. 2012 High

    Showed that IGSF11 adhesion has a developmental function in vivo, acting cell-autonomously in a migrating cell lineage.

    Evidence Zebrafish forward genetic screen with cell transplantation and genetic rescue in the melanophore lineage

    PMID:22916035

    Open questions at the time
    • Binding partner mediating adhesion in vivo not defined
    • Relevance to mammalian pigment or other lineages not tested
  3. 2015 High

    Defined the postsynaptic molecular complex of IGSF11, linking its adhesion to AMPA receptor stabilization and synaptic plasticity.

    Evidence Reciprocal Co-IP, single-molecule AMPAR tracking, knockdown, and KO mouse electrophysiology

    PMID:26595655

    Open questions at the time
    • How PSD-95 binding mechanically restrains AMPAR mobility not resolved
    • Trans-synaptic adhesion partner at the synapse not identified
  4. 2017 High

    Established IGSF11 as essential for functional blood-testis barrier integrity and connexin43 positioning in Sertoli cells.

    Evidence Global and Sertoli-conditional KO mice with in vivo BTB tracer permeability and connexin43 immunolocalization

    PMID:29123028

    Open questions at the time
    • Molecular link between IGSF11 and connexin43 localization not biochemically defined
    • Whether barrier defect is purely adhesion-based unclear
  5. 2018 High

    Identified VISTA as a binding partner of the IGSF11/VSIG3 extracellular domain and showed the interaction functions as an inhibitory immune checkpoint.

    Evidence Functional ELISA binding screen, T-cell proliferation and cytokine assays, and neutralizing-antibody blocking

    PMID:30220083

    Open questions at the time
    • Receptor signaling downstream of VISTA engagement not mapped
    • Reconciliation of homophilic adhesion with heterophilic VISTA binding unresolved
  6. 2018 Medium

    Extended IGSF11 function to neural progenitor differentiation in the cerebellum.

    Evidence Knockdown and overexpression in primary cerebellar granule cell precursors with differentiation readouts

    PMID:30176341

    Open questions at the time
    • No in vivo validation
    • Signaling mechanism driving the proliferation-to-differentiation switch not identified
  7. 2020 High

    Showed IGSF11 drives osteoclast differentiation through a defined C-terminal PSD-95 interaction, and that CD44 can substitute by converging on PSD-95.

    Evidence KO mice with bone histomorphometry, domain-truncation rescue, and CD44/hyaluronan rescue with PSD-95 RNAi epistasis

    PMID:32047704 PMID:32290171

    Open questions at the time
    • The CD44 compensation finding rests on a single Medium-confidence study
    • Downstream effectors of the IGSF11–PSD-95 complex not yet identified at this stage
  8. 2021 High

    Demonstrated that IGSF11 homophilic adhesion specifies layer-specific interneuron synaptic connectivity and is required for normal spermatocyte chromatin organization.

    Evidence Cell-type-specific loss- and gain-of-function with ectopic synapse induction in neocortex; KO mice with Hi-C and testicular cell transplantation

    PMID:34261648 PMID:34491997

    Open questions at the time
    • Intracellular signaling translating adhesion into bouton/synapse changes unknown
    • Mechanism connecting IGSF11 to heterochromatin dissociation in meiosis undefined
  9. 2021 High

    Provided the crystal structure of the IGSF11 extracellular domain and an orthogonal validation of the VISTA interaction, enabling small-molecule inhibitor design.

    Evidence X-ray crystallography at 2.64 Å, Co-IP, and docking-based inhibitor identification

    PMID:33841409

    Open questions at the time
    • No co-crystal structure of the IGSF11–VISTA complex
    • Inhibitor activity characterized only in vitro
  10. 2023 High

    Resolved the intracellular signaling cascade of osteoclast IGSF11, connecting it to a Src-kinase-driven metabolic switch on PKM2.

    Evidence Controlled IGSF11 activation, phosphoproteomic identification of PKM2, kinase assays, and bidirectional pharmacological rescue in KO cells and in vivo

    PMID:36928396

    Open questions at the time
    • How Src family kinases are recruited downstream of IGSF11–PSD-95 not detailed
    • Generalizability of the PKM2 mechanism to non-osteoclast lineages untested
  11. 2023 Medium

    Linked IGSF11/VSIG3 expression to post-transcriptional regulation and immune escape in tumors.

    Evidence CLIP, oligonucleotide pulldown, m6A-RIP, and Co-IP in lung cancer cells

    PMID:37370798

    Open questions at the time
    • Single-lab regulatory cascade
    • In vivo relevance of the miR-125a-5p/METTL3 axis not established
  12. 2024 High

    Showed IGSF11 maintains astrocyte gap-junction coupling by protecting connexin43 from lysosomal degradation, selectively among connexins.

    Evidence KO mice with biocytin coupling assay, proteolysis inhibition, and connexin selectivity controls

    PMID:38388443

    Open questions at the time
    • Direct physical interaction between IGSF11 and connexin43 not demonstrated
    • Mechanism by which IGSF11 restrains lysosomal targeting unknown
  13. 2025 Medium

    Identified a tumor-cell-intrinsic adhesion/signaling role via RAP1 recruitment and a microglia-dependent checkpoint function in brain tumors.

    Evidence IP-MS identification of RAP1 with domain mapping and migration assays in melanoma; single-nuclei/spatial transcriptomics and in vivo IGSF11–VISTA targeting in diffuse midline glioma

    PMID:40635001 PMID:41576930

    Open questions at the time
    • RAP1 complex characterized in a single lab without reciprocal in-tissue validation
    • Mechanism of microglia-mediated, T-cell-independent tumor control not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single homophilic adhesion molecule mechanistically reconciles its trans-adhesive role with heterophilic VISTA-checkpoint binding, and how the PSD-95/Src/PKM2 intracellular module relates to its connexin-stabilizing and chromatin-organizing functions, remains unresolved.
  • No co-structure of IGSF11 with VISTA or with homophilic partner
  • Unified model linking extracellular engagement to the diverse downstream effectors absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 3 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2 GO:0048018 receptor ligand activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-1500931 Cell-Cell communication 2 R-HSA-168256 Immune System 1
Partners
CD44GJA1GRIA/AMPARPKM2PSD-95RAP1VISTA

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 VSIG-3/IGSF11 binds specifically to the B7 family member VISTA (PD-1H) as determined by functional ELISA binding screening; this interaction inhibits human T-cell proliferation and reduces cytokine/chemokine production (IFN-γ, IL-2, IL-17, CCL5, CCL3, CXCL11). Anti-VISTA neutralizing antibodies attenuate both VSIG-3/VISTA binding and VSIG-3-induced T-cell inhibition. Functional ELISA binding assay, T-cell proliferation assay, cytokine production assay, neutralizing antibody blocking experiment Immunology High 30220083
2021 Crystal structure of the extracellular domain (ECD) of human VSIG3/IGSF11 was solved at 2.64 Å resolution; interaction of VSIG3 with VISTA was validated by co-immunoprecipitation. A small molecule inhibitor (K284-3046) of VSIG3 was identified based on protein-protein docking. X-ray crystallography (2.64 Å), co-immunoprecipitation, protein-protein docking, in vitro inhibitor evaluation Frontiers in immunology High 33841409
2015 IgSF11 is a dual-binding partner of PSD-95 (postsynaptic scaffolding protein) and AMPA glutamate receptors (AMPARs) at excitatory synapses. IgSF11 requires PSD-95 binding for its excitatory synaptic localization. IgSF11 stabilizes synaptic AMPARs: knockdown suppresses AMPAR-mediated synaptic transmission and increases surface mobility of AMPARs (single-molecule tracking). IgSF11 deletion in mice suppresses AMPAR-mediated synaptic transmission in dentate gyrus and LTP in CA1 hippocampus. Co-immunoprecipitation, single-molecule tracking (high-throughput), IgSF11 KD (knockdown), IgSF11 KO mouse electrophysiology (AMPAR-mediated currents, LTP recording) Nature neuroscience High 26595655
2005 BT-IgSF/IGSF11 functions as a cell adhesion molecule mediating homophilic, Ca2+/Mg2+-independent cell aggregation. The cytoplasmic tail is not required for adhesion function, and β1 integrin is not involved. Overexpression in TF-1-fms and NIH/3T3 cells, cell aggregation assay, neutralizing antibody (anti-β1 integrin), flow cytometric analysis, inducible expression system Journal of cellular physiology High 15795899
2012 Igsf11 (zebrafish ortholog) mediates adhesive interactions and is required cell-autonomously in the melanophore lineage for adult stripe development; igsf11 mutants show defects in melanophore migration and survival, as demonstrated by cell transplantation and genetic rescue experiments. Forward genetic screen (seurat mutant), cell transplantation, genetic rescue, in vitro/in vivo/ex vivo cell behavior analyses PLoS genetics High 22916035
2020 IgSF11 regulates osteoclast differentiation and bone resorption through interaction with PSD-95 scaffold protein. IgSF11 functions through homophilic interactions during osteoclast differentiation. The IgSF11–PSD-95 interaction requires the 75 C-terminal amino acids of IgSF11. IgSF11-deficient mice show impaired osteoclast differentiation and bone resorption but no bone formation defect, resulting in increased bone mass. IgSF11 KO mouse model, in vitro osteoclast culture, domain deletion rescue experiments, bone histomorphometry Bone research High 32047704
2023 IgSF11 controls osteoclast differentiation by regulating pyruvate kinase M2 (PKM2) activity. IgSF11 activates Src family kinases (c-Src, Fyn, HcK), which phosphorylate PKM2 on tyrosine residues, inhibiting PKM2 activity. IgSF11-deficient cells show higher PKM2 activity and defective osteoclast differentiation. Pharmacological inhibition of PKM2 (Shikonin) rescues differentiation in IgSF11-KO cells; PKM2 activation (TEPP46) suppresses wild-type osteoclast differentiation. Controlled IgSF11 activation system, phosphoproteomics (PKM2 identification), kinase activity assays, pharmacological rescue (Shikonin, TEPP46), IgSF11-KO cells, in vivo bone resorption assay Bone research High 36928396
2017 BT-IgSF/IgSF11 is localized in Sertoli cells at the blood-testis barrier (BTB) and apical ectoplasmic specialization. Conditional KO (AMHCre, Rosa26CreERT2) in Sertoli cells causes male infertility, azoospermia, and spermatogenesis arrest. BTB functional integrity is impaired (BTB-impermeable tracer assay) despite normal BTB ultrastructure. Absence of BT-IgSF leads to mislocalization of connexin43 throughout the seminiferous epithelium rather than being restricted to the BTB, suggesting impaired cell-cell communication. Global and conditional KO mouse models, BTB tracer injection (in vivo permeability assay), immunofluorescence localization, electron microscopy, RT-qPCR The Journal of biological chemistry High 29123028
2021 IGSF11 deficiency in mice leads to failure of pericentric heterochromatin dissociation during meiotic diplotene; spermatocytes accumulate interchromosomal interactions (detected by Hi-C) mostly at chromosome ends. IGSF11 is required in both Sertoli (somatic) cells and spermatogenic cells for primary spermatocyte development, demonstrated by testicular cell transplantation. IGSF11 KO mouse, meiotic fluorescent reporter system, testicular cell transplantation, Hi-C chromosome conformation capture PLoS genetics High 34491997
2021 IgSF11 homophilic adhesion proteins are preferentially expressed in chandelier cells (ChCs) and their postsynaptic target layer in the neocortex. Loss-of-function in either ChCs or postsynaptic pyramidal neurons impairs layer-specific ChC synaptic development. Overexpression of IgSF11 in ChCs enlarges presynaptic boutons; expressing IgSF11 in non-target layers induces ectopic ChC synapses, demonstrating that IgSF11 homophilic interactions determine layer-specific synaptic connectivity. IgSF11 KO, conditional loss-of-function in ChCs or postsynaptic cells, overexpression in ChCs and non-target layers, synaptic morphology analysis (imaging) Science advances High 34261648
2024 BT-IgSF/IgSF11 KO in mice causes increased clustering and reduced protein levels of connexin43 (Gja1) in astrocytes and ependymal cells, and decreased astrocyte-astrocyte gap junction coupling (biocytin spread assay in hippocampal/cortical slices). The lysosomal pathway mediates increased connexin43 degradation in the absence of BT-IgSF. Connexin30 (Gjb6) and neuronal connexin36 (Gjd2) are not affected. BT-IgSF global KO mouse, biocytin coupling assay in acute brain slices, protein biosynthesis/proteolysis inhibition experiments, immunofluorescence for connexin localization eNeuro High 38388443
2020 CD44 can compensate for IgSF11 deficiency in osteoclast differentiation by associating with PSD-95. Antibody-mediated CD44 stimulation or low-molecular-weight hyaluronan (LMW-HA) treatment rescues impaired osteoclast differentiation in IgSF11-KO cultures. PSD-95 knockdown abrogates these rescue effects, demonstrating that both IgSF11 and CD44 act through PSD-95. IgSF11 KO osteoclast cultures, antibody-mediated CD44 stimulation, LMW-HA treatment, RNAi knockdown of PSD-95, biochemical Co-IP analysis International journal of molecular sciences Medium 32290171
2018 BT-IgSF/IgSF11 suppresses proliferation and promotes differentiation of cerebellar granule cell precursors (CGCPs). BT-IgSF is expressed in the molecular layer where CGCPs are in the differentiation stage. Knockdown reduces differentiation; overexpression promotes differentiation into cerebellar granule cells. BT-IgSF KD and overexpression in primary cultured CGCPs, proliferation and differentiation assays, expression analysis in developing cerebellum Neuroscience letters Medium 30176341
2005 IGSF11 siRNA knockdown retards the growth of gastric cancer cells. siRNA knockdown, cell growth assay Cancer science Low 16108831
2025 IgSF11 forms a complex with RAS-associated protein 1 (RAP1), identified by immunoprecipitation-mass spectrometry. The L372-R378 region of IgSF11 is required for recruiting RAP1 and driving melanoma cell migration and invasion. IgSF11-expressing melanoma cells show enrichment of EMT gene signatures. Immunoprecipitation-mass spectrometry, IgSF11 KO and re-expression cell lines, domain deletion mutants, migration/invasion assays in vitro and in vivo Cell communication and signaling Medium 40635001
2023 miR-125a-5p represses IGSF11/VSIG3 expression, and adenosine methylation (m6A) of miR-125a-5p by METTL3 (read by KHDRBS3 and HuR) relieves this repression, leading to IGSF11 overexpression and immune escape in lung cancer. Anti-PD-1 therapy saturation of PD-1 induces this cascade. VSIG3/IGSF11 protein-protein interaction (with VISTA) was confirmed by Co-IP in this context. CLIP, oligonucleotide pulldown, Co-IP, qPCR, MemiRIP (m6A-RIP), cell-based assays Cancers Medium 37370798
2025 IGSF11/VISTA immune checkpoint axis is functionally operative in diffuse midline glioma (DMG); IGSF11 is primarily expressed by AOO-associated cancer cells while VISTA is detected in homeostatic microglia. Targeting IGSF11-VISTA results in tumor reduction and survival benefit mediated by brain-resident microglia and independent of T cell infiltration. Single-nuclei RNA sequencing, spatial transcriptomics, high-dimensional imaging, murine DMG model with IGSF11-VISTA targeting Cancer cell Medium 41576930

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 VSIG-3 as a ligand of VISTA inhibits human T-cell function. Immunology 228 30220083
2003 IGSF11 gene, frequently up-regulated in intestinal-type gastric cancer, encodes adhesion molecule homologous to CXADR, FLJ22415 and ESAM. International journal of oncology 88 12851705
2012 Melanophore migration and survival during zebrafish adult pigment stripe development require the immunoglobulin superfamily adhesion molecule Igsf11. PLoS genetics 74 22916035
2005 Identification of immunoglobulin superfamily 11 (IGSF11) as a novel target for cancer immunotherapy of gastrointestinal and hepatocellular carcinomas. Cancer science 57 16108831
2015 Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity. Nature neuroscience 49 26595655
2005 BT-IgSF, a novel immunoglobulin superfamily protein, functions as a cell adhesion molecule. Journal of cellular physiology 44 15795899
2021 Structural Basis of VSIG3: The Ligand for VISTA. Frontiers in immunology 43 33841409
2017 The cell adhesion molecule BT-IgSF is essential for a functional blood-testis barrier and male fertility in mice. The Journal of biological chemistry 29 29123028
2021 IgSF11 homophilic adhesion proteins promote layer-specific synaptic assembly of the cortical interneuron subtype. Science advances 25 34261648
2020 IgSF11 regulates osteoclast differentiation through association with the scaffold protein PSD-95. Bone research 25 32047704
2023 IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss. Bone research 22 36928396
2022 IGSF11 and VISTA: a pair of promising immune checkpoints in tumor immunotherapy. Biomarker research 18 35831836
2014 The IgCAMs CAR, BT-IgSF, and CLMP: structure, function, and diseases. Advances in neurobiology 14 25300131
2021 IGSF11 is required for pericentric heterochromatin dissociation during meiotic diplotene. PLoS genetics 13 34491997
2018 Promotion of differentiation in developing mouse cerebellar granule cells by a cell adhesion molecule BT-IgSF. Neuroscience letters 13 30176341
2024 The VISTA/VSIG3/PSGL-1 axis: crosstalk between immune effector cells and cancer cells in invasive ductal breast carcinoma. Cancer immunology, immunotherapy : CII 11 38833004
2020 CD44 Can Compensate for IgSF11 Deficiency by Associating with the Scaffold Protein PSD-95 during Osteoclast Differentiation. International journal of molecular sciences 9 32290171
2023 Adenosine Methylation Level of miR-125a-5p Promotes Anti-PD-1 Therapy Escape through the Regulation of IGSF11/VSIG3 Expression. Cancers 8 37370798
2023 IgSF11 deficiency alleviates osteoarthritis in mice by suppressing early subchondral bone changes. Experimental & molecular medicine 8 38036734
2024 The IgCAM BT-IgSF (IgSF11) Is Essential for Connexin43-Mediated Astrocyte-Astrocyte Coupling in Mice. eNeuro 7 38388443
2024 VSIG-3/IGSF11 silencing in A2058 melanoma cells simultaneously suppresses melanoma progression and induces anti-tumoral cytokine profile in human T cells: In silico and in vitro study. Naunyn-Schmiedeberg's archives of pharmacology 3 39365310
2023 Lack of the Ig cell adhesion molecule BT-IgSF (IgSF11) induced behavioral changes in the open maze, water maze and resident intruder test. PloS one 3 36607983
2025 IgSF11-RAP1 signaling promotes cell migration and invasion of cutaneous melanoma. Cell communication and signaling : CCS 2 40635001
2025 IGSF11-Mediated Immune Modulation: Unlocking a Novel Pathway in Emerging Cancer Immunotherapies. Cancers 2 40867265
2026 IGSF11-VISTA is a critical and targetable immune checkpoint axis in diffuse midline glioma. Cancer cell 0 41576930
2026 The miR-146a/IGSF11 Axis Potentially Mediates the Protective Effect of Dexmedetomidine Against Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease. Human mutation 0 42147813
2025 [IGSF11: A Novel Target for Cancer Immunotherapy]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 0 40506491
2025 Exploring IgSF11 as a potential immune checkpoint and immunotherapeutic target in breast cancer. Cancer immunology, immunotherapy : CII 0 40810781
2024 Dysregulated expression of IGSF11-AS1 and BVES-AS in azoospermia and its correlation with serum hormone levels. Biomarkers in medicine 0 38881522

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