{"gene":"JAML","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2003,"finding":"JAML is a member of the immunoglobulin superfamily with 2 extracellular Ig-like domains, a transmembrane segment, and a cytoplasmic tail; it localizes to cell-cell contact areas (not free cell borders), consistent with homophilic interactions, and a conserved dimerization motif shared among JAM family members is required for its membrane localization. Exogenous JAML expression in myeloid leukemia cells enhanced adhesion to endothelial cells.","method":"Molecular cloning, immunofluorescence localization, dimerization motif mutagenesis, cell adhesion assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2-3 — localization and adhesion data with mutagenesis of dimerization motif, single lab","pmids":["12869515"],"is_preprint":false},{"year":2010,"finding":"JAML acts as a costimulatory receptor on epithelial γδ T cells; its binding to the ligand coxsackie and adenovirus receptor (CAR) provides costimulation leading to cellular proliferation and cytokine/growth factor production. Inhibition of JAML–CAR interaction diminished γδ T cell activation and delayed wound closure.","method":"Binding assay (JAML–CAR interaction), functional inhibition with blocking antibody, in vivo wound closure model, genetic loss-of-function","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (binding, blockade, in vivo), replicated across two companion papers in the same issue","pmids":["20813954"],"is_preprint":false},{"year":2010,"finding":"Crystal structures of the JAML ectodomain (2.2 Å) and the JAML–CAR complex (2.8 Å) revealed an unusual Ig-domain assembly for JAML and a charged, high-specificity interface with CAR. Biochemical and mutagenesis studies showed that CAR-mediated clustering of JAML recruits PI3K to a JAML intracellular sequence motif homologous to the CD28 costimulatory receptor motif.","method":"X-ray crystallography, site-directed mutagenesis, biochemical PI3K recruitment assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — crystal structures of both apo and complex forms plus mutagenesis and biochemical validation in one study","pmids":["20813955"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of JAML bound to the stimulatory antibody HL4E10 Fab (2.95 Å) showed that HL4E10 binds the membrane-proximal domain of JAML through hydrophobic interactions (nanomolar affinity), whereas the endogenous ligand CAR binds the membrane-distal domain via hydrophilic interactions (micromolar affinity); despite different binding sites and mechanisms, both interactions trigger JAML signaling and γδ T cell costimulation.","method":"X-ray crystallography, surface plasmon resonance kinetics, functional γδ T cell costimulation assay","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus binding kinetics and functional validation","pmids":["21220118"],"is_preprint":false},{"year":2014,"finding":"During neutrophil transepithelial migration, JAML is cleaved from the neutrophil surface by zinc metalloproteases; the released soluble JAML binds to epithelial CAR, compromising barrier function and inhibiting epithelial wound repair through decreased epithelial proliferation. An anti-JAML monoclonal antibody blocking JAML–CAR binding reversed these deleterious effects.","method":"In vitro transepithelial migration assay, metalloprotease inhibition, anti-JAML antibody blockade, in vivo mucosal injury model","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway (metalloprotease cleavage → soluble JAML → CAR binding → barrier disruption) validated with multiple methods in vitro and in vivo","pmids":["24621992"],"is_preprint":false},{"year":2015,"finding":"JAML mediates monocyte and CD8 T cell transmigration across the blood-brain barrier; blocking JAML significantly compromised the migratory capacity of these cells, and JAML-positive trans-migratory cups were detected when cells adhered to the BBB endothelium.","method":"In vitro BBB transmigration assay, JAML blocking antibody, ex vivo and postmortem human tissue analysis","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional blockade in vitro and ex vivo, single lab","pmids":["26734656"],"is_preprint":false},{"year":2020,"finding":"JAML regulates podocyte lipid metabolism through a SIRT1-mediated SREBP1 signaling axis; podocyte-specific deletion of Jaml ameliorated podocyte injury, proteinuria, and lipid accumulation in two diabetic mouse models and an adriamycin nephropathy model.","method":"Conditional (podocyte-specific) Jaml knockout mice, diabetic mouse models, lipid staining, signaling pathway analysis (SIRT1/SREBP1)","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with specific cellular phenotype (lipid accumulation, proteinuria) and defined molecular pathway, validated in multiple disease models","pmids":["33186558"],"is_preprint":false},{"year":2021,"finding":"JAML on T cells interacts with CXADR (CAR) within tumor tissue to support CD8 and γδ T cell antitumor activity; JAML knockout mice showed accelerated tumor growth with impaired γδ TIL response and increased CD8 TIL dysfunction, and agonistic anti-JAML antibody treatment inhibited tumor growth and improved response to anti-PD-1 checkpoint blockade.","method":"JAML knockout mice, tumor implantation models, agonistic antibody treatment, flow cytometry of TIL populations, combination immunotherapy experiment","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic KO and therapeutic antibody with multiple orthogonal readouts in vivo","pmids":["34427588"],"is_preprint":false},{"year":2022,"finding":"JAML promotes acute kidney injury primarily through a macrophage-dependent mechanism; using bone marrow chimeric mice and macrophage-specific Jaml knockout mice, JAML was found to mediate macrophage phenotype polarization and efferocytosis, at least in part through a macrophage-inducible C-type lectin (Mincle)-dependent pathway.","method":"Bone marrow chimeric mice, macrophage-specific Jaml conditional KO, tubular-specific Jaml KO, renal IRI and cisplatin AKI models, signaling analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific genetic dissection across multiple models with defined signaling pathway","pmids":["35708906"],"is_preprint":false},{"year":2023,"finding":"JAML expression in T cells is induced by T cell receptor engagement, and this induction is linked to cis-regulatory interactions between the CD3D and JAML gene loci; JAML is preferentially expressed by tissue-resident memory CD8+ T cells in tumors, and agonistic anti-JAML therapy in a murine melanoma model specifically activates this population and synergizes with anti-PD-1.","method":"TCR stimulation assay, chromatin accessibility/cis-regulatory analysis, single-cell and bulk transcriptomics, murine melanoma model with agonistic antibody","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — TCR induction and cis-regulatory linkage shown, functional mode of action defined in vivo, single lab","pmids":["36701231"],"is_preprint":false},{"year":2025,"finding":"Macrophage-derived JAML promotes atherosclerosis by facilitating nuclear translocation of pyruvate kinase M2 (PKM2) and PKM2/p65 complex formation, thereby activating the NF-κB pathway and NLRP3 inflammasome; macrophage-specific JAML deletion attenuated atherosclerosis and inflammation, while overexpression exacerbated it.","method":"Macrophage-specific JAML KO and transgenic mice, co-immunoprecipitation (PKM2/p65 complex), RNA-sequencing, Oil Red O staining, high-fat diet atherosclerosis model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO/OE with co-IP for complex, defined mechanistic pathway, single lab","pmids":["40148467"],"is_preprint":false},{"year":2025,"finding":"Endothelial JAML inhibits inflammation and atherosclerosis by promoting STAT1 degradation; JAML facilitates interaction between STAT1 and the E3 ubiquitin ligase TRIM25, leading to ubiquitin-mediated proteolysis of STAT1 independent of changes in STAT1 gene expression. Endothelial-specific JAML deletion exacerbated atherosclerotic plaque formation and vascular inflammation.","method":"Endothelial-specific JAML KO mice, co-immunoprecipitation, immunoblotting for ubiquitination, TNF-α stimulation assay, high-fat diet atherosclerosis model","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP for STAT1/TRIM25 complex plus genetic KO, defined ubiquitination mechanism, single lab","pmids":["42001028"],"is_preprint":false},{"year":2025,"finding":"In tumor vascular endothelial cells, JAML promotes angiogenesis and tumor progression by activating the FAK/SRC/AKT/ERK signaling pathway and VEGF/VEGFR2 pathway; endothelial-specific JAML knockout normalized tumor blood vessels (increased pericyte coverage, vessel perfusion, T cell infiltration; decreased vessel density and leakage) and suppressed phosphorylation of FAK/SRC/AKT/ERK and VEGFR2.","method":"Endothelial-specific JAML KO mice, multiple tumor implantation models, immunofluorescence, western blot for pathway phosphorylation, HUVEC in vitro assays","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined signaling pathway in multiple tumor models, single lab","pmids":["39983824"],"is_preprint":false},{"year":2026,"finding":"In CD4+ tissue-resident memory T cells within non-small cell lung cancer, PD-1 signaling suppresses JAML expression; JAML is essential for CD4+ TRM-mediated XCL1 secretion and cDC1 recruitment/mobilization, and PD-1 blockade restores JAML expression and antitumor function. A JAML agonist enhanced the antitumor efficacy of PD-1 inhibitors in tumor-bearing mice.","method":"PD-1 signaling inhibition assay, JAML expression rescue, XCL1 functional assay, cDC1 recruitment in vivo, murine tumor model with agonistic anti-JAML antibody plus anti-PD-1 combination","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic link between PD-1 and JAML expression with downstream cDC1 mobilization defined in vitro and in vivo, single lab","pmids":["41486351"],"is_preprint":false}],"current_model":"JAML is a transmembrane immunoglobulin superfamily receptor that binds its ligand CAR/CXADR through a charged, membrane-distal Ig-domain interface (crystal structure resolved), recruits PI3K via a CD28-like intracellular motif to costimulate γδ and CD8 T cells, can be shed by zinc metalloproteases to act as a soluble CAR antagonist that disrupts epithelial barriers, and regulates lipid metabolism in podocytes via a SIRT1–SREBP1 axis, macrophage polarization/efferocytosis via a Mincle-dependent pathway, and endothelial inflammation via TRIM25-mediated ubiquitination and degradation of STAT1."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of JAML as a JAM-family Ig superfamily member that localizes to cell-cell contacts and promotes leukocyte-endothelial adhesion established the gene as a junctional adhesion molecule with potential roles in immune cell trafficking.","evidence":"Molecular cloning, immunofluorescence, dimerization motif mutagenesis, and adhesion assays in myeloid leukemia cells","pmids":["12869515"],"confidence":"Medium","gaps":["Endogenous ligand not identified","Physiological adhesion partners unknown","Signaling mechanism not addressed"]},{"year":2010,"claim":"Discovery that JAML binds CXADR (CAR) and costimulates γδ T cells, combined with crystal structures revealing the JAML–CAR interface and intracellular PI3K recruitment via a CD28-like motif, established the core costimulatory mechanism and its structural basis.","evidence":"X-ray crystallography (apo 2.2 Å; complex 2.8 Å), binding assays, site-directed mutagenesis, PI3K recruitment biochemistry, blocking antibody, in vivo wound closure model","pmids":["20813954","20813955"],"confidence":"High","gaps":["Downstream signaling cascade beyond PI3K not mapped","Role of JAML in αβ T cells versus γδ T cells not delineated","Whether JAML has additional ligands unresolved"]},{"year":2011,"claim":"Structural characterization of a stimulatory antibody bound to JAML's membrane-proximal domain showed that agonistic signaling can be triggered from a distinct site than the CAR-binding domain, informing therapeutic antibody design.","evidence":"X-ray crystallography (2.95 Å), surface plasmon resonance, γδ T cell costimulation assays","pmids":["21220118"],"confidence":"High","gaps":["Whether proximal-domain engagement activates identical intracellular pathways as CAR binding not resolved","No in vivo therapeutic testing of HL4E10"]},{"year":2014,"claim":"Demonstration that JAML is shed from neutrophils by zinc metalloproteases during transepithelial migration, with soluble JAML acting as a paracrine disruptor of epithelial barriers via CAR, revealed a non-cell-autonomous pathological mode of JAML action.","evidence":"In vitro transepithelial migration, metalloprotease inhibition, anti-JAML antibody blockade, in vivo mucosal injury model","pmids":["24621992"],"confidence":"High","gaps":["Specific metalloprotease(s) responsible for cleavage not identified","Cleavage site on JAML not mapped","Relevance to chronic inflammatory disease not tested"]},{"year":2015,"claim":"Showing that JAML mediates monocyte and CD8 T cell transmigration across the blood-brain barrier extended its adhesion/migration function to the CNS vascular compartment.","evidence":"In vitro BBB transmigration assay with JAML blocking antibody, ex vivo and postmortem human tissue analysis","pmids":["26734656"],"confidence":"Medium","gaps":["Single-lab observation without genetic confirmation","Ligand interaction at the BBB (CAR or other) not confirmed","In vivo neuroinflammation model not performed"]},{"year":2020,"claim":"Podocyte-specific Jaml deletion ameliorated proteinuria and lipid accumulation in diabetic and nephrotoxic models by modulating a SIRT1–SREBP1 lipid metabolism axis, establishing a non-immune, metabolic signaling role for JAML.","evidence":"Conditional podocyte-specific Jaml KO mice in db/db, STZ, and adriamycin nephropathy models; signaling pathway analysis","pmids":["33186558"],"confidence":"High","gaps":["How JAML engages or activates SIRT1 mechanistically unclear","Ligand triggering this pathway in podocytes unknown","Whether the metabolic role extends to other epithelia untested"]},{"year":2021,"claim":"Genetic and therapeutic evidence that JAML–CXADR interaction within tumors sustains γδ and CD8 T cell antitumor function, and that an agonistic anti-JAML antibody synergizes with anti-PD-1, positioned JAML as an immunotherapy target.","evidence":"JAML KO mice with tumor implantation, agonistic antibody monotherapy and combination with anti-PD-1, flow cytometry of TIL populations","pmids":["34427588"],"confidence":"High","gaps":["Human tumor relevance demonstrated only correlatively","Optimal antibody properties for clinical translation not defined","Whether JAML agonism activates exhausted versus naïve T cells not resolved"]},{"year":2022,"claim":"Using macrophage-specific Jaml KO and bone marrow chimeras, JAML was shown to drive acute kidney injury through macrophage polarization and Mincle-dependent efferocytosis, revealing a macrophage-intrinsic inflammatory axis distinct from its T cell costimulatory function.","evidence":"Macrophage-specific and tubular-specific Jaml conditional KO mice in renal IRI and cisplatin AKI models","pmids":["35708906"],"confidence":"High","gaps":["Direct JAML–Mincle physical interaction not demonstrated","Signal transduction between JAML and Mincle pathway not fully mapped","Whether macrophage JAML uses CXADR as ligand in this context unknown"]},{"year":2023,"claim":"TCR engagement was shown to induce JAML expression through cis-regulatory interactions between the CD3D and JAML loci, and JAML marks tissue-resident memory CD8+ T cells in tumors, linking JAML transcriptional control to its functional niche in antitumor immunity.","evidence":"TCR stimulation, chromatin accessibility/cis-regulatory analysis, single-cell transcriptomics, murine melanoma model with agonistic antibody","pmids":["36701231"],"confidence":"Medium","gaps":["Cis-regulatory mechanism single-lab, not independently confirmed","Transcription factor(s) mediating TCR-dependent JAML induction not identified","Whether this regulatory circuit operates in human tumors not shown"]},{"year":2025,"claim":"Cell-type-specific studies revealed opposing roles for JAML in atherosclerosis: macrophage JAML promotes plaque formation via PKM2-driven NF-κB/NLRP3 inflammasome activation, while endothelial JAML suppresses vascular inflammation by facilitating TRIM25-mediated STAT1 ubiquitination and degradation.","evidence":"Macrophage-specific and endothelial-specific JAML KO/overexpression mice, co-IP (PKM2/p65; STAT1/TRIM25), RNA-seq, high-fat diet atherosclerosis models","pmids":["40148467","42001028"],"confidence":"Medium","gaps":["Opposing cell-type roles from independent labs not yet reconciled in a unified model","Whether JAML directly binds PKM2 or TRIM25 versus acting as a scaffold unclear","CXADR involvement in vascular context not tested"]},{"year":2025,"claim":"Endothelial JAML was found to promote tumor angiogenesis through FAK/SRC/AKT/ERK and VEGF/VEGFR2 signaling, with endothelial-specific JAML deletion normalizing tumor vasculature, increasing pericyte coverage, and enhancing T cell infiltration.","evidence":"Endothelial-specific JAML KO mice in multiple tumor models, HUVEC in vitro assays, western blot for pathway phosphorylation","pmids":["39983824"],"confidence":"Medium","gaps":["Pro-angiogenic versus anti-inflammatory endothelial roles of JAML appear contradictory; context-dependence not resolved","Whether JAML directly activates FAK or acts upstream unclear","Single-lab finding"]},{"year":2026,"claim":"PD-1 signaling was shown to suppress JAML expression on CD4+ tissue-resident memory T cells, with JAML required for XCL1 secretion and cDC1 recruitment; PD-1 blockade restored JAML and antitumor function, extending the JAML costimulatory axis to CD4 TRM and DC cross-talk.","evidence":"PD-1 signaling inhibition, JAML expression rescue, XCL1 functional assay, cDC1 recruitment in vivo, murine tumor model with agonistic anti-JAML plus anti-PD-1","pmids":["41486351"],"confidence":"Medium","gaps":["Mechanism by which PD-1 transcriptionally represses JAML not defined","Single-lab observation in murine NSCLC model","Human clinical relevance of CD4 TRM JAML expression not validated"]},{"year":null,"claim":"A unified model integrating JAML's apparently opposing roles across different cell types (costimulatory in T cells, pro-inflammatory in macrophages, both pro-angiogenic and anti-inflammatory in endothelium, metabolic in podocytes) and the ligand dependencies in each context remains to be constructed.","evidence":"","pmids":[],"confidence":"Low","gaps":["No systematic comparison of JAML signaling pathways across cell types","Identity of ligand(s) engaging JAML in macrophages, podocytes, and endothelium unknown","Full interactome and post-translational modification landscape not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,11]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,7,8,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6,10,11,12]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6]}],"complexes":[],"partners":["CXADR","PIK3CA","TRIM25","STAT1","PKM2","CLEC4E","SIRT1"],"other_free_text":[]},"mechanistic_narrative":"JAML is a transmembrane immunoglobulin superfamily receptor that functions as a costimulatory molecule on γδ and CD8 T cells and as a context-dependent signaling scaffold in macrophages and endothelial cells. Engagement of its membrane-distal Ig domain by the epithelial ligand CXADR (CAR) through a charged, high-specificity interface recruits PI3K via a CD28-like intracellular motif, driving T cell proliferation, cytokine production, and antitumor immunity; agonistic anti-JAML antibodies synergize with PD-1 blockade to enhance tumor-infiltrating lymphocyte responses [PMID:20813954, PMID:20813955, PMID:34427588, PMID:41486351]. During neutrophil transepithelial migration, JAML is proteolytically shed by zinc metalloproteases, and the released soluble ectodomain binds epithelial CAR to compromise barrier integrity and wound repair [PMID:24621992]. Beyond its immune costimulatory role, JAML regulates lipid metabolism in podocytes through a SIRT1–SREBP1 axis, macrophage polarization and efferocytosis via Mincle, macrophage inflammatory signaling through PKM2/NF-κB/NLRP3, and endothelial inflammation through TRIM25-mediated ubiquitination and degradation of STAT1 [PMID:33186558, PMID:35708906, PMID:40148467, PMID:42001028]."},"prefetch_data":{"uniprot":{"accession":"Q86YT9","full_name":"Junctional adhesion molecule-like","aliases":["Adhesion molecule interacting with CXADR antigen 1","Dendritic cell-specific protein CREA7-1"],"length_aa":394,"mass_kda":44.3,"function":"Transmembrane protein of the plasma membrane of leukocytes that control their migration and activation through interaction with CXADR, a plasma membrane receptor found on adjacent epithelial and endothelial cells. The interaction between both receptors mediates the activation of gamma-delta T-cells, a subpopulation of T-cells residing in epithelia and involved in tissue homeostasis and repair. Upon epithelial CXADR-binding, JAML induces downstream cell signaling events in gamma-delta T-cells through PI3-kinase and MAP kinases. It results in proliferation and production of cytokines and growth factors by T-cells that in turn stimulate epithelial tissues repair. It also controls the transmigration of leukocytes within epithelial and endothelial tissues through adhesive interactions with epithelial and endothelial CXADR","subcellular_location":"Cell membrane; Cell junction","url":"https://www.uniprot.org/uniprotkb/Q86YT9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JAML","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/JAML","total_profiled":1310},"omim":[{"mim_id":"609770","title":"JUNCTIONAL ADHESION MOLECULE-LIKE; JAML","url":"https://www.omim.org/entry/609770"},{"mim_id":"602621","title":"COXSACKIEVIRUS AND ADENOVIRUS RECEPTOR; CXADR","url":"https://www.omim.org/entry/602621"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":40.7},{"tissue":"lymphoid tissue","ntpm":64.8}],"url":"https://www.proteinatlas.org/search/JAML"},"hgnc":{"alias_symbol":["Gm638","AMICA"],"prev_symbol":["AMICA1"]},"alphafold":{"accession":"Q86YT9","domains":[{"cath_id":"2.60.40.10","chopping":"30-137","consensus_level":"high","plddt":91.4644,"start":30,"end":137},{"cath_id":"2.60.40.10","chopping":"143-253","consensus_level":"high","plddt":89.3822,"start":143,"end":253}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YT9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YT9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YT9-F1-predicted_aligned_error_v6.png","plddt_mean":73.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JAML","jax_strain_url":"https://www.jax.org/strain/search?query=JAML"},"sequence":{"accession":"Q86YT9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86YT9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86YT9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YT9"}},"corpus_meta":[{"pmid":"33186558","id":"PMC_33186558","title":"Elevation of JAML Promotes Diabetic Kidney Disease by Modulating Podocyte Lipid Metabolism.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/33186558","citation_count":178,"is_preprint":false},{"pmid":"20813954","id":"PMC_20813954","title":"The junctional adhesion molecule JAML is a costimulatory receptor for epithelial gammadelta T cell activation.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20813954","citation_count":177,"is_preprint":false},{"pmid":"20813955","id":"PMC_20813955","title":"The molecular interaction of CAR and JAML recruits the central cell signal transducer PI3K.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20813955","citation_count":105,"is_preprint":false},{"pmid":"12869515","id":"PMC_12869515","title":"JAML, a novel protein with characteristics of a junctional adhesion molecule, is induced during differentiation of myeloid leukemia 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Exogenous JAML expression in myeloid leukemia cells enhanced adhesion to endothelial cells.\",\n      \"method\": \"Molecular cloning, immunofluorescence localization, dimerization motif mutagenesis, cell adhesion assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — localization and adhesion data with mutagenesis of dimerization motif, single lab\",\n      \"pmids\": [\"12869515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"JAML acts as a costimulatory receptor on epithelial γδ T cells; its binding to the ligand coxsackie and adenovirus receptor (CAR) provides costimulation leading to cellular proliferation and cytokine/growth factor production. Inhibition of JAML–CAR interaction diminished γδ T cell activation and delayed wound closure.\",\n      \"method\": \"Binding assay (JAML–CAR interaction), functional inhibition with blocking antibody, in vivo wound closure model, genetic loss-of-function\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (binding, blockade, in vivo), replicated across two companion papers in the same issue\",\n      \"pmids\": [\"20813954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structures of the JAML ectodomain (2.2 Å) and the JAML–CAR complex (2.8 Å) revealed an unusual Ig-domain assembly for JAML and a charged, high-specificity interface with CAR. Biochemical and mutagenesis studies showed that CAR-mediated clustering of JAML recruits PI3K to a JAML intracellular sequence motif homologous to the CD28 costimulatory receptor motif.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, biochemical PI3K recruitment assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures of both apo and complex forms plus mutagenesis and biochemical validation in one study\",\n      \"pmids\": [\"20813955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of JAML bound to the stimulatory antibody HL4E10 Fab (2.95 Å) showed that HL4E10 binds the membrane-proximal domain of JAML through hydrophobic interactions (nanomolar affinity), whereas the endogenous ligand CAR binds the membrane-distal domain via hydrophilic interactions (micromolar affinity); despite different binding sites and mechanisms, both interactions trigger JAML signaling and γδ T cell costimulation.\",\n      \"method\": \"X-ray crystallography, surface plasmon resonance kinetics, functional γδ T cell costimulation assay\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus binding kinetics and functional validation\",\n      \"pmids\": [\"21220118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"During neutrophil transepithelial migration, JAML is cleaved from the neutrophil surface by zinc metalloproteases; the released soluble JAML binds to epithelial CAR, compromising barrier function and inhibiting epithelial wound repair through decreased epithelial proliferation. An anti-JAML monoclonal antibody blocking JAML–CAR binding reversed these deleterious effects.\",\n      \"method\": \"In vitro transepithelial migration assay, metalloprotease inhibition, anti-JAML antibody blockade, in vivo mucosal injury model\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (metalloprotease cleavage → soluble JAML → CAR binding → barrier disruption) validated with multiple methods in vitro and in vivo\",\n      \"pmids\": [\"24621992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JAML mediates monocyte and CD8 T cell transmigration across the blood-brain barrier; blocking JAML significantly compromised the migratory capacity of these cells, and JAML-positive trans-migratory cups were detected when cells adhered to the BBB endothelium.\",\n      \"method\": \"In vitro BBB transmigration assay, JAML blocking antibody, ex vivo and postmortem human tissue analysis\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional blockade in vitro and ex vivo, single lab\",\n      \"pmids\": [\"26734656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JAML regulates podocyte lipid metabolism through a SIRT1-mediated SREBP1 signaling axis; podocyte-specific deletion of Jaml ameliorated podocyte injury, proteinuria, and lipid accumulation in two diabetic mouse models and an adriamycin nephropathy model.\",\n      \"method\": \"Conditional (podocyte-specific) Jaml knockout mice, diabetic mouse models, lipid staining, signaling pathway analysis (SIRT1/SREBP1)\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific cellular phenotype (lipid accumulation, proteinuria) and defined molecular pathway, validated in multiple disease models\",\n      \"pmids\": [\"33186558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JAML on T cells interacts with CXADR (CAR) within tumor tissue to support CD8 and γδ T cell antitumor activity; JAML knockout mice showed accelerated tumor growth with impaired γδ TIL response and increased CD8 TIL dysfunction, and agonistic anti-JAML antibody treatment inhibited tumor growth and improved response to anti-PD-1 checkpoint blockade.\",\n      \"method\": \"JAML knockout mice, tumor implantation models, agonistic antibody treatment, flow cytometry of TIL populations, combination immunotherapy experiment\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and therapeutic antibody with multiple orthogonal readouts in vivo\",\n      \"pmids\": [\"34427588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAML promotes acute kidney injury primarily through a macrophage-dependent mechanism; using bone marrow chimeric mice and macrophage-specific Jaml knockout mice, JAML was found to mediate macrophage phenotype polarization and efferocytosis, at least in part through a macrophage-inducible C-type lectin (Mincle)-dependent pathway.\",\n      \"method\": \"Bone marrow chimeric mice, macrophage-specific Jaml conditional KO, tubular-specific Jaml KO, renal IRI and cisplatin AKI models, signaling analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific genetic dissection across multiple models with defined signaling pathway\",\n      \"pmids\": [\"35708906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"JAML expression in T cells is induced by T cell receptor engagement, and this induction is linked to cis-regulatory interactions between the CD3D and JAML gene loci; JAML is preferentially expressed by tissue-resident memory CD8+ T cells in tumors, and agonistic anti-JAML therapy in a murine melanoma model specifically activates this population and synergizes with anti-PD-1.\",\n      \"method\": \"TCR stimulation assay, chromatin accessibility/cis-regulatory analysis, single-cell and bulk transcriptomics, murine melanoma model with agonistic antibody\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — TCR induction and cis-regulatory linkage shown, functional mode of action defined in vivo, single lab\",\n      \"pmids\": [\"36701231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Macrophage-derived JAML promotes atherosclerosis by facilitating nuclear translocation of pyruvate kinase M2 (PKM2) and PKM2/p65 complex formation, thereby activating the NF-κB pathway and NLRP3 inflammasome; macrophage-specific JAML deletion attenuated atherosclerosis and inflammation, while overexpression exacerbated it.\",\n      \"method\": \"Macrophage-specific JAML KO and transgenic mice, co-immunoprecipitation (PKM2/p65 complex), RNA-sequencing, Oil Red O staining, high-fat diet atherosclerosis model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO/OE with co-IP for complex, defined mechanistic pathway, single lab\",\n      \"pmids\": [\"40148467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endothelial JAML inhibits inflammation and atherosclerosis by promoting STAT1 degradation; JAML facilitates interaction between STAT1 and the E3 ubiquitin ligase TRIM25, leading to ubiquitin-mediated proteolysis of STAT1 independent of changes in STAT1 gene expression. Endothelial-specific JAML deletion exacerbated atherosclerotic plaque formation and vascular inflammation.\",\n      \"method\": \"Endothelial-specific JAML KO mice, co-immunoprecipitation, immunoblotting for ubiquitination, TNF-α stimulation assay, high-fat diet atherosclerosis model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP for STAT1/TRIM25 complex plus genetic KO, defined ubiquitination mechanism, single lab\",\n      \"pmids\": [\"42001028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In tumor vascular endothelial cells, JAML promotes angiogenesis and tumor progression by activating the FAK/SRC/AKT/ERK signaling pathway and VEGF/VEGFR2 pathway; endothelial-specific JAML knockout normalized tumor blood vessels (increased pericyte coverage, vessel perfusion, T cell infiltration; decreased vessel density and leakage) and suppressed phosphorylation of FAK/SRC/AKT/ERK and VEGFR2.\",\n      \"method\": \"Endothelial-specific JAML KO mice, multiple tumor implantation models, immunofluorescence, western blot for pathway phosphorylation, HUVEC in vitro assays\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined signaling pathway in multiple tumor models, single lab\",\n      \"pmids\": [\"39983824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In CD4+ tissue-resident memory T cells within non-small cell lung cancer, PD-1 signaling suppresses JAML expression; JAML is essential for CD4+ TRM-mediated XCL1 secretion and cDC1 recruitment/mobilization, and PD-1 blockade restores JAML expression and antitumor function. A JAML agonist enhanced the antitumor efficacy of PD-1 inhibitors in tumor-bearing mice.\",\n      \"method\": \"PD-1 signaling inhibition assay, JAML expression rescue, XCL1 functional assay, cDC1 recruitment in vivo, murine tumor model with agonistic anti-JAML antibody plus anti-PD-1 combination\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic link between PD-1 and JAML expression with downstream cDC1 mobilization defined in vitro and in vivo, single lab\",\n      \"pmids\": [\"41486351\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JAML is a transmembrane immunoglobulin superfamily receptor that binds its ligand CAR/CXADR through a charged, membrane-distal Ig-domain interface (crystal structure resolved), recruits PI3K via a CD28-like intracellular motif to costimulate γδ and CD8 T cells, can be shed by zinc metalloproteases to act as a soluble CAR antagonist that disrupts epithelial barriers, and regulates lipid metabolism in podocytes via a SIRT1–SREBP1 axis, macrophage polarization/efferocytosis via a Mincle-dependent pathway, and endothelial inflammation via TRIM25-mediated ubiquitination and degradation of STAT1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"JAML is a transmembrane immunoglobulin superfamily receptor that functions as a costimulatory molecule on γδ and CD8 T cells and as a context-dependent signaling scaffold in macrophages and endothelial cells. Engagement of its membrane-distal Ig domain by the epithelial ligand CXADR (CAR) through a charged, high-specificity interface recruits PI3K via a CD28-like intracellular motif, driving T cell proliferation, cytokine production, and antitumor immunity; agonistic anti-JAML antibodies synergize with PD-1 blockade to enhance tumor-infiltrating lymphocyte responses [PMID:20813954, PMID:20813955, PMID:34427588, PMID:41486351]. During neutrophil transepithelial migration, JAML is proteolytically shed by zinc metalloproteases, and the released soluble ectodomain binds epithelial CAR to compromise barrier integrity and wound repair [PMID:24621992]. Beyond its immune costimulatory role, JAML regulates lipid metabolism in podocytes through a SIRT1–SREBP1 axis, macrophage polarization and efferocytosis via Mincle, macrophage inflammatory signaling through PKM2/NF-κB/NLRP3, and endothelial inflammation through TRIM25-mediated ubiquitination and degradation of STAT1 [PMID:33186558, PMID:35708906, PMID:40148467, PMID:42001028].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of JAML as a JAM-family Ig superfamily member that localizes to cell-cell contacts and promotes leukocyte-endothelial adhesion established the gene as a junctional adhesion molecule with potential roles in immune cell trafficking.\",\n      \"evidence\": \"Molecular cloning, immunofluorescence, dimerization motif mutagenesis, and adhesion assays in myeloid leukemia cells\",\n      \"pmids\": [\"12869515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous ligand not identified\", \"Physiological adhesion partners unknown\", \"Signaling mechanism not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that JAML binds CXADR (CAR) and costimulates γδ T cells, combined with crystal structures revealing the JAML–CAR interface and intracellular PI3K recruitment via a CD28-like motif, established the core costimulatory mechanism and its structural basis.\",\n      \"evidence\": \"X-ray crystallography (apo 2.2 Å; complex 2.8 Å), binding assays, site-directed mutagenesis, PI3K recruitment biochemistry, blocking antibody, in vivo wound closure model\",\n      \"pmids\": [\"20813954\", \"20813955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling cascade beyond PI3K not mapped\", \"Role of JAML in αβ T cells versus γδ T cells not delineated\", \"Whether JAML has additional ligands unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Structural characterization of a stimulatory antibody bound to JAML's membrane-proximal domain showed that agonistic signaling can be triggered from a distinct site than the CAR-binding domain, informing therapeutic antibody design.\",\n      \"evidence\": \"X-ray crystallography (2.95 Å), surface plasmon resonance, γδ T cell costimulation assays\",\n      \"pmids\": [\"21220118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether proximal-domain engagement activates identical intracellular pathways as CAR binding not resolved\", \"No in vivo therapeutic testing of HL4E10\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that JAML is shed from neutrophils by zinc metalloproteases during transepithelial migration, with soluble JAML acting as a paracrine disruptor of epithelial barriers via CAR, revealed a non-cell-autonomous pathological mode of JAML action.\",\n      \"evidence\": \"In vitro transepithelial migration, metalloprotease inhibition, anti-JAML antibody blockade, in vivo mucosal injury model\",\n      \"pmids\": [\"24621992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific metalloprotease(s) responsible for cleavage not identified\", \"Cleavage site on JAML not mapped\", \"Relevance to chronic inflammatory disease not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that JAML mediates monocyte and CD8 T cell transmigration across the blood-brain barrier extended its adhesion/migration function to the CNS vascular compartment.\",\n      \"evidence\": \"In vitro BBB transmigration assay with JAML blocking antibody, ex vivo and postmortem human tissue analysis\",\n      \"pmids\": [\"26734656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab observation without genetic confirmation\", \"Ligand interaction at the BBB (CAR or other) not confirmed\", \"In vivo neuroinflammation model not performed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Podocyte-specific Jaml deletion ameliorated proteinuria and lipid accumulation in diabetic and nephrotoxic models by modulating a SIRT1–SREBP1 lipid metabolism axis, establishing a non-immune, metabolic signaling role for JAML.\",\n      \"evidence\": \"Conditional podocyte-specific Jaml KO mice in db/db, STZ, and adriamycin nephropathy models; signaling pathway analysis\",\n      \"pmids\": [\"33186558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How JAML engages or activates SIRT1 mechanistically unclear\", \"Ligand triggering this pathway in podocytes unknown\", \"Whether the metabolic role extends to other epithelia untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic and therapeutic evidence that JAML–CXADR interaction within tumors sustains γδ and CD8 T cell antitumor function, and that an agonistic anti-JAML antibody synergizes with anti-PD-1, positioned JAML as an immunotherapy target.\",\n      \"evidence\": \"JAML KO mice with tumor implantation, agonistic antibody monotherapy and combination with anti-PD-1, flow cytometry of TIL populations\",\n      \"pmids\": [\"34427588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human tumor relevance demonstrated only correlatively\", \"Optimal antibody properties for clinical translation not defined\", \"Whether JAML agonism activates exhausted versus naïve T cells not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Using macrophage-specific Jaml KO and bone marrow chimeras, JAML was shown to drive acute kidney injury through macrophage polarization and Mincle-dependent efferocytosis, revealing a macrophage-intrinsic inflammatory axis distinct from its T cell costimulatory function.\",\n      \"evidence\": \"Macrophage-specific and tubular-specific Jaml conditional KO mice in renal IRI and cisplatin AKI models\",\n      \"pmids\": [\"35708906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct JAML–Mincle physical interaction not demonstrated\", \"Signal transduction between JAML and Mincle pathway not fully mapped\", \"Whether macrophage JAML uses CXADR as ligand in this context unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"TCR engagement was shown to induce JAML expression through cis-regulatory interactions between the CD3D and JAML loci, and JAML marks tissue-resident memory CD8+ T cells in tumors, linking JAML transcriptional control to its functional niche in antitumor immunity.\",\n      \"evidence\": \"TCR stimulation, chromatin accessibility/cis-regulatory analysis, single-cell transcriptomics, murine melanoma model with agonistic antibody\",\n      \"pmids\": [\"36701231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cis-regulatory mechanism single-lab, not independently confirmed\", \"Transcription factor(s) mediating TCR-dependent JAML induction not identified\", \"Whether this regulatory circuit operates in human tumors not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cell-type-specific studies revealed opposing roles for JAML in atherosclerosis: macrophage JAML promotes plaque formation via PKM2-driven NF-κB/NLRP3 inflammasome activation, while endothelial JAML suppresses vascular inflammation by facilitating TRIM25-mediated STAT1 ubiquitination and degradation.\",\n      \"evidence\": \"Macrophage-specific and endothelial-specific JAML KO/overexpression mice, co-IP (PKM2/p65; STAT1/TRIM25), RNA-seq, high-fat diet atherosclerosis models\",\n      \"pmids\": [\"40148467\", \"42001028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing cell-type roles from independent labs not yet reconciled in a unified model\", \"Whether JAML directly binds PKM2 or TRIM25 versus acting as a scaffold unclear\", \"CXADR involvement in vascular context not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Endothelial JAML was found to promote tumor angiogenesis through FAK/SRC/AKT/ERK and VEGF/VEGFR2 signaling, with endothelial-specific JAML deletion normalizing tumor vasculature, increasing pericyte coverage, and enhancing T cell infiltration.\",\n      \"evidence\": \"Endothelial-specific JAML KO mice in multiple tumor models, HUVEC in vitro assays, western blot for pathway phosphorylation\",\n      \"pmids\": [\"39983824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pro-angiogenic versus anti-inflammatory endothelial roles of JAML appear contradictory; context-dependence not resolved\", \"Whether JAML directly activates FAK or acts upstream unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"PD-1 signaling was shown to suppress JAML expression on CD4+ tissue-resident memory T cells, with JAML required for XCL1 secretion and cDC1 recruitment; PD-1 blockade restored JAML and antitumor function, extending the JAML costimulatory axis to CD4 TRM and DC cross-talk.\",\n      \"evidence\": \"PD-1 signaling inhibition, JAML expression rescue, XCL1 functional assay, cDC1 recruitment in vivo, murine tumor model with agonistic anti-JAML plus anti-PD-1\",\n      \"pmids\": [\"41486351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PD-1 transcriptionally represses JAML not defined\", \"Single-lab observation in murine NSCLC model\", \"Human clinical relevance of CD4 TRM JAML expression not validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified model integrating JAML's apparently opposing roles across different cell types (costimulatory in T cells, pro-inflammatory in macrophages, both pro-angiogenic and anti-inflammatory in endothelium, metabolic in podocytes) and the ligand dependencies in each context remains to be constructed.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No systematic comparison of JAML signaling pathways across cell types\", \"Identity of ligand(s) engaging JAML in macrophages, podocytes, and endothelium unknown\", \"Full interactome and post-translational modification landscape not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 7, 8, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6, 10, 11, 12]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CXADR\",\n      \"PIK3CA\",\n      \"TRIM25\",\n      \"STAT1\",\n      \"PKM2\",\n      \"CLEC4E\",\n      \"SIRT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}