{"gene":"JAM3","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2001,"finding":"JAM3 (JAM-C) was identified as the counter-receptor for JAM2 (JAM-B); JAM3 ectodomain binds firmly to JAM2-Fc in heterotypic interactions, and JAM3 was demonstrated to be the previously uncharacterized 43-kDa counter-receptor mediating JAM2 adhesion to T cells.","method":"Ectodomain binding assays, JAM2-Fc pulldown, static adhesion assays with CHO cells expressing full-length JAM2, polyclonal anti-JAM3 serum","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal binding assays (Fc pulldown, cell adhesion, neutralization) in a single focused study establishing the receptor-ligand pair","pmids":["11590146"],"is_preprint":false},{"year":2002,"finding":"JAM3 on T cells facilitates JAM2 engagement of alpha4beta1 integrin: prior adhesion of JAM2 to JAM3 is required for JAM2/alpha4beta1 interaction; neutralizing JAM3 serum or soluble JAM3 ectodomain blocked both JAM2/JAM3 and JAM2/alpha4beta1 interactions. The first Ig-like fold of JAM2 is competent for binding both JAM3 and alpha4beta1.","method":"Neutralizing integrin antibodies, alpha4-specific inhibitor TBC 772, soluble JAM3 ectodomain competition, mutagenesis of JAM2 Asp-82","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (antibody blockade, pharmacological inhibitor, soluble competitor, mutagenesis) in a single rigorous study","pmids":["12070135"],"is_preprint":false},{"year":2002,"finding":"VE-JAM/JAM2 interacts with T cells, NK cells, and dendritic cells through JAM3, identifying JAM3 as the functional receptor for JAM2-mediated leukocyte adhesion.","method":"Cloning and functional characterization; cell adhesion assays with J45 T cell line and primary immune cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional adhesion assays, independent replication of JAM2/JAM3 heterophilic interaction across two labs","pmids":["11823489"],"is_preprint":false},{"year":2003,"finding":"JAM3 directly associates with the cell polarity protein PAR-3 through the first PDZ domain of PAR-3; JAM3 also associates with ZO-1 in a PDZ domain-dependent manner, implicating JAM3 in tight junction formation and endothelial cell polarity.","method":"Direct binding assays, PDZ domain interaction studies, ectopic expression of JAM-2 in CHO cells showing junctional localization regulated by serine phosphorylation and recruitment of endogenous PAR-3 and ZO-1","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assays, domain mutagenesis (PDZ), ectopic expression with functional readout, in vivo confirmation","pmids":["12953056"],"is_preprint":false},{"year":2004,"finding":"JAM-C localizes to desmosomes (not tight junctions) in intestinal epithelia and functions as a ligand for CD11b/CD18 (Mac-1) on neutrophils, mediating PMN transepithelial migration. Specific binding of JAM-C to CD11b/CD18 was demonstrated.","method":"Selective disruption of tight junctions and desmosomes, JAM-C mAb and JAM-C/Fc chimera inhibition of PMN transmigration assays, direct binding assays with CD11b/CD18","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (subcellular fractionation/disruption, functional transmigration assay, direct binding), clear mechanistic link","pmids":["15194813"],"is_preprint":false},{"year":2005,"finding":"JAM-C undergoes heterophilic interaction with JAM-B at cell-cell contacts; JAM-B stabilizes JAM-C in junctional complexes and soluble JAM-B dissociates JAM-C homodimers to form higher-affinity JAM-B/JAM-C heterodimers. JAM-C liberated from junctional JAM-B becomes available for interaction with leukocyte counter-receptor alphaM-beta2 integrin, modulating leukocyte adhesion.","method":"Co-immunoprecipitation, soluble protein competition assays, antibody blockade, cell adhesion assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal binding assays, competition experiments, functional leukocyte adhesion readout, single rigorous study with multiple orthogonal methods","pmids":["16093349"],"is_preprint":false},{"year":2006,"finding":"JAM-C regulates tight junctions and cell polarity through serine 281 in its cytoplasmic tail; mutation S281A abolishes junctional localization of JAM-C and establishment of cell polarity, and stimulates integrin-mediated cell migration and adhesion via modulation of beta1 and beta3 integrin activation.","method":"Transfection of JAM-C and serine-to-alanine mutant in carcinoma cells, tight junction barrier assays, cell migration/adhesion assays, integrin activation measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-directed mutagenesis (S281A) with multiple functional readouts (polarity, barrier, migration, integrin activation)","pmids":["17099249"],"is_preprint":false},{"year":2006,"finding":"CAR (coxsackievirus and adenovirus receptor) forms a complex with JAM-C in mouse testis, as demonstrated by co-immunoprecipitation in germ cells.","method":"Co-immunoprecipitation, RT-PCR, Western analysis, GST pulldown, indirect immunofluorescence","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — co-IP demonstrating interaction, single lab, single paper","pmids":["16410001"],"is_preprint":false},{"year":2007,"finding":"Platelet JAM-C mediates firm adhesion of dendritic cells to platelets via CD11b/CD18 (Mac-1); soluble JAM-C reduced DC adhesion to platelets, and platelet/DC interaction resulted in DC apoptosis mediated by a JAM-C-dependent mechanism.","method":"Adhesion assays, preincubation with soluble JAM-C, in vivo carotid artery injury model, phagocytosis assays, apoptosis assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional adhesion assays with soluble JAM-C inhibition plus in vivo model, single lab","pmids":["17379836"],"is_preprint":false},{"year":2009,"finding":"JAM-C modulates endothelial permeability through association with alphavbeta3 integrin and regulation of its localization and activity; JAM-C also inhibits beta1 integrin activation (without direct association) through regulation of the small GTPase Rap1b (not Rap1a). Thrombin induces JAM-C localization to junctions increasing permeability; angiopoietin-1 prevents JAM-C translocation.","method":"siRNA knockdown, overexpression, co-immunoprecipitation with alphavbeta3, integrin activity assays, Rap1 isoform-specific knockdown, permeability assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, KD/OE, Rap1 isoform specificity, multiple functional readouts in one rigorous study","pmids":["19461049"],"is_preprint":false},{"year":2011,"finding":"JAM-C at endothelial cell junctions regulates the directionality (polarity) of neutrophil transendothelial migration in vivo; lower JAM-C expression at EC junctions (or blockade/genetic deletion of JAM-C) promotes 'reverse' TEM of neutrophils back into the vasculature, contributing to systemic inflammation dissemination.","method":"Real-time confocal intravital imaging, ischemia-reperfusion inflammation model, JAM-C blocking antibodies, genetic deletion of JAM-C in ECs","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo real-time imaging plus genetic deletion with defined directional migration phenotype, replicated across models","pmids":["21706006"],"is_preprint":false},{"year":2011,"finding":"Zebrafish orthologs Jamb and Jamc are essential for myocyte fusion during vertebrate skeletal muscle development; Jamb and Jamc physically interact and must act in trans between neighboring cells. Loss of either gene prevents myocyte fusion, producing mononuclear fast-twitch fibers. Ectopic jamc expression in slow muscle precursors causes inappropriate fusion.","method":"Forward genetic screen, heritable mutations in jamb and jamc, cell transplantation experiments, in vivo receptor interaction studies","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, transplantation experiments establishing trans interaction requirement, in vivo","pmids":["22180726"],"is_preprint":false},{"year":2011,"finding":"JAM-C expressed in Schwann cells is required for the structural integrity and function of peripheral nerves: SC-specific JAM-C knockout mice show electrophysiological defects, muscular weakness, mechanical hypersensitivity, and morphological defects in the paranodal region with increased nodal length.","method":"Conditional knockout (Schwann cell-specific JAM-C deletion), electrophysiology, histomorphological analysis of paranodal regions","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with multiple orthogonal phenotypic readouts (electrophysiology, morphology, behavior)","pmids":["22090315"],"is_preprint":false},{"year":2011,"finding":"JAM-C in lymph node fibroblastic reticular cells (identified by thrombomodulin and PDGFRalpha) controls homeostatic chemokine secretion (CXCL12/SDF-1alpha, CCL21, CCL19); Jam-C-deficient mice and anti-JAM-C-treated mice show decreased intranodal content of these chemokines, correlated with reduced naive T cell egress from lymph nodes.","method":"JAM-C knockout mice, anti-JAM-C antibody treatment, chemokine measurement in lymph nodes, naive T cell egress assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic KO plus antibody blockade with defined chemokine and cellular readouts, single lab","pmids":["21685324"],"is_preprint":false},{"year":2012,"finding":"JAM-B expressed by endothelial cells contributes to B16 melanoma cell metastasis through heterophilic interaction with JAM-C on tumor cells, mediating melanoma cell adhesion to lung microvascular endothelial cells; metastasis of B16 cells was reduced in Jam-b deficient mice.","method":"Jam-b knockout mice, in vivo metastasis assay, cell adhesion assays to primary lung microvascular endothelial cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic KO in vivo plus cell adhesion assay, single lab","pmids":["23068611"],"is_preprint":false},{"year":2012,"finding":"JAM-C is expressed on the apical surface of neural stem cells in embryonic and adult mouse brain and is asymmetrically distributed during cell divisions, enriched at the apical membrane.","method":"In vivo immunohistochemistry, live imaging of neural stem cells, subcellular localization during division","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments in vivo across embryonic and adult brain, single lab","pmids":["22114908"],"is_preprint":false},{"year":2012,"finding":"JAM-C deficiency in C57BL/6 mice causes severe hydrocephalus associated with a block or reduction of CSF drainage from the lateral to the 3rd ventricle; endothelial re-expression of JAM-C failed to rescue the hydrocephalus, indicating the relevant JAM-C function is not endothelial but likely ependymal/choroid plexus epithelial.","method":"JAM-C knockout mice on C57BL/6 background, endothelial rescue experiments, CSF circulation analysis, immunohistochemistry","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with rescue experiment dissecting cell-type specificity, CSF flow analysis","pmids":["23029139"],"is_preprint":false},{"year":2012,"finding":"JAM-C on B lymphocytes mediates homing to bone marrow, lymph nodes, and spleen via heterophilic interaction with JAM-B on lymphatic endothelial cells (identified by plasmon resonance as the major JAM-C ligand, with homotypic JAM-C interactions at background levels). Anti-JAM-C antibodies blocked adhesion of JAM-C-expressing B cells to JAM-B and reduced lymphoma engraftment.","method":"Xenogeneic NOD/SCID mouse model, short- and long-term anti-JAM-C antibody treatment, plasmon resonance binding studies, immunofluorescence for JAM-B on endothelium","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — plasmon resonance quantifying binding hierarchy, in vivo homing assay, antibody blockade with defined molecular mechanism","pmids":["23221386"],"is_preprint":false},{"year":2014,"finding":"JAM-B/JAM-C interaction between hematopoietic stem and progenitor cells (HSPC) and bone marrow stromal/mesenchymal cells is required for HSPC homing to bone marrow; anti-JAM-C blocking antibody inhibited hematopoietic reconstitution, progenitor homing, and induced HSPC mobilization in a JAM-B-dependent manner. This interaction occurs between HSPC and mesenchymal stem cells but not endothelial cells or osteoblasts.","method":"Blocking monoclonal antibodies, bone marrow transplantation, HSPC mobilization assays, human CD34+ hematopoietic progenitor homing in mouse BM","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — blocking antibody with JAM-B dependency demonstrated, homing and mobilization functional readouts, translated to human system","pmids":["24357068"],"is_preprint":false},{"year":2017,"finding":"GRASP55 interacts with JAM-C via PDZ-mediated interactions in developing germ cells (proteomic identification confirmed by crystal structure); GRASP55 knockout disrupts acrosome formation and polarized localization of JAM-C in spermatids. Crystal structures of GRASP55 in complex with JAM-C or JAM-B reveal that GRASP55 interaction induces a conformational change in GRASP55. A chemical compound (Graspin) inhibiting PDZ-mediated GRASP55/JAM interactions disrupted JAM-C polarized localization in spermatids in vivo.","method":"Proteomic pulldown, Gorasp2 knockout mice, crystal structure determination of GRASP55–JAM-C/JAM-B complexes, in silico pharmacophore/chemical inhibitor (Graspin), mouse treatment with Graspin","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, knockout mouse, chemical inhibitor in vivo, multiple orthogonal methods","pmids":["28617811"],"is_preprint":false},{"year":2018,"finding":"JAM3 directly associates with LRP5 to activate the PDK1/AKT pathway, leading to GSK3beta downregulation and beta-catenin/CCND1 activation, maintaining leukemia-initiating cell (LIC) self-renewal and cell cycle entry. This function is independent of JAM3's canonical role in cell junctions and migration.","method":"Co-immunoprecipitation (JAM3–LRP5 association), Jam3 genetic deletion in MLL-AF9 AML model, serial transplantation, JAM3 knockdown in human leukemia cell lines and primary LICs, Western blotting for pathway components","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, genetic deletion with serial transplantation, pathway knockdown with multiple readouts, translated to human cells","pmids":["29584620"],"is_preprint":false},{"year":2018,"finding":"JAM-C dimerization sites E66 and K68 are critical for JAM-C/JAM-B interaction and correct junctional localization; mutations at these sites increase cell adhesion, reduce migration and proliferation, and abolish metastatic lung nodule formation in mice, demonstrating that JAM-C dimerization drives pro-metastatic behavior.","method":"Directed mutagenesis of E66 and K68, cell adhesion assays, migration/proliferation assays, in vivo lung metastasis model","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis identifying critical residues with in vitro and in vivo functional validation","pmids":["29378216"],"is_preprint":false},{"year":2019,"finding":"Dynamic trafficking and lysosomal degradation of JAM-C, regulated by ubiquitylation via the E3 ligase CBL, are necessary for junctional remodelling during endothelial cell migration and angiogenesis. JAM-C co-traffics with VE-Cadherin and neuropilin-1/2 but not with leukocyte transmigration-associated junctional proteins.","method":"Receptor mutagenesis, HRP and APEX-2 proximity labelling, light and electron microscopy, co-trafficking analysis, CBL-mediated ubiquitylation assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — proximity labelling, receptor mutagenesis, identification of E3 ligase CBL with multiple orthogonal methods","pmids":["31790392"],"is_preprint":false},{"year":2008,"finding":"JAM-C localizes specifically to tight junctions in human retinal pigment epithelium (hfRPE); JAM-C knockdown disrupts N-cadherin and ZO-1 organization at cell contacts, delays hfRPE cell polarization (reduced apical ezrin), and significantly decreases chemokine-induced transmigration of granulocytes (but not monocytes) through the hfRPE monolayer.","method":"siRNA knockdown, immunofluorescence, Western blot, transepithelial migration assay","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD with multiple cellular readouts (polarity, junction organization, leukocyte transmigration), single lab","pmids":["19060272"],"is_preprint":false},{"year":2018,"finding":"LPS reduces JAM-3 expression in renal tubular epithelial cells via the RhoT1/SMAD-4/JAM-3 pathway: LPS increases SMAD-4 (which suppresses JAM-3), and RhoT1 inhibits SMAD-4 to maintain JAM-3 expression; downregulation of SMAD-4 via RNAi increased JAM-3 levels in LPS-treated cells.","method":"siRNA knockdown of SMAD-4 and RhoT1, Western blot, transepithelial permeability and resistance assays, immunofluorescence","journal":"International journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNAi epistasis placing JAM-3 downstream of SMAD-4/RhoT1, functional permeability readout, single lab","pmids":["29725250"],"is_preprint":false},{"year":2020,"finding":"In cerebellar granule cells, Pard3a and JamC operate in the same molecular pathway to regulate radial migration initiation from the external granule cell layer; normalizing expression of Pard3a and JamC in organotypic cerebellar slice cultures rescued both migratory and apoptotic defects caused by intrauterine growth restriction.","method":"Organotypic cerebellar slice cultures, gene expression normalization experiments, in vivo pig IUGR model with IHC/gene expression analysis","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional rescue in organotypic culture placing JamC and Pard3a in same pathway, supported by in vivo expression analysis","pmids":["33259808"],"is_preprint":false},{"year":2017,"finding":"JAM-C is required to maintain VEGFR2 expression in retinal pigment epithelial cells under oxidative stress; JAM-C knockdown decreased RPE cell survival, and overexpression of VEGFR2 partially restored impaired RPE survival caused by JAM-C knockdown. JAM-C regulates VEGFR2 expression and modulates downstream p38 phosphorylation.","method":"siRNA knockdown, overexpression rescue with VEGFR2, cell survival assays, Western blot for VEGFR2 and p-p38","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD with overexpression rescue establishing mechanistic link, single lab","pmids":["28203682"],"is_preprint":false},{"year":2022,"finding":"ADAM10 processes/cleaves JAM-C to increase Rap1GAP activity, promoting neural stem cell transit from the apical to basal compartment of the subventricular zone and subsequent lineage progression.","method":"ADAM10 conditional manipulation, RAP1GAP activity assays, neural stem cell localization and lineage analysis","journal":"Neural regeneration research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ADAM10 identified as JAM-C processing enzyme with Rap1GAP as downstream effector, functional NSC positioning readout, single lab","pmids":["35535899"],"is_preprint":false},{"year":2022,"finding":"JAM-C deficiency in mouse lenses causes nuclear cataract with defective degradation of nuclei and organelles in lens fiber cells, accompanied by activation of the unfolded protein response (upregulation of BiP, CHOP, TRIB3, CHAC1) and increased cell death.","method":"Jamc knockout mice (C57BL/6), RNA sequencing, RT-qPCR, Western blot, immunofluorescence, TUNEL staining","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic KO with transcriptomic and protein-level validation of UPR activation, single lab","pmids":["36048019"],"is_preprint":false},{"year":2022,"finding":"Epigenetic silencing of JAM3 by promoter methylation activates Wnt/beta-catenin signaling in esophageal cancer cells; JAM3 restoration suppressed EC cell proliferation, colony formation, migration and invasion by inhibiting Wnt/beta-catenin signaling, and 5-aza-2'-deoxycytidine treatment restored JAM3 expression.","method":"Methylation-specific PCR, Western blot, MTT/colony/migration assays, xenograft mouse models, 5-aza treatment","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — overexpression with pathway (Wnt) readout, in vivo xenograft, demethylation rescue, single lab","pmids":["36461092"],"is_preprint":false},{"year":2025,"finding":"JAM-C inhibits ocular fibrosis by suppressing the nuclear localization and function of TAZ, which otherwise binds to KLF6 to promote its expression and activate the EMT cascade; AAV-mediated JAM-C augmentation alleviated ocular fibrosis in mouse models.","method":"Co-IP, ChIP-qPCR, luciferase reporter assay, RNA sequencing, siRNA knockdown, Jam-c KO mice, AAV overexpression in vivo","journal":"Journal of advanced research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, ChIP-qPCR, luciferase reporter, genetic KO, and AAV rescue—multiple orthogonal methods in one study","pmids":["40398745"],"is_preprint":false},{"year":2024,"finding":"JAM-C mediates ferroptosis resistance in high-adhesion ovarian cancer cells through NRF2-induced upregulation of FSP1 (a lipid peroxidation suppressor); JAM3 knockdown/blockade sensitized cells to ferroptosis inducers RSL3 and erastin, while JAM3 overexpression conferred resistance; inhibition of the NRF2/FSP1 pathway eliminated JAM3-mediated ferroptosis resistance.","method":"siRNA knockdown, JAM3 overexpression, ferroptosis inducers (RSL3, erastin), NRF2/FSP1 pathway inhibition, in vitro and in vivo cisplatin resistance assays","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD/OE with pathway inhibition rescue establishing NRF2/FSP1 as downstream effectors, in vitro and in vivo, single lab","pmids":["39706500"],"is_preprint":false},{"year":2025,"finding":"Pard3 polarity protein and JAM-C cooperate to promote surface recruitment of the DCC receptor, gating Netrin-1-dependent repulsion that drives cerebellar granule neuron exit from the germinal zone; the E3 ubiquitin ligase Siah2 antagonizes this Pard3/JAM-C function by inhibiting DCC surface recruitment.","method":"In vivo mouse cerebellar genetics, DCC surface recruitment assays, epistasis between Siah2, Pard3, JamC, and DCC","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic epistasis in vivo establishing pathway order (Pard3/JamC→DCC surface recruitment→Netrin-1 signaling), single lab","pmids":["39774925"],"is_preprint":false},{"year":2025,"finding":"JAM-C maintains lens cell adhesion and ball-and-socket junction integrity; JAM-C deficiency elevates intracellular Ca2+ in lens cells, activates calpain (evidenced by degradation of IIα spectrin and F-actin), and disrupts FGF/ERK signaling in lens epithelial cells.","method":"Jamc knockout mice, calcium imaging, Western blot for calpain substrates (IIα spectrin, F-actin), FGF/ERK pathway analysis, electron microscopy of junctions","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KO with multiple mechanistic readouts (Ca2+, calpain substrates, signaling), single lab","pmids":["41173413"],"is_preprint":false},{"year":2021,"finding":"Soluble JAM-C ectodomain (sJAM-C), which is cleaved and secreted by adipose-derived stromal/stem cells (ADSCs), forms a complex with JAM-B and stimulates ADSC adhesion, proliferation, and expression of mesenchymal stem cell markers. CRISPR/Cas9 deletion confirmed that sJAM-C/JAM-B coupling mediates ADSC adhesion and maintenance.","method":"Immunoprecipitation, CRISPR/Cas9 genome editing, culture plate coating with sJAM-C, cell adhesion and proliferation assays, flow cytometry for MSC markers","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus CRISPR KO plus functional assays, single lab","pmids":["33801826"],"is_preprint":false},{"year":2016,"finding":"JAM-C at homeostatic copy numbers forms a unidirectional vascular barrier for leukocyte TEM; overexpression or gene silencing of JAM-C in endothelium under flow conditions both result in higher rates of monocyte reverse-TEM, and anti-JAM-C blockade in atherosclerotic recipients induced monocyte-derived cell emigration from plaques and reduced plaque size.","method":"siRNA and overexpression in human endothelium under flow, aortic arch transplantation model (ApoE-/- into wild-type), JAM-C blockade in vivo","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vitro flow assay plus in vivo transplantation model, single lab","pmids":["27442505"],"is_preprint":false},{"year":2026,"finding":"JAM3 promotes meningioma development by interacting with Mac-1 (CD11b) on neutrophils (confirmed by Co-IP) to activate AKT phosphorylation, thereby promoting neutrophil migration and neutrophil extracellular trap (NET) formation; JAM3 knockdown in meningioma cells suppressed AKT phosphorylation, reduced NET formation, and inhibited tumor growth in xenograft models.","method":"Co-IP confirming JAM3/Mac-1 interaction, siRNA knockdown, AKT activator rescue (SC79), neutrophil migration and NET assays, xenograft tumor model, DNase I NET abolition","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus KD with AKT rescue and in vivo xenograft, single lab","pmids":["41500374"],"is_preprint":false},{"year":2023,"finding":"JAM-C deletion in mice results in decreased lens epithelial cell (LEC) quantity and proliferation, downregulation of the transcription factor FOXE3, disorganization of lens fibers, and altered distribution of gap junction proteins Cx46 and Cx50 and reduced gamma-crystallin in fiber cells.","method":"Jamc knockout mice, BrdU incorporation assay, TUNEL staining, immunofluorescence, Western blot, histological analysis across developmental stages","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic KO with multiple downstream molecular markers across developmental time points, single lab","pmids":["38095908"],"is_preprint":false},{"year":2025,"finding":"JAM3 promotes laryngeal squamous cell carcinoma oncogenesis by inhibiting the Hippo pathway; JAM3 overexpression activated Hippo signaling suppressing proliferation, migration and invasion, whereas JAM3 knockdown enhanced these behaviors by inhibiting the Hippo pathway, both in vitro and in vivo.","method":"Western blot, immunofluorescence, Cell Counting Kit-8, colony formation, Transwell assays, 5-Aza-2'-deoxycytidine treatment, in vivo experiments","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD/OE with Hippo pathway readout in vitro and in vivo, single lab","pmids":["39749700"],"is_preprint":false},{"year":2025,"finding":"In serous ovarian carcinoma cells, JAM3 overexpression suppresses proliferation, migration, and invasion and promotes apoptosis by inhibiting the PI3K/AKT signaling pathway; JAM3 knockdown produced opposite effects, confirmed by AKT inhibitor (MK2206) rescue experiments.","method":"RNA sequencing, Western blot, CCK8, flow cytometry, scratch-wound, Transwell assays, AKT inhibitor rescue, immunohistochemistry","journal":"Epigenomics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD/OE with pathway inhibitor rescue, multiple functional assays, single lab","pmids":["40711818"],"is_preprint":false}],"current_model":"JAM3 (JAM-C) is a two-Ig-domain adhesion molecule that functions primarily as a heterophilic counter-receptor for JAM-B, directs polarized leukocyte transendothelial migration by forming a unidirectional junctional barrier, organizes tight junctions and cell polarity via PDZ-mediated interactions with PAR-3 and ZO-1, controls integrin activation (alphavbeta3, beta1) and vascular permeability through Rap1b signaling, supports myocyte and germ-cell fusion by trans JAM-B/JAM-C interaction, maintains hematopoietic stem cell niche retention through JAM-B binding on stromal cells, regulates neuronal germinal zone exit by promoting DCC surface recruitment in concert with Pard3, and in leukemia-initiating cells activates an LRP5/PDK1/AKT/beta-catenin/CCND1 self-renewal pathway independent of its junctional role; its junctional trafficking is controlled by CBL-mediated ubiquitylation, and its polarized localization in spermatids requires GRASP55 PDZ-domain interactions."},"narrative":{"mechanistic_narrative":"JAM3 (JAM-C) is a two-Ig-domain junctional adhesion molecule whose defining biochemical activity is heterophilic engagement of its counter-receptor JAM-B (JAM2): JAM-C was first identified as the 43-kDa counter-receptor mediating JAM-B adhesion to T cells [PMID:11590146], and JAM-B reciprocally stabilizes junctional JAM-C while soluble JAM-B dissociates JAM-C homodimers into higher-affinity heterodimers, releasing JAM-C for leukocyte engagement [PMID:16093349]. Through this adhesive system JAM-C organizes epithelial and endothelial junctions and cell polarity, binding the polarity protein PAR-3 and the scaffold ZO-1 via PDZ-domain interactions [PMID:12953056] and requiring a cytoplasmic serine (S281) for junctional localization, polarity establishment, and restraint of beta1/beta3 integrin activation [PMID:17099249]. At endothelial junctions JAM-C maintains a unidirectional barrier that sets the directionality of neutrophil transendothelial migration, such that loss or imbalance of JAM-C promotes reverse migration [PMID:21706006, PMID:27442505]; it also tunes vascular permeability by associating with alphavbeta3 integrin and signaling through the GTPase Rap1b [PMID:19461049], and its junctional turnover is controlled by CBL-mediated ubiquitylation and lysosomal degradation during angiogenic remodeling [PMID:31790392]. Beyond leukocytes, JAM-C serves as a counter-receptor for the Mac-1 (CD11b/CD18) integrin to drive transmigration and platelet–leukocyte interactions [PMID:15194813, PMID:17379836], and its trans JAM-B/JAM-C interaction is essential for myocyte fusion [PMID:22180726] and for hematopoietic stem/progenitor retention in the marrow stromal niche [PMID:24357068]. In neural development JAM-C acts in a Pard3-dependent pathway to promote DCC surface recruitment and germinal-zone exit of cerebellar granule neurons [PMID:39774925, PMID:33259808], and its polarized localization in spermatids requires PDZ-mediated binding to GRASP55 [PMID:28617811]. JAM-C is processed by ADAM10 [PMID:35535899] and is genetically required for peripheral nerve paranodal integrity [PMID:22090315], cerebrospinal fluid drainage [PMID:23029139], and lens fiber/epithelial homeostasis [PMID:36048019, PMID:38095908, PMID:41173413]. In cancer, JAM-C dimerization drives pro-metastatic behavior [PMID:29378216], and JAM3 supports leukemia-initiating-cell self-renewal through a junction-independent LRP5/PDK1/AKT/beta-catenin/CCND1 axis [PMID:29584620].","teleology":[{"year":2001,"claim":"Establishing JAM-C's binding partner was the foundational question; identifying it as the counter-receptor for JAM-B defined the molecular adhesion pair around which all later function is organized.","evidence":"Ectodomain binding, JAM2-Fc pulldown, and static adhesion assays in CHO cells","pmids":["11590146"],"confidence":"High","gaps":["Affinity and stoichiometry of the interaction not quantified","Cytoplasmic signaling consequences not addressed"]},{"year":2002,"claim":"Resolved how JAM-C couples to integrin-mediated leukocyte adhesion, showing JAM-C/JAM-B engagement is a prerequisite for JAM-B binding to alpha4beta1 integrin and confirming JAM-C as the functional leukocyte receptor.","evidence":"Antibody blockade, alpha4 inhibitor, soluble JAM-C competition, JAM2 mutagenesis; adhesion assays with T/NK/dendritic cells","pmids":["12070135","11823489"],"confidence":"High","gaps":["Whether JAM-C directly contacts integrin or only positions JAM-B not fully resolved"]},{"year":2003,"claim":"Connected JAM-C to junctional architecture by identifying PDZ-mediated binding to PAR-3 and ZO-1, placing it in the cell polarity and tight junction machinery.","evidence":"Direct PDZ binding assays, domain mutagenesis, ectopic expression in CHO cells","pmids":["12953056"],"confidence":"High","gaps":["Functional consequence of each interaction in vivo not separated"]},{"year":2004,"claim":"Broadened JAM-C's adhesive repertoire by demonstrating direct binding to the Mac-1 (CD11b/CD18) integrin and a role in PMN transepithelial migration, with localization to desmosomes rather than tight junctions in intestinal epithelium.","evidence":"Junction disruption, transmigration assays, direct CD11b/CD18 binding","pmids":["15194813"],"confidence":"High","gaps":["Cell-type variability of subcellular localization unexplained"]},{"year":2005,"claim":"Defined the regulatory logic of the JAM-B/JAM-C system, showing soluble JAM-B converts JAM-C homodimers into heterodimers and liberates JAM-C for integrin engagement, linking junctional state to leukocyte adhesion.","evidence":"Co-IP, soluble competition, antibody blockade, adhesion assays","pmids":["16093349"],"confidence":"High","gaps":["In vivo trigger for homodimer-to-heterodimer switching not identified"]},{"year":2006,"claim":"Identified the cytoplasmic determinant (S281) controlling junctional localization, polarity, and integrin restraint, providing a phosphoregulatable switch in JAM-C function.","evidence":"S281A mutagenesis with barrier, migration, and integrin activation readouts in carcinoma cells","pmids":["17099249"],"confidence":"High","gaps":["Kinase responsible for S281 phosphorylation not identified"]},{"year":2009,"claim":"Mechanistically separated JAM-C's effects on vascular permeability into an alphavbeta3-association arm and a Rap1b-dependent beta1 integrin inhibition arm, with stimulus-dependent junctional translocation.","evidence":"siRNA/overexpression, Co-IP, Rap1 isoform-specific knockdown, permeability assays","pmids":["19461049"],"confidence":"High","gaps":["Link between JAM-C and Rap1b activation upstream not defined"]},{"year":2011,"claim":"Demonstrated in vivo that junctional JAM-C levels set the directionality of neutrophil transendothelial migration, establishing reverse-TEM as a consequence of JAM-C loss.","evidence":"Intravital imaging, ischemia-reperfusion model, blocking antibody, endothelial JAM-C deletion","pmids":["21706006"],"confidence":"High","gaps":["Molecular signal that imposes unidirectionality not defined"]},{"year":2011,"claim":"Extended JAM-C function beyond leukocytes by showing trans JAM-B/JAM-C interaction is required for myocyte fusion and that Schwann-cell JAM-C maintains peripheral nerve paranodal integrity.","evidence":"Zebrafish forward genetics and transplantation; Schwann-cell conditional knockout with electrophysiology and morphology","pmids":["22180726","22090315"],"confidence":"High","gaps":["Downstream fusion machinery engaged by JAM-B/JAM-C not identified","Mechanism linking JAM-C to paranodal structure unresolved"]},{"year":2012,"claim":"Defined cell-type-specific physiological requirements for JAM-C, including non-endothelial control of CSF drainage and stromal control of lymph node chemokine secretion and T cell egress.","evidence":"JAM-C knockout with endothelial rescue (hydrocephalus); knockout/antibody blockade with chemokine and egress readouts; B-cell homing via JAM-B","pmids":["23029139","21685324","23221386"],"confidence":"High","gaps":["Effector cell type for CSF phenotype not pinpointed","Mechanism linking JAM-C to chemokine secretion unknown"]},{"year":2014,"claim":"Established JAM-C's role in the hematopoietic niche, showing JAM-B/JAM-C interaction between HSPCs and mesenchymal stromal cells governs marrow homing and retention.","evidence":"Blocking antibody, bone marrow transplantation, mobilization assays, human CD34+ homing","pmids":["24357068"],"confidence":"High","gaps":["Signaling downstream of niche JAM-B/JAM-C engagement not defined"]},{"year":2017,"claim":"Provided structural and functional insight into PDZ-driven polarized localization by identifying GRASP55 as a JAM-C partner whose interaction is required for spermatid acrosome formation and JAM-C polarization.","evidence":"Proteomics, knockout mice, crystal structures of GRASP55–JAM-C/JAM-B, and an in vivo PDZ-inhibitor (Graspin)","pmids":["28617811"],"confidence":"High","gaps":["Generality of GRASP55-mediated polarization to other tissues untested"]},{"year":2018,"claim":"Uncovered a junction-independent signaling role in cancer, showing JAM3 associates with LRP5 to drive a PDK1/AKT/beta-catenin/CCND1 self-renewal program in leukemia-initiating cells, and that dimerization residues E66/K68 drive pro-metastatic behavior.","evidence":"Reciprocal Co-IP, Jam3 deletion in MLL-AF9 AML with serial transplantation; E66/K68 mutagenesis with in vitro and metastasis readouts","pmids":["29584620","29378216"],"confidence":"High","gaps":["How LRP5 binding is regulated relative to junctional pools unknown","Whether dimerization couples to the LRP5 signaling axis untested"]},{"year":2019,"claim":"Defined the trafficking control of junctional JAM-C, identifying CBL-mediated ubiquitylation and lysosomal degradation as required for endothelial junctional remodeling and angiogenesis.","evidence":"Receptor mutagenesis, APEX-2/HRP proximity labeling, microscopy, ubiquitylation assays","pmids":["31790392"],"confidence":"High","gaps":["Signal triggering CBL recruitment not defined"]},{"year":2022,"claim":"Identified ADAM10 as a JAM-C-processing protease coupling cleavage to Rap1GAP activity and neural stem cell compartment transit.","evidence":"ADAM10 manipulation, Rap1GAP activity assays, NSC localization analysis","pmids":["35535899"],"confidence":"Medium","gaps":["Cleavage site and fate of fragments not mapped","Single lab"]},{"year":2025,"claim":"Resolved a developmental pathway in which Pard3 and JAM-C promote DCC surface recruitment to gate Netrin-1 repulsion and germinal-zone exit, antagonized by Siah2.","evidence":"In vivo cerebellar genetics, DCC surface recruitment assays, genetic epistasis (Siah2/Pard3/JamC/DCC)","pmids":["39774925","33259808"],"confidence":"Medium","gaps":["Biochemical basis of JAM-C-driven DCC trafficking unclear","Single lab"]},{"year":2026,"claim":"Extended JAM-C's Mac-1 engagement to solid-tumor immunology, showing JAM3/Mac-1 interaction activates AKT to drive neutrophil migration and NET formation in meningioma.","evidence":"Co-IP, knockdown with AKT activator rescue, NET assays, xenograft model","pmids":["41500374"],"confidence":"Medium","gaps":["Whether tumor JAM-C signals cell-autonomously or only via neutrophils unresolved","Single lab"]},{"year":null,"claim":"How JAM-C's adhesive/junctional pools are biochemically switched to its junction-independent signaling roles (LRP5, NRF2/FSP1, Hippo, PI3K/AKT) reported across diverse cancers remains unresolved, as does whether these context-specific outputs share a unifying mechanism.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking ectodomain engagement to intracellular signaling outputs","Tissue-context determinants of tumor-suppressive versus oncogenic roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,5,11,17]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,20]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,5,15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,10,35]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,19,32]}],"complexes":["tight junction","JAM-B/JAM-C heterodimer"],"partners":["JAM2","PARD3","TJP1","ITGB3","ITGAM","LRP5","GORASP2","CBL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BX67","full_name":"Junctional adhesion molecule C","aliases":["JAM-2","Junctional adhesion molecule 3","JAM-3"],"length_aa":310,"mass_kda":35.0,"function":"Junctional adhesion protein that mediates heterotypic cell-cell interactions with its cognate receptor JAM2 to regulate different cellular processes (PubMed:11590146, PubMed:11823489). Plays a role in homing and mobilization of hematopoietic stem and progenitor cells within the bone marrow. At the surface of bone marrow stromal cells, it contributes to the retention of the hematopoietic stem and progenitor cells expressing JAM3 (PubMed:11590146, PubMed:24357068). Plays a central role in leukocytes extravasation by facilitating transmigration through the endothelium (By similarity). Plays a role in spermatogenesis where JAM2 and JAM3, which are respectively expressed by Sertoli and germ cells, mediate an interaction between both cell types and play an essential role in the anchorage of germ cells onto Sertoli cells and the assembly of cell polarity complexes during spermatid differentiation (By similarity). Also functions as a counter-receptor for ITGAM, mediating leukocyte-platelet interactions and is involved in the regulation of transepithelial migration of polymorphonuclear neutrophils (PMN) (PubMed:12208882, PubMed:15194813). Plays a role in angiogenesis (PubMed:23255084). Plays a role in the regulation of cell migration (Probable). During myogenesis, it is involved in myocyte fusion (By similarity) Promotes chemotaxis of vascular endothelial cells and stimulates angiogenesis","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9BX67/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JAM3","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":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JAM3","total_profiled":1310},"omim":[{"mim_id":"613730","title":"HEMORRHAGIC DESTRUCTION OF THE BRAIN, SUBEPENDYMAL CALCIFICATION, AND CATARACTS; HDBSCC","url":"https://www.omim.org/entry/613730"},{"mim_id":"606871","title":"JUNCTIONAL ADHESION MOLECULE 3; JAM3","url":"https://www.omim.org/entry/606871"},{"mim_id":"606870","title":"JUNCTIONAL ADHESION MOLECULE 2; JAM2","url":"https://www.omim.org/entry/606870"},{"mim_id":"605721","title":"JUNCTION ADHESION MOLECULE 1; JAM1","url":"https://www.omim.org/entry/605721"},{"mim_id":"192975","title":"INTEGRIN, ALPHA-4; ITGA4","url":"https://www.omim.org/entry/192975"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Golgi apparatus","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/JAM3"},"hgnc":{"alias_symbol":["JAM-C","JAMC","JAM-3"],"prev_symbol":[]},"alphafold":{"accession":"Q9BX67","domains":[{"cath_id":"2.60.40.10","chopping":"32-135","consensus_level":"high","plddt":95.32,"start":32,"end":135},{"cath_id":"2.60.40.10","chopping":"142-237","consensus_level":"high","plddt":96.8291,"start":142,"end":237}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BX67","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BX67-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BX67-F1-predicted_aligned_error_v6.png","plddt_mean":85.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JAM3","jax_strain_url":"https://www.jax.org/strain/search?query=JAM3"},"sequence":{"accession":"Q9BX67","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BX67.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BX67/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BX67"}},"corpus_meta":[{"pmid":"21706006","id":"PMC_21706006","title":"The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo.","date":"2011","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21706006","citation_count":476,"is_preprint":false},{"pmid":"12953056","id":"PMC_12953056","title":"The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity.","date":"2003","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12953056","citation_count":204,"is_preprint":false},{"pmid":"11590146","id":"PMC_11590146","title":"Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11590146","citation_count":172,"is_preprint":false},{"pmid":"12070135","id":"PMC_12070135","title":"JAM2 interacts with alpha4beta1. 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pulldown, static adhesion assays with CHO cells expressing full-length JAM2, polyclonal anti-JAM3 serum\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal binding assays (Fc pulldown, cell adhesion, neutralization) in a single focused study establishing the receptor-ligand pair\",\n      \"pmids\": [\"11590146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"JAM3 on T cells facilitates JAM2 engagement of alpha4beta1 integrin: prior adhesion of JAM2 to JAM3 is required for JAM2/alpha4beta1 interaction; neutralizing JAM3 serum or soluble JAM3 ectodomain blocked both JAM2/JAM3 and JAM2/alpha4beta1 interactions. The first Ig-like fold of JAM2 is competent for binding both JAM3 and alpha4beta1.\",\n      \"method\": \"Neutralizing integrin antibodies, alpha4-specific inhibitor TBC 772, soluble JAM3 ectodomain competition, mutagenesis of JAM2 Asp-82\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (antibody blockade, pharmacological inhibitor, soluble competitor, mutagenesis) in a single rigorous study\",\n      \"pmids\": [\"12070135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"VE-JAM/JAM2 interacts with T cells, NK cells, and dendritic cells through JAM3, identifying JAM3 as the functional receptor for JAM2-mediated leukocyte adhesion.\",\n      \"method\": \"Cloning and functional characterization; cell adhesion assays with J45 T cell line and primary immune cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional adhesion assays, independent replication of JAM2/JAM3 heterophilic interaction across two labs\",\n      \"pmids\": [\"11823489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JAM3 directly associates with the cell polarity protein PAR-3 through the first PDZ domain of PAR-3; JAM3 also associates with ZO-1 in a PDZ domain-dependent manner, implicating JAM3 in tight junction formation and endothelial cell polarity.\",\n      \"method\": \"Direct binding assays, PDZ domain interaction studies, ectopic expression of JAM-2 in CHO cells showing junctional localization regulated by serine phosphorylation and recruitment of endogenous PAR-3 and ZO-1\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assays, domain mutagenesis (PDZ), ectopic expression with functional readout, in vivo confirmation\",\n      \"pmids\": [\"12953056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"JAM-C localizes to desmosomes (not tight junctions) in intestinal epithelia and functions as a ligand for CD11b/CD18 (Mac-1) on neutrophils, mediating PMN transepithelial migration. Specific binding of JAM-C to CD11b/CD18 was demonstrated.\",\n      \"method\": \"Selective disruption of tight junctions and desmosomes, JAM-C mAb and JAM-C/Fc chimera inhibition of PMN transmigration assays, direct binding assays with CD11b/CD18\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (subcellular fractionation/disruption, functional transmigration assay, direct binding), clear mechanistic link\",\n      \"pmids\": [\"15194813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"JAM-C undergoes heterophilic interaction with JAM-B at cell-cell contacts; JAM-B stabilizes JAM-C in junctional complexes and soluble JAM-B dissociates JAM-C homodimers to form higher-affinity JAM-B/JAM-C heterodimers. JAM-C liberated from junctional JAM-B becomes available for interaction with leukocyte counter-receptor alphaM-beta2 integrin, modulating leukocyte adhesion.\",\n      \"method\": \"Co-immunoprecipitation, soluble protein competition assays, antibody blockade, cell adhesion assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal binding assays, competition experiments, functional leukocyte adhesion readout, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"16093349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"JAM-C regulates tight junctions and cell polarity through serine 281 in its cytoplasmic tail; mutation S281A abolishes junctional localization of JAM-C and establishment of cell polarity, and stimulates integrin-mediated cell migration and adhesion via modulation of beta1 and beta3 integrin activation.\",\n      \"method\": \"Transfection of JAM-C and serine-to-alanine mutant in carcinoma cells, tight junction barrier assays, cell migration/adhesion assays, integrin activation measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-directed mutagenesis (S281A) with multiple functional readouts (polarity, barrier, migration, integrin activation)\",\n      \"pmids\": [\"17099249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CAR (coxsackievirus and adenovirus receptor) forms a complex with JAM-C in mouse testis, as demonstrated by co-immunoprecipitation in germ cells.\",\n      \"method\": \"Co-immunoprecipitation, RT-PCR, Western analysis, GST pulldown, indirect immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — co-IP demonstrating interaction, single lab, single paper\",\n      \"pmids\": [\"16410001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Platelet JAM-C mediates firm adhesion of dendritic cells to platelets via CD11b/CD18 (Mac-1); soluble JAM-C reduced DC adhesion to platelets, and platelet/DC interaction resulted in DC apoptosis mediated by a JAM-C-dependent mechanism.\",\n      \"method\": \"Adhesion assays, preincubation with soluble JAM-C, in vivo carotid artery injury model, phagocytosis assays, apoptosis assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional adhesion assays with soluble JAM-C inhibition plus in vivo model, single lab\",\n      \"pmids\": [\"17379836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JAM-C modulates endothelial permeability through association with alphavbeta3 integrin and regulation of its localization and activity; JAM-C also inhibits beta1 integrin activation (without direct association) through regulation of the small GTPase Rap1b (not Rap1a). Thrombin induces JAM-C localization to junctions increasing permeability; angiopoietin-1 prevents JAM-C translocation.\",\n      \"method\": \"siRNA knockdown, overexpression, co-immunoprecipitation with alphavbeta3, integrin activity assays, Rap1 isoform-specific knockdown, permeability assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, KD/OE, Rap1 isoform specificity, multiple functional readouts in one rigorous study\",\n      \"pmids\": [\"19461049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JAM-C at endothelial cell junctions regulates the directionality (polarity) of neutrophil transendothelial migration in vivo; lower JAM-C expression at EC junctions (or blockade/genetic deletion of JAM-C) promotes 'reverse' TEM of neutrophils back into the vasculature, contributing to systemic inflammation dissemination.\",\n      \"method\": \"Real-time confocal intravital imaging, ischemia-reperfusion inflammation model, JAM-C blocking antibodies, genetic deletion of JAM-C in ECs\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo real-time imaging plus genetic deletion with defined directional migration phenotype, replicated across models\",\n      \"pmids\": [\"21706006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Zebrafish orthologs Jamb and Jamc are essential for myocyte fusion during vertebrate skeletal muscle development; Jamb and Jamc physically interact and must act in trans between neighboring cells. Loss of either gene prevents myocyte fusion, producing mononuclear fast-twitch fibers. Ectopic jamc expression in slow muscle precursors causes inappropriate fusion.\",\n      \"method\": \"Forward genetic screen, heritable mutations in jamb and jamc, cell transplantation experiments, in vivo receptor interaction studies\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, transplantation experiments establishing trans interaction requirement, in vivo\",\n      \"pmids\": [\"22180726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JAM-C expressed in Schwann cells is required for the structural integrity and function of peripheral nerves: SC-specific JAM-C knockout mice show electrophysiological defects, muscular weakness, mechanical hypersensitivity, and morphological defects in the paranodal region with increased nodal length.\",\n      \"method\": \"Conditional knockout (Schwann cell-specific JAM-C deletion), electrophysiology, histomorphological analysis of paranodal regions\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with multiple orthogonal phenotypic readouts (electrophysiology, morphology, behavior)\",\n      \"pmids\": [\"22090315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JAM-C in lymph node fibroblastic reticular cells (identified by thrombomodulin and PDGFRalpha) controls homeostatic chemokine secretion (CXCL12/SDF-1alpha, CCL21, CCL19); Jam-C-deficient mice and anti-JAM-C-treated mice show decreased intranodal content of these chemokines, correlated with reduced naive T cell egress from lymph nodes.\",\n      \"method\": \"JAM-C knockout mice, anti-JAM-C antibody treatment, chemokine measurement in lymph nodes, naive T cell egress assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic KO plus antibody blockade with defined chemokine and cellular readouts, single lab\",\n      \"pmids\": [\"21685324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JAM-B expressed by endothelial cells contributes to B16 melanoma cell metastasis through heterophilic interaction with JAM-C on tumor cells, mediating melanoma cell adhesion to lung microvascular endothelial cells; metastasis of B16 cells was reduced in Jam-b deficient mice.\",\n      \"method\": \"Jam-b knockout mice, in vivo metastasis assay, cell adhesion assays to primary lung microvascular endothelial cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic KO in vivo plus cell adhesion assay, single lab\",\n      \"pmids\": [\"23068611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JAM-C is expressed on the apical surface of neural stem cells in embryonic and adult mouse brain and is asymmetrically distributed during cell divisions, enriched at the apical membrane.\",\n      \"method\": \"In vivo immunohistochemistry, live imaging of neural stem cells, subcellular localization during division\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments in vivo across embryonic and adult brain, single lab\",\n      \"pmids\": [\"22114908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JAM-C deficiency in C57BL/6 mice causes severe hydrocephalus associated with a block or reduction of CSF drainage from the lateral to the 3rd ventricle; endothelial re-expression of JAM-C failed to rescue the hydrocephalus, indicating the relevant JAM-C function is not endothelial but likely ependymal/choroid plexus epithelial.\",\n      \"method\": \"JAM-C knockout mice on C57BL/6 background, endothelial rescue experiments, CSF circulation analysis, immunohistochemistry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with rescue experiment dissecting cell-type specificity, CSF flow analysis\",\n      \"pmids\": [\"23029139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JAM-C on B lymphocytes mediates homing to bone marrow, lymph nodes, and spleen via heterophilic interaction with JAM-B on lymphatic endothelial cells (identified by plasmon resonance as the major JAM-C ligand, with homotypic JAM-C interactions at background levels). Anti-JAM-C antibodies blocked adhesion of JAM-C-expressing B cells to JAM-B and reduced lymphoma engraftment.\",\n      \"method\": \"Xenogeneic NOD/SCID mouse model, short- and long-term anti-JAM-C antibody treatment, plasmon resonance binding studies, immunofluorescence for JAM-B on endothelium\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — plasmon resonance quantifying binding hierarchy, in vivo homing assay, antibody blockade with defined molecular mechanism\",\n      \"pmids\": [\"23221386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JAM-B/JAM-C interaction between hematopoietic stem and progenitor cells (HSPC) and bone marrow stromal/mesenchymal cells is required for HSPC homing to bone marrow; anti-JAM-C blocking antibody inhibited hematopoietic reconstitution, progenitor homing, and induced HSPC mobilization in a JAM-B-dependent manner. This interaction occurs between HSPC and mesenchymal stem cells but not endothelial cells or osteoblasts.\",\n      \"method\": \"Blocking monoclonal antibodies, bone marrow transplantation, HSPC mobilization assays, human CD34+ hematopoietic progenitor homing in mouse BM\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — blocking antibody with JAM-B dependency demonstrated, homing and mobilization functional readouts, translated to human system\",\n      \"pmids\": [\"24357068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GRASP55 interacts with JAM-C via PDZ-mediated interactions in developing germ cells (proteomic identification confirmed by crystal structure); GRASP55 knockout disrupts acrosome formation and polarized localization of JAM-C in spermatids. Crystal structures of GRASP55 in complex with JAM-C or JAM-B reveal that GRASP55 interaction induces a conformational change in GRASP55. A chemical compound (Graspin) inhibiting PDZ-mediated GRASP55/JAM interactions disrupted JAM-C polarized localization in spermatids in vivo.\",\n      \"method\": \"Proteomic pulldown, Gorasp2 knockout mice, crystal structure determination of GRASP55–JAM-C/JAM-B complexes, in silico pharmacophore/chemical inhibitor (Graspin), mouse treatment with Graspin\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, knockout mouse, chemical inhibitor in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"28617811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JAM3 directly associates with LRP5 to activate the PDK1/AKT pathway, leading to GSK3beta downregulation and beta-catenin/CCND1 activation, maintaining leukemia-initiating cell (LIC) self-renewal and cell cycle entry. This function is independent of JAM3's canonical role in cell junctions and migration.\",\n      \"method\": \"Co-immunoprecipitation (JAM3–LRP5 association), Jam3 genetic deletion in MLL-AF9 AML model, serial transplantation, JAM3 knockdown in human leukemia cell lines and primary LICs, Western blotting for pathway components\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, genetic deletion with serial transplantation, pathway knockdown with multiple readouts, translated to human cells\",\n      \"pmids\": [\"29584620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JAM-C dimerization sites E66 and K68 are critical for JAM-C/JAM-B interaction and correct junctional localization; mutations at these sites increase cell adhesion, reduce migration and proliferation, and abolish metastatic lung nodule formation in mice, demonstrating that JAM-C dimerization drives pro-metastatic behavior.\",\n      \"method\": \"Directed mutagenesis of E66 and K68, cell adhesion assays, migration/proliferation assays, in vivo lung metastasis model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis identifying critical residues with in vitro and in vivo functional validation\",\n      \"pmids\": [\"29378216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dynamic trafficking and lysosomal degradation of JAM-C, regulated by ubiquitylation via the E3 ligase CBL, are necessary for junctional remodelling during endothelial cell migration and angiogenesis. JAM-C co-traffics with VE-Cadherin and neuropilin-1/2 but not with leukocyte transmigration-associated junctional proteins.\",\n      \"method\": \"Receptor mutagenesis, HRP and APEX-2 proximity labelling, light and electron microscopy, co-trafficking analysis, CBL-mediated ubiquitylation assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — proximity labelling, receptor mutagenesis, identification of E3 ligase CBL with multiple orthogonal methods\",\n      \"pmids\": [\"31790392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"JAM-C localizes specifically to tight junctions in human retinal pigment epithelium (hfRPE); JAM-C knockdown disrupts N-cadherin and ZO-1 organization at cell contacts, delays hfRPE cell polarization (reduced apical ezrin), and significantly decreases chemokine-induced transmigration of granulocytes (but not monocytes) through the hfRPE monolayer.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, Western blot, transepithelial migration assay\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD with multiple cellular readouts (polarity, junction organization, leukocyte transmigration), single lab\",\n      \"pmids\": [\"19060272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LPS reduces JAM-3 expression in renal tubular epithelial cells via the RhoT1/SMAD-4/JAM-3 pathway: LPS increases SMAD-4 (which suppresses JAM-3), and RhoT1 inhibits SMAD-4 to maintain JAM-3 expression; downregulation of SMAD-4 via RNAi increased JAM-3 levels in LPS-treated cells.\",\n      \"method\": \"siRNA knockdown of SMAD-4 and RhoT1, Western blot, transepithelial permeability and resistance assays, immunofluorescence\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNAi epistasis placing JAM-3 downstream of SMAD-4/RhoT1, functional permeability readout, single lab\",\n      \"pmids\": [\"29725250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In cerebellar granule cells, Pard3a and JamC operate in the same molecular pathway to regulate radial migration initiation from the external granule cell layer; normalizing expression of Pard3a and JamC in organotypic cerebellar slice cultures rescued both migratory and apoptotic defects caused by intrauterine growth restriction.\",\n      \"method\": \"Organotypic cerebellar slice cultures, gene expression normalization experiments, in vivo pig IUGR model with IHC/gene expression analysis\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional rescue in organotypic culture placing JamC and Pard3a in same pathway, supported by in vivo expression analysis\",\n      \"pmids\": [\"33259808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JAM-C is required to maintain VEGFR2 expression in retinal pigment epithelial cells under oxidative stress; JAM-C knockdown decreased RPE cell survival, and overexpression of VEGFR2 partially restored impaired RPE survival caused by JAM-C knockdown. JAM-C regulates VEGFR2 expression and modulates downstream p38 phosphorylation.\",\n      \"method\": \"siRNA knockdown, overexpression rescue with VEGFR2, cell survival assays, Western blot for VEGFR2 and p-p38\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD with overexpression rescue establishing mechanistic link, single lab\",\n      \"pmids\": [\"28203682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAM10 processes/cleaves JAM-C to increase Rap1GAP activity, promoting neural stem cell transit from the apical to basal compartment of the subventricular zone and subsequent lineage progression.\",\n      \"method\": \"ADAM10 conditional manipulation, RAP1GAP activity assays, neural stem cell localization and lineage analysis\",\n      \"journal\": \"Neural regeneration research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ADAM10 identified as JAM-C processing enzyme with Rap1GAP as downstream effector, functional NSC positioning readout, single lab\",\n      \"pmids\": [\"35535899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAM-C deficiency in mouse lenses causes nuclear cataract with defective degradation of nuclei and organelles in lens fiber cells, accompanied by activation of the unfolded protein response (upregulation of BiP, CHOP, TRIB3, CHAC1) and increased cell death.\",\n      \"method\": \"Jamc knockout mice (C57BL/6), RNA sequencing, RT-qPCR, Western blot, immunofluorescence, TUNEL staining\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic KO with transcriptomic and protein-level validation of UPR activation, single lab\",\n      \"pmids\": [\"36048019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Epigenetic silencing of JAM3 by promoter methylation activates Wnt/beta-catenin signaling in esophageal cancer cells; JAM3 restoration suppressed EC cell proliferation, colony formation, migration and invasion by inhibiting Wnt/beta-catenin signaling, and 5-aza-2'-deoxycytidine treatment restored JAM3 expression.\",\n      \"method\": \"Methylation-specific PCR, Western blot, MTT/colony/migration assays, xenograft mouse models, 5-aza treatment\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — overexpression with pathway (Wnt) readout, in vivo xenograft, demethylation rescue, single lab\",\n      \"pmids\": [\"36461092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"JAM-C inhibits ocular fibrosis by suppressing the nuclear localization and function of TAZ, which otherwise binds to KLF6 to promote its expression and activate the EMT cascade; AAV-mediated JAM-C augmentation alleviated ocular fibrosis in mouse models.\",\n      \"method\": \"Co-IP, ChIP-qPCR, luciferase reporter assay, RNA sequencing, siRNA knockdown, Jam-c KO mice, AAV overexpression in vivo\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, ChIP-qPCR, luciferase reporter, genetic KO, and AAV rescue—multiple orthogonal methods in one study\",\n      \"pmids\": [\"40398745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JAM-C mediates ferroptosis resistance in high-adhesion ovarian cancer cells through NRF2-induced upregulation of FSP1 (a lipid peroxidation suppressor); JAM3 knockdown/blockade sensitized cells to ferroptosis inducers RSL3 and erastin, while JAM3 overexpression conferred resistance; inhibition of the NRF2/FSP1 pathway eliminated JAM3-mediated ferroptosis resistance.\",\n      \"method\": \"siRNA knockdown, JAM3 overexpression, ferroptosis inducers (RSL3, erastin), NRF2/FSP1 pathway inhibition, in vitro and in vivo cisplatin resistance assays\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD/OE with pathway inhibition rescue establishing NRF2/FSP1 as downstream effectors, in vitro and in vivo, single lab\",\n      \"pmids\": [\"39706500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pard3 polarity protein and JAM-C cooperate to promote surface recruitment of the DCC receptor, gating Netrin-1-dependent repulsion that drives cerebellar granule neuron exit from the germinal zone; the E3 ubiquitin ligase Siah2 antagonizes this Pard3/JAM-C function by inhibiting DCC surface recruitment.\",\n      \"method\": \"In vivo mouse cerebellar genetics, DCC surface recruitment assays, epistasis between Siah2, Pard3, JamC, and DCC\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic epistasis in vivo establishing pathway order (Pard3/JamC→DCC surface recruitment→Netrin-1 signaling), single lab\",\n      \"pmids\": [\"39774925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"JAM-C maintains lens cell adhesion and ball-and-socket junction integrity; JAM-C deficiency elevates intracellular Ca2+ in lens cells, activates calpain (evidenced by degradation of IIα spectrin and F-actin), and disrupts FGF/ERK signaling in lens epithelial cells.\",\n      \"method\": \"Jamc knockout mice, calcium imaging, Western blot for calpain substrates (IIα spectrin, F-actin), FGF/ERK pathway analysis, electron microscopy of junctions\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KO with multiple mechanistic readouts (Ca2+, calpain substrates, signaling), single lab\",\n      \"pmids\": [\"41173413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Soluble JAM-C ectodomain (sJAM-C), which is cleaved and secreted by adipose-derived stromal/stem cells (ADSCs), forms a complex with JAM-B and stimulates ADSC adhesion, proliferation, and expression of mesenchymal stem cell markers. CRISPR/Cas9 deletion confirmed that sJAM-C/JAM-B coupling mediates ADSC adhesion and maintenance.\",\n      \"method\": \"Immunoprecipitation, CRISPR/Cas9 genome editing, culture plate coating with sJAM-C, cell adhesion and proliferation assays, flow cytometry for MSC markers\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus CRISPR KO plus functional assays, single lab\",\n      \"pmids\": [\"33801826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"JAM-C at homeostatic copy numbers forms a unidirectional vascular barrier for leukocyte TEM; overexpression or gene silencing of JAM-C in endothelium under flow conditions both result in higher rates of monocyte reverse-TEM, and anti-JAM-C blockade in atherosclerotic recipients induced monocyte-derived cell emigration from plaques and reduced plaque size.\",\n      \"method\": \"siRNA and overexpression in human endothelium under flow, aortic arch transplantation model (ApoE-/- into wild-type), JAM-C blockade in vivo\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vitro flow assay plus in vivo transplantation model, single lab\",\n      \"pmids\": [\"27442505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"JAM3 promotes meningioma development by interacting with Mac-1 (CD11b) on neutrophils (confirmed by Co-IP) to activate AKT phosphorylation, thereby promoting neutrophil migration and neutrophil extracellular trap (NET) formation; JAM3 knockdown in meningioma cells suppressed AKT phosphorylation, reduced NET formation, and inhibited tumor growth in xenograft models.\",\n      \"method\": \"Co-IP confirming JAM3/Mac-1 interaction, siRNA knockdown, AKT activator rescue (SC79), neutrophil migration and NET assays, xenograft tumor model, DNase I NET abolition\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus KD with AKT rescue and in vivo xenograft, single lab\",\n      \"pmids\": [\"41500374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"JAM-C deletion in mice results in decreased lens epithelial cell (LEC) quantity and proliferation, downregulation of the transcription factor FOXE3, disorganization of lens fibers, and altered distribution of gap junction proteins Cx46 and Cx50 and reduced gamma-crystallin in fiber cells.\",\n      \"method\": \"Jamc knockout mice, BrdU incorporation assay, TUNEL staining, immunofluorescence, Western blot, histological analysis across developmental stages\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic KO with multiple downstream molecular markers across developmental time points, single lab\",\n      \"pmids\": [\"38095908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"JAM3 promotes laryngeal squamous cell carcinoma oncogenesis by inhibiting the Hippo pathway; JAM3 overexpression activated Hippo signaling suppressing proliferation, migration and invasion, whereas JAM3 knockdown enhanced these behaviors by inhibiting the Hippo pathway, both in vitro and in vivo.\",\n      \"method\": \"Western blot, immunofluorescence, Cell Counting Kit-8, colony formation, Transwell assays, 5-Aza-2'-deoxycytidine treatment, in vivo experiments\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD/OE with Hippo pathway readout in vitro and in vivo, single lab\",\n      \"pmids\": [\"39749700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In serous ovarian carcinoma cells, JAM3 overexpression suppresses proliferation, migration, and invasion and promotes apoptosis by inhibiting the PI3K/AKT signaling pathway; JAM3 knockdown produced opposite effects, confirmed by AKT inhibitor (MK2206) rescue experiments.\",\n      \"method\": \"RNA sequencing, Western blot, CCK8, flow cytometry, scratch-wound, Transwell assays, AKT inhibitor rescue, immunohistochemistry\",\n      \"journal\": \"Epigenomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD/OE with pathway inhibitor rescue, multiple functional assays, single lab\",\n      \"pmids\": [\"40711818\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JAM3 (JAM-C) is a two-Ig-domain adhesion molecule that functions primarily as a heterophilic counter-receptor for JAM-B, directs polarized leukocyte transendothelial migration by forming a unidirectional junctional barrier, organizes tight junctions and cell polarity via PDZ-mediated interactions with PAR-3 and ZO-1, controls integrin activation (alphavbeta3, beta1) and vascular permeability through Rap1b signaling, supports myocyte and germ-cell fusion by trans JAM-B/JAM-C interaction, maintains hematopoietic stem cell niche retention through JAM-B binding on stromal cells, regulates neuronal germinal zone exit by promoting DCC surface recruitment in concert with Pard3, and in leukemia-initiating cells activates an LRP5/PDK1/AKT/beta-catenin/CCND1 self-renewal pathway independent of its junctional role; its junctional trafficking is controlled by CBL-mediated ubiquitylation, and its polarized localization in spermatids requires GRASP55 PDZ-domain interactions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JAM3 (JAM-C) is a two-Ig-domain junctional adhesion molecule whose defining biochemical activity is heterophilic engagement of its counter-receptor JAM-B (JAM2): JAM-C was first identified as the 43-kDa counter-receptor mediating JAM-B adhesion to T cells [#0], and JAM-B reciprocally stabilizes junctional JAM-C while soluble JAM-B dissociates JAM-C homodimers into higher-affinity heterodimers, releasing JAM-C for leukocyte engagement [#5]. Through this adhesive system JAM-C organizes epithelial and endothelial junctions and cell polarity, binding the polarity protein PAR-3 and the scaffold ZO-1 via PDZ-domain interactions [#3] and requiring a cytoplasmic serine (S281) for junctional localization, polarity establishment, and restraint of beta1/beta3 integrin activation [#6]. At endothelial junctions JAM-C maintains a unidirectional barrier that sets the directionality of neutrophil transendothelial migration, such that loss or imbalance of JAM-C promotes reverse migration [#10, #35]; it also tunes vascular permeability by associating with alphavbeta3 integrin and signaling through the GTPase Rap1b [#9], and its junctional turnover is controlled by CBL-mediated ubiquitylation and lysosomal degradation during angiogenic remodeling [#22]. Beyond leukocytes, JAM-C serves as a counter-receptor for the Mac-1 (CD11b/CD18) integrin to drive transmigration and platelet–leukocyte interactions [#4, #8], and its trans JAM-B/JAM-C interaction is essential for myocyte fusion [#11] and for hematopoietic stem/progenitor retention in the marrow stromal niche [#18]. In neural development JAM-C acts in a Pard3-dependent pathway to promote DCC surface recruitment and germinal-zone exit of cerebellar granule neurons [#32, #25], and its polarized localization in spermatids requires PDZ-mediated binding to GRASP55 [#19]. JAM-C is processed by ADAM10 [#27] and is genetically required for peripheral nerve paranodal integrity [#12], cerebrospinal fluid drainage [#16], and lens fiber/epithelial homeostasis [#28, #37, #33]. In cancer, JAM-C dimerization drives pro-metastatic behavior [#21], and JAM3 supports leukemia-initiating-cell self-renewal through a junction-independent LRP5/PDK1/AKT/beta-catenin/CCND1 axis [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing JAM-C's binding partner was the foundational question; identifying it as the counter-receptor for JAM-B defined the molecular adhesion pair around which all later function is organized.\",\n      \"evidence\": \"Ectodomain binding, JAM2-Fc pulldown, and static adhesion assays in CHO cells\",\n      \"pmids\": [\"11590146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity and stoichiometry of the interaction not quantified\", \"Cytoplasmic signaling consequences not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved how JAM-C couples to integrin-mediated leukocyte adhesion, showing JAM-C/JAM-B engagement is a prerequisite for JAM-B binding to alpha4beta1 integrin and confirming JAM-C as the functional leukocyte receptor.\",\n      \"evidence\": \"Antibody blockade, alpha4 inhibitor, soluble JAM-C competition, JAM2 mutagenesis; adhesion assays with T/NK/dendritic cells\",\n      \"pmids\": [\"12070135\", \"11823489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether JAM-C directly contacts integrin or only positions JAM-B not fully resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected JAM-C to junctional architecture by identifying PDZ-mediated binding to PAR-3 and ZO-1, placing it in the cell polarity and tight junction machinery.\",\n      \"evidence\": \"Direct PDZ binding assays, domain mutagenesis, ectopic expression in CHO cells\",\n      \"pmids\": [\"12953056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of each interaction in vivo not separated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Broadened JAM-C's adhesive repertoire by demonstrating direct binding to the Mac-1 (CD11b/CD18) integrin and a role in PMN transepithelial migration, with localization to desmosomes rather than tight junctions in intestinal epithelium.\",\n      \"evidence\": \"Junction disruption, transmigration assays, direct CD11b/CD18 binding\",\n      \"pmids\": [\"15194813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type variability of subcellular localization unexplained\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the regulatory logic of the JAM-B/JAM-C system, showing soluble JAM-B converts JAM-C homodimers into heterodimers and liberates JAM-C for integrin engagement, linking junctional state to leukocyte adhesion.\",\n      \"evidence\": \"Co-IP, soluble competition, antibody blockade, adhesion assays\",\n      \"pmids\": [\"16093349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo trigger for homodimer-to-heterodimer switching not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the cytoplasmic determinant (S281) controlling junctional localization, polarity, and integrin restraint, providing a phosphoregulatable switch in JAM-C function.\",\n      \"evidence\": \"S281A mutagenesis with barrier, migration, and integrin activation readouts in carcinoma cells\",\n      \"pmids\": [\"17099249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for S281 phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mechanistically separated JAM-C's effects on vascular permeability into an alphavbeta3-association arm and a Rap1b-dependent beta1 integrin inhibition arm, with stimulus-dependent junctional translocation.\",\n      \"evidence\": \"siRNA/overexpression, Co-IP, Rap1 isoform-specific knockdown, permeability assays\",\n      \"pmids\": [\"19461049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between JAM-C and Rap1b activation upstream not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated in vivo that junctional JAM-C levels set the directionality of neutrophil transendothelial migration, establishing reverse-TEM as a consequence of JAM-C loss.\",\n      \"evidence\": \"Intravital imaging, ischemia-reperfusion model, blocking antibody, endothelial JAM-C deletion\",\n      \"pmids\": [\"21706006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signal that imposes unidirectionality not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended JAM-C function beyond leukocytes by showing trans JAM-B/JAM-C interaction is required for myocyte fusion and that Schwann-cell JAM-C maintains peripheral nerve paranodal integrity.\",\n      \"evidence\": \"Zebrafish forward genetics and transplantation; Schwann-cell conditional knockout with electrophysiology and morphology\",\n      \"pmids\": [\"22180726\", \"22090315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream fusion machinery engaged by JAM-B/JAM-C not identified\", \"Mechanism linking JAM-C to paranodal structure unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined cell-type-specific physiological requirements for JAM-C, including non-endothelial control of CSF drainage and stromal control of lymph node chemokine secretion and T cell egress.\",\n      \"evidence\": \"JAM-C knockout with endothelial rescue (hydrocephalus); knockout/antibody blockade with chemokine and egress readouts; B-cell homing via JAM-B\",\n      \"pmids\": [\"23029139\", \"21685324\", \"23221386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector cell type for CSF phenotype not pinpointed\", \"Mechanism linking JAM-C to chemokine secretion unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established JAM-C's role in the hematopoietic niche, showing JAM-B/JAM-C interaction between HSPCs and mesenchymal stromal cells governs marrow homing and retention.\",\n      \"evidence\": \"Blocking antibody, bone marrow transplantation, mobilization assays, human CD34+ homing\",\n      \"pmids\": [\"24357068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling downstream of niche JAM-B/JAM-C engagement not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided structural and functional insight into PDZ-driven polarized localization by identifying GRASP55 as a JAM-C partner whose interaction is required for spermatid acrosome formation and JAM-C polarization.\",\n      \"evidence\": \"Proteomics, knockout mice, crystal structures of GRASP55–JAM-C/JAM-B, and an in vivo PDZ-inhibitor (Graspin)\",\n      \"pmids\": [\"28617811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of GRASP55-mediated polarization to other tissues untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a junction-independent signaling role in cancer, showing JAM3 associates with LRP5 to drive a PDK1/AKT/beta-catenin/CCND1 self-renewal program in leukemia-initiating cells, and that dimerization residues E66/K68 drive pro-metastatic behavior.\",\n      \"evidence\": \"Reciprocal Co-IP, Jam3 deletion in MLL-AF9 AML with serial transplantation; E66/K68 mutagenesis with in vitro and metastasis readouts\",\n      \"pmids\": [\"29584620\", \"29378216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LRP5 binding is regulated relative to junctional pools unknown\", \"Whether dimerization couples to the LRP5 signaling axis untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the trafficking control of junctional JAM-C, identifying CBL-mediated ubiquitylation and lysosomal degradation as required for endothelial junctional remodeling and angiogenesis.\",\n      \"evidence\": \"Receptor mutagenesis, APEX-2/HRP proximity labeling, microscopy, ubiquitylation assays\",\n      \"pmids\": [\"31790392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering CBL recruitment not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified ADAM10 as a JAM-C-processing protease coupling cleavage to Rap1GAP activity and neural stem cell compartment transit.\",\n      \"evidence\": \"ADAM10 manipulation, Rap1GAP activity assays, NSC localization analysis\",\n      \"pmids\": [\"35535899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site and fate of fragments not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved a developmental pathway in which Pard3 and JAM-C promote DCC surface recruitment to gate Netrin-1 repulsion and germinal-zone exit, antagonized by Siah2.\",\n      \"evidence\": \"In vivo cerebellar genetics, DCC surface recruitment assays, genetic epistasis (Siah2/Pard3/JamC/DCC)\",\n      \"pmids\": [\"39774925\", \"33259808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical basis of JAM-C-driven DCC trafficking unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended JAM-C's Mac-1 engagement to solid-tumor immunology, showing JAM3/Mac-1 interaction activates AKT to drive neutrophil migration and NET formation in meningioma.\",\n      \"evidence\": \"Co-IP, knockdown with AKT activator rescue, NET assays, xenograft model\",\n      \"pmids\": [\"41500374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether tumor JAM-C signals cell-autonomously or only via neutrophils unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How JAM-C's adhesive/junctional pools are biochemically switched to its junction-independent signaling roles (LRP5, NRF2/FSP1, Hippo, PI3K/AKT) reported across diverse cancers remains unresolved, as does whether these context-specific outputs share a unifying mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model linking ectodomain engagement to intracellular signaling outputs\", \"Tissue-context determinants of tumor-suppressive versus oncogenic roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 5, 11, 17]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 20]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 5, 15]},\n      {\"term_id\": \"GO:0005923\", \"supporting_discovery_ids\": [3, 6, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 10, 35]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 19, 32]}\n    ],\n    \"complexes\": [\"tight junction\", \"JAM-B/JAM-C heterodimer\"],\n    \"partners\": [\"JAM2\", \"PARD3\", \"TJP1\", \"ITGB3\", \"ITGAM\", \"LRP5\", \"GORASP2\", \"CBL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}