{"gene":"IGSF11","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2018,"finding":"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.","method":"Functional ELISA binding assay, T-cell proliferation assay, cytokine production assay, neutralizing antibody blocking experiment","journal":"Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (binding ELISA, proliferation, cytokine readouts, antibody blocking) in a single study establishing the ligand-receptor pair and its functional consequence","pmids":["30220083"],"is_preprint":false},{"year":2021,"finding":"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.","method":"X-ray crystallography (2.64 Å), co-immunoprecipitation, protein-protein docking, in vitro inhibitor evaluation","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus orthogonal Co-IP validation of the VISTA interaction, single lab but multiple rigorous methods","pmids":["33841409"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, single-molecule tracking (high-throughput), IgSF11 KD (knockdown), IgSF11 KO mouse electrophysiology (AMPAR-mediated currents, LTP recording)","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (reciprocal Co-IP, single-molecule tracking, KD, KO with defined electrophysiological phenotype) in a single rigorous study","pmids":["26595655"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Overexpression in TF-1-fms and NIH/3T3 cells, cell aggregation assay, neutralizing antibody (anti-β1 integrin), flow cytometric analysis, inducible expression system","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple cell line systems and flow cytometry confirming homophilic adhesion mechanism, two independent cell systems","pmids":["15795899"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Forward genetic screen (seurat mutant), cell transplantation, genetic rescue, in vitro/in vivo/ex vivo cell behavior analyses","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue and cell transplantation establish cell-autonomous function; multiple experimental approaches (in vitro, in vivo, ex vivo) in a single study","pmids":["22916035"],"is_preprint":false},{"year":2020,"finding":"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.","method":"IgSF11 KO mouse model, in vitro osteoclast culture, domain deletion rescue experiments, bone histomorphometry","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined phenotype, in vitro rescue with domain truncation pinpointing the PSD-95 interaction region, multiple orthogonal approaches","pmids":["32047704"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Controlled IgSF11 activation system, phosphoproteomics (PKM2 identification), kinase activity assays, pharmacological rescue (Shikonin, TEPP46), IgSF11-KO cells, in vivo bone resorption assay","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphoproteomic identification of PKM2 as substrate, pharmacological rescue from both sides (inhibitor and activator), in vivo confirmation, multiple orthogonal methods","pmids":["36928396"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Global and conditional KO mouse models, BTB tracer injection (in vivo permeability assay), immunofluorescence localization, electron microscopy, RT-qPCR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with Sertoli-specific drivers, functional BTB permeability assay, and connexin43 mislocalization establish mechanism; multiple orthogonal approaches","pmids":["29123028"],"is_preprint":false},{"year":2021,"finding":"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.","method":"IGSF11 KO mouse, meiotic fluorescent reporter system, testicular cell transplantation, Hi-C chromosome conformation capture","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with mechanistic readout (Hi-C), cell transplantation establishing cell-autonomous vs non-cell-autonomous requirements, multiple orthogonal methods in one study","pmids":["34491997"],"is_preprint":false},{"year":2021,"finding":"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.","method":"IgSF11 KO, conditional loss-of-function in ChCs or postsynaptic cells, overexpression in ChCs and non-target layers, synaptic morphology analysis (imaging)","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific loss- and gain-of-function with defined synaptic phenotypes; ectopic synapse induction experiments demonstrate sufficiency","pmids":["34261648"],"is_preprint":false},{"year":2024,"finding":"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.","method":"BT-IgSF global KO mouse, biocytin coupling assay in acute brain slices, protein biosynthesis/proteolysis inhibition experiments, immunofluorescence for connexin localization","journal":"eNeuro","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with functional gap junction coupling assay (biocytin spread), pharmacological dissection of degradation pathway, selectivity controls (Cx30, Cx36 not affected)","pmids":["38388443"],"is_preprint":false},{"year":2020,"finding":"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.","method":"IgSF11 KO osteoclast cultures, antibody-mediated CD44 stimulation, LMW-HA treatment, RNAi knockdown of PSD-95, biochemical Co-IP analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional rescue in KO cells with RNAi epistasis, single lab","pmids":["32290171"],"is_preprint":false},{"year":2018,"finding":"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.","method":"BT-IgSF KD and overexpression in primary cultured CGCPs, proliferation and differentiation assays, expression analysis in developing cerebellum","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD and overexpression in primary cells with differentiation readout, single lab, no in vivo validation","pmids":["30176341"],"is_preprint":false},{"year":2005,"finding":"IGSF11 siRNA knockdown retards the growth of gastric cancer cells.","method":"siRNA knockdown, cell growth assay","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA experiment with growth readout, no pathway mechanism identified, single lab","pmids":["16108831"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Immunoprecipitation-mass spectrometry, IgSF11 KO and re-expression cell lines, domain deletion mutants, migration/invasion assays in vitro and in vivo","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identification of RAP1, domain mapping by deletion mutants, KO rescue with specific region, single lab","pmids":["40635001"],"is_preprint":false},{"year":2023,"finding":"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.","method":"CLIP, oligonucleotide pulldown, Co-IP, qPCR, MemiRIP (m6A-RIP), cell-based assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple RNA-protein interaction methods (CLIP, pulldown, MemiRIP) plus Co-IP for protein interaction, single lab","pmids":["37370798"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Single-nuclei RNA sequencing, spatial transcriptomics, high-dimensional imaging, murine DMG model with IGSF11-VISTA targeting","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics spatial mapping plus functional in vivo targeting in murine model, single study, novel finding","pmids":["41576930"],"is_preprint":false}],"current_model":"IGSF11 (BT-IgSF/VSIG3) is a type I transmembrane immunoglobulin superfamily cell adhesion molecule that functions through homophilic interactions to mediate cell-cell adhesion in the brain and testis, acts as an inhibitory ligand for the immune checkpoint receptor VISTA to suppress T-cell proliferation and cytokine production, stabilizes synaptic AMPA receptors at excitatory synapses through tripartite interactions with PSD-95 and AMPARs, promotes osteoclast differentiation via PSD-95-dependent activation of Src family kinases that phosphorylate and inhibit PKM2, is required for functional blood-testis barrier integrity and connexin43-mediated astrocyte gap junction coupling, and determines layer-specific synaptic connectivity of cortical chandelier interneurons through homophilic adhesion."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2005,"claim":"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","pmids":["15795899"],"confidence":"High","gaps":["Did not identify physiological tissues where homophilic adhesion operates","Cytoplasmic signaling consequences of adhesion not addressed"]},{"year":2012,"claim":"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","pmids":["22916035"],"confidence":"High","gaps":["Binding partner mediating adhesion in vivo not defined","Relevance to mammalian pigment or other lineages not tested"]},{"year":2015,"claim":"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","pmids":["26595655"],"confidence":"High","gaps":["How PSD-95 binding mechanically restrains AMPAR mobility not resolved","Trans-synaptic adhesion partner at the synapse not identified"]},{"year":2017,"claim":"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","pmids":["29123028"],"confidence":"High","gaps":["Molecular link between IGSF11 and connexin43 localization not biochemically defined","Whether barrier defect is purely adhesion-based unclear"]},{"year":2018,"claim":"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","pmids":["30220083"],"confidence":"High","gaps":["Receptor signaling downstream of VISTA engagement not mapped","Reconciliation of homophilic adhesion with heterophilic VISTA binding unresolved"]},{"year":2018,"claim":"Extended IGSF11 function to neural progenitor differentiation in the cerebellum.","evidence":"Knockdown and overexpression in primary cerebellar granule cell precursors with differentiation readouts","pmids":["30176341"],"confidence":"Medium","gaps":["No in vivo validation","Signaling mechanism driving the proliferation-to-differentiation switch not identified"]},{"year":2020,"claim":"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","pmids":["32047704","32290171"],"confidence":"High","gaps":["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"]},{"year":2021,"claim":"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","pmids":["34261648","34491997"],"confidence":"High","gaps":["Intracellular signaling translating adhesion into bouton/synapse changes unknown","Mechanism connecting IGSF11 to heterochromatin dissociation in meiosis undefined"]},{"year":2021,"claim":"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","pmids":["33841409"],"confidence":"High","gaps":["No co-crystal structure of the IGSF11–VISTA complex","Inhibitor activity characterized only in vitro"]},{"year":2023,"claim":"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","pmids":["36928396"],"confidence":"High","gaps":["How Src family kinases are recruited downstream of IGSF11–PSD-95 not detailed","Generalizability of the PKM2 mechanism to non-osteoclast lineages untested"]},{"year":2023,"claim":"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","pmids":["37370798"],"confidence":"Medium","gaps":["Single-lab regulatory cascade","In vivo relevance of the miR-125a-5p/METTL3 axis not established"]},{"year":2024,"claim":"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","pmids":["38388443"],"confidence":"High","gaps":["Direct physical interaction between IGSF11 and connexin43 not demonstrated","Mechanism by which IGSF11 restrains lysosomal targeting unknown"]},{"year":2025,"claim":"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","pmids":["40635001","41576930"],"confidence":"Medium","gaps":["RAP1 complex characterized in a single lab without reciprocal in-tissue validation","Mechanism of microglia-mediated, T-cell-independent tumor control not fully resolved"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No co-structure of IGSF11 with VISTA or with homophilic partner","Unified model linking extracellular engagement to the diverse downstream effectors absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,4,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,9]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[7,10]}],"complexes":[],"partners":["VISTA","PSD-95","GRIA/AMPAR","PKM2","CD44","RAP1","GJA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5DX21","full_name":"Immunoglobulin superfamily member 11","aliases":["Brain and testis-specific immunoglobulin superfamily protein","Bt-IGSF","V-set and immunoglobulin domain-containing protein 3"],"length_aa":431,"mass_kda":46.1,"function":"Functions as a cell adhesion molecule through homophilic interaction. Stimulates cell growth","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q5DX21/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IGSF11","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IGSF11","total_profiled":1310},"omim":[{"mim_id":"615608","title":"V-SET IMMUNOREGULATORY RECEPTOR; VSIR","url":"https://www.omim.org/entry/615608"},{"mim_id":"608351","title":"IMMUNOGLOBULIN SUPERFAMILY, MEMBER 11; IGSF11","url":"https://www.omim.org/entry/608351"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":28.2},{"tissue":"retina","ntpm":46.9},{"tissue":"testis","ntpm":33.4}],"url":"https://www.proteinatlas.org/search/IGSF11"},"hgnc":{"alias_symbol":["BT-IgSF","MGC35227","Igsf13","VSIG3","CT119"],"prev_symbol":[]},"alphafold":{"accession":"Q5DX21","domains":[{"cath_id":"2.60.40.10","chopping":"25-142","consensus_level":"high","plddt":94.5828,"start":25,"end":142},{"cath_id":"2.60.40.10","chopping":"148-231","consensus_level":"high","plddt":94.9762,"start":148,"end":231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5DX21","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5DX21-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5DX21-F1-predicted_aligned_error_v6.png","plddt_mean":73.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IGSF11","jax_strain_url":"https://www.jax.org/strain/search?query=IGSF11"},"sequence":{"accession":"Q5DX21","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5DX21.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5DX21/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5DX21"}},"corpus_meta":[{"pmid":"30220083","id":"PMC_30220083","title":"VSIG-3 as a ligand of VISTA inhibits human T-cell function.","date":"2018","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30220083","citation_count":228,"is_preprint":false},{"pmid":"12851705","id":"PMC_12851705","title":"IGSF11 gene, frequently up-regulated in intestinal-type gastric cancer, encodes adhesion molecule homologous to CXADR, FLJ22415 and ESAM.","date":"2003","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12851705","citation_count":88,"is_preprint":false},{"pmid":"22916035","id":"PMC_22916035","title":"Melanophore migration and survival during zebrafish adult pigment stripe development require the immunoglobulin superfamily adhesion molecule Igsf11.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22916035","citation_count":74,"is_preprint":false},{"pmid":"16108831","id":"PMC_16108831","title":"Identification of immunoglobulin superfamily 11 (IGSF11) as a novel target for cancer immunotherapy of gastrointestinal and hepatocellular carcinomas.","date":"2005","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/16108831","citation_count":57,"is_preprint":false},{"pmid":"26595655","id":"PMC_26595655","title":"Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity.","date":"2015","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26595655","citation_count":49,"is_preprint":false},{"pmid":"15795899","id":"PMC_15795899","title":"BT-IgSF, a novel immunoglobulin superfamily protein, functions as a cell adhesion molecule.","date":"2005","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15795899","citation_count":44,"is_preprint":false},{"pmid":"33841409","id":"PMC_33841409","title":"Structural Basis of VSIG3: The Ligand for VISTA.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33841409","citation_count":43,"is_preprint":false},{"pmid":"29123028","id":"PMC_29123028","title":"The cell adhesion molecule BT-IgSF is essential for a functional blood-testis barrier and male fertility in mice.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29123028","citation_count":29,"is_preprint":false},{"pmid":"32047704","id":"PMC_32047704","title":"IgSF11 regulates osteoclast differentiation through association with the scaffold protein PSD-95.","date":"2020","source":"Bone research","url":"https://pubmed.ncbi.nlm.nih.gov/32047704","citation_count":25,"is_preprint":false},{"pmid":"34261648","id":"PMC_34261648","title":"IgSF11 homophilic adhesion proteins promote layer-specific synaptic assembly of the cortical interneuron subtype.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34261648","citation_count":25,"is_preprint":false},{"pmid":"36928396","id":"PMC_36928396","title":"IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss.","date":"2023","source":"Bone research","url":"https://pubmed.ncbi.nlm.nih.gov/36928396","citation_count":22,"is_preprint":false},{"pmid":"35831836","id":"PMC_35831836","title":"IGSF11 and VISTA: a pair of promising immune checkpoints in tumor immunotherapy.","date":"2022","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/35831836","citation_count":18,"is_preprint":false},{"pmid":"25300131","id":"PMC_25300131","title":"The IgCAMs CAR, BT-IgSF, and CLMP: structure, function, and diseases.","date":"2014","source":"Advances in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25300131","citation_count":14,"is_preprint":false},{"pmid":"34491997","id":"PMC_34491997","title":"IGSF11 is required for pericentric heterochromatin dissociation during meiotic diplotene.","date":"2021","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34491997","citation_count":13,"is_preprint":false},{"pmid":"30176341","id":"PMC_30176341","title":"Promotion of differentiation in developing mouse cerebellar granule cells by a cell adhesion molecule BT-IgSF.","date":"2018","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/30176341","citation_count":13,"is_preprint":false},{"pmid":"38833004","id":"PMC_38833004","title":"The VISTA/VSIG3/PSGL-1 axis: crosstalk between immune effector cells and cancer cells in invasive ductal breast carcinoma.","date":"2024","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/38833004","citation_count":11,"is_preprint":false},{"pmid":"32290171","id":"PMC_32290171","title":"CD44 Can Compensate for IgSF11 Deficiency by Associating with the Scaffold Protein PSD-95 during Osteoclast Differentiation.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32290171","citation_count":9,"is_preprint":false},{"pmid":"37370798","id":"PMC_37370798","title":"Adenosine Methylation Level of miR-125a-5p Promotes Anti-PD-1 Therapy Escape through the Regulation of IGSF11/VSIG3 Expression.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37370798","citation_count":8,"is_preprint":false},{"pmid":"38036734","id":"PMC_38036734","title":"IgSF11 deficiency alleviates osteoarthritis in mice by suppressing early subchondral bone changes.","date":"2023","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38036734","citation_count":8,"is_preprint":false},{"pmid":"38388443","id":"PMC_38388443","title":"The IgCAM BT-IgSF (IgSF11) Is Essential for Connexin43-Mediated Astrocyte-Astrocyte Coupling in Mice.","date":"2024","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/38388443","citation_count":7,"is_preprint":false},{"pmid":"36607983","id":"PMC_36607983","title":"Lack of the Ig cell adhesion molecule BT-IgSF (IgSF11) induced behavioral changes in the open maze, water maze and resident intruder test.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36607983","citation_count":3,"is_preprint":false},{"pmid":"39365310","id":"PMC_39365310","title":"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.","date":"2024","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39365310","citation_count":3,"is_preprint":false},{"pmid":"40635001","id":"PMC_40635001","title":"IgSF11-RAP1 signaling promotes cell migration and invasion of cutaneous melanoma.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/40635001","citation_count":2,"is_preprint":false},{"pmid":"40867265","id":"PMC_40867265","title":"IGSF11-Mediated Immune Modulation: Unlocking a Novel Pathway in Emerging Cancer Immunotherapies.","date":"2025","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/40867265","citation_count":2,"is_preprint":false},{"pmid":"41576930","id":"PMC_41576930","title":"IGSF11-VISTA is a critical and targetable immune checkpoint axis in diffuse midline glioma.","date":"2026","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/41576930","citation_count":0,"is_preprint":false},{"pmid":"38881522","id":"PMC_38881522","title":"Dysregulated expression of IGSF11-AS1 and BVES-AS in azoospermia and its correlation with serum hormone levels.","date":"2024","source":"Biomarkers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38881522","citation_count":0,"is_preprint":false},{"pmid":"40810781","id":"PMC_40810781","title":"Exploring IgSF11 as a potential immune checkpoint and immunotherapeutic target in breast cancer.","date":"2025","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/40810781","citation_count":0,"is_preprint":false},{"pmid":"40506491","id":"PMC_40506491","title":"[IGSF11: A Novel Target for Cancer Immunotherapy].","date":"2025","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40506491","citation_count":0,"is_preprint":false},{"pmid":"42147813","id":"PMC_42147813","title":"The miR-146a/IGSF11 Axis Potentially Mediates the Protective Effect of Dexmedetomidine Against Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease.","date":"2026","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/42147813","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.20.24319465","title":"Common and rare genetic variation intersects with ancestry to influence human skin and plasma carotenoid concentrations","date":"2024-12-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.20.24319465","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.19.24317559","title":"Multi-ancestry GWAS of severe pregnancy nausea and vomiting identifies risk loci associated with appetite, insulin signaling, and brain plasticity","date":"2024-11-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.19.24317559","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.17.682988","title":"Genomic and genetic insights into speciation and pigment pattern diversification in  <i>Danio</i>  fishes","date":"2025-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.17.682988","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17449,"output_tokens":4713,"usd":0.061521,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12812,"output_tokens":4111,"usd":0.083418,"stage2_stop_reason":"end_turn"},"total_usd":0.144939,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Functional ELISA binding assay, T-cell proliferation assay, cytokine production assay, neutralizing antibody blocking experiment\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (binding ELISA, proliferation, cytokine readouts, antibody blocking) in a single study establishing the ligand-receptor pair and its functional consequence\",\n      \"pmids\": [\"30220083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography (2.64 Å), co-immunoprecipitation, protein-protein docking, in vitro inhibitor evaluation\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus orthogonal Co-IP validation of the VISTA interaction, single lab but multiple rigorous methods\",\n      \"pmids\": [\"33841409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, single-molecule tracking (high-throughput), IgSF11 KD (knockdown), IgSF11 KO mouse electrophysiology (AMPAR-mediated currents, LTP recording)\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (reciprocal Co-IP, single-molecule tracking, KD, KO with defined electrophysiological phenotype) in a single rigorous study\",\n      \"pmids\": [\"26595655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression in TF-1-fms and NIH/3T3 cells, cell aggregation assay, neutralizing antibody (anti-β1 integrin), flow cytometric analysis, inducible expression system\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell line systems and flow cytometry confirming homophilic adhesion mechanism, two independent cell systems\",\n      \"pmids\": [\"15795899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Forward genetic screen (seurat mutant), cell transplantation, genetic rescue, in vitro/in vivo/ex vivo cell behavior analyses\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue and cell transplantation establish cell-autonomous function; multiple experimental approaches (in vitro, in vivo, ex vivo) in a single study\",\n      \"pmids\": [\"22916035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"IgSF11 KO mouse model, in vitro osteoclast culture, domain deletion rescue experiments, bone histomorphometry\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined phenotype, in vitro rescue with domain truncation pinpointing the PSD-95 interaction region, multiple orthogonal approaches\",\n      \"pmids\": [\"32047704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Controlled IgSF11 activation system, phosphoproteomics (PKM2 identification), kinase activity assays, pharmacological rescue (Shikonin, TEPP46), IgSF11-KO cells, in vivo bone resorption assay\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphoproteomic identification of PKM2 as substrate, pharmacological rescue from both sides (inhibitor and activator), in vivo confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"36928396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Global and conditional KO mouse models, BTB tracer injection (in vivo permeability assay), immunofluorescence localization, electron microscopy, RT-qPCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with Sertoli-specific drivers, functional BTB permeability assay, and connexin43 mislocalization establish mechanism; multiple orthogonal approaches\",\n      \"pmids\": [\"29123028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"IGSF11 KO mouse, meiotic fluorescent reporter system, testicular cell transplantation, Hi-C chromosome conformation capture\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with mechanistic readout (Hi-C), cell transplantation establishing cell-autonomous vs non-cell-autonomous requirements, multiple orthogonal methods in one study\",\n      \"pmids\": [\"34491997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"IgSF11 KO, conditional loss-of-function in ChCs or postsynaptic cells, overexpression in ChCs and non-target layers, synaptic morphology analysis (imaging)\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific loss- and gain-of-function with defined synaptic phenotypes; ectopic synapse induction experiments demonstrate sufficiency\",\n      \"pmids\": [\"34261648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"BT-IgSF global KO mouse, biocytin coupling assay in acute brain slices, protein biosynthesis/proteolysis inhibition experiments, immunofluorescence for connexin localization\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with functional gap junction coupling assay (biocytin spread), pharmacological dissection of degradation pathway, selectivity controls (Cx30, Cx36 not affected)\",\n      \"pmids\": [\"38388443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"IgSF11 KO osteoclast cultures, antibody-mediated CD44 stimulation, LMW-HA treatment, RNAi knockdown of PSD-95, biochemical Co-IP analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional rescue in KO cells with RNAi epistasis, single lab\",\n      \"pmids\": [\"32290171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"BT-IgSF KD and overexpression in primary cultured CGCPs, proliferation and differentiation assays, expression analysis in developing cerebellum\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD and overexpression in primary cells with differentiation readout, single lab, no in vivo validation\",\n      \"pmids\": [\"30176341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IGSF11 siRNA knockdown retards the growth of gastric cancer cells.\",\n      \"method\": \"siRNA knockdown, cell growth assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA experiment with growth readout, no pathway mechanism identified, single lab\",\n      \"pmids\": [\"16108831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, IgSF11 KO and re-expression cell lines, domain deletion mutants, migration/invasion assays in vitro and in vivo\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identification of RAP1, domain mapping by deletion mutants, KO rescue with specific region, single lab\",\n      \"pmids\": [\"40635001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"CLIP, oligonucleotide pulldown, Co-IP, qPCR, MemiRIP (m6A-RIP), cell-based assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple RNA-protein interaction methods (CLIP, pulldown, MemiRIP) plus Co-IP for protein interaction, single lab\",\n      \"pmids\": [\"37370798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Single-nuclei RNA sequencing, spatial transcriptomics, high-dimensional imaging, murine DMG model with IGSF11-VISTA targeting\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics spatial mapping plus functional in vivo targeting in murine model, single study, novel finding\",\n      \"pmids\": [\"41576930\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGSF11 (BT-IgSF/VSIG3) is a type I transmembrane immunoglobulin superfamily cell adhesion molecule that functions through homophilic interactions to mediate cell-cell adhesion in the brain and testis, acts as an inhibitory ligand for the immune checkpoint receptor VISTA to suppress T-cell proliferation and cytokine production, stabilizes synaptic AMPA receptors at excitatory synapses through tripartite interactions with PSD-95 and AMPARs, promotes osteoclast differentiation via PSD-95-dependent activation of Src family kinases that phosphorylate and inhibit PKM2, is required for functional blood-testis barrier integrity and connexin43-mediated astrocyte gap junction coupling, and determines layer-specific synaptic connectivity of cortical chandelier interneurons through homophilic adhesion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#3]. 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 [#9], and it is required cell-autonomously in pigment cell lineages for adult patterning [#4]. 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 [#2]. The same C-terminal PSD-95-binding module drives osteoclast differentiation [#5], 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 [#6]. 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 [#7, #8], and in the brain it maintains astrocyte connexin43 levels and gap-junction coupling by limiting lysosomal connexin43 degradation [#10]. 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 [#0, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the founding molecular activity of IGSF11 as a cell adhesion molecule and defined the structural basis of that activity.\",\n      \"evidence\": \"Overexpression cell aggregation assays in two cell lines with antibody and inducible-expression controls\",\n      \"pmids\": [\"15795899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify physiological tissues where homophilic adhesion operates\", \"Cytoplasmic signaling consequences of adhesion not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed that IGSF11 adhesion has a developmental function in vivo, acting cell-autonomously in a migrating cell lineage.\",\n      \"evidence\": \"Zebrafish forward genetic screen with cell transplantation and genetic rescue in the melanophore lineage\",\n      \"pmids\": [\"22916035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding partner mediating adhesion in vivo not defined\", \"Relevance to mammalian pigment or other lineages not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the postsynaptic molecular complex of IGSF11, linking its adhesion to AMPA receptor stabilization and synaptic plasticity.\",\n      \"evidence\": \"Reciprocal Co-IP, single-molecule AMPAR tracking, knockdown, and KO mouse electrophysiology\",\n      \"pmids\": [\"26595655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PSD-95 binding mechanically restrains AMPAR mobility not resolved\", \"Trans-synaptic adhesion partner at the synapse not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established IGSF11 as essential for functional blood-testis barrier integrity and connexin43 positioning in Sertoli cells.\",\n      \"evidence\": \"Global and Sertoli-conditional KO mice with in vivo BTB tracer permeability and connexin43 immunolocalization\",\n      \"pmids\": [\"29123028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between IGSF11 and connexin43 localization not biochemically defined\", \"Whether barrier defect is purely adhesion-based unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified VISTA as a binding partner of the IGSF11/VSIG3 extracellular domain and showed the interaction functions as an inhibitory immune checkpoint.\",\n      \"evidence\": \"Functional ELISA binding screen, T-cell proliferation and cytokine assays, and neutralizing-antibody blocking\",\n      \"pmids\": [\"30220083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor signaling downstream of VISTA engagement not mapped\", \"Reconciliation of homophilic adhesion with heterophilic VISTA binding unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended IGSF11 function to neural progenitor differentiation in the cerebellum.\",\n      \"evidence\": \"Knockdown and overexpression in primary cerebellar granule cell precursors with differentiation readouts\",\n      \"pmids\": [\"30176341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation\", \"Signaling mechanism driving the proliferation-to-differentiation switch not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed IGSF11 drives osteoclast differentiation through a defined C-terminal PSD-95 interaction, and that CD44 can substitute by converging on PSD-95.\",\n      \"evidence\": \"KO mice with bone histomorphometry, domain-truncation rescue, and CD44/hyaluronan rescue with PSD-95 RNAi epistasis\",\n      \"pmids\": [\"32047704\", \"32290171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that IGSF11 homophilic adhesion specifies layer-specific interneuron synaptic connectivity and is required for normal spermatocyte chromatin organization.\",\n      \"evidence\": \"Cell-type-specific loss- and gain-of-function with ectopic synapse induction in neocortex; KO mice with Hi-C and testicular cell transplantation\",\n      \"pmids\": [\"34261648\", \"34491997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling translating adhesion into bouton/synapse changes unknown\", \"Mechanism connecting IGSF11 to heterochromatin dissociation in meiosis undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the crystal structure of the IGSF11 extracellular domain and an orthogonal validation of the VISTA interaction, enabling small-molecule inhibitor design.\",\n      \"evidence\": \"X-ray crystallography at 2.64 Å, Co-IP, and docking-based inhibitor identification\",\n      \"pmids\": [\"33841409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of the IGSF11–VISTA complex\", \"Inhibitor activity characterized only in vitro\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the intracellular signaling cascade of osteoclast IGSF11, connecting it to a Src-kinase-driven metabolic switch on PKM2.\",\n      \"evidence\": \"Controlled IGSF11 activation, phosphoproteomic identification of PKM2, kinase assays, and bidirectional pharmacological rescue in KO cells and in vivo\",\n      \"pmids\": [\"36928396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Src family kinases are recruited downstream of IGSF11–PSD-95 not detailed\", \"Generalizability of the PKM2 mechanism to non-osteoclast lineages untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked IGSF11/VSIG3 expression to post-transcriptional regulation and immune escape in tumors.\",\n      \"evidence\": \"CLIP, oligonucleotide pulldown, m6A-RIP, and Co-IP in lung cancer cells\",\n      \"pmids\": [\"37370798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab regulatory cascade\", \"In vivo relevance of the miR-125a-5p/METTL3 axis not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed IGSF11 maintains astrocyte gap-junction coupling by protecting connexin43 from lysosomal degradation, selectively among connexins.\",\n      \"evidence\": \"KO mice with biocytin coupling assay, proteolysis inhibition, and connexin selectivity controls\",\n      \"pmids\": [\"38388443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between IGSF11 and connexin43 not demonstrated\", \"Mechanism by which IGSF11 restrains lysosomal targeting unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a tumor-cell-intrinsic adhesion/signaling role via RAP1 recruitment and a microglia-dependent checkpoint function in brain tumors.\",\n      \"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\",\n      \"pmids\": [\"40635001\", \"41576930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RAP1 complex characterized in a single lab without reciprocal in-tissue validation\", \"Mechanism of microglia-mediated, T-cell-independent tumor control not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-structure of IGSF11 with VISTA or with homophilic partner\", \"Unified model linking extracellular engagement to the diverse downstream effectors absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 4, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [7, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VISTA\", \"PSD-95\", \"GRIA/AMPAR\", \"PKM2\", \"CD44\", \"RAP1\", \"GJA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}